WorldWideScience

Sample records for aging mice show

  1. Female CREBαδ- deficient mice show earlier age-related cognitive deficits than males

    OpenAIRE

    Hebda-Bauer, Elaine K.; Luo, Jie; Watson, Stanley J.; Akil, Huda

    2007-01-01

    Age-related changes in the hippocampus increase vulnerability to impaired learning and memory. Our goal is to understand how a genetic vulnerability to cognitive impairment can be modified by aging and sex. Mice with a mutation in the cAMP response element binding (CREB) protein gene (CREBαδ- deficient mice) have a mild cognitive impairment and show test condition-dependent learning and memory deficits. We tested 3 ages of CREBαδ- deficient and wild-type (WT) mice in 2 Morris water maze (MWM)...

  2. Long-Lived αMUPA Mice Show Attenuation of Cardiac Aging and Leptin-Dependent Cardioprotection.

    Directory of Open Access Journals (Sweden)

    Esther Levy

    Full Text Available αMUPA transgenic mice spontaneously consume less food compared with their wild type (WT ancestors due to endogenously increased levels of the satiety hormone leptin. αMUPA mice share many benefits with mice under caloric restriction (CR including an extended life span. To understand mechanisms linked to cardiac aging, we explored the response of αMUPA hearts to ischemic conditions at the age of 6, 18, or 24 months. Mice were subjected to myocardial infarction (MI in vivo and to ischemia/reperfusion ex vivo. Compared to WT mice, αMUPA showed functional and histological advantages under all experimental conditions. At 24 months, none of the WT mice survived the first ischemic day while αMUPA mice demonstrated 50% survival after 7 ischemic days. Leptin, an adipokine decreasing under CR, was consistently ~60% higher in αMUPA sera at baseline. Leptin levels gradually increased in both genotypes 24h post MI but were doubled in αMUPA. Pretreatment with leptin neutralizing antibodies or with inhibitors of leptin signaling (AG-490 and Wortmannin abrogated the αMUPA benefits. The antibodies also reduced phosphorylation of the leptin signaling components STAT3 and AKT specifically in the αMUPA myocardium. αMUPA mice did not show elevation in adiponectin, an adipokine previously implicated in CR-induced cardioprotection. WT mice treated for short-term CR exhibited cardioprotection similar to that of αMUPA, however, along with increased adiponectin at baseline. Collectively, the results demonstrate a life-long increased ischemic tolerance in αMUPA mice, indicating the attenuation of cardiac aging. αMUPA cardioprotection is mediated through endogenous leptin, suggesting a protective pathway distinct from that elicited under CR.

  3. Histamine 1 receptor knock out mice show age-dependent susceptibility to status epilepticus and consequent neuronal damage.

    Science.gov (United States)

    Kukko-Lukjanov, Tiina-Kaisa; Grönman, Maria; Lintunen, Minnamaija; Laurén, Hanna B; Michelsen, Kimmo A; Panula, Pertti; Holopainen, Irma E

    2012-06-01

    The central histaminergic neuron system is an important regulator of activity stages such as arousal and sleep. In several epilepsy models, histamine has been shown to modulate epileptic activity and histamine 1 (H1) receptors seem to play a key role in this process. However, little is known about the H1 receptor-mediated seizure regulation during the early postnatal development, and therefore we examined differences in severity of kainic acid (KA)-induced status epilepticus (SE) and consequent neuronal damage in H1 receptor knock out (KO) and wild type (WT) mice at postnatal days 14, 21, and 60 (P14, P21, and P60). Our results show that in P14 H1 receptor KO mice, SE severity and neuronal damage were comparable to those of WT mice, whereas P21 KO mice had significantly decreased survival, more severe seizures, and enhanced neuronal damage in various brain regions, which were observed only in males. In P60 mice, SE severity did not differ between the genotypes, but in KO group, neuronal damage was significantly increased. Our results suggest that H1 receptors could contribute to regulation of seizures and neuronal damage age-dependently thus making the histaminergic system as a challenging target for novel drug design in epilepsy. PMID:22348791

  4. Aged neuronal nitric oxide knockout mice show preserved olfactory learning in both social recognition and odor-conditioning tasks

    OpenAIRE

    Keith Maurice Kendrick

    2015-01-01

    There is evidence for both neurotoxic and neuroprotective roles of nitric oxide (NO) in the brain and changes in the expression of the neuronal isoform of nitric oxide synthase (nNOS) gene occur during aging. The current studies have investigated potential support for either a neurotoxic or neuroprotective role of NO derived from nNOS in the context of aging by comparing olfactory learning and locomotor function in young compared to old nNOS knockout (nNOS/-) and wildtype control mice. Tasks ...

  5. Aged neuronal nitric oxide knockout mice show preserved olfactory learning in both social recognition and odor-conditioning tasks

    OpenAIRE

    James, Bronwen M.; Li, Qin; Luo, Lizhu; Kendrick, Keith M.

    2015-01-01

    There is evidence for both neurotoxic and neuroprotective roles of nitric oxide (NO) in the brain and changes in the expression of the neuronal isoform of NO synthase (nNOS) gene occur during aging. The current studies have investigated potential support for either a neurotoxic or neuroprotective role of NO derived from nNOS in the context of aging by comparing olfactory learning and locomotor function in young compared to old nNOS knockout (nNOS−/−) and wildtype control mice. Tasks involving...

  6. Aged Tgfβ2/Gdnf double-heterozygous mice show no morphological and functional alterations in the nigrostriatal system

    OpenAIRE

    Heermann, Stephan; Opazo, Felipe; Falkenburger, Björn; Krieglstein, Kerstin; Spittau, Björn

    2010-01-01

    Loss of dopaminergic neurons in the substantia nigra pars compacta and the resulting decrease in striatal dopamine levels are the hallmarks of Parkinson’s disease. Tgfβ and Gdnf have been identified as neurotrophic factors for dopaminergic midbrain neurons in vivo and in vitro. Haploinsufficiency for either Tgfβ or Gdnf led to dopaminergic deficits. In this study we therefore analyzed the nigrostriatal system of aged Tgfβ2 +/−/Gdnf +/− double-heterozygous mice. Unexpectedly, we found no morph...

  7. Practical pathology of aging mice

    Directory of Open Access Journals (Sweden)

    Piper M. M. Treuting

    2011-06-01

    Full Text Available Old mice will have a subset of lesions as part of the progressive decline in organ function that defines aging. External and palpable lesions will be noted by the research, husbandry, or veterinary staff during testing, cage changing, or physical exams. While these readily observable lesions may cause alarm, not all cause undue distress or are life-threatening. In aging research, mice are maintained until near end of life that, depending on strain and genetic manipulation, can be upwards of 33 months. Aging research has unique welfare issues related to age-related decline, debilitation, fragility, and associated pain of chronic diseases. An effective aging research program includes the collaboration and education of the research, husbandry, and veterinary staff, and of the members of the institution animal care and use committee. This collaborative effort is critical to humanely maintaining older mice and preventing excessive censorship due to non-lethal diseases. Part of the educational process is becoming familiar with how old mice appear clinically, at necropsy and histopathologically. This baseline knowledge is important in making the determination of humane end points, defining health span, contributing causes of death and effects of interventions. The goal of this paper is to introduce investigators to age-associated diseases and lesion patterns in mice from clinical presentation to pathologic assessment. To do so, we present and illustrate the common clinical appearances, necropsy and histopathological lesions seen in subsets of the aging colonies maintained at the University of Washington.

  8. Unexpected regeneration in middle-aged mice.

    Science.gov (United States)

    Reines, Brandon; Cheng, Lily I; Matzinger, Polly

    2009-02-01

    Complete regeneration of damaged extremities, including both the epithelium and the underlying tissues, is thought to occur mainly in embryos, fetuses, and juvenile mammals, but only very rarely in adult mammals. Surprisingly, we found that common strains of mice are able to regenerate all of the tissues necessary to completely fill experimentally punched ear holes, but only if punched at middle age. Although young postweaning mice regrew the epithelium without typical pre-scar granulation tissue, they showed only minimal regeneration of connective tissues. In contrast, mice punched at 5-11 months of age showed true amphibian-like blastema formation and regrowth of cartilage, fat, and dermis, with blood vessels, sebaceous glands, hair follicles, and, in black mice, melanocytes. These data suggest that at least partial appendage regeneration may be more common in adult mammals than previously thought and call into question the common view that regenerative ability is lost with age. The data suggest that the age at which various inbred mouse strains become capable of epimorphic regeneration may be correlated with adult body weight. PMID:19226206

  9. Mice lacking neuropeptide Y show increased sensitivity to cocaine

    DEFF Research Database (Denmark)

    Sørensen, Gunnar; Woldbye, David Paul Drucker

    2012-01-01

    There is increasing data implicating neuropeptide Y (NPY) in the neurobiology of addiction. This study explored the possible role of NPY in cocaine-induced behavior using NPY knockout mice. The transgenic mice showed a hypersensitive response to cocaine in three animal models of cocaine addiction...

  10. Taurine increases hippocampal neurogenesis in aging mice

    Directory of Open Access Journals (Sweden)

    Elias Gebara

    2015-05-01

    Full Text Available Aging is associated with increased inflammation and reduced hippocampal neurogenesis, which may in turn contribute to cognitive impairment. Taurine is a free amino acid found in numerous diets, with anti-inflammatory properties. Although abundant in the young brain, the decrease in taurine concentration with age may underlie reduced neurogenesis. Here, we assessed the effect of taurine on hippocampal neurogenesis in middle-aged mice. We found that taurine increased cell proliferation in the dentate gyrus through the activation of quiescent stem cells, resulting in increased number of stem cells and intermediate neural progenitors. Taurine had a direct effect on stem/progenitor cells proliferation, as observed in vitro, and also reduced activated microglia. Furthermore, taurine increased the survival of newborn neurons, resulting in a net increase in adult neurogenesis. Together, these results show that taurine increases several steps of adult neurogenesis and support a beneficial role of taurine on hippocampal neurogenesis in the context of brain aging.

  11. Testosterone and Dihydrotestosterone Differentially Improve Cognition in Aged Female Mice

    Science.gov (United States)

    Benice, Ted S.; Raber, Jacob

    2009-01-01

    Compared with age-matched male mice, female mice experience a more severe age-related cognitive decline (ACD). Since androgens are less abundant in aged female mice compared with aged male mice, androgen supplementation may enhance cognition in aged female mice. To test this, we assessed behavioral performance on a variety of tasks in 22- to…

  12. Inhaled Anesthetic Potency in Aged Alzheimer Mice

    Science.gov (United States)

    Bianchi, Shannon L.; Caltagarone, Breanna M.; LaFerla, Frank M.; Eckenhoff, Roderic G.; Kelz, Max B.

    2016-01-01

    BACKGROUND The number of elderly patients with frank or incipient Alzheimer’s disease (AD) requiring surgery is growing as the population ages. General anesthesia may exacerbate symptoms of and the pathology underlying AD, so minimizing anesthetic exposure may be important. This requires knowledge of whether the continuing AD pathogenesis alters anesthetic potency. METHODS We determined the induction potency and emergence time for isoflurane, halothane, and sevoflurane using the minimum alveolar anesthetic concentration for loss of righting reflex as an end point in 12- to 14-mo-old triple transgenic Alzheimer (3xTgAD) mice and wild type C57BL6 controls. 3xTgAD mice model AD by harboring three distinct mutations: the APPSwe, Tau, and PS1 human transgenes, each of which has been associated with familial forms of human AD. RESULTS The 3xTgAD mice exhibited mild resistance (from 8% to 30%) to volatile anesthetics but displayed indistinguishable emergence patterns from all three inhaled anesthetics. CONCLUSIONS These results show that the genetic vulnerabilities and neuropathology associated with AD produce a small but significant decrease in sensitivity to the hypnotic actions of three inhaled anesthetics. Emergence times were not altered. PMID:19820240

  13. Effectiveness of BCG vaccination to aged mice

    Directory of Open Access Journals (Sweden)

    Ito Tsukasa

    2010-09-01

    Full Text Available Abstract Background The tuberculosis (TB still increases in the number of new cases, which is estimated to approach 10 million in 2010. The number of aged people has been growing all over the world. Ageing is one of risk factors in tuberculosis because of decreased immune responses in aged people. Mycobacterium bovis Bacillus Calmette Guérin (BCG is a sole vaccine currently used for TB, however, the efficacy of BCG in adults is still a matter of debate. Emerging the multidrug resistant Mycobacterium tuberculosis (MDR-TB make us to see the importance of vaccination against TB in new light. In this study, we evaluated the efficacy of BCG vaccination in aged mice. Results The Th1 responses, interferon-γ production and interleukin 2, in BCG inoculated aged mice (24-month-old were comparable to those of young mice (4- to 6-week-old. The protection activity of BCG in aged mice against Mycobacterium tuberculosis H37Rv was also the same as young mice. Conclusion These findings suggest that vaccination in aged generation is still effective for protection against tuberculosis.

  14. Testosterone and dihydrotestosterone differentially improve cognition in aged female mice

    OpenAIRE

    Benice, Ted S.; Raber, Jacob

    2009-01-01

    Compared with age-matched male mice, female mice experience a more severe age-related cognitive decline (ACD). Since androgens are less abundant in aged female mice compared with aged male mice, androgen supplementation may enhance cognition in aged female mice. To test this, we assessed behavioral performance on a variety of tasks in 22- to 24-mo-old gonadally intact female mice treated for 6 wk with silastic capsules containing either testosterone (T) or dihydrotestosterone (DHT) or empty c...

  15. Age-related retinopathy in NRF2-deficient mice.

    Directory of Open Access Journals (Sweden)

    Zhenyang Zhao

    Full Text Available BACKGROUND: Cumulative oxidative damage is implicated in the pathogenesis of age-related macular degeneration (AMD. Nuclear factor erythroid 2-related factor 2 (NRF2 is a transcription factor that plays key roles in retinal antioxidant and detoxification responses. The purposes of this study were to determine whether NRF2-deficient mice would develop AMD-like retinal pathology with aging and to explore the underlying mechanisms. METHODS AND FINDINGS: Eyes of both wild type and Nrf2(-/- mice were examined in vivo by fundus photography and electroretinography (ERG. Structural changes of the outer retina in aged animals were examined by light and electron microscopy, and immunofluorescence labeling. Our results showed that Nrf2(-/- mice developed age-dependent degenerative pathology in the retinal pigment epithelium (RPE. Drusen-like deposits, accumulation of lipofuscin, spontaneous choroidal neovascularization (CNV and sub-RPE deposition of inflammatory proteins were present in Nrf2(-/- mice after 12 months. Accumulation of autophagy-related vacuoles and multivesicular bodies was identified by electron microscopy both within the RPE and in Bruch's membrane of aged Nrf2(-/- mice. CONCLUSIONS: Our data suggest that disruption of Nfe2l2 gene increased the vulnerability of outer retina to age-related degeneration. NRF2-deficient mice developed ocular pathology similar to cardinal features of human AMD and deregulated autophagy is likely a mechanistic link between oxidative injury and inflammation. The Nrf2(-/- mice can provide a novel model for mechanistic and translational research on AMD.

  16. High percentage of New Zealand white mice show anti-DNA antibodies

    International Nuclear Information System (INIS)

    Autoimmune anti-nDNA activity was detected in sera of 57% of New Zealand White (NZW) mice tested. This percentage was established for anti-DNA positive females as a percent of total female NZW tested, and was identical for male NZW. Anti-DNA positive mice ranged in age from 137 days to 619 days, compared to an age range for anti-DNA negative NZW of 137 days to 523 days. Total NZW mice tested was 40. This compared to 40% anti-DNA positive sera of 59 (NZB x NZW) F1 mice (BW), ranging in age from 218 to 345 days which were predominantly male (95%). Only 65% of NZW tested were male. Positive sera were established as those sera at a 1:10 dilution, that showed 6X or greater the background activity of sera of non-autoimmune Balb/cV mice at any concentration. All sera were assayed by a solid phase radioimmunoassay using 125I radiolabelled protein A, and therefore, reflect protein A binding isotypes only. These data implicate NZW mice significantly in the anti-DNA activity exhibited by their autoimmune BW progeny

  17. Taurine increases hippocampal neurogenesis in aging mice

    OpenAIRE

    Elias Gebara; Florian Udry; Sébastien Sultan; Nicolas Toni

    2015-01-01

    Aging is associated with increased inflammation and reduced hippocampal neurogenesis, which may in turn contribute to cognitive impairment. Taurine is a free amino acid found in numerous diets, with anti-inflammatory properties. Although abundant in the young brain, the decrease in taurine concentration with age may underlie reduced neurogenesis. Here, we assessed the effect of taurine on hippocampal neurogenesis in middle-aged mice. We found that taurine increased cell proliferation in the d...

  18. Croton grewioides Baill. (Euphorbiaceae) Shows Antidiarrheal Activity in Mice

    Science.gov (United States)

    da Silva, Anne Dayse Soares; de Melo e Silva, Karoline; Neto, José Clementino; Costa, Vicente Carlos de Oliveira; Pessôa, Hilzeth de Luna F.; Tavares, Josean Fechine; da Silva, Marcelo Sobral; Cavalcante, Fabiana de Andrade

    2016-01-01

    Based on chemotaxonomy, we decided to investigate the possible antidiarrheal activity in mice of a crude ethanolic extract obtained from aerial parts of Croton grewioides (CG-EtOH). We tested for any possible toxicity in rat erythrocytes and acute toxicity in mice. Antidiarrheal activity was assessed by determining the effect of CG-EtOH on defecation frequency, liquid stool, intestinal motility and intestinal fluid accumulation. CG-EtOH showed no in vitro cytotoxicity and was not orally lethal. In contrast, the extract given intraperitoneally (at 2000 mg/kg) was lethal, but only in females. CG-EtOH produced a significant and equipotent antidiarrheal activity, both in defecation frequency (ED50 = 106.0 ± 8.1 mg/kg) and liquid stools (ED50 = 105.0 ± 9.2 mg/kg). However, CG-EtOH (125 mg/kg) decreased intestinal motility by only 22.7% ± 4.4%. Moreover, extract markedly inhibited the castor oil-induced intestinal contents (ED50 = 34.6 ± 5.4 mg/kg). We thus conclude that CG-EtOH is not orally lethal and contains active principles with antidiarrheal activity, and this effect seems to involve mostly changes in intestinal secretion. SUMMARY CG-EtOH showed no in vitro cytotoxicity and was not orally lethal. In contrast, the extract given intraperitoneally (at 2000 mg/kg) was lethal, but only in females.CG-EtOH probably contains active metabolites with antidiarrheal activity.CG-EtOH reduced the frequency and number of liquid stools.Metabolites presents in the CG-EtOH act mainly by reducing intestinal fluid and, to a lesser extent, reducing intestinal motility. Abbreviations Used: CG-EtOH: crude ethanolic extract obtained from the aerial parts of C. grewioides; WHO: World Health Organization; ED50: dose of a drug that produces 50% of its maximum effect; Emax: maximum effect PMID:27365990

  19. Administration of Glucosylceramide Ameliorated the Memory Impairment in Aged Mice

    OpenAIRE

    Yeonju Lee; Sergiy Oliynyk; Jae-Chul Jung; Jeong Jun Han; Seikwan Oh

    2013-01-01

    The function and the role of glucosylceramide have not been well studied in the central nervous system. This study was aimed to investigate the possible roles of glucosylceramide in memory function in aged mice. Glucosylceramide (50 mg/kg, p.o.) showed memory enhancing activity after 3-month treatment in the aged mice (C56BL/6, 18–20 months old) through Y-maze, novel objective test, and Morris water maze test. Long-term treatment of glucosylceramide decreased the expression of iNOS and COX-2 ...

  20. Female migraineurs show lack of insular thinning with age.

    Science.gov (United States)

    Maleki, Nasim; Barmettler, Gabi; Moulton, Eric A; Scrivani, Steven; Veggeberg, Rosanna; Spierings, Egilius L H; Burstein, Rami; Becerra, Lino; Borsook, David

    2015-07-01

    Gray matter loss in cortical regions is a normal ageing process for the healthy brain. There have been few studies on the process of ageing of the brain in chronic neurological disorders. In this study, we evaluated changes in the cortical thickness by age in 92 female subjects (46 patients with migraine and 46 healthy controls) using high-field magnetic resonance imaging. The results indicate that in contrast to healthy subjects, migraineurs show a lack of thinning in the insula by age. The functional significance of the lack of thinning is unknown, but it may contribute to the overall cortical hyperexcitability of the migraine brain because the region is tightly involved in a number of major brain networks involved in interoception, salience, nociception, and autonomic function, including the default mode network. PMID:25775358

  1. Novel Drug Delivery System Shows Early Promise for Treating Lupus in Mice

    Science.gov (United States)

    ... System Shows Early Promise for Treating Lupus in Mice A drug delivery system using nanoparticle technology that ... administered the MPA-loaded nanogel to lupus-prone mice that had not yet developed symptoms of the ...

  2. Spatial Cognition in Adult and Aged Mice Exposed to High-Fat Diet.

    Science.gov (United States)

    Kesby, James P; Kim, Jane J; Scadeng, Miriam; Woods, Gina; Kado, Deborah M; Olefsky, Jerrold M; Jeste, Dilip V; Achim, Cristian L; Semenova, Svetlana

    2015-01-01

    Aging is associated with a decline in multiple aspects of cognitive function, with spatial cognition being particularly sensitive to age-related decline. Environmental stressors, such as high-fat diet (HFD) exposure, that produce a diabetic phenotype and metabolic dysfunction may indirectly lead to exacerbated brain aging and promote the development of cognitive deficits. The present work investigated whether exposure to HFD exacerbates age-related cognitive deficits in adult versus aged mice. Adult (5 months old) and aged (15 months old) mice were exposed to control diet or HFD for three months prior to, and throughout, behavioral testing. Anxiety-like behavior in the light-dark box test, discrimination learning and memory in the novel object/place recognition tests, and spatial learning and memory in the Barnes maze test were assessed. HFD resulted in significant gains in body weight and fat mass content with adult mice gaining significantly more weight and adipose tissue due to HFD than aged mice. Weight gain was attributed to food calories sourced from fat, but not total calorie intake. HFD increased fasting insulin levels in all mice, but adult mice showed a greater increase relative to aged mice. Behaviorally, HFD increased anxiety-like behavior in adult but not aged mice without significantly affecting spatial cognition. In contrast, aged mice fed either control or HFD diet displayed deficits in novel place discrimination and spatial learning. Our results suggest that adult mice are more susceptible to the physiological and anxiety-like effects of HFD consumption than aged mice, while aged mice displayed deficits in spatial cognition regardless of dietary influence. We conclude that although HFD induces systemic metabolic dysfunction in both adult and aged mice, overall cognitive function was not adversely affected under the current experimental conditions. PMID:26448649

  3. Spatial Cognition in Adult and Aged Mice Exposed to High-Fat Diet.

    Directory of Open Access Journals (Sweden)

    James P Kesby

    Full Text Available Aging is associated with a decline in multiple aspects of cognitive function, with spatial cognition being particularly sensitive to age-related decline. Environmental stressors, such as high-fat diet (HFD exposure, that produce a diabetic phenotype and metabolic dysfunction may indirectly lead to exacerbated brain aging and promote the development of cognitive deficits. The present work investigated whether exposure to HFD exacerbates age-related cognitive deficits in adult versus aged mice. Adult (5 months old and aged (15 months old mice were exposed to control diet or HFD for three months prior to, and throughout, behavioral testing. Anxiety-like behavior in the light-dark box test, discrimination learning and memory in the novel object/place recognition tests, and spatial learning and memory in the Barnes maze test were assessed. HFD resulted in significant gains in body weight and fat mass content with adult mice gaining significantly more weight and adipose tissue due to HFD than aged mice. Weight gain was attributed to food calories sourced from fat, but not total calorie intake. HFD increased fasting insulin levels in all mice, but adult mice showed a greater increase relative to aged mice. Behaviorally, HFD increased anxiety-like behavior in adult but not aged mice without significantly affecting spatial cognition. In contrast, aged mice fed either control or HFD diet displayed deficits in novel place discrimination and spatial learning. Our results suggest that adult mice are more susceptible to the physiological and anxiety-like effects of HFD consumption than aged mice, while aged mice displayed deficits in spatial cognition regardless of dietary influence. We conclude that although HFD induces systemic metabolic dysfunction in both adult and aged mice, overall cognitive function was not adversely affected under the current experimental conditions.

  4. Visceral adipose tissue inflammation is associated with age-related brain changes and ischemic brain damage in aged mice.

    Science.gov (United States)

    Shin, Jin A; Jeong, Sae Im; Kim, Minsuk; Yoon, Joo Chun; Kim, Hee-Sun; Park, Eun-Mi

    2015-11-01

    Visceral adipose tissue is accumulated with aging. An increase in visceral fat accompanied by low-grade inflammation is associated with several adult-onset diseases. However, the effects of visceral adipose tissue inflammation on the normal and ischemic brains of aged are not clearly defined. To examine the role of visceral adipose tissue inflammation, we evaluated inflammatory cytokines in the serum, visceral adipose tissue, and brain as well as blood-brain barrier (BBB) permeability in aged male mice (20 months) underwent sham or visceral fat removal surgery compared with the young mice (2.5 months). Additionally, ischemic brain injury was compared in young and aged mice with sham and visceral fat removal surgery. Interleukin (IL)-1β, IL-6, and tumor necrosis factor-α levels in examined organs were increased in aged mice compared with the young mice, and these levels were reduced in the mice with visceral fat removal. Increased BBB permeability with reduced expression of tight junction proteins in aged sham mice were also decreased in mice with visceral fat removal. After focal ischemic injury, aged mice with visceral fat removal showed a reduction in infarct volumes, BBB permeability, and levels of proinflammatory cytokines in the ischemic brain compared with sham mice, although the neurological outcomes were not significantly improved. In addition, further upregulated visceral adipose tissue inflammation in response to ischemic brain injury was attenuated in mice with visceral fat removal. These results suggest that visceral adipose tissue inflammation is associated with age-related changes in the brain and contributes to the ischemic brain damage in the aged mice. We suggest that visceral adiposity should be considered as a factor affecting brain health and ischemic brain damage in the aged population. PMID:26184082

  5. Administration of Glucosylceramide Ameliorated the Memory Impairment in Aged Mice

    Directory of Open Access Journals (Sweden)

    Yeonju Lee

    2013-01-01

    Full Text Available The function and the role of glucosylceramide have not been well studied in the central nervous system. This study was aimed to investigate the possible roles of glucosylceramide in memory function in aged mice. Glucosylceramide (50 mg/kg, p.o. showed memory enhancing activity after 3-month treatment in the aged mice (C56BL/6, 18–20 months old through Y-maze, novel objective test, and Morris water maze test. Long-term treatment of glucosylceramide decreased the expression of iNOS and COX-2 in the brain of aged mice. The LPS-induced mRNA level of iNOS, COX-2, IL-1β, and TNF-α was reduced by the acute treatment with glucosylceramide in adult mice. These results suggest that glucosylceramide plays an important role in anti-inflammatory and memory enhancement, and it could be a potential new therapeutic agent for the treatment of neurodegenerative diseases such as Alzheimer’s disease.

  6. Proteomic study on gender differences in aging kidney of mice

    Directory of Open Access Journals (Sweden)

    Cristobal Susana

    2009-04-01

    Full Text Available Abstract Background This study aims to analyze sex differences in mice aging kidney. We applied a proteomic technique based on subfractionation, and liquid chromatography coupled with 2-DE. Samples from male and female CD1-Swiss outbred mice from 28 weeks, 52 weeks, and 76 weeks were analysed by 2-DE, and selected proteins were identified by matrix assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS. Results This proteomic analysis detected age-related changes in protein expression in 55 protein-spots, corresponding to 22 spots in males and 33 spots in females. We found a protein expression signature (PES of aging composed by 8 spots, common for both genders. The identified proteins indicated increases in oxidative and proteolytic proteins and decreases in glycolytic proteins, and antioxidant enzymes. Conclusion Our results provide insights into the gender differences associated to the decline of kidney function in aging. Thus, we show that proteomics can provide valuable information on age-related changes in expression levels of proteins and related modifications. This pilot study is still far from providing candidates for aging-biomarkers. However, we suggest that the analysis of these proteins could suggest mechanisms of cellular aging in kidney, and improve the kidney selection for transplantation.

  7. The PDE4 Inhibitor HT-0712 Improves Hippocampus-Dependent Memory in Aged Mice

    OpenAIRE

    Peters, Marco; Bletsch, Matthew; Stanley, Jennifer; Wheeler, Damian; Scott, Roderick; Tully, Tim

    2014-01-01

    Aging is associated with declines in memory and cognitive function. Here, we evaluate the effects of HT-0712 on memory formation and on cAMP response element-binding protein (CREB)-regulated genes in aged mice. HT-0712 enhanced long-term memory formation in normal young mice at brain concentrations similar to those found to increase CRE-mediated gene expression in hippocampal neurons. Aged mice showed significantly poorer contextual and trace conditioning compared with young–adult mice. In ag...

  8. Young Little Mice Express a Premature Cardiovascular Aging Phenotype

    OpenAIRE

    Reddy, Anilkumar K.; Hartley, Craig J.; Pham, Thuy T.; Darlington, Gretchen; Entman, Mark L.; Taffet, George E.

    2013-01-01

    To investigate the effect of growth hormone and insulin-like growth factor 1 deficiency on the aging mouse arterial system, we compared the hemodynamics in young (4 months) and old (30 months) growth hormone–releasing hormone receptor null dwarf (Little) mice and their wild-type littermates. Young Little mice had significantly lower peak and mean aortic velocity and significantly higher aortic impedance than young wild-type mice. However, unlike the wild-type mice, there were no significant c...

  9. BDNF-Deficient Mice Show Reduced Psychosis-Related Behaviors Following Chronic Methamphetamine

    OpenAIRE

    Manning, Elizabeth E.; Halberstadt, Adam L.; van den Buuse, Maarten

    2015-01-01

    Background: One of the most devastating consequences of methamphetamine abuse is increased risk of psychosis. Brain-derived neurotrophic factor has been implicated in both psychosis and neuronal responses to methamphetamine. We therefore examined persistent psychosis-like behavioral effects of methamphetamine in brain-derived neurotrophic factor heterozygous mice. Methods: Mice were chronically treated with methamphetamine from 6 to 9 weeks of age, and locomotor hyperactivity to an acute D-am...

  10. Exercise Enhances Learning and Hippocampal Neurogenesis in Aged Mice

    OpenAIRE

    van Praag, Henriette; Shubert, Tiffany; Zhao, Chunmei; GAGE, FRED H.

    2005-01-01

    Aging causes changes in the hippocampus that may lead to cognitive decline in older adults. In young animals, exercise increases hippocampal neurogenesis and improves learning. We investigated whether voluntary wheel running would benefit mice that were sedentary until 19 months of age. Specifically, young and aged mice were housed with or without a running wheel and injected with bromodeoxyuridine or retrovirus to label newborn cells. After 1 month, learning was tested in the Morris water ma...

  11. Augmented Senile Plaque Load in Aged Female β-Amyloid Precursor Protein-Transgenic Mice

    OpenAIRE

    Callahan, Michael J.; Lipinski, William J.; Bian, Feng; Durham, Robert A.; Pack, Amy; Walker, Lary C.

    2001-01-01

    Transgenic mice (Tg2576) overexpressing human β-amyloid precursor protein with the Swedish mutation (APP695SWE) develop Alzheimer’s disease-like amyloid β protein (Aβ) deposits by 8 to 10 months of age. These mice show elevated levels of Aβ40 and Aβ42, as well as an age-related increase in diffuse and compact senile plaques in the brain. Senile plaque load was quantitated in the hippocampus and neocortex of 8- to 19-month-old male and female Tg2576 mice. In all mice, plaque burden increased m...

  12. Vital mitochondrial functions show profound changes during yeast culture ageing

    Czech Academy of Sciences Publication Activity Database

    Volejníková, Andrea; Hlousková, Jana; Sigler, Karel; Pichová, Alena

    2013-01-01

    Roč. 13, č. 1 (2013), s. 7-15. ISSN 1567-1356 R&D Projects: GA ČR GA301/07/0339; GA MŠk ME09043; GA MŠk 1M0570 Institutional support: RVO:61388971 Keywords : Saccharomyces cerevisiae * chronological ageing * mitochondria Subject RIV: EE - Microbiology, Virology Impact factor: 2.436, year: 2013

  13. A metabolic signature predicts biological age in mice

    OpenAIRE

    Tomás-Loba, Antonia; Bernardes de Jesus, Bruno; Mato, Jose M.; Blasco, Maria A.

    2012-01-01

    Our understanding of the mechanisms by which aging is produced is still very limited. Here, we have determined the sera metabolite profile of 117 wild-type mice of different genetic backgrounds ranging from 8-129 weeks of age. This has allowed us to define a robust metabolomic signature and a derived metabolomic score that reliably/accurately predicts the age of wild-type mice. In the case of telomerase-deficient mice, which have a shortened lifespan, their metabolomic score predicts older ag...

  14. Altered Allogeneic Immune Responses in Middle-Aged Mice

    Institute of Scientific and Technical Information of China (English)

    YiminSun; HanhanLi; AlanN.Langnas

    2004-01-01

    It is well known that leukocyte composition, T cell phenotypes and immune function change in aged mice and humans. However, limited and conflicting results on the age-related immune changes in middle-aged mice were reported. Identification of the characteristics of allogeneic immune responses in aging mice may offer important information for transplantation immunology. The major age-related changes in the immune cell phenotypes and function of 12 months old mice include: 1) the significantly decreased CD4+ cell population in the peripheral blood, the major peripheral CD4+ cells is CD45RBlowCD62Llow memory phenotype; 2) the in vitro responses to alloantigens and Con A of splenocytes markedly reduced; 3) the in vivo secondary humoral immune responses to alloantigens significantly declined; 4) the age-related alteration in the thymus mainly occurred in CD4/CD8 double positive (DP) stage; and 5) increased CD80+ and MHC class II+ cell population in spleens. Thus, the major age-related immune changes in 12 months old mice occurred in CD4+ T cells in the periphery and DP stage in the thymus, which may subsequently lead to the decreased allogeneic immune responses and the different sensitivity to immunosuppressive drugs and treatments. Further studies on the characteristics of allogeneic immunity in aging individuals may help to determine the appropriated treatment for transplant aging individuals. Cellular & Molecular Immunology. 2004;1(6):440-446.

  15. Altered Allogeneic Immune Responses in Middle-Aged Mice

    Institute of Scientific and Technical Information of China (English)

    Yimin Sun; Hanhan Li; Alan N. Langnas; Yong Zhao

    2004-01-01

    It is well known that leukocyte composition, T cell phenotypes and immune function change in aged mice and humans. However, limited and conflicting results on the age-related immune changes in middle-aged mice were reported. Identification of the characteristics of allogeneic immune responses in aging mice may offer important information for transplantation immunology. The major age-related changes in the immune cell phenotypes and function of 12 months old mice include: 1) the significantly decreased CD4+ cell population in the peripheral blood, the major peripheral CD4+ cells is CD45RBlowCD62Llow memory phenotype; 2) the in vitro responses to alloantigens and Con A of splenocytes markedly reduced; 3) the in vivo secondary humoral immune responses to alloantigens significantly declined; 4) the age-related alteration in the thymus mainly occurred in CD4/CD8 double positive (DP) stage; and 5) increased CD80+ and MHC class Ⅱ+ cell population in spleens. Thus, the major age-related immune changes in 12 months old mice occurred in CD4+ T cells in the periphery and DP stage in the thymus, which may subsequently lead to the decreased allogeneic immune responses and the different sensitivity to immunosuppressive drugs and treatments. Further studies on the characteristics of allogeneic immunity in aging individuals may help to determine the appropriated treatment for transplant aging individuals. Cellular & Molecular Immunology. 2004; 1(6) :440-446.

  16. Proteomic study on gender differences in aging kidney of mice

    OpenAIRE

    Cristobal Susana; Amelina Hanna

    2009-01-01

    Abstract Background This study aims to analyze sex differences in mice aging kidney. We applied a proteomic technique based on subfractionation, and liquid chromatography coupled with 2-DE. Samples from male and female CD1-Swiss outbred mice from 28 weeks, 52 weeks, and 76 weeks were analysed by 2-DE, and selected proteins were identified by matrix assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS). Results This proteomic analysis detected age-related changes...

  17. Peripheral surgical wounding and age-dependent neuroinflammation in mice.

    Directory of Open Access Journals (Sweden)

    Zhipeng Xu

    Full Text Available Post-operative cognitive dysfunction is associated with morbidity and mortality. However, its neuropathogenesis remains largely to be determined. Neuroinflammation and accumulation of β-amyloid (Aβ have been reported to contribute to cognitive dysfunction in humans and cognitive impairment in animals. Our recent studies have established a pre-clinical model in mice, and have found that the peripheral surgical wounding without the influence of general anesthesia induces an age-dependent Aβ accumulation and cognitive impairment in mice. We therefore set out to assess the effects of peripheral surgical wounding, in the absence of general anesthesia, on neuroinflammation in mice with different ages. Abdominal surgery under local anesthesia was established in 9 and 18 month-old mice. The levels of tumor necrosis factor-α (TNF-α, interleukin-6 (IL-6, Iba1 positive cells (the marker of microglia activation, CD33, and cognitive function in mice were determined. The peripheral surgical wounding increased the levels of TNF-α, IL-6, and Iba1 positive cells in the hippocampus of both 9 and 18 month-old mice, and age potentiated these effects. The peripheral surgical wounding increased the levels of CD33 in the hippocampus of 18, but not 9, month-old mice. Finally, anti-inflammatory drug ibuprofen ameliorated the peripheral surgical wounding-induced cognitive impairment in 18 month-old mice. These data suggested that the peripheral surgical wounding could induce an age-dependent neuroinflammation and elevation of CD33 levels in the hippocampus of mice, which could lead to cognitive impairment in aged mice. Pending further studies, anti-inflammatory therapies may reduce the risk of postoperative cognitive dysfunction in elderly patients.

  18. Cathepsin K null mice show reduced adiposity during the rapid accumulation of fat stores.

    Directory of Open Access Journals (Sweden)

    Marcella Funicello

    Full Text Available Growing evidences indicate that proteases are implicated in adipogenesis and in the onset of obesity. We previously reported that the cysteine protease cathepsin K (ctsk is overexpressed in the white adipose tissue (WAT of obese individuals. We herein characterized the WAT and the metabolic phenotype of ctsk deficient animals (ctsk-/-. When the growth rate of ctsk-/- was compared to that of the wild type animals (WT, we could establish a time window (5-8 weeks of age within which ctsk-/-display significantly lower body weight and WAT size as compared to WT. Such a difference was not observable in older mice. Upon treatment with high fat diet (HFD for 12 weeks ctsk-/- gained significantly less weight than WT and showed reduced brown adipose tissue, liver mass and a lower percentage of body fat. Plasma triglycerides, cholesterol and leptin were significantly lower in HFD-fed-ctsk-/- as compared to HFD-fed WT animals. Adipocyte lipolysis rates were increased in both young and HFD-fed-ctsk-/-, as compared to WT. Carnitine palmitoyl transferase-1 activity, was higher in mitochondria isolated from the WAT of HFD treated ctsk-/- as compared to WT. Together, these data indicate that ctsk ablation in mice results in reduced body fat content under conditions requiring a rapid accumulation of fat stores. This observation could be partly explained by an increased release and/or utilization of FFA and by an augmented ratio of lipolysis/lipogenesis. These results also demonstrate that under a HFD, ctsk deficiency confers a partial resistance to the development of dyslipidemia.

  19. RhTFAM treatment stimulates mitochondrial oxidative metabolism and improves memory in aged mice

    OpenAIRE

    Thomas, Ravindar R.; Khan, Shaharyar M.; Smigrodzki, Rafal M.; Onyango, Isaac G.; Dennis, Jameel; Khan, Omer M.; Portell, Francisco R.; Bennett, James P

    2012-01-01

    Mitochondrial function declines with age in postmitotic tissues such as brain, heart and skeletal muscle. Despite weekly exercise, aged mice showed substantial losses of mtDNA gene copy numbers and reductions in mtDNA gene transcription and mitobiogenesis signaling in brain and heart. We treated these mice with weekly intravenous injections of recombinant human mitochondrial transcription factor A (rhTFAM). RhTFAM treatment for one month increased mitochondrial respiration in brain, heart and...

  20. Relaxin-3-deficient mice showed slight alteration in anxiety-related behavior

    Directory of Open Access Journals (Sweden)

    Yoshihisa eWatanabe

    2011-08-01

    Full Text Available Relaxin-3 is a neuropeptide belonging to the relaxin/insulin superfamily. Studies using rodents have revealed that relaxin-3 is predominantly expressed in neurons in the nucleus incertus of the pons, the axons of which project to forebrain regions including the hypothalamus. There is evidence that relaxin-3 is involved in several functions, including food intake and stress responses. In the present study, we generated relaxin-3 gene knockout (KO mice and examined them using a range of behavioral tests of sensory/motor functions and emotion-related behaviors. The results revealed that relaxin-3 KO mice exhibited normal growth and appearance, and were generally indistinguishable from wild genotype littermates. There was no difference in bodyweight among genotypes until at least 28 weeks after birth. In addition, there were no significant differences between wild-type and KO mice in locomotor activity, social interaction, hot plate test performance, fear conditioning, depression-like behavior, and Y-maze test performance. However, in the elevated plus maze test, KO mice exhibited a robust increase in the tendency to enter open arms, although they exhibited normal performance in a light/dark transition test and showed no difference from wild-type mice in the time spent in central area in the open field test. On the other hand, a significant increase in the acoustic startle response was observed in KO mice. These results indicate that relaxin-3 is slightly involved in the anxiety-related behavior.

  1. Adipose-Derived Mesenchymal Stem Cells Restore Impaired Mucosal Immune Responses in Aged Mice

    Science.gov (United States)

    Aso, Kazuyoshi; Tsuruhara, Akitoshi; Takagaki, Kentaro; Oki, Katsuyuki; Ota, Megumi; Nose, Yasuhiro; Tanemura, Hideki; Urushihata, Naoki; Sasanuma, Jinichi; Sano, Masayuki; Hirano, Atsuyuki; Aso, Rio; McGhee, Jerry R.; Fujihashi, Kohtaro

    2016-01-01

    It has been shown that adipose-derived mesenchymal stem cells (AMSCs) can differentiate into adipocytes, chondrocytes and osteoblasts. Several clinical trials have shown the ability of AMSCs to regenerate these differentiated cell types. Age-associated dysregulation of the gastrointestinal (GI) immune system has been well documented. Our previous studies showed that impaired mucosal immunity in the GI tract occurs earlier during agingthan is seen in the systemic compartment. In this study, we examined the potential of AMSCs to restore the GI mucosal immune system in aged mice. Aged (>18 mo old) mice were adoptively transferred with AMSCs. Two weeks later, mice were orally immunized with ovalbumin (OVA) plus cholera toxin (CT) three times at weekly intervals. Seven days after the final immunization, when fecal extract samples and plasma were subjected to OVA- and CT-B-specific ELISA, elevated levels of mucosal secretory IgA (SIgA) and plasma IgG antibody (Ab) responses were noted in aged mouse recipients. Similar results were also seen aged mice which received AMSCs at one year of age. When cytokine production was examined, OVA-stimulated Peyer’s patch CD4+ T cells produced increased levels of IL-4. Further, CD4+ T cells from the lamina propria revealed elevated levels of IL-4 and IFN-γ production. In contrast, aged mice without AMSC transfer showed essentially no OVA- or CT-B-specific mucosal SIgA or plasma IgG Ab or cytokine responses. Of importance, fecal extracts from AMSC transferred aged mice showed neutralization activity to CT intoxication. These results suggest that AMSCs can restore impaired mucosal immunity in the GI tract of aged mice. PMID:26840058

  2. Age-related changes in antral endocrine cells in mice

    OpenAIRE

    Sandstrom, O.; Mahdavi, J.; El-Salhy, M.

    1999-01-01

    Antral endocrine cells in four age groups of mice, namely prepubertal (1 month old), young (3 months old), ageing (12 months old) and senescent (24 months old), were detected by immunocytochemistry and quantified by computerized image analysis. A statistical difference was detected between the different age groups regarding the numbers of gastrin-, somatostatin-, and serotonin-immunoreactive cells. The number of gastrin-immunoreactive cells significantly increa...

  3. Decreased body weight and hepatic steatosis with altered fatty acid ethanolamide metabolism in aged L-Fabp −/− mice[S

    OpenAIRE

    Newberry, Elizabeth P.; Kennedy, Susan M; Xie, Yan; Luo, Jianyang; Crooke, Rosanne M.; Graham, Mark J.; Fu, Jin; Piomelli, Daniele; Davidson, Nicholas O.

    2012-01-01

    The tissue-specific sources and regulated production of physiological signals that modulate food intake are incompletely understood. Previous work showed that L-Fabp−/− mice are protected against obesity and hepatic steatosis induced by a high-fat diet, findings at odds with an apparent obesity phenotype in a distinct line of aged L-Fabp−/− mice. Here we show that the lean phenotype in L-Fabp−/− mice is recapitulated in aged, chow-fed mice and correlates with alterations in hepatic, but not i...

  4. MELATONIN AND IMMUNOMODULATION IN AGED AND IMMUNODEFICIENT MICE

    Institute of Scientific and Technical Information of China (English)

    周爱民; 袁育康; 范桂香

    2003-01-01

    Objective To investigate melatonin-related mechanisms of action on immunoregulation in aged and immunodeficient mice. Methods T lymPhocytes subunit CD4+,CD8+ and CD4+/CD8+ ratio were measured by Flow Cytometer in normal, aged and Cyclophosphamide injected mice which treated with melatonin, and compared with the results of T lymphocytes subunit in the group without melatonin as control group. Results The percentage of CD4+, CD8+ T cells in the normal mice which treated with melatonin was significantly higher than that in control group (P<0.01), CD4+/CD8+ ratio was higher but had no significant difference. In the cyclophosphamide injected group which melatonin treated, the percentage of CD4+ T cells and CD4+/CD8+ ratio were higher than those in control, The difference was significant (P<0.01), while CD8+ was lower (P<0.01). In aged melatonin treated mice group, the percentage of CD4+, CD8+ T cells and CD4+/CD8+ ratio were significantly higher than those in control (P<0.01). Conclusion Melatonin could adjust the quantity and the ratio of CD4+, CD8+ T cells in aged and immunodeficient mice. it implied that melatonin could mediate helper and suppression T lymphocytes to reinforce their immunodefence.

  5. Ginseng berry extract supplementation improves age-related decline of insulin signaling in mice.

    Science.gov (United States)

    Seo, Eunhui; Kim, Sunmi; Lee, Sang Jun; Oh, Byung-Chul; Jun, Hee-Sook

    2015-04-01

    The aim of this study was to evaluate the effects of ginseng berry extract on insulin sensitivity and associated molecular mechanisms in aged mice. C57BL/6 mice (15 months old) were maintained on a regular diet (CON) or a regular diet supplemented with 0.05% ginseng berry extract (GBD) for 24 or 32 weeks. GBD-fed mice showed significantly lower serum insulin levels (p = 0.016) and insulin resistance scores (HOMA-IR) (p = 0.012), suggesting that GBD improved insulin sensitivity. Pancreatic islet hypertrophy was also ameliorated in GBD-fed mice (p = 0.007). Protein levels of tyrosine phosphorylated insulin receptor substrate (IRS)-1 (p = 0.047), and protein kinase B (AKT) (p = 0.037), were up-regulated in the muscle of insulin-injected GBD-fed mice compared with CON-fed mice. The expressions of forkhead box protein O1 (FOXO1) (p = 0.036) and peroxisome proliferator-activated receptor gamma (PPARγ) (p = 0.032), which are known as aging- and insulin resistance-related genes, were also increased in the muscle of GBD-fed mice. We conclude that ginseng berry extract consumption might increase activation of IRS-1 and AKT, contributing to the improvement of insulin sensitivity in aged mice. PMID:25912041

  6. Ginseng Berry Extract Supplementation Improves Age-Related Decline of Insulin Signaling in Mice

    Directory of Open Access Journals (Sweden)

    Eunhui Seo

    2015-04-01

    Full Text Available The aim of this study was to evaluate the effects of ginseng berry extract on insulin sensitivity and associated molecular mechanisms in aged mice. C57BL/6 mice (15 months old were maintained on a regular diet (CON or a regular diet supplemented with 0.05% ginseng berry extract (GBD for 24 or 32 weeks. GBD-fed mice showed significantly lower serum insulin levels (p = 0.016 and insulin resistance scores (HOMA-IR (p = 0.012, suggesting that GBD improved insulin sensitivity. Pancreatic islet hypertrophy was also ameliorated in GBD-fed mice (p = 0.007. Protein levels of tyrosine phosphorylated insulin receptor substrate (IRS-1 (p = 0.047, and protein kinase B (AKT (p = 0.037, were up-regulated in the muscle of insulin-injected GBD-fed mice compared with CON-fed mice. The expressions of forkhead box protein O1 (FOXO1 (p = 0.036 and peroxisome proliferator-activated receptor gamma (PPARγ (p = 0.032, which are known as aging- and insulin resistance-related genes, were also increased in the muscle of GBD-fed mice. We conclude that ginseng berry extract consumption might increase activation of IRS-1 and AKT, contributing to the improvement of insulin sensitivity in aged mice.

  7. Minimal impact of age and housing temperature on the metabolic phenotype of Acc2-/- mice.

    Science.gov (United States)

    Brandon, Amanda E; Stuart, Ella; Leslie, Simon J; Hoehn, Kyle L; James, David E; Kraegen, Edward W; Turner, Nigel; Cooney, Gregory J

    2016-03-01

    An important regulator of fatty acid oxidation (FAO) is the allosteric inhibition of CPT-1 by malonyl-CoA produced by the enzyme acetyl-CoA carboxylase 2 (ACC2). Initial studies suggested that deletion of Acc2 (Acacb) increased fat oxidation and reduced adipose tissue mass but in an independently generated strain of Acc2 knockout mice we observed increased whole-body and skeletal muscle FAO and a compensatory increase in muscle glycogen stores without changes in glucose tolerance, energy expenditure or fat mass in young mice (12-16 weeks). The aim of the present study was to determine whether there was any effect of age or housing at thermoneutrality (29 °C; which reduces total energy expenditure) on the phenotype of Acc2 knockout mice. At 42-54 weeks of age, male WT and Acc2(-/-) mice had similar body weight, fat mass, muscle triglyceride content and glucose tolerance. Consistent with younger Acc2(-/-) mice, aged Acc2(-/-) mice showed increased whole-body FAO (24 h average respiratory exchange ratio=0.95±0.02 and 0.92±0.02 for WT and Acc2(-/-) mice respectively, PFAO in mice, but this has little impact on body composition or insulin action. PMID:26668208

  8. RasGrf1 deficiency delays aging in mice

    OpenAIRE

    Borrás, Consuelo; Monleón, Daniel; López-Grueso, Raul; Gambini, Juan; Orlando, Leonardo; Federico V Pallardó; Santos, Eugenio; Viña, José; Font de Mora, Jaime

    2011-01-01

    RasGRF1 is a Ras-guanine nucleotide exchange factor implicated in a variety of physiological processes including learning and memory and glucose homeostasis. To determine the role of RASGRF1 in aging, lifespan and metabolic parameters were analyzed in aged RasGrf1−/− mice. We observed that mice deficient for RasGrf1−/− display an increase in average and most importantly, in maximal lifespan (20% higher than controls). This was not due to the role of Ras in cancer because tumor-free survival w...

  9. Effects of Myostatin Deletion in Aging Mice

    OpenAIRE

    Morissette, Michael R.; Stricker, Janelle C.; Rosenberg, Michael A; Buranasombati, Cattleya; Levitan, Emily B.; Mittleman, Murray A; Rosenzweig, Anthony

    2009-01-01

    Inhibitors of myostatin, a negative regulator of skeletal muscle mass, are being developed to mitigate aging-related muscle loss. Knockout mouse studies suggest myostatin also affects adiposity, glucose handling, and cardiac growth. However, the cardiac consequences of inhibiting myostatin remain unclear. Myostatin inhibition can potentiate cardiac growth in specific settings (Morissette et al. 2006), a concern since cardiac hypertrophy is associated with adverse clinical outcomes. Therefore ...

  10. Improvement of mount preparations in showing myenteric nerve plexus from intestines of mice

    Institute of Scientific and Technical Information of China (English)

    王红; 张远强; 孙岚; 王春杨; 尹岭

    2003-01-01

    Objective: The whole mount preparations of digestive tract is an effective experimental way to study the appearance and distribution of nerve plexus in digestive tract. Although myentric nerve plexus preparations technique was reported very early. But we have done experiment over and over during our research work in order to improve this traditional method and to meet the needs of our research work, we made some progresses in regular mount preparations after many experiments, which helped offer better situation in observing myentric nerve plexus. Methods: Five healthy male adult Kunming mice (20-30 g in weight) were used in this study. After intraperitoneal injection of muscle relaxant, with dislocation of cervical vertebra method, the abdominal cavity was exposed through abdominal median incision. After several steps of mount preparations the mucous layer and longitudinal muscle layer mount preparations with myentric nerve plexus were stripped under anatomical microscope. Immunohistochemical staining was also used in our study. Results: The mount preparation samples with myentric nerve plexus from intestines of mice showed positive SP immunoreaction. The positive cells were dark brown. Many of the cytons appeared circular and oval, while some appeared triangular or irregular. Conclusion: Our improved method is really a good method to show enteric nerve plexus. The method has many advantages and is particularly applied to small animals such as Kunming mice and BALB/c mice, weighing from 20 g to 30 g.

  11. Proteomic data show an increase in autoantibodies and alpha-fetoprotein and a decrease in apolipoprotein A-II with time in sera from senescence-accelerated mice

    International Nuclear Information System (INIS)

    We evaluated changes in levels by comparing serum proteins in senescence-accelerated mouse-prone 8 (SAMP8) mice at 2, 6, 12, and 15 months of age (SAMP8-2 m, -6 m, -12 m, -15 m) to age-matched SAM-resistant 1 (SAMR1) mice. Mice were sacrificed, and blood was analyzed by 2-dimensional electrophoresis combined with mass spectrometry. Five protein spots were present in all SAMP8 serum samples, but only appeared in SAMR1 samples at 15 months of age except for spot 3, which also showed a slight expression in SAMR1-12 m sera. Two proteins decreased in the sera from SAMP8-2 m, -6 m, and -12 m mice, and divided into 2 spots each in SAMP8-15 m sera. Thus, the total number of altered spots in SAMP8 sera was 7; of these, 4 were identified as Ig kappa chain V region (M-T413), chain A of an activity suppressing Fab fragment to cytochrome P450 aromatase (32C2-A), alpha-fetoprotein, and apolipoprotein A-II. M-T413 is a monoclonal CD4 antibody, which inhibits T cell proliferation. We found that M-T413 RNA level was significantly enhanced in splenocytes from SAMP8-2 m mice. This agreed with serum M-T413 protein alterations and a strikingly lower blood CD4+ T cell count in SAMP8 mice when compared to the age-matched SAMR1 mice, with the latter negatively correlating with serum M-T413 protein volume. Age-related changes in serum proteins favored an increase in autoantibodies and alpha-fetoprotein and a decrease of apolipoprotein A-II, which occurred in SAMP8 mice at 2 months of age and onwards. These proteins may serve as candidate biomarkers for early aging

  12. Mice doubly-deficient in lysosomal hexosaminidase A and neuraminidase 4 show epileptic crises and rapid neuronal loss.

    Science.gov (United States)

    Seyrantepe, Volkan; Lema, Pablo; Caqueret, Aurore; Dridi, Larbi; Bel Hadj, Samar; Carpentier, Stephane; Boucher, Francine; Levade, Thierry; Carmant, Lionel; Gravel, Roy A; Hamel, Edith; Vachon, Pascal; Di Cristo, Graziella; Michaud, Jacques L; Morales, Carlos R; Pshezhetsky, Alexey V

    2010-09-01

    Tay-Sachs disease is a severe lysosomal disorder caused by mutations in the HexA gene coding for the α-subunit of lysosomal β-hexosaminidase A, which converts G(M2) to G(M3) ganglioside. Hexa(-/-) mice, depleted of β-hexosaminidase A, remain asymptomatic to 1 year of age, because they catabolise G(M2) ganglioside via a lysosomal sialidase into glycolipid G(A2), which is further processed by β-hexosaminidase B to lactosyl-ceramide, thereby bypassing the β-hexosaminidase A defect. Since this bypass is not effective in humans, infantile Tay-Sachs disease is fatal in the first years of life. Previously, we identified a novel ganglioside metabolizing sialidase, Neu4, abundantly expressed in mouse brain neurons. Now we demonstrate that mice with targeted disruption of both Neu4 and Hexa genes (Neu4(-/-);Hexa(-/-)) show epileptic seizures with 40% penetrance correlating with polyspike discharges on the cortical electrodes of the electroencephalogram. Single knockout Hexa(-/-) or Neu4(-/-) siblings do not show such symptoms. Further, double-knockout but not single-knockout mice have multiple degenerating neurons in the cortex and hippocampus and multiple layers of cortical neurons accumulating G(M2) ganglioside. Together, our data suggest that the Neu4 block exacerbates the disease in Hexa(-/-) mice, indicating that Neu4 is a modifier gene in the mouse model of Tay-Sachs disease, reducing the disease severity through the metabolic bypass. However, while disease severity in the double mutant is increased, it is not profound suggesting that Neu4 is not the only sialidase contributing to the metabolic bypass in Hexa(-/-) mice. PMID:20862357

  13. Mice doubly-deficient in lysosomal hexosaminidase A and neuraminidase 4 show epileptic crises and rapid neuronal loss.

    Directory of Open Access Journals (Sweden)

    Volkan Seyrantepe

    2010-09-01

    Full Text Available Tay-Sachs disease is a severe lysosomal disorder caused by mutations in the HexA gene coding for the α-subunit of lysosomal β-hexosaminidase A, which converts G(M2 to G(M3 ganglioside. Hexa(-/- mice, depleted of β-hexosaminidase A, remain asymptomatic to 1 year of age, because they catabolise G(M2 ganglioside via a lysosomal sialidase into glycolipid G(A2, which is further processed by β-hexosaminidase B to lactosyl-ceramide, thereby bypassing the β-hexosaminidase A defect. Since this bypass is not effective in humans, infantile Tay-Sachs disease is fatal in the first years of life. Previously, we identified a novel ganglioside metabolizing sialidase, Neu4, abundantly expressed in mouse brain neurons. Now we demonstrate that mice with targeted disruption of both Neu4 and Hexa genes (Neu4(-/-;Hexa(-/- show epileptic seizures with 40% penetrance correlating with polyspike discharges on the cortical electrodes of the electroencephalogram. Single knockout Hexa(-/- or Neu4(-/- siblings do not show such symptoms. Further, double-knockout but not single-knockout mice have multiple degenerating neurons in the cortex and hippocampus and multiple layers of cortical neurons accumulating G(M2 ganglioside. Together, our data suggest that the Neu4 block exacerbates the disease in Hexa(-/- mice, indicating that Neu4 is a modifier gene in the mouse model of Tay-Sachs disease, reducing the disease severity through the metabolic bypass. However, while disease severity in the double mutant is increased, it is not profound suggesting that Neu4 is not the only sialidase contributing to the metabolic bypass in Hexa(-/- mice.

  14. Pulmonary effects of inhaled diesel exhaust in aged mice

    International Nuclear Information System (INIS)

    Pulmonary morbidity and mortality resulting from exposure to fine particulate matter (PM) increases with age. The present studies analyzed potential mechanisms underlying increased susceptibility of the elderly to PM using diesel exhaust (DE) as a model. Mice (2 m and 18 m) were exposed to DE (0, 300, and 1000 μg/m3) for 3 h once (single) or 3 h/day for 3 days (repeated). Bronchoalveolar lavage fluid (BAL), serum and lung tissue were collected 0 and 24 h later. Exposure to DE resulted in structural alterations in the lungs of older but not younger mice, including patchy thickening of the alveolar septa and inflammatory cell localization in alveolar spaces. These effects were most pronounced 24 h after a single exposure to the higher dose of DE. Significant increases in BAL nitrogen oxides were also noted in older mice, as well as expression of lipocalin 24p3, an oxidative stress marker in the lung with no effects in younger mice. Following DE inhalation, expression of Tumor Necrosis Factor alpha (TNFα) was upregulated in lungs of both younger and older mice; however, this was attenuated in older animals. Whereas exposure to DE resulted in increases in lung Interleukin-6 (IL-6) expression in both older and younger mice, IL-8 increased only in older animals. In younger mice, constitutive expression of manganese superoxide dismutase (MnSOD) decreased after DE exposure, while in older mice, constitutive MnSOD was not detectable and DE had no effect on expression of this antioxidant. Taken together, these results suggest that altered generation of inflammatory mediators and MnSOD may contribute to increased susceptibility of older mice to inhaled DE.

  15. Age and isolation influence steroids release and chemical signaling in male mice.

    Science.gov (United States)

    Mucignat-Caretta, Carla; Cavaggioni, Andrea; Redaelli, Marco; Da Dalt, Laura; Zagotto, Giuseppe; Gabai, Gianfranco

    2014-05-01

    Social interactions in mice involve olfactory signals, which convey information about the emitter. In turn, the mouse social and physiological status may modify the release of chemical cues. In this study, the influences of age and social isolation on the endocrine response and the release of chemical signals were investigated in male CD1 mice, allocated into four groups: Young Isolated (from weaning till 60days; N=6), Adult Isolated (till 180days; N=6), Young Grouped (6 mice/cage; till 60days; N=18), Adult Grouped (6 mice/cage; till 180days; N=18). Mice were transferred in a clean cage to observe the micturition pattern and then sacrificed. Body and organs weights, serum testosterone, dehydroepiandrosterone, corticosterone and the ratio Major Urinary Protein/creatinine were measured. Urinary volatile molecules potentially involved in pheromonal communication were identified. Androgen secretion was greater in isolated mice (P<0.05), suggesting a greater reactivity of the Hypothalamic-Pituitary-Gonadal axis. Grouped mice presented a higher degree of adrenal activity, and young mice showed a higher serum corticosterone (P<0.05) suggesting a greater stimulation of the Hypothalamic-Pituitary-Adrenal axis. The micturition pattern typical of dominant male, consisting in voiding numerous droplets, was observed in Young Isolated mice only, which showed a higher protein/creatinine ratio (P<0.05). Urinary 2-s-butyl-thiazoline was higher in both Young and Adult Isolated mice (P<0.005). Young Isolated mice showed the most prominent difference in both micturition pattern and potentially active substance emission, while long term isolation resulted in a less extreme phenotype; therefore social isolation had a higher impact on young mice hormone and pheromone release. PMID:24525008

  16. Factor analysis of attentional set-shifting performance in young and aged mice

    Directory of Open Access Journals (Sweden)

    Geyer Mark A

    2011-08-01

    Full Text Available Abstract Background Executive dysfunction may play a major role in cognitive decline with aging because frontal lobe structures are particularly vulnerable to advancing age. Lesion studies in rats and mice have suggested that intradimensional shifts (IDSs, extradimensional shifts (EDSs, and reversal learning are mediated by the anterior cingulate cortex, the medial prefrontal cortex, and the orbitofrontal cortex, respectively. We hypothesized that the latent structure of cognitive performance would reflect functional localization in the brain and would be altered by aging. Methods Young (4 months, n = 16 and aged (23 months, n = 18 C57BL/6N mice performed an attentional set-shifting task (ASST that evaluates simple discrimination (SD, compound discrimination (CD, IDS, EDS, and reversal learning. The performance data were subjected to an exploratory factor analysis to extract the latent structures of ASST performance in young and aged mice. Results The factor analysis extracted two- and three-factor models. In the two-factor model, the factor associated with SD and CD was clearly separated from the factor associated with the rest of the ASST stages in the young mice only. In the three-factor model, the SD and CD loaded on distinct factors. The three-factor model also showed a separation of factors associated with IDS, EDS, and CD reversal. However, the other reversal learning variables, ID reversal and ED reversal, had somewhat inconsistent factor loadings. Conclusions The separation of performance factors in aged mice was less clear than in young mice, which suggests that aged mice utilize neuronal networks more broadly for specific cognitive functions. The result that the factors associated with SD and CD were separated in the three-factor model may suggest that the introduction of an irrelevant or distracting dimension results in the use of a new/orthogonal strategy for better discrimination.

  17. Ginseng Berry Extract Supplementation Improves Age-Related Decline of Insulin Signaling in Mice

    OpenAIRE

    Eunhui Seo; Sunmi Kim; Sang Jun Lee; Byung-Chul Oh; Hee-Sook Jun

    2015-01-01

    The aim of this study was to evaluate the effects of ginseng berry extract on insulin sensitivity and associated molecular mechanisms in aged mice. C57BL/6 mice (15 months old) were maintained on a regular diet (CON) or a regular diet supplemented with 0.05% ginseng berry extract (GBD) for 24 or 32 weeks. GBD-fed mice showed significantly lower serum insulin levels (p = 0.016) and insulin resistance scores (HOMA-IR) (p = 0.012), suggesting that GBD improved insulin sensitivity. Pancreatic isl...

  18. Genetic analysis of intracapillary glomerular lipoprotein deposits in aging mice.

    Directory of Open Access Journals (Sweden)

    Gerda A Noordmans

    Full Text Available BACKGROUND: Renal aging is characterized by functional and structural changes like decreased glomerular filtration rate, and glomerular, tubular and interstitial damage. To gain insight in pathways involved in renal aging, we studied aged mouse strains and used genetic analysis to identify genes associated with aging phenotypes. METHODS: Upon morphological screening in kidneys from 20-month-old mice from 26 inbred strains we noted intracapillary PAS-positive deposits. The severity of these deposits was quantified by scoring of a total of 50 glomeruli per section (grade 0-4. Electron microscopy and immunohistochemical staining for apoE, apoB, apoA-IV and perilipin-2 was performed to further characterize the lesions. To identify loci associated with these PAS-positive intracapillary glomerular deposits, we performed haplotype association mapping. RESULTS: Six out of 26 mouse strains showed glomerular PAS-positive deposits. The severity of these deposits varied: NOD(0.97, NZW(0.41, NON(0.30, B10(0.21, C3 H(0.9 and C57BR(0.7. The intracapillary deposits were strongly positive for apoE and weakly positive for apoB and apoA-IV. Haplotype association mapping showed a strong association with a 30-Kb haplotype block on Chr 1 within the Esrrg gene. We investigated 1 Mb on each site of this region, which includes the genes Spata17, Gpatch2, Esrrg, Ush2a and Kctd3. CONCLUSIONS: By analyzing 26 aged mouse strains we found that some strains developed an intracapillary PAS and apoE-positive lesion and identified a small haplotype block on Chr 1 within the Esrrg gene to be associated with these lipoprotein deposits. The region spanning this haplotype block contains the genes Spata17, Gpatch2, Esrrg, Ush2a and Kctd3, which are all highly expressed in the kidney. Esrrg might be involved in the evolvement of these glomerular deposits by influencing lipid metabolism and possibly immune reponses.

  19. High Sensitivity of Aged Mice to Deoxynivalenol (Vomitoxin)-Induced Anorexia Corresponds to Elevated Proinflammatory Cytokine and Satiety Hormone Responses

    Science.gov (United States)

    Clark, Erica S.; Flannery, Brenna M.; Gardner, Elizabeth M.; Pestka, James J.

    2015-01-01

    Deoxynivalenol (DON), a trichothecene mycotoxin that commonly contaminates cereal grains, is a public health concern because of its adverse effects on the gastrointestinal and immune systems. The objective of this study was to compare effects of DON on anorectic responses in aged (22 mos) and adult (3 mos) mice. Aged mice showed increased feed refusal with both acute i.p. (1 mg/kg and 5 mg/kg) and dietary (1, 2.5, 10 ppm) DON exposure in comparison to adult mice. In addition to greater suppression of food intake from dietary DON exposure, aged mice also exhibited greater but transient body weight suppression. When aged mice were acutely exposed to 1 mg/kg bw DON i.p., aged mice displayed elevated DON and DON3GlcA tissue levels and delayed clearance in comparison with adult mice. Acute DON exposure also elicited higher proinflammatory cytokine and satiety hormone responses in the plasma of the aged group compared with the adult group. Increased susceptibility to DON-induced anorexia in aged mice relative to adult mice suggests that advanced life stage could be a critical component in accurate human risk assessments for DON and other trichothecenes. PMID:26492270

  20. Administration of red ginseng ameliorates memory decline in aged mice

    OpenAIRE

    Lee, Yeonju; Oh, Seikwan

    2015-01-01

    Background It has been known that ginseng can be applied as a potential nutraceutical for memory impairment; however, experiments with animals of old age are few. Methods To determine the memory enhancing effect of red ginseng, C57BL/6 mice (21 mo old) were given experimental diet pellets containing 0.12% red ginseng extract (approximately 200 mg/kg/d) for 3 mo. Young and old mice (4 mo and 21 mo old, respectively) were used as the control group. The effect of red ginseng, which ameliorated m...

  1. Early activation defects in T lymphocytes from aged mice.

    Science.gov (United States)

    Miller, R A; Garcia, G; Kirk, C J; Witkowski, J M

    1997-12-01

    Aging affects both calcium signals and protein kinase cascades in mouse T lymphocytes. The decline in calcium signal development largely represents differences between naive and memory T cells; the latter are resistant to increases in calcium concentration, and are more common in aged mice. Aging leads to declines in phosphorylation of a wide range of substrates in T cells stimulated by either anti-CD3 antibodies or by substances, such as phorbol myristate acetate (PMA) or ionomycin, that act at intracellular sites, but some phosphoproteins respond only in old T cells, and others respond regardless of age. Tyrosine phosphorylation of the CD3 zeta chain declines with age, both in resting T cells and after activation, but the proportion of Zap-70 that is bound to CD3 zeta increases in T cells from old mice. Zap-70 function and phosphorylation of CD3 zeta-associated Zap-70 change only slightly after stimulation of T cells by anti-CD3 and anti-CD4, and are at similar levels in activated old and young T cells. Nonetheless, induction of Raf-1, MEK, and ERK kinase activity declines with age in CD4 T cells. The effect of aging on T-cell activation is not simply an overall decline in signal intensity, but a set of qualitative changes that differ among subsets and depend at least partly on the nature of the stimulus. PMID:9476667

  2. Reduced thermal sensitivity and Nav1.8 and TRPV1 channel expression in sensory neurons of aged mice

    OpenAIRE

    Wang, Shuying; Davis, Brian M.; Zwick, Melissa; Waxman, Stephen G.; Albers, Kathryn M.

    2005-01-01

    Sensory neurons in aging mammals undergo changes in anatomy, physiology and gene expression that correlate with reduced sensory perception. In this study we compared young and aged mice to identify proteins that might contribute to this loss of sensation. We first show using behavioral testing that thermal sensitivity in aged male and female mice is reduced. Expression of sodium channel (Nav1.8 and Nav1.9) and transient receptor potential vanilloid (TRPV) channels in DRG and peripheral nerves...

  3. Effects of Sleep Deprivation and Aging on Long-Term and Remote Memory in Mice

    Science.gov (United States)

    Vecsey, Christopher G.; Park, Alan J.; Khatib, Nora; Abel, Ted

    2015-01-01

    Sleep deprivation (SD) following hippocampus-dependent learning in young mice impairs memory when tested the following day. Here, we examined the effects of SD on remote memory in both young and aged mice. In young mice, we found that memory is still impaired 1 mo after training. SD also impaired memory in aged mice 1 d after training, but, by a…

  4. Influence of age and ways of treatment in the parasitemia in mice infected with Trypanosoma cruzi treated with high potency biotherapy

    OpenAIRE

    Silvana Marques Araujo; Fabiana Nabarro Ferraz; Camila Fernanda Brustolin; Neide Martins Moreira; Caroline Felicio Braga; Paula Fernanda Massini; Denise Lessa Aleixo

    2011-01-01

    Introduction: The infection of mice by Trypanosoma cruzi is well known, making this a good model for understanding the effect of highly diluted medications. Mice of different ages show different responses to biotherapic T. cruzi [1]. Other data from our laboratory using biotherapic treatment at low potencies show that long lasting treatment has a better effect in mice infected with T. cruzi. However, the use of high potency biotherapics in mice of different ages infected with T. cruzi has not...

  5. Functional recovery in aging mice after experimental stroke

    OpenAIRE

    Manwani, Bharti; Liu, Fudong; Xu, Yan; Persky, Rebecca; Li, Jun; McCullough, Louise D.

    2011-01-01

    Aging is a non modifiable risk factor for stroke. Since not all strokes can be prevented, a major emerging area of research is the development of effective strategies to enhance functional recovery after stroke. However, in the vast majority of pre-clinical stroke studies, the behavioral tests used to assess functional recovery have only been validated for use in young animals, or are designed for rats. Mice are increasingly utilized in stroke models but well validated behavioral tests design...

  6. Beta-lapachone, a modulator of NAD metabolism, prevents health declines in aged mice.

    Directory of Open Access Journals (Sweden)

    Jeong-sook Lee

    Full Text Available NADH-quinone oxidoreductase 1 (NQO1 modulates cellular NAD(+/NADH ratio which has been associated with the aging and anti-aging mechanisms of calorie restriction (CR. Here, we demonstrate that the facilitation of NQO1 activity by feeding β-lapachone (βL, an exogenous NQO1 co-substrate, prevented age-dependent decline of motor and cognitive function in aged mice. βL-fed mice did not alter their food-intake or locomotor activity but did increase their energy expenditure as measured by oxygen consumption and heat generation. Mitochondrial structure and numbers were disorganized and decreased in the muscles of control diet group but those defects were less severe in βL-fed aged mice. Furthermore, for a subset of genes associated with energy metabolism, mice fed the βL-diet showed similar changes in gene expression to the CR group (fed 70% of the control diet. These results support the potentiation of NQO1 activity by a βL diet and could be an option for preventing age-related decline of muscle and brain functions.

  7. Pretargeting in tumored mice with radiolabeled morpholino oligomer showing low kidney uptake

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Guozheng; He, Jiang; Dou, Shuping; Gupta, Suresh; Vanderheyden, Jean-Luc; Rusckowski, Mary; Hnatowich, Donald J. [Division of Nuclear Medicine, Department of Radiology, University of Massachusetts Medical School, 55 Lake Avenue North, MA 01655-0243, Worcester (United States)

    2004-03-01

    We have recently shown that accumulation in mouse kidneys of technetium-99m labeled phosphorodiamidate morpholinos (MORFs) increases with the number of cytosines in the base sequence. To improve tumor/kidney ratios in tumored mice, pretargeting studies were performed with a cytosine-free MORF. An 18-mer MORF (5'-TCTTCTACTTCACAACTA) was conjugated to the anti-CEA antibody MN14 (Immunomedics) and administered to nude mice bearing LS174T tumors. Thereafter, the {sup 99m}Tc-labeled cytosine-free cMORF (5'-TAGTTGTGAAGTAGAAGA-amide-MAG{sub 3}) was administered. For comparison, the identical study was repeated but with our original pair of 18-mer MORFs (5'-GGGTGTACGTCACAACTA-conjugated MN14 and {sup 99m}Tc-labeled 5'-TAGTTGTGACGTACACCC-amide-MAG{sub 3}). Surface plasmon resonance was used to show that the hybridization affinities of the original and the modified pair of MORFs were essentially equal. Hybridization of the cytosine-free cMORF-{sup 99m}Tc to MN14-MORF was demonstrated in vitro by size-exclusion high-performance liquid chromatography. At 3 h, kidney levels in normal mice were 2.0%ID/organ for the modified cMORF vs. 4.1%ID/organ for the original cMORF sequence, while at 24 h, these values were 0.9% vs 1.8%ID/organ. Pretargeting studies in tumored mice receiving 25 {mu}g of conjugated antibody, 0.5 {mu}g of labeled cMORF 48 h later, followed by imaging and sacrifice at 3 h showed that kidney levels were reduced using the cytosine-free cMORF. Moreover, tumor accumulation was about 3.6%ID/g and was independent of sequence. The whole-body images clearly reflected the improved tumor to kidney ratios. By choosing a cytosine-free base sequence for pretargeting studies, kidney accumulation of cMORF-{sup 99m}Tc was reduced without adversely influencing tumor accumulation. The lowering of kidney radioactivity levels in this way may be important to reduce toxicity to this organ in connection with pretargeting radiotherapy studies. (orig.)

  8. Pretargeting in tumored mice with radiolabeled morpholino oligomer showing low kidney uptake.

    Science.gov (United States)

    Liu, Guozheng; He, Jiang; Dou, Shuping; Gupta, Suresh; Vanderheyden, Jean-Luc; Rusckowski, Mary; Hnatowich, Donald J

    2004-03-01

    We have recently shown that accumulation in mouse kidneys of technetium-99m labeled phosphorodiamidate morpholinos (MORFs) increases with the number of cytosines in the base sequence. To improve tumor/kidney ratios in tumored mice, pretargeting studies were performed with a cytosine-free MORF. An 18-mer MORF (5'-TCTTCTACTTCACAACTA) was conjugated to the anti-CEA antibody MN14 (Immunomedics) and administered to nude mice bearing LS174T tumors. Thereafter, the (99m)Tc-labeled cytosine-free cMORF (5'-TAGTTGTGAAGTAGAAGA-amide-MAG(3)) was administered. For comparison, the identical study was repeated but with our original pair of 18-mer MORFs (5'-GGGTGTACGTCACAACTA-conjugated MN14 and (99m)Tc-labeled 5'-TAGTTGTGACGTACACCC-amide-MAG(3)). Surface plasmon resonance was used to show that the hybridization affinities of the original and the modified pair of MORFs were essentially equal. Hybridization of the cytosine-free cMORF-(99m)Tc to MN14-MORF was demonstrated in vitro by size-exclusion high-performance liquid chromatography. At 3 h, kidney levels in normal mice were 2.0%ID/organ for the modified cMORF vs. 4.1%ID/organ for the original cMORF sequence, while at 24 h, these values were 0.9% vs 1.8%ID/organ. Pretargeting studies in tumored mice receiving 25 microg of conjugated antibody, 0.5 microg of labeled cMORF 48 h later, followed by imaging and sacrifice at 3 h showed that kidney levels were reduced using the cytosine-free cMORF. Moreover, tumor accumulation was about 3.6%ID/g and was independent of sequence. The whole-body images clearly reflected the improved tumor to kidney ratios. By choosing a cytosine-free base sequence for pretargeting studies, kidney accumulation of cMORF-(99m)Tc was reduced without adversely influencing tumor accumulation. The lowering of kidney radioactivity levels in this way may be important to reduce toxicity to this organ in connection with pretargeting radiotherapy studies. PMID:14691611

  9. Reversal of glial and neurovascular markers of unhealthy brain aging by exercise in middle-aged female mice.

    Directory of Open Access Journals (Sweden)

    Caitlin S Latimer

    Full Text Available Healthy brain aging and cognitive function are promoted by exercise. The benefits of exercise are attributed to several mechanisms, many which highlight its neuroprotective role via actions that enhance neurogenesis, neuronal morphology and/or neurotrophin release. However, the brain is also composed of glial and vascular elements, and comparatively less is known regarding the effects of exercise on these components in the aging brain. Here, we show that aerobic exercise at mid-age decreased markers of unhealthy brain aging including astrocyte hypertrophy, a hallmark of brain aging. Middle-aged female mice were assigned to a sedentary group or provided a running wheel for six weeks. Exercise decreased hippocampal astrocyte and myelin markers of aging but increased VEGF, a marker of angiogenesis. Brain vascular casts revealed exercise-induced structural modifications associated with improved endothelial function in the periphery. Our results suggest that age-related astrocyte hypertrophy/reactivity and myelin dysregulation are aggravated by a sedentary lifestyle and accompanying reductions in vascular function. However, these effects appear reversible with exercise initiated at mid-age. As this period of the lifespan coincides with the appearance of multiple markers of brain aging, including initial signs of cognitive decline, it may represent a window of opportunity for intervention as the brain appears to still possess significant vascular plasticity. These results may also have particular implications for aging females who are more susceptible than males to certain risk factors which contribute to vascular aging.

  10. In vivo and in vitro study of the primary and secondary antibody response to a bacterial antigen in aged mice.

    OpenAIRE

    Borghesi, C.; Nicoletti, C.

    1995-01-01

    One of the most important manifestations of aging in both humans and laboratory animals is a gradual decline in immune effectiveness. However, it is not clear as to how general is this decline. We here report that aged BALB/c mice showed no decline in the magnitude of the in vivo primary antibody response to phosphorylcholine (PC), an immunodominant epitope of the Streptococcus pneumoniae R36a (Pn). Often it appeared that aged mice responded better than young syngeneic mice. In contrast, the ...

  11. Accumulation of point mutations in mitochondrial DNA of aging mice

    Energy Technology Data Exchange (ETDEWEB)

    Khaidakov, Magomed; Heflich, Robert H.; Manjanatha, Mugimane G.; Myers, Meagan B.; Aidoo, Anane

    2003-05-15

    Mitochondrial DNA (mtDNA) exists in a highly genotoxic environment created by exposure to reactive oxygen species, somewhat deficient DNA repair, and the relatively low fidelity of polymerase gamma. Given the severity of the environment, it was anticipated that mutation accumulation in the mtDNA of aging animals should exceed that of nuclear genes by several orders of magnitude. We have analyzed fragments amplified from the D-loop region of mtDNA from 2 to 22-month-old mice. The amplified 432 bp fragments were cloned into plasmid vectors, and plasmid DNAs from individual clones were purified and sequenced. None of 110 fragments from young mice contained a mutation, while 9 of 87 clones originating from old animals contained base substitutions (chi square = 11.9, P<0.001). The estimated mutation frequency in mtDNA from old mice was 11.6{+-}2.7 or 25.4{+-}7.8 per 10{sup 5} nucleotides (depending on assumptions of clonality), which exceeds existing estimates for mutation frequencies for nuclear genes by approximately 1000-fold. Our data suggest that at 22 months of age, which roughly corresponds to 3/4 of the mouse natural life span, most mtDNA molecules carry multiple point mutations.

  12. Resveratrol attenuates peripheral and brain inflammation and reduces ischemic brain injury in aged female mice.

    Science.gov (United States)

    Jeong, Sae Im; Shin, Jin A; Cho, Sunghee; Kim, Hye Won; Lee, Ji Yoon; Kang, Jihee Lee; Park, Eun-Mi

    2016-08-01

    Resveratrol is known to improve metabolic dysfunction associated with obesity. Visceral obesity is a sign of aging and is considered a risk factor for ischemic stroke. In this study, we investigated the effects of resveratrol on inflammation in visceral adipose tissue and the brain and its effects on ischemic brain injury in aged female mice. Mice treated with resveratrol (0.1 mg/kg, p.o.) for 10 days showed reduced levels of interleukin-1β and tumor necrosis factor-α, as well as a reduction in the size of adipocytes in visceral adipose tissue. Resveratrol also reduced interleukin-1β and tumor necrosis factor-α protein levels and immunoglobulin G extravasation in the brain. Mice treated with resveratrol demonstrated smaller infarct size, improved neurological function, and blunted peripheral inflammation at 3 days postischemic stroke. These results showed that resveratrol counteracted inflammation in visceral adipose tissue and in the brain and reduced stroke-induced brain injury and peripheral inflammation in aged female mice. Therefore, resveratrol administration can be a valuable strategy for the prevention of age-associated and disease-provoked inflammation in postmenopausal women. PMID:27318135

  13. Grip strength is potentially an early indicator of age-related decline in mice.

    Science.gov (United States)

    Ge, Xuan; Cho, Anthony; Ciol, Marcia A; Pettan-Brewer, Christina; Snyder, Jessica; Rabinovitch, Peter; Ladiges, Warren

    2016-01-01

    The hand grip test has been correlated with mobility and physical performance in older people and has been shown to be a long-term predictor of mortality. Implementation of new strategies for enhancing healthy aging and maintaining independent living are dependent on predictable preclinical studies. The mouse is used extensively as a model in these types of studies, and the paw grip strength test is similar to the hand grip test for people in that it assesses the ability to grip a device with the paw, is non-invasive and easy to perform, and provides reproducible information. However, little has been reported on how grip strength declines with increasing age in mice. This report shows that grip strength was decreased in C57BL/6 (B6) NIA and C57BL/6×BALB/c F1 (CB6F1) NIA male mice at 12 months of age compared to 8-month-old mice, and continued a robust decline to 20 months and then 28 months of age, when the study was terminated. The decline was not related to lean muscle mass, but extensive age-related carpal and digital exostosis could help explain the decreased grip strength times with increasing age. In conclusion, the grip strength test could be useful in mouse preclinical studies to help make translational predictions on treatment strategies to enhance healthy aging. PMID:27613499

  14. Age Sensitivity of Behavioral Tests and Brain Substrates of Normal Aging in Mice

    Directory of Open Access Journals (Sweden)

    John A. Kennard

    2011-05-01

    Full Text Available Knowledge of age sensitivity, the capacity of a behavioral test to reliably detect age-related changes, has utility in the design of experiments to elucidate processes of normal aging. We review the application of these tests in studies of normal aging and compare and contrast the age sensitivity of the Barnes maze, eyeblink classical conditioning, fear conditioning, Morris water maze and rotorod. These tests have all been implemented to assess normal age-related changes in learning and memory in rodents, which generalize in many cases to age-related changes in learning and memory in all mammals, including humans. Behavioral assessments are a valuable means to measure functional outcomes of neuroscientific studies of aging. Highlighted in this review are the attributes and limitations of these measures in mice in the context of age sensitivity and processes of brain aging. Attributes of these tests include reliability and validity as assessments of learning and memory, well-defined neural substrates, and sensitivity to neural and pharmacological manipulations and disruptions. These tests engage the hippocampus and/or the cerebellum, two structures centrally involved in learning and memory that undergo functional and anatomical changes in normal aging. A test that is less well represented in studies of normal aging, the context pre-exposure facilitation effect (CPFE in fear conditioning, is described as a method to increase sensitivity of contextual fear conditioning to changes in the hippocampus. Recommendations for increasing the age sensitivity of all measures of normal aging in mice are included, as well as a discussion of the potential of the under-studied CPFE to advance understanding of subtle hippocampus-mediated phenomena.

  15. Beneficial effects of cornel iridoid glycoside on behavioral impairment and senescence status in SAMP8 mice at different ages.

    Science.gov (United States)

    Ma, Denglei; Zhu, Yanqiu; Li, Yanzheng; Yang, Cuicui; Zhang, Li; Li, Yali; Li, Lin; Zhang, Lan

    2016-10-01

    The aim of the present study was to investigate the effects of cornel iridoid glycoside (CIG) on behavioral changes and senescent status in senescence-accelerated mouse-prone 8 (SAMP8) mice at different ages (6, 10, and 14 months old). The learning and memory ability, the motor function and the aging conditions of SAMP8 mice were evaluated after CIG treatment in this study. Results showed that intragastrical administration of CIG (100 and 200mg/kg) for two months obviously improved the impaired cognitive ability of SAMP8 mice at the age of 6 months and 10 months, respectively. The treatment with CIG significantly increased the motor function of SAMP8 mice at 10 months and 14 months of age, respectively. CIG also evidently decreased the high grading score of senescence and increased the low surviving rate of SAMP8 mice at the age of 14 months. In addition, CIG treatment inhibited tau hyperphosphorylation in the hippocampus and striatum of SAMP8 mice at different ages. Together, these results indicate that CIG represent a potentially useful treatment for ameliorating the impaired cognitive ability, the motor dysfunction, aging conditions and hyperphosphorylation of tau in aging and age-related neurodegenerative diseases, such as Alzheimer's disease. PMID:27283974

  16. Memory Deficits Are Associated with Impaired Ability to Modulate Neuronal Excitability in Middle-Aged Mice

    Science.gov (United States)

    Kaczorowski, Catherine C.; Disterhoft, John F.

    2009-01-01

    Normal aging disrupts hippocampal neuroplasticity and learning and memory. Aging deficits were exposed in a subset (30%) of middle-aged mice that performed below criterion on a hippocampal-dependent contextual fear conditioning task. Basal neuronal excitability was comparable in middle-aged and young mice, but learning-related modulation of the…

  17. Influence of age and caloric restriction on liver glycolytic enzyme activities and metabolite concentrations in mice.

    Science.gov (United States)

    Hagopian, Kevork; Ramsey, Jon J; Weindruch, Richard

    2003-03-01

    The influence of caloric restriction (CR) from 2 months of age on the activities of liver glycolytic enzymes and metabolite levels was studied in young and old mice. Livers were sampled 48 h after the last scheduled feeding time. Old mice on CR showed significant decreases in the activities of all the enzymes studied, except for aldolase, triosephosphate isomerase and phosphoglycerate mutase, which were unchanged. The metabolites glucose, glucose-6-phosphate, fructose-6-phosphate, pyruvate and lactate were lower while fructose-1,6-bisphosphate, glyceraldehyde-3-phosphate, dihydroxyacetone phosphate, 3-phosphoglycerate and phosphoenolpyruvate were increased in old CR. Young mice on CR also showed reduced enzyme activities, except for aldolase, triosephosphate isomerase and enolase which were unchanged when compared with young controls. The metabolites glucose, glucose-6-phosphate, fructose-6-phosphate and pyruvate were decreased when compared with young controls, while phosphoenolpyruvate was increased. Ketone bodies increased (65%) in old, but not young, CR mice while fructose-2,6-bisphosphate decreased in both young (22%) and old CR (28%) mice. The results indicate that decreased hepatic glucose levels in CR mice are associated with decreased enzyme activities but not a uniform decrease in metabolite levels. Increased ketone body levels indicate increased utilization of non-carbohydrate fuels while decreased fructose-2,6-bisphosphate level suggests its importance in the control of glycolysis in CR. PMID:12581789

  18. Dynamics of chromosomal aberrations in male mice of various strains during aging.

    Science.gov (United States)

    Rozenfel'd, S V; Togo, E F; Mikheev, V S; Popovich, I G; Zabezhinskii, M A; Anisimov, V N

    2001-05-01

    We studied the incidence of chromosome aberrations in bone marrow cells and primary spermatocytes in various mouse strains. Experiments were performed on SAMP mice (accelerated aging), control SAMR mice, and long-living CBA and SHR mice. Experiments revealed a positive correlation between the age and the incidence of mutations in their somatic cells and gametes. PMID:11550060

  19. Intestine-specific deletion of microsomal triglyceride transfer protein increases mortality in aged mice.

    Directory of Open Access Journals (Sweden)

    Zhe Liang

    Full Text Available BACKGROUND: Mice with conditional, intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO exhibit a complete block in chylomicron assembly together with lipid malabsorption. Young (8-10 week Mttp-IKO mice have improved survival when subjected to a murine model of Pseudomonas aeruginosa-induced sepsis. However, 80% of deaths in sepsis occur in patients over age 65. The purpose of this study was to determine whether age impacts outcome in Mttp-IKO mice subjected to sepsis. METHODS: Aged (20-24 months Mttp-IKO mice and WT mice underwent intratracheal injection with P. aeruginosa. Mice were either sacrificed 24 hours post-operatively for mechanistic studies or followed seven days for survival. RESULTS: In contrast to young septic Mttp-IKO mice, aged septic Mttp-IKO mice had a significantly higher mortality than aged septic WT mice (80% vs. 39%, p = 0.005. Aged septic Mttp-IKO mice exhibited increased gut epithelial apoptosis, increased jejunal Bax/Bcl-2 and Bax/Bcl-XL ratios yet simultaneously demonstrated increased crypt proliferation and villus length. Aged septic Mttp-IKO mice also manifested increased pulmonary myeloperoxidase levels, suggesting increased neutrophil infiltration, as well as decreased systemic TNFα compared to aged septic WT mice. CONCLUSIONS: Blocking intestinal chylomicron secretion alters mortality following sepsis in an age-dependent manner. Increases in gut apoptosis and pulmonary neutrophil infiltration, and decreased systemic TNFα represent potential mechanisms for why intestine-specific Mttp deletion is beneficial in young septic mice but harmful in aged mice as each of these parameters are altered differently in young and aged septic WT and Mttp-IKO mice.

  20. Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yuehai [Cardiovascular Department, Liaocheng People’s Hospital of Shandong University, Liaocheng, Shandong 252000 (China); Cardiovascular Department, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China); Lu, Huixia [The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong 250012 (China); Huang, Ziyang, E-mail: huangziyang666@126.com [Cardiovascular Department, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China); Lin, Huili [Cardiovascular Department, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China); Lei, Zhenmin [Department of OB/GYN, University of Louisville School of Medicine, Louisville, KY 40292 (United States); Chen, Xiaoqing [Department of Rheumatism and Immunology, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China); Tang, Mengxiong; Gao, Fei; Dong, Mei [The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong 250012 (China); Li, Rongda [Department of Rheumatism and Immunology, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China); Lin, Ling, E-mail: qzlinl@163.com [Department of Rheumatism and Immunology, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China)

    2014-07-18

    Highlights: • Titers of ANA and anti-dsDNA antibodies were similar in ApoE{sup −/−} and Fas{sup −/−} mice. • The spleen weights and glomerular areas were similar in ApoE{sup −/−} and Fas{sup −/−} mice. • Expressions of IgG and C3 in glomeruli were similar in ApoE{sup −/−} and Fas{sup −/−} mice. • IgG, C3 and macrophage infiltration in aortic plaques were found in ApoE{sup −/−} mice. - Abstract: Background: Apolipoprotein E-knockout (ApoE{sup −/−}) mice is a classic model of atherosclerosis. We have found that ApoE{sup −/−} mice showed splenomegaly, higher titers of serum anti-nuclear antibody (ANA) and anti-dsDNA antibody compared with C57B6/L (B6) mice. However, whether ApoE{sup −/−} mice show autoimmune injury remains unclear. Methods and results: Six females and six males in each group, ApoE{sup −/−}, Fas{sup −/−} and B6 mice, were used in this study. The titers of serum ANA, anti-dsDNA antibody and creatinine and urine protein were measured by ELISA after 4 months of high-fat diet. The spleen weight and the glomerular area were determined. The expressions of IgG, C3 and macrophage in kidney and atherosclerotic plaque were detected by immunostaining followed by morphometric analysis. Similar to the characteristics of Fas{sup −/−} mice, a model of systemic lupus erythematosus (SLE), ApoE{sup −/−} mice, especially female, displayed significant increases of spleen weight and glomerular area when compared to B6 mice. Also, elevated titers of serum ANA, anti-dsDNA antibody and creatinine and urine protein. Moreover, the expressions of IgG, C3 and macrophage in glomeruli and aortic plaques were found in ApoE{sup −/−} mice. In addition, the IgG and C3 expressions in glomeruli and plaques significantly increased (or a trend of increase) in female ApoE{sup −/−} mice compared with males. Conclusions: Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta.

  1. Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta

    International Nuclear Information System (INIS)

    Highlights: • Titers of ANA and anti-dsDNA antibodies were similar in ApoE−/− and Fas−/− mice. • The spleen weights and glomerular areas were similar in ApoE−/− and Fas−/− mice. • Expressions of IgG and C3 in glomeruli were similar in ApoE−/− and Fas−/− mice. • IgG, C3 and macrophage infiltration in aortic plaques were found in ApoE−/− mice. - Abstract: Background: Apolipoprotein E-knockout (ApoE−/−) mice is a classic model of atherosclerosis. We have found that ApoE−/− mice showed splenomegaly, higher titers of serum anti-nuclear antibody (ANA) and anti-dsDNA antibody compared with C57B6/L (B6) mice. However, whether ApoE−/− mice show autoimmune injury remains unclear. Methods and results: Six females and six males in each group, ApoE−/−, Fas−/− and B6 mice, were used in this study. The titers of serum ANA, anti-dsDNA antibody and creatinine and urine protein were measured by ELISA after 4 months of high-fat diet. The spleen weight and the glomerular area were determined. The expressions of IgG, C3 and macrophage in kidney and atherosclerotic plaque were detected by immunostaining followed by morphometric analysis. Similar to the characteristics of Fas−/− mice, a model of systemic lupus erythematosus (SLE), ApoE−/− mice, especially female, displayed significant increases of spleen weight and glomerular area when compared to B6 mice. Also, elevated titers of serum ANA, anti-dsDNA antibody and creatinine and urine protein. Moreover, the expressions of IgG, C3 and macrophage in glomeruli and aortic plaques were found in ApoE−/− mice. In addition, the IgG and C3 expressions in glomeruli and plaques significantly increased (or a trend of increase) in female ApoE−/− mice compared with males. Conclusions: Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta

  2. Qing'E formula alleviates the aging process in D-galactose-induced aging mice

    Science.gov (United States)

    ZHONG, LIN; HUANG, FEI; SHI, HAILIAN; WU, HUI; ZHANG, BEIBEI; WU, XIAOJUN; WEI, XIAOHUI; WANG, ZHENGTAO

    2016-01-01

    Qing'E formula (QEF) is a clinically used prescription with four ingredients, Eucommiae Cortex, Psoraleae Fructus, Juglandis Semen and Garlic Rhizoma, from the Song dynasty (10th century CE). The present study aimed to investigate the anti-aging effect and mechanisms of QEF on D-galactose-induced aging mice. A mouse subacute aging model was established by subcutaneous injection of D-galactose at the neck consecutively for 8 weeks. Motor activity and memory impairment of the mice were evaluated by the rotarod test and passive avoidance test, respectively. Serum and liver parameters were analyzed with biochemical kits. Hippocampal mRNA and protein expression levels were examined by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. QEF administration significantly ameliorated the impaired motor and memory of aging mice. In the serum, QEF reduced blood urea nitrogen, creatinine, nitric oxide (NO) and malondialdehyde (MDA) levels, and inhibited alanine aminotransferase and aspartate aminotransferase activities. In the liver, QEF increased the glutathione level, enhanced total antioxidant capacity and catalase activity, deceased NO and MDA production, and reduced NO synthase activity. In the hippocampus, QEF elevated gene expression levels of Klotho, sirtuin 1 (SIRT1), forkhead box transcription factor O3, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), insulin-like growth factor-1 and peroxiredoxin-3. QEF increased protein expression levels of Klotho and SIRT1, and decreased that of PGC-1α in the hippocampus. In conclusion, QEF attenuated the aging process in D-galactose-treated mice, which may be mediated through enhancing the antioxidants in the body, protecting renal and hepatic health, and balancing hippocampal expression levels of the longevity-related genes. PMID:27347412

  3. Accumulation of point mutations in mitochondrial DNA of aging mice

    International Nuclear Information System (INIS)

    Mitochondrial DNA (mtDNA) exists in a highly genotoxic environment created by exposure to reactive oxygen species, somewhat deficient DNA repair, and the relatively low fidelity of polymerase gamma. Given the severity of the environment, it was anticipated that mutation accumulation in the mtDNA of aging animals should exceed that of nuclear genes by several orders of magnitude. We have analyzed fragments amplified from the D-loop region of mtDNA from 2 to 22-month-old mice. The amplified 432 bp fragments were cloned into plasmid vectors, and plasmid DNAs from individual clones were purified and sequenced. None of 110 fragments from young mice contained a mutation, while 9 of 87 clones originating from old animals contained base substitutions (chi square = 11.9, P5 nucleotides (depending on assumptions of clonality), which exceeds existing estimates for mutation frequencies for nuclear genes by approximately 1000-fold. Our data suggest that at 22 months of age, which roughly corresponds to 3/4 of the mouse natural life span, most mtDNA molecules carry multiple point mutations

  4. Glutathione restores the mechanism of synaptic plasticity in aged mice to that of the adult.

    Directory of Open Access Journals (Sweden)

    Julie M Robillard

    Full Text Available Glutathione (GSH, the major endogenous antioxidant produced by cells, can modulate the activity of N-methyl-D-aspartate receptors (NMDARs through its reducing functions. During aging, an increase in oxidative stress leads to decreased levels of GSH in the brain. Concurrently, aging is characterized by calcium dysregulation, thought to underlie impairments in hippocampal NMDAR-dependent long-term potentiation (LTP, a form of synaptic plasticity thought to represent a cellular model for memory. Here we show that orally supplementing aged mice with N-acetylcysteine, a precursor for the formation of glutathione, reverses the L-type calcium channel-dependent LTP seen in aged animals to NMDAR-dependent LTP. In addition, introducing glutathione in the intrapipette solution during whole-cell recordings restores LTP obtained in whole-cell conditions in the aged hippocampus. We conclude that aging leads to a reduced redox potential in hippocampal neurons, triggering impairments in LTP.

  5. Ageing research on vertebrates shows knowledge gaps and opportunities for species conservation and management

    DEFF Research Database (Denmark)

    Conde, Dalia Amor

    Ageing theories predict that evolution should inevitably lead to an increase of mortality and decrease of fertility with age. However, a recent study across different species shows that this prediction only applies to really few species. In fact there is a great diversity of mortality trajectorie...... that highlight the urgency to fill up knowledge gaps to manage populations of threatened species....

  6. Limb ischemia after iliac ligation in aged mice stimulates angiogenesis without arteriogenesis

    Science.gov (United States)

    Westvik, Tormod S; Fitzgerald, Tamara N; Muto, Akihito; Maloney, Stephen P; Pimiento, Jose M; Fancher, Tiffany T; Magri, Dania; Westvik, Hilde H; Nishibe, Toshiya; Velazquez, Omaida C; Dardik, Alan

    2009-01-01

    . Clinical Relevance The incidence of chronic limb ischemia increases with age as do the consequences of acute ischemia. We show, using a new model of severe acute limb ischemia that does not wound the ischemic limb, that aged mice increase angiogenesis in response to acute ischemia, but do not show arteriogenesis, i.e. large collateral formation. These results suggest why elderly patients develop large vessel disease such as claudication but can still heal small wounds. They also suggest that strategies to treat ischemia in elderly patients should focus on stimulating large vessel arteriogenesis, rather than solely small vessel angiogenesis. PMID:19028053

  7. CD36 expression contributes to age induced cardiomyopathy in mice

    Science.gov (United States)

    Cardiac remodeling and impaired cardiac performance in the elderly significantly increase the risk of developing heart disease. Although vascular abnormalities associated with aging contribute to the age-related decline in cardiac function, myocardium-specific events may also be involved. We show th...

  8. Altered intrinsic excitability of hippocampal CA1 pyramidal neurons in aged PDAPP mice

    Directory of Open Access Journals (Sweden)

    Francesco Tamagnini

    2015-10-01

    These data show that Aβ-overexpression in aged mice altered the capacitance, the neuronal firing and the AP waveform of CA1 pyramidal neurons. Some of these findings are consistent with previous work on younger PDAPP, they also show important differences that can be potentially ascribed to the interaction between amyloidopathy and ageing. Such a change of IE properties over time underlies that the increased incidence of seizure observed in AD patients might rely on different mechanistic pathways during progression of the disease.

  9. Mice lacking desmocollin 1 show epidermal fragility accompanied by barrier defects and abnormal differentiation

    DEFF Research Database (Denmark)

    Chidgey, M; Brakebusch, C; Gustafsson, E;

    2001-01-01

    epidermis because environmental insults are more stringent and wound healing is less rapid than in neonatal mice. This dermatitis is accompanied by localized hair loss associated with formation of utriculi and dermal cysts, denoting hair follicle degeneration. Possible resemblance of the lesions to human......The desmosomal cadherin desmocollin (Dsc)1 is expressed in upper epidermis where strong adhesion is required. To investigate its role in vivo, we have genetically engineered mice with a targeted disruption in the Dsc1 gene. Soon after birth, null mice exhibit flaky skin and a striking punctate...

  10. Improved muscle function and quality after diet intervention with leucine-enriched whey and antioxidants in antioxidant deficient aged mice

    Science.gov (United States)

    van Dijk, Miriam; Dijk, Francina J.; Bunschoten, Annelies; van Dartel, Dorien A.M.; van Norren, Klaske; Walrand, Stephane; Jourdan, Marion; Verlaan, Sjors; Luiking, Yvette

    2016-01-01

    Antioxidant (AOX) deficiencies are commonly observed in older adults and oxidative stress has been suggested to contribute to sarcopenia. Here we investigate if 1) low levels of dietary antioxidants had a negative impact on parameters of muscle mass, function and quality, and 2) to study if nutritional interventions with AOX and/or leucine-enriched whey protein could improve these muscle parameters in aged mice. 18-months-old mice were fed a casein-based antioxidant-deficient (lowox) diet or a casein-based control-diet (CTRL) for 7 months. During the last 3 months, lowox-mice were subjected to either: a) continued lowox, b) supplementation with vitamin A/E, Selenium and Zinc (AOX), c) substitution of casein with leucine-enriched whey protein (PROT) or d) a combination of both AOX and PROT (TOTAL). After 7 months lowox-mice displayed lower muscle strength and more muscle fatigue compared to CTRL. Compared to lowox-mice, PROT-mice showed improved muscle power, grip strength and less muscle fatigue. AOX-mice showed improved oxidative status, less muscle fatigue, improved grip strength and mitochondrial dynamics compared to lowox-mice. The TOTAL-mice showed the combined effects of both interventions compared to lowox-mice. In conclusion, nutritional intervention with AOX and/or leucine-enriched whey protein can play a role in improving muscle health in a AOX-deficient mouse model. PMID:26943770

  11. Improved muscle function and quality after diet intervention with leucine-enriched whey and antioxidants in antioxidant deficient aged mice.

    Science.gov (United States)

    van Dijk, Miriam; Dijk, Francina J; Bunschoten, Annelies; van Dartel, Dorien A M; van Norren, Klaske; Walrand, Stephane; Jourdan, Marion; Verlaan, Sjors; Luiking, Yvette

    2016-04-01

    Antioxidant (AOX) deficiencies are commonly observed in older adults and oxidative stress has been suggested to contribute to sarcopenia. Here we investigate if 1) low levels of dietary antioxidants had a negative impact on parameters of muscle mass, function and quality, and 2) to study if nutritional interventions with AOX and/or leucine-enriched whey protein could improve these muscle parameters in aged mice. 18-months-old mice were fed a casein-based antioxidant-deficient (lowox) diet or a casein-based control-diet (CTRL) for 7 months. During the last 3 months, lowox-mice were subjected to either: a) continued lowox, b) supplementation with vitamin A/E, Selenium and Zinc (AOX), c) substitution of casein with leucine-enriched whey protein (PROT) or d) a combination of both AOX and PROT (TOTAL). After 7 months lowox-mice displayed lower muscle strength and more muscle fatigue compared to CTRL. Compared to lowox-mice, PROT-mice showed improved muscle power, grip strength and less muscle fatigue. AOX-mice showed improved oxidative status, less muscle fatigue, improved grip strength and mitochondrial dynamics compared to lowox-mice. The TOTAL-mice showed the combined effects of both interventions compared to lowox-mice. In conclusion, nutritional intervention with AOX and/or leucine-enriched whey protein can play a role in improving muscle health in a AOX-deficient mouse model. PMID:26943770

  12. Complement C3-Deficient Mice Fail to Display Age-Related Hippocampal Decline.

    Science.gov (United States)

    Shi, Qiaoqiao; Colodner, Kenneth J; Matousek, Sarah B; Merry, Katherine; Hong, Soyon; Kenison, Jessica E; Frost, Jeffrey L; Le, Kevin X; Li, Shaomin; Dodart, Jean-Cosme; Caldarone, Barbara J; Stevens, Beth; Lemere, Cynthia A

    2015-09-23

    The complement system is part of the innate immune response responsible for removing pathogens and cellular debris, in addition to helping to refine CNS neuronal connections via microglia-mediated pruning of inappropriate synapses during brain development. However, less is known about the role of complement during normal aging. Here, we studied the role of the central complement component, C3, in synaptic health and aging. We examined behavior as well as electrophysiological, synaptic, and neuronal changes in the brains of C3-deficient male mice (C3 KO) compared with age-, strain-, and gender-matched C57BL/6J (wild-type, WT) control mice at postnatal day 30, 4 months, and 16 months of age. We found the following: (1) region-specific and age-dependent synapse loss in aged WT mice that was not observed in C3 KO mice; (2) age-dependent neuron loss in hippocampal CA3 (but not in CA1) that followed synapse loss in aged WT mice, neither of which were observed in aged C3 KO mice; and (3) significantly enhanced LTP and cognition and less anxiety in aged C3 KO mice compared with aged WT mice. Importantly, CA3 synaptic puncta were similar between WT and C3 KO mice at P30. Together, our results suggest a novel and prominent role for complement protein C3 in mediating aged-related and region-specific changes in synaptic function and plasticity in the aging brain. Significance statement: The complement cascade, part of the innate immune response to remove pathogens, also plays a role in synaptic refinement during brain development by the removal of weak synapses. We investigated whether complement C3, a central component, affects synapse loss during aging. Wild-type (WT) and C3 knock-out (C3 KO) mice were examined at different ages. The mice were similar at 1 month of age. However, with aging, WT mice lost synapses in specific brain regions, especially in hippocampus, an area important for memory, whereas C3 KO mice were protected. Aged C3 KO mice also performed better on

  13. Sterols from Mytilidae Show Anti-Aging and Neuroprotective Effects via Anti-Oxidative Activity

    OpenAIRE

    Yujuan Sun; Yanfei Lin; Xueli Cao; Lan Xiang; Jianhua Qi

    2014-01-01

    For screening anti-aging samples from marine natural products, K6001 yeast strain was employed as a bioassay system. The active mussel extract was separated to give an active sterol fraction (SF). SF was further purified, and four sterol compounds were obtained. Their structures were determined to be cholesterol (CHOL), brassicasterol, crinosterol, and 24-methylenecholesterol. All compounds showed similar anti-aging activity. To understand the action mechanism involved, anti-oxidative experim...

  14. Effects of sleep deprivation and aging on long-term and remote memory in mice

    OpenAIRE

    Vecsey, Christopher G.; Park, Alan J.; Khatib, Nora; Abel, Ted

    2015-01-01

    Sleep deprivation (SD) following hippocampus-dependent learning in young mice impairs memory when tested the following day. Here, we examined the effects of SD on remote memory in both young and aged mice. In young mice, we found that memory is still impaired 1 mo after training. SD also impaired memory in aged mice 1 d after training, but, by a month after training, sleep-deprived and control aged animals performed similarly, primarily due to remote memory decay in the control aged animals. ...

  15. Deficiency in Poly(ADP-ribose Polymerase-1 (PARP-1 Accelerates Aging and Spontaneous Carcinogenesis in Mice

    Directory of Open Access Journals (Sweden)

    Vladimir N. Anisimov

    2008-04-01

    Full Text Available Genetic and biochemical studies have shown that PARP-1 and poly(ADP-ribosylation play an important role in DNA repair, genomic stability, cell death, inflammation, telomere maintenance, and suppressing tumorigenesis, suggesting that the homeostasis of poly(ADP-ribosylation and PARP-1 may also play an important role in aging. Here we show that PARP-1-/- mice exhibit a reduction of life span and a significant increase of population aging rate. Analysis of noninvasive parameters, including body weight gain, body temperature, estrous function, behavior, and a number of biochemical indices suggests the acceleration of biological aging in PARP-1-/- mice. The incidence of spontaneous tumors in both PARP-1-/- and PARP-1+/+ groups is similar; however, malignant tumors including uterine tumors, lung adenocarcinomas and hepatocellular carcinomas, develop at a significantly higher frequency in PARP-1-/- mice than PARP-1+/+ mice (72% and 49%, resp.; P< .05. In addition, spontaneous tumors appear earlier in PARP-1-/- mice compared to the wild type group. Histopathological studies revealed a wide spectrum of tumors in uterus, ovaries, liver, lungs, mammary gland, soft tissues, and lymphoid organs in both groups of the mice. These results demonstrate that inactivation of DNA repair gene PARP-1 in mice leads to acceleration of aging, shortened life span, and increased spontaneous carcinogenesis.

  16. Effects of chronic estrogen treatment on modulating age-related bone loss in female mice.

    Science.gov (United States)

    Syed, Farhan A; Mödder, Ulrike Il; Roforth, Matthew; Hensen, Ira; Fraser, Daniel G; Peterson, James M; Oursler, Merry Jo; Khosla, Sundeep

    2010-11-01

    While female mice do not have the equivalent of a menopause, they do undergo reproductive senescence. Thus, to dissociate the effects of aging versus estrogen deficiency on age-related bone loss, we sham-operated, ovariectomized, or ovariectomized and estrogen-replaced female C57/BL6 mice at 6 months of age and followed them to age 18 to 22 months. Lumbar spines and femurs were excised for analysis, and bone marrow hematopoietic lineage negative (lin-) cells (enriched for osteoprogenitor cells) were isolated for gene expression studies. Six-month-old intact control mice were euthanized to define baseline parameters. Compared with young mice, aged/sham-operated mice had a 42% reduction in lumbar spine bone volume/total volume (BV/TV), and maintaining constant estrogen levels over life in ovariectomized/estrogen-treated mice did not prevent age-related trabecular bone loss at this site. By contrast, lifelong estrogen treatment of ovariectomized mice completely prevented the age-related reduction in cortical volumetric bone mineral density (vBMD) and thickness at the tibial diaphysis present in the aged/sham-operated mice. As compared with cells from young mice, lin- cells from aged/sham-operated mice expressed significantly higher mRNA levels for osteoblast differentiation and proliferation marker genes. These data thus demonstrate that, in mice, age-related loss of cortical bone in the appendicular skeleton, but not loss of trabecular bone in the spine, can be prevented by maintaining constant estrogen levels over life. The observed increase in osteoblastic differentiation and proliferation marker gene expression in progenitor bone marrow cells from aged versus young mice may represent a compensatory mechanism in response to ongoing bone loss. PMID:20499336

  17. Kcne4 deletion sex- and age-specifically impairs cardiac repolarization in mice.

    Science.gov (United States)

    Crump, Shawn M; Hu, Zhaoyang; Kant, Ritu; Levy, Daniel I; Goldstein, Steve A N; Abbott, Geoffrey W

    2016-01-01

    Myocardial repolarization capacity varies with sex, age, and pathology; the molecular basis for this variation is incompletely understood. Here, we show that the transcript for KCNE4, a voltage-gated potassium (Kv) channel β subunit associated with human atrial fibrillation, was 8-fold more highly expressed in the male left ventricle compared with females in young adult C57BL/6 mice (P 45% (P 3-fold (P = 0.01) to match noncastrated levels. KCNE4 is thereby shown to be a DHT-regulated determinant of cardiac excitability and a molecular substrate for sex- and age-dependent cardiac arrhythmogenesis. PMID:26399785

  18. Increased Adipocyte Area in Injured Muscle With Aging and Impaired Remodeling in Female Mice.

    Science.gov (United States)

    Fearing, Caitlin M; Melton, David W; Lei, Xiufen; Hancock, Heather; Wang, Hanzhou; Sarwar, Zaheer U; Porter, Laurel; McHale, Matthew; McManus, Linda M; Shireman, Paula K

    2016-08-01

    We demonstrated that young male and female mice similarly regenerated injured skeletal muscle; however, female mice transiently increased adipocyte area within regenerated muscle in a sex hormone-dependent manner. We extended these observations to investigate the effect of aging and sex on sarcopenia and muscle regeneration. Cardiotoxin injury to the tibialis anterior muscle of young, middle, and old-aged C57Bl/6J male and female mice was used to measure regenerated myofiber cross-sectional area (CSA), adipocyte area, residual necrosis, and inflammatory cell recruitment. Baseline (uninjured) myofiber CSA was decreased in old mice of both sexes compared to young and middle-aged mice. Regenerated CSA was similar in male mice in all age groups until baseline CSA was attained but decreased in middle and old age female mice compared to young females. Furthermore, adipocyte area within regenerated muscle was transiently increased in young females compared to young males and these sex-dependent increases persisted in middle and old age female mice and were associated with increased Pparg Young female mice had more pro-inflammatory monocytes/macrophages in regenerating muscle than young male mice and increased Sca-1(+)CD45(-)cells. In conclusion, sex and age influence pro-inflammatory cell recruitment, muscle regeneration, and adipocyte area following skeletal muscle injury. PMID:26273023

  19. Apolipoprotein E-knockout mice show increased titers of serum anti-nuclear and anti-dsDNA antibodies

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yuehai [Cardiovascular Department, Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000 (China); Huang, Ziyang, E-mail: huangziyang666@126.com [Cardiovascular Department, Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000 (China); Lu, Huixia [Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University, Qilu Hospital, Jinan, Shandong 250012 (China); Lin, Huili; Wang, Zhenhua [Cardiovascular Department, Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000 (China); Chen, Xiaoqing [Department of Rheumatism and Immunology, Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000 (China); Ouyang, Qiufang [Cardiovascular Department, Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000 (China); Tang, Mengxiong; Hao, Panpan [Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University, Qilu Hospital, Jinan, Shandong 250012 (China); Ni, Jingqin [Cardiovascular Department, Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000 (China); Xu, Dongming [Department of Rheumatism and Immunology, Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000 (China); Zhang, Mingxiang; Zhang, Qunye [Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University, Qilu Hospital, Jinan, Shandong 250012 (China); Lin, Ling [Department of Rheumatism and Immunology, Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000 (China); and others

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer Titers of ANA and anti-dsDNA antibodies were higher in ApoE{sup -/-} than C57B6/L mice. Black-Right-Pointing-Pointer Spleen was greater and splenocyte apoptosis lower in ApoE{sup -/-} than B6 mice. Black-Right-Pointing-Pointer Level of TLR4 was lower in spleen tissue of ApoE{sup -/-} than B6 mice. Black-Right-Pointing-Pointer The TLR4 pathway may participate in maintaining the balance of splenocyte apoptosis. Black-Right-Pointing-Pointer The TLR4 pathway may participate in antibody production in spleen tissue. -- Abstract: Apolipoprotein E-knockout (ApoE{sup -/-}) mice, atherosclerosis-prone mice, show an autoimmune response, but the pathogenesis is not fully understood. We investigated the pathogenesis in female and male ApoE{sup -/-} mice. The spleens of all ApoE{sup -/-} and C57BL/6 (B6) mice were weighed. The serum IgG level and titers of anti-nuclear antibody (ANA) and anti-double-stranded DNA (anti-dsDNA) antibody were assayed by ELISA. Apoptosis of spleen tissue was evaluated by TUNEL. TLR4 level in spleen tissue was tested by immunohistochemistry and Western blot analysis. Levels of MyD88, p38, phosphorylated p38 (pp38), interferon regulatory factor 3 (IRF3) and Bcl-2-associated X protein (Bax) in spleen tissue were detected by Western blot analysis. We also survey the changes of serum autoantibodies, spleen weight, splenocyte apoptosis and the expressions of TLR4, MyD88, pp38, IRF3 and Bax in spleen tissue in male ApoE{sup -/-} mice after 4 weeks of lipopolysaccharide (LPS), Toll-like receptor 4 ligand, administration. ApoE{sup -/-} mice showed splenomegaly and significantly increased serum level of IgG and titers of ANA and anti-dsDNA antibody as compared with B6 mice. Splenocyte apoptosis and the expression of TLR4, MyD88, pp38, IRF3 and Bax in spleen tissue were significantly lower in ApoE{sup -/-} than B6 mice. The expression of TLR4, MyD88, IRF3, pp38, and Bax differed by sex in ApoE{sup -/-} spleen tissue. The

  20. Apolipoprotein E-knockout mice show increased titers of serum anti-nuclear and anti-dsDNA antibodies

    International Nuclear Information System (INIS)

    Highlights: ► Titers of ANA and anti-dsDNA antibodies were higher in ApoE−/− than C57B6/L mice. ► Spleen was greater and splenocyte apoptosis lower in ApoE−/− than B6 mice. ► Level of TLR4 was lower in spleen tissue of ApoE−/− than B6 mice. ► The TLR4 pathway may participate in maintaining the balance of splenocyte apoptosis. ► The TLR4 pathway may participate in antibody production in spleen tissue. -- Abstract: Apolipoprotein E-knockout (ApoE−/−) mice, atherosclerosis-prone mice, show an autoimmune response, but the pathogenesis is not fully understood. We investigated the pathogenesis in female and male ApoE−/− mice. The spleens of all ApoE−/− and C57BL/6 (B6) mice were weighed. The serum IgG level and titers of anti-nuclear antibody (ANA) and anti-double-stranded DNA (anti-dsDNA) antibody were assayed by ELISA. Apoptosis of spleen tissue was evaluated by TUNEL. TLR4 level in spleen tissue was tested by immunohistochemistry and Western blot analysis. Levels of MyD88, p38, phosphorylated p38 (pp38), interferon regulatory factor 3 (IRF3) and Bcl-2-associated X protein (Bax) in spleen tissue were detected by Western blot analysis. We also survey the changes of serum autoantibodies, spleen weight, splenocyte apoptosis and the expressions of TLR4, MyD88, pp38, IRF3 and Bax in spleen tissue in male ApoE−/− mice after 4 weeks of lipopolysaccharide (LPS), Toll-like receptor 4 ligand, administration. ApoE−/− mice showed splenomegaly and significantly increased serum level of IgG and titers of ANA and anti-dsDNA antibody as compared with B6 mice. Splenocyte apoptosis and the expression of TLR4, MyD88, pp38, IRF3 and Bax in spleen tissue were significantly lower in ApoE−/− than B6 mice. The expression of TLR4, MyD88, IRF3, pp38, and Bax differed by sex in ApoE−/− spleen tissue. The down-regulation of TLR4 signal molecules induced by LPS led to decreased expression of Bax and increased serum titers of ANA and anti

  1. Expression of complement system components during aging and amyloid deposition in APP transgenic mice

    Directory of Open Access Journals (Sweden)

    Wiederhold Karl-Heinz

    2009-11-01

    Full Text Available Abstract Background A causal role of the complement system in Alzheimer's disease pathogenesis has been postulated based on the identification of different activated components up to the membrane attack complex at amyloid plaques in brain. However, histological studies of amyloid plaque bearing APP transgenic mice provided only evidence for an activation of the early parts of the complement cascade. To better understand the contribution of normal aging and amyloid deposition to the increase in complement activation we performed a detailed characterization of the expression of the major mouse complement components. Methods APP23 mice expressing human APP751 with the Swedish double mutation as well as C57BL/6 mice were used at different ages. mRNA was quantified by Realtime PCR and the age- as well as amyloid induced changes determined. The protein levels of complement C1q and C3 were analysed by Western blotting. Histology was done to test for amyloid plaque association and activation of the complement cascade. Results High mRNA levels were detected for C1q and some inhibitory complement components. The expression of most activating components starting at C3 was low. Expression of C1q, C3, C4, C5 and factor B mRNA increased with age in control C57BL/6 mice. C1q and C3 mRNA showed a substantial additional elevation during amyloid formation in APP23 mice. This increase was confirmed on the protein level using Western blotting, whereas immunohistology indicated a recruitment of complement to amyloid plaques up to the C3 convertase. Conclusion Early but not late components of the mouse complement system show an age-dependent increase in expression. The response to amyloid deposition is comparatively smaller. The low expression of C3 and C5 and failure to upregulate C5 and downstream components differs from human AD brain and likely contributes to the lack of full complement activation in APP transgenic mice.

  2. Interleukin-18 gene-deficient mice show enhanced defense and reduced inflammation during pneumococcal meningitis.

    NARCIS (Netherlands)

    Zwijnenburg, P.J.G.; Poll, van der T.; Florquin, S; Akira, S; Takeda, K; Roord, J.J.; Furth, van A.M.

    2003-01-01

    To determine the role of endogenous interleukin-18 (IL-18) in pneumococcal meningitis, meningitis was induced in IL-18 gene-deficient (IL-18(-/-)) and wild-type (WT) mice by intranasal inoculation of Streptococcus pneumoniae with hyaluronidase. Induction of meningitis resulted in an upregulation of

  3. Probiotic microbes sustain youthful serum testosterone levels and testicular size in aging mice.

    Directory of Open Access Journals (Sweden)

    Theofilos Poutahidis

    Full Text Available The decline of circulating testosterone levels in aging men is associated with adverse health effects. During studies of probiotic bacteria and obesity, we discovered that male mice routinely consuming purified lactic acid bacteria originally isolated from human milk had larger testicles and increased serum testosterone levels compared to their age-matched controls. Further investigation using microscopy-assisted histomorphometry of testicular tissue showed that mice consuming Lactobacillus reuteri in their drinking water had significantly increased seminiferous tubule cross-sectional profiles and increased spermatogenesis and Leydig cell numbers per testis when compared with matched diet counterparts This showed that criteria of gonadal aging were reduced after routinely consuming a purified microbe such as L. reuteri. We tested whether these features typical of sustained reproductive fitness may be due to anti-inflammatory properties of L. reuteri, and found that testicular mass and other indicators typical of old age were similarly restored to youthful levels using systemic administration of antibodies blocking pro-inflammatory cytokine interleukin-17A. This indicated that uncontrolled host inflammatory responses contributed to the testicular atrophy phenotype in aged mice. Reduced circulating testosterone levels have been implicated in many adverse effects; dietary L. reuteri or other probiotic supplementation may provide a viable natural approach to prevention of male hypogonadism, absent the controversy and side-effects of traditional therapies, and yield practical options for management of disorders typically associated with normal aging. These novel findings suggest a potential high impact for microbe therapy in public health by imparting hormonal and gonad features of reproductive fitness typical of much younger healthy individuals.

  4. Female Nur77-deficient mice show increased susceptibility to diet-induced obesity.

    Directory of Open Access Journals (Sweden)

    Sonia Perez-Sieira

    Full Text Available Adipose tissue is essential in the regulation of body weight. The key process in fat catabolism and the provision of energy substrate during times of nutrient deprivation or enhanced energy demand is the hydrolysis of triglycerides and the release of fatty acids and glycerol. Nur77 is a member of the NR4A subfamily of nuclear receptors that plays an important metabolic role, modulating hepatic glucose metabolism and lipolysis in muscle. However, its endogenous role on white adipose tissue, as well as the gender dependency of these mechanisms, remains largely unknown. Male and female wild type and Nur77 deficient mice were fed with a high fat diet (45% calories from fat for 4 months. Mice were analyzed in vivo with the indirect calorimetry system, and tissues were analyzed by real-time PCR and Western blot analysis. Female, but not male Nur77 deficient mice, gained more weight and fat mass when compared to wild type mice fed with high fat diet, which can be explained by decreased energy expenditure. The lack of Nur77 also led to a decreased pHSL/HSL ratio in white adipose tissue and increased expression of CIDEA in brown adipose tissue of female Nur77 deficient mice. Overall, these findings suggest that Nur77 is an important physiological modulator of lipid metabolism in adipose tissue and that there are gender differences in the sensitivity to deletion of the Nur77 signaling. The decreased energy expenditure and the actions of Nur77 on liver, muscle, brown and white adipose tissue contribute to the increased susceptibility to diet-induced obesity in females lacking Nur77.

  5. Effect of aging and radiation in mice of different genotypes

    International Nuclear Information System (INIS)

    Data are presented on the life span of nine inbred strains and five hybrid strains of mice based on 400 mice of each sex for inbred and 200 mice of each sex for hybrid. Some of these mice were exposed when 120 days old to 250 R or 450 R of x radiation delivered at a dose rate of 60 R/min. Data on strain, sample size, and mean survival times are presented in tables

  6. Regenerative hair waves in aging mice and extra-follicular modulators Follistatin, Dkk1 and Sfrp4

    OpenAIRE

    Chen, Chih-Chiang; Murray, Philip J.; Jiang, Ting Xin; Plikus, Maksim V; Chang, Yun-Ting; Lee, Oscar K.; Widelitz, Randall B; Chuong, Cheng Ming

    2014-01-01

    Hair cycling is modulated by factors both intrinsic and extrinsic to hair follicles. Cycling defects lead to conditions such as aging associated alopecia. Recently we demonstrated that mouse skin exhibits regenerative hair waves, reflecting a coordinated regenerative behavior in follicle populations. Here, we use this model to explore the regenerative behavior of aging mouse skin. Old mice (>18 months) tracked over several months show that with progressing age hair waves slow down, wave propa...

  7. Coumarin Compounds of Biebersteinia Multifida Roots Show Potential Anxiolytic Effects In Mice

    OpenAIRE

    Hamid Reza Monsef-Esfahani; Mohsen Amini; Navid Goodarzi; Fatemeh Saiedmohammadi; Reza Hajiaghaee; Mohammad Ali Faramarzi; Zahra Tofighi; Mohammad Hossein Ghahremani

    2013-01-01

    Background Traditional preparations of the root of Biebersteinia multifida DC (Geraniaceae), a native medicinal plant of Irano-Turanian floristic region, have been used for the treatment of phobias as anxiolytic herbal preparation. Methods We utilized the phobic behavior of mice in an elevated plus-maze as a model to evaluate the anxiolytic effect of the plant extract and bio-guided fractionation was applied to isolate the active compounds. Total root extract, alkaline and ether fraction were...

  8. Dietary wolfberry supplementation enhances the protective effect of flu vaccine against influenza challenge in aged mice.

    Science.gov (United States)

    Du, Xiaogang; Wang, Junpeng; Niu, Xinli; Smith, Donald; Wu, Dayong; Meydani, Simin Nikbin

    2014-02-01

    Current vaccines for influenza do not fully protect the aged against influenza infection. Although wolfberry (goji berry) has been shown to improve immune response, including enhanced antibody production, after vaccination in the aged, it is not known if this effect would translate to better protection after influenza infection, nor is its underlying mechanism well understood. To address these issues, we conducted a study using a 2 × 2 design in which aged male mice (20-22 mo) were fed a control or a 5% wolfberry diet for 30 d, then immunized with an influenza vaccine or saline (control) on days 31 and 52 of the dietary intervention, and finally challenged with influenza A/Puerto Rico/8/34 virus. Mice fed wolfberry had higher influenza antibody titers and improved symptoms (less postinfection weight loss) compared with the mice treated by vaccine alone. Furthermore, an in vitro mechanistic study showed that wolfberry supplementation enhanced maturation and activity of antigen-presenting dendritic cells (DCs) in aged mice, as indicated by phenotypic change in expression of DC activation markers major histocompatibility complex class II, cluster of differentiation (CD) 40, CD80, and CD86, and functional change in DC production of cytokines interleukin-12 and tumor necrosis factor-α as well as DC endocytosis. Also, adoptive transfer of wolfberry-treated bone marrow DCs (loaded with ovalbumin(323-339)-peptide) promoted antigen-specific T cell proliferation as well as interleukin-4 and interferon-γ production in CD4(+) T cells. In summary, our data indicate that dietary wolfberry enhances the efficacy of influenza vaccination, resulting in better host protection to prevent subsequent influenza infection; this effect may be partly attributed to improved DC function. PMID:24336457

  9. Moderate exercise prevents neurodegeneration in D-galactose-induced aging mice

    OpenAIRE

    Li Li; Meng Xu; Bo Shen; Man Li; Qian Gao; Shou-gang Wei

    2016-01-01

    D-galactose has been widely used in aging research because of its efficacy in inducing senescence and accelerating aging in animal models. The present study investigated the benefits of exercise for preventing neurodegeneration, such as synaptic plasticity, spatial learning and memory abilities, in mouse models of aging. D-galactose-induced aging mice were administered daily subcutaneous injections of D-galactose at the base of the neck for 10 consecutive weeks. Then, the mice were subjected ...

  10. Bach1 Deficiency and Accompanying Overexpression of Heme Oxygenase-1 Do Not Influence Aging or Tumorigenesis in Mice

    Directory of Open Access Journals (Sweden)

    Kazushige Ota

    2014-01-01

    Full Text Available Oxidative stress contributes to both aging and tumorigenesis. The transcription factor Bach1, a regulator of oxidative stress response, augments oxidative stress by repressing the expression of heme oxygenase-1 (HO-1 gene (Hmox1 and suppresses oxidative stress-induced cellular senescence by restricting the p53 transcriptional activity. Here we investigated the lifelong effects of Bach1 deficiency on mice. Bach1-deficient mice showed longevity similar to wild-type mice. Although HO-1 was upregulated in the cells of Bach1-deficient animals, the levels of ROS in Bach1-deficient HSCs were comparable to those in wild-type cells. Bach1−/−; p53−/− mice succumbed to spontaneous cancers as frequently as p53-deficient mice. Bach1 deficiency significantly altered transcriptome in the liver of the young mice, which surprisingly became similar to that of wild-type mice during the course of aging. The transcriptome adaptation to Bach1 deficiency may reflect how oxidative stress response is tuned upon genetic and environmental perturbations. We concluded that Bach1 deficiency and accompanying overexpression of HO-1 did not influence aging or p53 deficiency-driven tumorigenesis. Our results suggest that it is useful to target Bach1 for acute injury responses without inducing any apparent deteriorative effect.

  11. αβγ-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction

    Science.gov (United States)

    Greten-Harrison, Becket; Polydoro, Manuela; Morimoto-Tomita, Megumi; Diao, Ling; Williams, Andrew M.; Nie, Esther H.; Makani, Sachin; Tian, Ning; Castillo, Pablo E.; Buchman, Vladimir L.; Chandra, Sreeganga S.

    2010-01-01

    Synucleins are a vertebrate-specific family of abundant neuronal proteins. They comprise three closely related members, α-, β-, and γ-synuclein. α-Synuclein has been the focus of intense attention since mutations in it were identified as a cause for familial Parkinson's disease. Despite their disease relevance, the normal physiological function of synucleins has remained elusive. To address this, we generated and characterized αβγ-synuclein knockout mice, which lack all members of this protein family. Deletion of synucleins causes alterations in synaptic structure and transmission, age-dependent neuronal dysfunction, as well as diminished survival. Abrogation of synuclein expression decreased excitatory synapse size by ∼30% both in vivo and in vitro, revealing that synucleins are important determinants of presynaptic terminal size. Young synuclein null mice show improved basic transmission, whereas older mice show a pronounced decrement. The late onset phenotypes in synuclein null mice were not due to a loss of synapses or neurons but rather reflect specific changes in synaptic protein composition and axonal structure. Our results demonstrate that synucleins contribute importantly to the long-term operation of the nervous system and that alterations in their physiological function could contribute to the development of Parkinson's disease. PMID:20974939

  12. Mice age - Does the age of the mother predict offspring behaviour?

    Science.gov (United States)

    Lerch, Sandra; Brandwein, Christiane; Dormann, Christof; Gass, Peter; Chourbaji, Sabine

    2015-08-01

    Increasing paternal age is known to be associated with a great variety of psychiatric disorders such as schizophrenia or autism. Hence the factor "age" may be taken as strategic tool to analyse specific scientific hypotheses. Additionally, this finding also needs to be addressed in rather pragmatically performed breeding protocols of model organisms, since otherwise artefacts may challenge the validity of the results. Our study was performed to investigate influences of advanced age of mouse dams (30 vs. 16weeks) on maternal- and offspring behaviour. Adult offspring of both sexes was analysed in a test battery comprising paradigms for exploration, anxiety and depressive-like behaviours. Final blood sampling was conducted for stressphysiological analysis. Interestingly, advanced age of the mothers was associated with increased nest-building quality while maternal activity was unaffected. Moreover "maternal (mice) age" (MA) affected emotionality in the offspring, which became apparent in the dark-light box and the social recognition paradigm. These findings not only emphasize MA to model a potent risk factor with regard to emotional stability, but also underscore the vast necessity to include information about breeding protocols into the methods section of any animal study. PMID:25914174

  13. Rate of lens lesion development and the age of mice at time of irradiation

    International Nuclear Information System (INIS)

    The rate of lens lesion development has been studied in mice irradiated at different age ranging from one day up to one year old mice. The time needed for the first appearance of lens lesion was shortest in groups of mice irradiated at the age of one, two and three days of life, and longest in groups of mice irradiated at the age of 5 days, 1 week and 2 weeks of life. The time needed for the first appearance of lens lesion for mice irradiated between the third week and one year of life was constant. It was longer than for mice irradiated during the first three days of life and shorter than for mice irradiated at 5 up to 14 days of life. In all but one irradiated groups the age at which the first lens lesion occurred differed significantly from the age at which the first senile changes occurred in the lens of control mice. The one exception was the group of mice irradiated at the age of one year. (author)

  14. Mice lacking multidrug resistance protein 1a show altered dopaminergic responses to methylenedioxymethamphetamine (MDMA) in striatum

    OpenAIRE

    Scheidweiler, Karl B.; Ladenheim, Bruce; Cadet, Jean Lud; Huestis, Marilyn A.

    2009-01-01

    Multidrug resistance protein 1a (MDR1a) potentiated methylenedioxymethamphetamine (MDMA)-induced decreases of dopamine (DA) and dopamine transport protein in mouse brain one week after MDMA administration. In the present study, we examined if mdr1a wild-type (mdr1a +/+) and knock-out (mdr1a −/−) mice differentially handle the acute effects of MDMA on the nigrostriatal DA system 0–24 h following a single drug injection. 3-way ANOVA revealed significant 2-way interactions of strain X time (F5,1...

  15. Anti–DNA B Cells in MRL/lpr Mice Show Altered Differentiation and Editing Pattern

    OpenAIRE

    Li, Yijin; Li, Hui; Ni, Dongyao; Weigert, Martin

    2002-01-01

    We have studied the regulation of anti–DNA B cells in transgenic mice with a heavy chain transgene (3H9H/56R). This transgene codes for a heavy chain that forms anti–double-stranded DNA (dsDNA) antibody when paired with most members of the endogenous Vκ repertoire, but certain L chains, referred to as Vκ editors, do not sustain dsDNA binding in combination with 3H9H/56R. In the nonautoimmune 3H9H/56R BALB/c, most B cells generated do not bind DNA because the transgene itself is edited or is a...

  16. Sterols from Mytilidae Show Anti-Aging and Neuroprotective Effects via Anti-Oxidative Activity

    Directory of Open Access Journals (Sweden)

    Yujuan Sun

    2014-11-01

    Full Text Available For screening anti-aging samples from marine natural products, K6001 yeast strain was employed as a bioassay system. The active mussel extract was separated to give an active sterol fraction (SF. SF was further purified, and four sterol compounds were obtained. Their structures were determined to be cholesterol (CHOL, brassicasterol, crinosterol, and 24-methylenecholesterol. All compounds showed similar anti-aging activity. To understand the action mechanism involved, anti-oxidative experiments, reactive oxygen species (ROS assays, and malondialdehyde (MDA tests were performed on the most abundant compound, CHOL. Results indicated that treatment with CHOL increases the survival rate of yeast under oxidative stress and decreases ROS and MDA levels. In addition, mutations of uth1, skn7, sod1, and sod2, which feature a K6001 background, were employed and the lifespans of the mutations were not affected by CHOL. These results demonstrate that CHOL exerts anti-aging effects via anti-oxidative stress. Based on the connection between neuroprotection and anti-aging, neuroprotective experiments were performed in PC12 cells. Paraquat was used to induce oxidative stress and the results showed that the CHOL and SF protect the PC12 cells from the injury induced by paraquat. In addition, these substance exhibited nerve growth factor (NGF mimic activities again confirmed their neuroprotective function.

  17. Altered Hippocampal Transcript Profile Accompanies an Age-Related Spatial Memory Deficit in Mice

    OpenAIRE

    Verbitsky, Miguel; Yonan, Amanda L.; Malleret, Gaël; Kandel, Eric R.; Gilliam, T. Conrad; Pavlidis, Paul

    2004-01-01

    We have carried out a global survey of age-related changes in mRNA levels in the C57BL/6NIA mouse hippocampus and found a difference in the hippocampal gene expression profile between 2-month-old young mice and 15-month-old middle-aged mice correlated with an age-related cognitive deficit in hippocampal-based explicit memory formation. Middle-aged mice displayed a mild but specific deficit in spatial memory in the Morris water maze. By using Affymetrix GeneChip microarrays, we found a distinc...

  18. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer

    OpenAIRE

    Bernardes de Jesus, Bruno; Vera, Elsa; Schneeberger, Kerstin; Tejera, Agueda M.; Ayuso, Eduard; Bosch, Fatima; Blasco, Maria A.

    2012-01-01

    A major goal in aging research is to improve health during aging. In the case of mice, genetic manipulations that shorten or lengthen telomeres result, respectively, in decreased or increased longevity. Based on this, we have tested the effects of a telomerase gene therapy in adult (1 year of age) and old (2 years of age) mice. Treatment of 1- and 2-year old mice with an adeno associated virus (AAV) of wide tropism expressing mouse TERT had remarkable beneficial effects on health and fitness,...

  19. Short-term long chain omega3 diet protects from neuroinflammatory processes and memory impairment in aged mice.

    Directory of Open Access Journals (Sweden)

    Virginie F Labrousse

    Full Text Available Regular consumption of food enriched in omega3 polyunsaturated fatty acids (ω3 PUFAs has been shown to reduce risk of cognitive decline in elderly, and possibly development of Alzheimer's disease. Docosahexaenoic acid (DHA and eicosapentaenoic acid (EPA are the most likely active components of ω3-rich PUFAs diets in the brain. We therefore hypothesized that exposing mice to a DHA and EPA enriched diet may reduce neuroinflammation and protect against memory impairment in aged mice. For this purpose, mice were exposed to a control diet throughout life and were further submitted to a diet enriched in EPA and DHA during 2 additional months. Cytokine expression together with a thorough analysis of astrocytes morphology assessed by a 3D reconstruction was measured in the hippocampus of young (3-month-old and aged (22-month-old mice. In addition, the effects of EPA and DHA on spatial memory and associated Fos activation in the hippocampus were assessed. We showed that a 2-month EPA/DHA treatment increased these long-chain ω3 PUFAs in the brain, prevented cytokines expression and astrocytes morphology changes in the hippocampus and restored spatial memory deficits and Fos-associated activation in the hippocampus of aged mice. Collectively, these data indicated that diet-induced accumulation of EPA and DHA in the brain protects against neuroinflammation and cognitive impairment linked to aging, further reinforcing the idea that increased EPA and DHA intake may provide protection to the brain of aged subjects.

  20. Age-related skeletal dynamics and decrease in bone strength in DNA repair deficient male trichothiodystrophy mice.

    Directory of Open Access Journals (Sweden)

    Claudia Nicolaije

    Full Text Available Accumulation of DNA damage caused by oxidative stress is thought to be one of the main contributors of human tissue aging. Trichothiodystrophy (TTD mice have a mutation in the Ercc2 DNA repair gene, resulting in accumulation of DNA damage and several features of segmental accelerated aging. We used male TTD mice to study the impact of DNA repair on bone metabolism with age. Analysis of bone parameters, measured by micro-computed tomography, displayed an earlier decrease in trabecular and cortical bone as well as a loss of periosteal apposition and a reduction in bone strength in TTD mice with age compared to wild type mice. Ex vivo analysis of bone marrow differentiation potential showed an accelerated reduction in the number of osteogenic and osteoprogenitor cells with unaltered differentiation capacity. Adipocyte differentiation was normal. Early in life, osteoclast number tended to be increased while at 78 weeks it was significantly lower in TTD mice. Our findings reveal the importance of genome stability and proper DNA repair for skeletal homeostasis with age and support the idea that accumulation of damage interferes with normal skeletal maintenance, causing reduction in the number of osteoblast precursors that are required for normal bone remodeling leading to a loss of bone structure and strength.

  1. Influence of Age on Brain Edema Formation, Secondary Brain Damage and Inflammatory Response after Brain Trauma in Mice

    Science.gov (United States)

    Timaru-Kast, Ralph; Luh, Clara; Gotthardt, Philipp; Huang, Changsheng; Schäfer, Michael K.; Engelhard, Kristin; Thal, Serge C.

    2012-01-01

    After traumatic brain injury (TBI) elderly patients suffer from higher mortality rate and worse functional outcome compared to young patients. However, experimental TBI research is primarily performed in young animals. Aim of the present study was to clarify whether age affects functional outcome, neuroinflammation and secondary brain damage after brain trauma in mice. Young (2 months) and old (21 months) male C57Bl6N mice were anesthetized and subjected to a controlled cortical impact injury (CCI) on the right parietal cortex. Animals of both ages were randomly assigned to 15 min, 24 h, and 72 h survival. At the end of the observation periods, contusion volume, brain water content, neurologic function, cerebral and systemic inflammation (CD3+ T cell migration, inflammatory cytokine expression in brain and lung, blood differential cell count) were determined. Old animals showed worse neurological function 72 h after CCI and a high mortality rate (19.2%) compared to young (0%). This did not correlate with histopathological damage, as contusion volumes were equal in both age groups. Although a more pronounced brain edema formation was detected in old mice 24 hours after TBI, lack of correlation between brain water content and neurological deficit indicated that brain edema formation is not solely responsible for age-dependent differences in neurological outcome. Brains of old naïve mice were about 8% smaller compared to young naïve brains, suggesting age-related brain atrophy with possible decline in plasticity. Onset of cerebral inflammation started earlier and primarily ipsilateral to damage in old mice, whereas in young mice inflammation was delayed and present in both hemispheres with a characteristic T cell migration pattern. Pulmonary interleukin 1β expression was up-regulated after cerebral injury only in young, not aged mice. The results therefore indicate that old animals are prone to functional deficits and strong ipsilateral cerebral inflammation

  2. Influence of age on brain edema formation, secondary brain damage and inflammatory response after brain trauma in mice.

    Directory of Open Access Journals (Sweden)

    Ralph Timaru-Kast

    Full Text Available After traumatic brain injury (TBI elderly patients suffer from higher mortality rate and worse functional outcome compared to young patients. However, experimental TBI research is primarily performed in young animals. Aim of the present study was to clarify whether age affects functional outcome, neuroinflammation and secondary brain damage after brain trauma in mice. Young (2 months and old (21 months male C57Bl6N mice were anesthetized and subjected to a controlled cortical impact injury (CCI on the right parietal cortex. Animals of both ages were randomly assigned to 15 min, 24 h, and 72 h survival. At the end of the observation periods, contusion volume, brain water content, neurologic function, cerebral and systemic inflammation (CD3+ T cell migration, inflammatory cytokine expression in brain and lung, blood differential cell count were determined. Old animals showed worse neurological function 72 h after CCI and a high mortality rate (19.2% compared to young (0%. This did not correlate with histopathological damage, as contusion volumes were equal in both age groups. Although a more pronounced brain edema formation was detected in old mice 24 hours after TBI, lack of correlation between brain water content and neurological deficit indicated that brain edema formation is not solely responsible for age-dependent differences in neurological outcome. Brains of old naïve mice were about 8% smaller compared to young naïve brains, suggesting age-related brain atrophy with possible decline in plasticity. Onset of cerebral inflammation started earlier and primarily ipsilateral to damage in old mice, whereas in young mice inflammation was delayed and present in both hemispheres with a characteristic T cell migration pattern. Pulmonary interleukin 1β expression was up-regulated after cerebral injury only in young, not aged mice. The results therefore indicate that old animals are prone to functional deficits and strong ipsilateral cerebral

  3. Knock-in reporter mice demonstrate that DNA repair by non-homologous end joining declines with age.

    Directory of Open Access Journals (Sweden)

    Amita Vaidya

    2014-07-01

    Full Text Available Accumulation of genome rearrangements is a characteristic of aged tissues. Since genome rearrangements result from faulty repair of DNA double strand breaks (DSBs, we hypothesized that DNA DSB repair becomes less efficient with age. The Non-Homologous End Joining (NHEJ pathway repairs a majority of DSBs in vertebrates. To examine age-associated changes in NHEJ, we have generated an R26NHEJ mouse model in which a GFP-based NHEJ reporter cassette is knocked-in to the ROSA26 locus. In this model, NHEJ repair of DSBs generated by the site-specific endonuclease, I-SceI, reconstitutes a functional GFP gene. In this system NHEJ efficiency can be compared across tissues of the same mouse and in mice of different age. Using R26NHEJ mice, we found that NHEJ efficiency was higher in the skin, lung, and kidney fibroblasts, and lower in the heart fibroblasts and brain astrocytes. Furthermore, we observed that NHEJ efficiency declined with age. In the 24-month old animals compared to the 5-month old animals, NHEJ efficiency declined 1.8 to 3.8-fold, depending on the tissue, with the strongest decline observed in the skin fibroblasts. The sequence analysis of 300 independent NHEJ repair events showed that, regardless of age, mice utilize microhomology sequences at a significantly higher frequency than expected by chance. Furthermore, the frequency of microhomology-mediated end joining (MMEJ events increased in the heart and lung fibroblasts of old mice, suggesting that NHEJ becomes more mutagenic with age. In summary, our study provides a versatile mouse model for the analysis of NHEJ in a wide range of tissues and demonstrates that DNA repair by NHEJ declines with age in mice, which could provide a mechanism for age-related genomic instability and increased cancer incidence with age.

  4. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice

    Science.gov (United States)

    Bitto, Alessandro; Ito, Takashi K; Pineda, Victor V; LeTexier, Nicolas J; Huang, Heather Z; Sutlief, Elissa; Tung, Herman; Vizzini, Nicholas; Chen, Belle; Smith, Kaleb; Meza, Daniel; Yajima, Masanao; Beyer, Richard P; Kerr, Kathleen F; Davis, Daniel J; Gillespie, Catherine H; Snyder, Jessica M; Treuting, Piper M; Kaeberlein, Matt

    2016-01-01

    The FDA approved drug rapamycin increases lifespan in rodents and delays age-related dysfunction in rodents and humans. Nevertheless, important questions remain regarding the optimal dose, duration, and mechanisms of action in the context of healthy aging. Here we show that 3 months of rapamycin treatment is sufficient to increase life expectancy by up to 60% and improve measures of healthspan in middle-aged mice. This transient treatment is also associated with a remodeling of the microbiome, including dramatically increased prevalence of segmented filamentous bacteria in the small intestine. We also define a dose in female mice that does not extend lifespan, but is associated with a striking shift in cancer prevalence toward aggressive hematopoietic cancers and away from non-hematopoietic malignancies. These data suggest that a short-term rapamycin treatment late in life has persistent effects that can robustly delay aging, influence cancer prevalence, and modulate the microbiome. DOI: http://dx.doi.org/10.7554/eLife.16351.001 PMID:27549339

  5. Effect on fertility of aging female mice exposed to different doses of X-rays

    International Nuclear Information System (INIS)

    The reproductive performance of aging female mice of CFW/pzh strain was observed after irradiation with doses from 8 to 256 cGy. The reproductive capacity decreased statistically after irradiation of 26 weeks old mice with doses higher than 8 cGy. For mice irradiated at 40 weeks of age the same effect was observed only after irradiation with doses from 32 to 128 cGy. Comparison of these results with the effects of neonatal irradiation indicates that in the case of reproduction the sensitivity of the ovaries of 26 and 40 weeks old mice is higher than in that of newborns. 7 refs., 1 fig., 2 tabs. (author)

  6. Effects of Environmental Enrichment on Spatial Memory and Neurochemistry in Middle-Aged Mice

    OpenAIRE

    Frick, Karyn M.; Stearns, Nancy A.; Pan, Jing-Yu; Berger-Sweeney, Joanne

    2003-01-01

    The present study compared the effects of environmental enrichment on spatial memory, glutamic acid decarboxylase (GAD) activity, and synaptophysin levels in middle-aged male and female mice. Prior to testing, a subset of 18-month-old male and female C57BL/6 mice was housed with two to three toys and a running wheel in the home cage for up to 29 d. Adult mice (7 mo) of both sexes and the remaining middle-aged mice were group (social) housed, but not exposed to enrichin...

  7. Altered Hippocampal Transcript Profile Accompanies an Age-Related Spatial Memory Deficit in Mice

    Science.gov (United States)

    Verbitsky, Miguel; Yonan, Amanda L.; Malleret, Gael; Kandel, Eric R.; Gilliam, T. Conrad; Pavlidis, Paul

    2004-01-01

    We have carried out a global survey of age-related changes in mRNA levels in the 57BL/6NIA mouse hippocampus and found a difference in the hippocampal gene expression profile between 2-month-old young mice and 15-month-old middle-aged mice correlated with an age-related cognitive deficit in hippocampal-based explicit memory formation. Middle-aged…

  8. Female Mice Deficient in Alpha-Fetoprotein Show Female-Typical Neural Responses to Conspecific-Derived Pheromones

    OpenAIRE

    Olivier Brock; Matthieu Keller; Quentin Douhard; Julie Bakker

    2012-01-01

    The neural mechanisms controlling sexual behavior are sexually differentiated by the perinatal actions of sex steroid hormones. We recently observed using female mice deficient in alpha-fetoprotein (AFP-KO) and which lack the protective actions of AFP against maternal estradiol, that exposure to prenatal estradiol completely defeminized the potential to show lordosis behavior in adulthood. Furthermore, AFP-KO females failed to show any male-directed mate preferences following treatment with e...

  9. A Dietary Treatment Improves Cerebral Blood Flow and Brain Connectivity in Aging apoE4 Mice.

    Science.gov (United States)

    Wiesmann, Maximilian; Zerbi, Valerio; Jansen, Diane; Haast, Roy; Lütjohann, Dieter; Broersen, Laus M; Heerschap, Arend; Kiliaan, Amanda J

    2016-01-01

    APOE ε4 (apoE4) polymorphism is the main genetic determinant of sporadic Alzheimer's disease (AD). A dietary approach (Fortasyn) including docosahexaenoic acid, eicosapentaenoic acid, uridine, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium has been proposed for dietary management of AD. We hypothesize that the diet could inhibit AD-like pathologies in apoE4 mice, specifically cerebrovascular and connectivity impairment. Moreover, we evaluated the diet effect on cerebral blood flow (CBF), functional connectivity (FC), gray/white matter integrity, and postsynaptic density in aging apoE4 mice. At 10-12 months, apoE4 mice did not display prominent pathological differences compared to wild-type (WT) mice. However, 16-18-month-old apoE4 mice revealed reduced CBF and accelerated synaptic loss. The diet increased cortical CBF and amount of synapses and improved white matter integrity and FC in both aging apoE4 and WT mice. We demonstrated that protective mechanisms on vascular and synapse health are enhanced by Fortasyn, independent of apoE genotype. We further showed the efficacy of a multimodal translational approach, including advanced MR neuroimaging, to study dietary intervention on brain structure and function in aging. PMID:27034849

  10. A Dietary Treatment Improves Cerebral Blood Flow and Brain Connectivity in Aging apoE4 Mice

    Directory of Open Access Journals (Sweden)

    Maximilian Wiesmann

    2016-01-01

    Full Text Available APOE ε4 (apoE4 polymorphism is the main genetic determinant of sporadic Alzheimer’s disease (AD. A dietary approach (Fortasyn including docosahexaenoic acid, eicosapentaenoic acid, uridine, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium has been proposed for dietary management of AD. We hypothesize that the diet could inhibit AD-like pathologies in apoE4 mice, specifically cerebrovascular and connectivity impairment. Moreover, we evaluated the diet effect on cerebral blood flow (CBF, functional connectivity (FC, gray/white matter integrity, and postsynaptic density in aging apoE4 mice. At 10–12 months, apoE4 mice did not display prominent pathological differences compared to wild-type (WT mice. However, 16–18-month-old apoE4 mice revealed reduced CBF and accelerated synaptic loss. The diet increased cortical CBF and amount of synapses and improved white matter integrity and FC in both aging apoE4 and WT mice. We demonstrated that protective mechanisms on vascular and synapse health are enhanced by Fortasyn, independent of apoE genotype. We further showed the efficacy of a multimodal translational approach, including advanced MR neuroimaging, to study dietary intervention on brain structure and function in aging.

  11. Mice with mutant Inf2 show impaired podocyte and slit diaphragm integrity in response to protamine-induced kidney injury.

    Science.gov (United States)

    Subramanian, Balajikarthick; Sun, Hua; Yan, Paul; Charoonratana, Victoria T; Higgs, Henry N; Wang, Fang; Lai, Ka-Man V; Valenzuela, David M; Brown, Elizabeth J; Schlöndorff, Johannes S; Pollak, Martin R

    2016-08-01

    Mutations in the INF2 (inverted formin 2) gene, encoding a diaphanous formin family protein that regulates actin cytoskeleton dynamics, cause human focal segmental glomerulosclerosis (FSGS). INF2 interacts directly with certain other mammalian diaphanous formin proteins (mDia) that function as RhoA effector molecules. FSGS-causing INF2 mutations impair these interactions and disrupt the ability of INF2 to regulate Rho/Dia-mediated actin dynamics in vitro. However, the precise mechanisms by which INF2 regulates and INF2 mutations impair glomerular structure and function remain unknown. Here, we characterize an Inf2 R218Q point-mutant (knockin) mouse to help answer these questions. Knockin mice have no significant renal pathology or proteinuria at baseline despite diminished INF2 protein levels. INF2 mutant podocytes do show impaired reversal of protamine sulfate-induced foot process effacement by heparin sulfate perfusion. This is associated with persistent podocyte cytoplasmic aggregation, nephrin phosphorylation, and nephrin and podocin mislocalization, as well as impaired recovery of mDia membrane localization. These changes were partially mimicked in podocyte outgrowth cultures, in which podocytes from knockin mice show altered cellular protrusions compared to those from wild-type mice. Thus, in mice, normal INF2 function is not required for glomerular development but normal INF2 is required for regulation of the actin-based behaviors necessary for response to and/or recovery from injury. PMID:27350175

  12. Coumarin Compounds of Biebersteinia Multifida Roots Show Potential Anxiolytic Effects In Mice

    Directory of Open Access Journals (Sweden)

    Hamid Reza Monsef-Esfahani

    2013-06-01

    Full Text Available Background:Traditional preparations of the root of Biebersteinia multifida DC (Geraniaceae, a native medicinal plant of Irano-Turanian floristic region, have been used for the treatment of phobias as anxiolytic herbal preparation.Methods:We utilized the phobic behavior of mice in an elevated plus-maze as a model to evaluate the anxiolytic effect of the plant extract and bio-guided fractionation was applied to isolate the active compounds. Total root extract, alkaline and ether fraction were administered to mice at different doses 30 and 90 min prior to the maze test. Saline and diazepam were administered as negative and positive controls, respectively. The time spent in open and closed arms, an index of anxiety behavior and entry time, was measured as an index of animal activity.Results:The total root extract exhibited anxiolytic effect which was comparable to diazepam but with longer duration. This sustained effect of the crude extract was sustained for 90 min and was even more after injection of 45 mg/kg while the effect of diazepam had been reduced by 90 min. The anxiolytic effect factor was only present in the alkaline fraction and displayed its effect at lower doses than diazepam while pure vasicinone as the previously known alkaloid did not shown anxiolytic effect. The effect of the alkaline fraction was in a dose dependent manner starting at 0.2 mg/kg with a maximum at 1.0 mg/kg. Bio-guided fractionation using a variety of chromatographic methods led to isolation and purification of three coumarin derivatives from the bioactive fraction, including umbelliferone, scopoletin, and ferulic acid.Conclusion:For the first time, bio-guided fractionation of the root extract of B. multifida indicates significant sustained anxiolytic effects which led to isolation of three coumarin derivatives with well-known potent MAO inhibitory and anti-anxiety effects. These data contribute to evidence-based traditional use of B. multifida root for anxiety

  13. The adipokine leptin increases skeletal muscle mass and significantly alters skeletal muscle miRNA expression profile in aged mice

    International Nuclear Information System (INIS)

    Research highlights: → Aging is associated with muscle atrophy and loss of muscle mass, known as the sarcopenia of aging. → We demonstrate that age-related muscle atrophy is associated with marked changes in miRNA expression in muscle. → Treating aged mice with the adipokine leptin significantly increased muscle mass and the expression of miRNAs involved in muscle repair. → Recombinant leptin therapy may therefore be a novel approach for treating age-related muscle atrophy. -- Abstract: Age-associated loss of muscle mass, or sarcopenia, contributes directly to frailty and an increased risk of falls and fractures among the elderly. Aged mice and elderly adults both show decreased muscle mass as well as relatively low levels of the fat-derived hormone leptin. Here we demonstrate that loss of muscle mass and myofiber size with aging in mice is associated with significant changes in the expression of specific miRNAs. Aging altered the expression of 57 miRNAs in mouse skeletal muscle, and many of these miRNAs are now reported to be associated specifically with age-related muscle atrophy. These include miR-221, previously identified in studies of myogenesis and muscle development as playing a role in the proliferation and terminal differentiation of myogenic precursors. We also treated aged mice with recombinant leptin, to determine whether leptin therapy could improve muscle mass and alter the miRNA expression profile of aging skeletal muscle. Leptin treatment significantly increased hindlimb muscle mass and extensor digitorum longus fiber size in aged mice. Furthermore, the expression of 37 miRNAs was altered in muscles of leptin-treated mice. In particular, leptin treatment increased the expression of miR-31 and miR-223, miRNAs known to be elevated during muscle regeneration and repair. These findings suggest that aging in skeletal muscle is associated with marked changes in the expression of specific miRNAs, and that nutrient-related hormones such as leptin

  14. The adipokine leptin increases skeletal muscle mass and significantly alters skeletal muscle miRNA expression profile in aged mice

    Energy Technology Data Exchange (ETDEWEB)

    Hamrick, Mark W., E-mail: mhamrick@mail.mcg.edu [Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Herberg, Samuel; Arounleut, Phonepasong [Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); He, Hong-Zhi [Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI (United States); Department of Dermatology, Henry Ford Health System, Detroit, MI (United States); Shiver, Austin [Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Qi, Rui-Qun [Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI (United States); Department of Dermatology, Henry Ford Health System, Detroit, MI (United States); Zhou, Li [Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI (United States); Department of Dermatology, Henry Ford Health System, Detroit, MI (United States); Department of Internal Medicine, Henry Ford Health System, Detroit, MI (United States); Isales, Carlos M. [Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); and others

    2010-09-24

    Research highlights: {yields} Aging is associated with muscle atrophy and loss of muscle mass, known as the sarcopenia of aging. {yields} We demonstrate that age-related muscle atrophy is associated with marked changes in miRNA expression in muscle. {yields} Treating aged mice with the adipokine leptin significantly increased muscle mass and the expression of miRNAs involved in muscle repair. {yields} Recombinant leptin therapy may therefore be a novel approach for treating age-related muscle atrophy. -- Abstract: Age-associated loss of muscle mass, or sarcopenia, contributes directly to frailty and an increased risk of falls and fractures among the elderly. Aged mice and elderly adults both show decreased muscle mass as well as relatively low levels of the fat-derived hormone leptin. Here we demonstrate that loss of muscle mass and myofiber size with aging in mice is associated with significant changes in the expression of specific miRNAs. Aging altered the expression of 57 miRNAs in mouse skeletal muscle, and many of these miRNAs are now reported to be associated specifically with age-related muscle atrophy. These include miR-221, previously identified in studies of myogenesis and muscle development as playing a role in the proliferation and terminal differentiation of myogenic precursors. We also treated aged mice with recombinant leptin, to determine whether leptin therapy could improve muscle mass and alter the miRNA expression profile of aging skeletal muscle. Leptin treatment significantly increased hindlimb muscle mass and extensor digitorum longus fiber size in aged mice. Furthermore, the expression of 37 miRNAs was altered in muscles of leptin-treated mice. In particular, leptin treatment increased the expression of miR-31 and miR-223, miRNAs known to be elevated during muscle regeneration and repair. These findings suggest that aging in skeletal muscle is associated with marked changes in the expression of specific miRNAs, and that nutrient

  15. Mice Doubly-Deficient in Lysosomal Hexosaminidase A and Neuraminidase 4 Show Epileptic Crises and Rapid Neuronal Loss

    OpenAIRE

    Volkan Seyrantepe; Pablo Lema; Aurore Caqueret; Larbi Dridi; Samar Bel Hadj; Stephane Carpentier; Francine Boucher; Thierry Levade; Lionel Carmant; Gravel, Roy A; Edith Hamel; Pascal Vachon; Graziella Di Cristo; Michaud, Jacques L; Morales, Carlos R.

    2010-01-01

    Tay-Sachs disease is a severe lysosomal disorder caused by mutations in the HexA gene coding for the α-subunit of lysosomal β-hexosaminidase A, which converts G(M2) to G(M3) ganglioside. Hexa(-/-) mice, depleted of β-hexosaminidase A, remain asymptomatic to 1 year of age, because they catabolise G(M2) ganglioside via a lysosomal sialidase into glycolipid G(A2), which is further processed by β-hexosaminidase B to lactosyl-ceramide, thereby bypassing the β-hexosaminidase A defect. Since this by...

  16. Reciprocal translocations in ageing mice and mice with long-term low-level 239Pu contamination

    International Nuclear Information System (INIS)

    Single intravenous injections of 185 Bq monomeric 239Pu were given to male mice, and the frequency of primary spermatocytes with reciprocal translocations, determined 724 days after treatment, was not significantly different from that of age-matched untreated controls. These old animals showed significantly higher aberration frequencies than young adults. The data therefore show that for low initial activity and very long retention time the possible cytogenetic effects of incorporated nuclide does not change the age-related pattern of increase of spontaneous chromosome aberrations. Considerations of the main variables involved in the induction of cytogenetic effects of incorporated plutonium, based on literature data, indicate that the initial injected activity, the estimated total accumulated average organ dose, and the retention time interact in a complex way; as far as can be seen at present, the effects seem to be dependent mainly on the initial activity at short times after contamination, while the retention time appears to be predominant in the case of long-term observations. (author)

  17. Streamwater ages derived from tritium show power law variation with discharge like silica concentrations

    Science.gov (United States)

    Stewart, Michael; Morgenstern, Uwe

    2013-04-01

    Understanding runoff generation is important for management of freshwater systems. Determining transit time distributions of streamwaters and how they change with discharge gives information on the flowpaths and recharge sources of streams - vital information for determining the responses of streams to stressors such as pollution, landuse change, or climate change. This work takes a first look at unique information on how transit time distributions change with discharge in some New Zealand catchments. Transit time distributions of streamwaters have been determined from tritium measurements on single samples in this work. This allows changes with stream discharge to be observed, in contrast to previous isotope studies which have given averaged transit time distributions based on series of samples. In addition, tritium reveals the wide spectrum of ages present in streams whereas oxygen-18 or chloride variations only show the younger ages (Stewart et al., 2010). It was found that the mean transit time (MTT) data could be reasonably represented by straight lines in log-log plots, indicating power law relationships between MTT and discharge. Similar power law behaviour has been observed for the rock forming elements such as silica in streamwaters (Godsey et al., 2009). Case studies are presented for two New Zealand catchments, both with volcanic ash substrates. Toenepi is a dairy catchment near Hamilton, which shows well-constrained power law relationships between MTT and discharge, and between silica concentration and discharge (Morgenstern et al., 2010). Baseflow MTTs vary from 2.5 to 157 years. Tutaeuaua is a pastoral farming catchment near Taupo. Results for nested catchments along the stream also show power law relationships for both MTT and silica with discharge. Streamwater MTTs vary from 1 to 11 years. The results indicate that (1) relatively old waters dominate many streams, (2) streamwater ages vary with discharge, and (3) age, like silica, varies according to

  18. Hearts of dystonia musculorum mice display normal morphological and histological features but show signs of cardiac stress.

    Directory of Open Access Journals (Sweden)

    Justin G Boyer

    Full Text Available Dystonin is a giant cytoskeletal protein belonging to the plakin protein family and is believed to crosslink the major filament systems in contractile cells. Previous work has demonstrated skeletal muscle defects in dystonin-deficient dystonia musculorum (dt mice. In this study, we show that the dystonin muscle isoform is localized at the Z-disc, the H zone, the sarcolemma and intercalated discs in cardiac tissue. Based on this localization pattern, we tested whether dystonin-deficiency leads to structural defects in cardiac muscle. Desmin intermediate filament, microfilament, and microtubule subcellular organization appeared normal in dt hearts. Nevertheless, increased transcript levels of atrial natriuretic factor (ANF, 66% beta-myosin heavy chain (beta-MHC, 95% and decreased levels of sarcoplasmic reticulum calcium pump isoform 2A (SERCA2a, 26%, all signs of cardiac muscle stress, were noted in dt hearts. Hearts from two-week old dt mice were assessed for the presence of morphological and histological alterations. Heart to body weight ratios as well as left ventricular wall thickness and left chamber volume measurements were similar between dt and wild-type control mice. Hearts from dt mice also displayed no signs of fibrosis or calcification. Taken together, our data provide new insights into the intricate structure of the sarcomere by situating dystonin in cardiac muscle fibers and suggest that dystonin does not significantly influence the structural organization of cardiac muscle fibers during early postnatal development.

  19. Shank3-mutant mice lacking exon 9 show altered excitation/inhibition balance, enhanced rearing, and spatial memory deficit

    Directory of Open Access Journals (Sweden)

    Jiseok Lee

    2015-03-01

    Full Text Available Shank3 is a postsynaptic scaffolding protein implicated in synapse development and autism spectrum disorders. The Shank3 gene is known to produce diverse splice variants whose functions have not been fully explored. In the present study, we generated mice lacking Shank3 exon 9 (Shank3∆9 mice, and thus missing 5 out of 10 known Shank3 splice variants containing the N-terminal ankyrin repeat region, including the longest splice variant, Shank3a. Our X-gal staining results revealed that Shank3 proteins encoded by exon 9-containing splice variants are abundant in upper cortical layers, striatum, hippocampus, and thalamus, but not in the olfactory bulb or cerebellum, despite the significant Shank3 mRNA levels in these regions. The hippocampal CA1 region of Shank3∆9 mice exhibited reduced excitatory transmission at Schaffer collateral synapses and increased frequency of spontaneous inhibitory synaptic events in pyramidal neurons. In contrast, prelimbic layer 2/3 pyramidal neurons in the medial prefrontal cortex displayed decreased frequency of spontaneous inhibitory synaptic events, indicating alterations in the ratio of excitation/inhibition (E/I ratio in the Shank3∆9 brain. These mice displayed a mild increase in rearing in a novel environment and mildly impaired spatial memory, but showed normal social interaction and repetitive behavior. These results suggest that ankyrin repeat-containing Shank3 splice variants are important for E/I balance, rearing behavior, and spatial memory.

  20. Swietenia mahagony extract shows agonistic activity to PPARγ and gives ameliorative effects on diabetic db/db mice

    Institute of Scientific and Technical Information of China (English)

    Dan-dan LI; Xu SHEN; Hua-liang JIANG; Jun-hua CHEN; Qing CHEN; Guo-wei LI; Jing CHEN; Jian-min YUE; Min-li CHEN; Xiao-ping WANG; Jian-hua SHEN

    2005-01-01

    Aim: To search the peroxisome proliferator-activated receptor γ (PPARγ) agonists from Swietenia mahagony extract (SmE) and observe the possible ameliorative effects of SmE on diabetic db/db mice. Methods: The PPARγ agonistic activity of SmE was screened by yeast-two hybrid system. The blood glucose levels of diabetic db/db mice were measured using a blood glucose level monitor and the data were statistically analyzed by NDST8.8W software. Results: By using the clinical drug rosiglitazone as a positive control, it was found that the PPARγ agonistic activity of SmE at a concentration of 50 μg/L was approximately half that of 35.7 μg/L (0.1 μmol/L) of rosiglitazone. At the dose of 1000 mg/kg, SmE remark ably decreased the blood glucose concentration of db/db mice from (15.26±2.98) to (7.58±2.20) mmol/L, and reduced the blood glucose levels by 55.49% compared with the control group (P<0.01). Conclusion: SmE shows agonistic activity to PPARγ and can ameliorate the blood glucose levels of diabetic db/db mice. SmE may be thus used as a potential agent for diabetes therapy.

  1. Impaired burrowing is the most prominent behavioral deficit of aging htau mice.

    Science.gov (United States)

    Geiszler, Philippine Camilla; Barron, Matthew Richard; Pardon, Marie-Christine

    2016-08-01

    htau mice are deficient of murine tau but express all six human tau isoforms, leading to gradual tau misprocessing and aggregation in brain areas relevant to Alzheimer's disease. While histopathological changes in htau mice have been researched in the past, we focused here on functional consequences of human tau accumulation. htau mice and their background controls - murine tau knock-out (mtau(-/-)) and C57Bl/6J mice - underwent a comprehensive trial battery to investigate species-specific behavior, locomotor activity, emotional responses, exploratory traits, spatial and recognition memory as well as acquisition, retention and extinction of contextual fear at two, four, six, nine and twelve months of age. In htau mice, tau pathology was already present at two months of age, whereas deficits in food burrowing and spatial working memory were first noted at four months of age. At later stages the presence of human tau on a mtau(-/-) background appeared to guard cognitive performance; as mtau(-/-) but not htau mice differed from C57Bl/6J mice in the food burrowing, spontaneous alternation and object discrimination tasks. Aging mtau(-/-) mice also exhibited increased body mass and locomotor activity. These data highlight that reduced food-burrowing performance was the most robust aspect of the htau phenotype with aging. htau and mtau(-/-) deficits in food burrowing pointed at the necessity of intact tau systems for daily life activities. While some htau and mtau(-/-) deficits overlap, age differences between the two genotypes may reflect distinct functional effects and compared to C57Bl/6J mice, the htau phenotype appeared stronger than the mtau(-/-) phenotype at young ages but milder with aging. PMID:27167086

  2. Transgenic mice with increased astrocyte expression of IL-6 show altered effects of acute ethanol on synaptic function.

    Science.gov (United States)

    Hernandez, Ruben V; Puro, Alana C; Manos, Jessica C; Huitron-Resendiz, Salvador; Reyes, Kenneth C; Liu, Kevin; Vo, Khanh; Roberts, Amanda J; Gruol, Donna L

    2016-04-01

    A growing body of evidence has revealed that resident cells of the central nervous system (CNS), and particularly the glial cells, comprise a neuroimmune system that serves a number of functions in the normal CNS and during adverse conditions. Cells of the neuroimmune system regulate CNS functions through the production of signaling factors, referred to as neuroimmune factors. Recent studies show that ethanol can activate cells of the neuroimmune system, resulting in the elevated production of neuroimmune factors, including the cytokine interleukin-6 (IL-6). Here we analyzed the consequences of this CNS action of ethanol using transgenic mice that express elevated levels of IL-6 through increased astrocyte expression (IL-6-tg) to model the increased IL-6 expression that occurs with ethanol use. Results show that increased IL-6 expression induces neuroadaptive changes that alter the effects of ethanol. In hippocampal slices from non-transgenic (non-tg) littermate control mice, synaptically evoked dendritic field excitatory postsynaptic potential (fEPSP) and somatic population spike (PS) at the Schaffer collateral to CA1 pyramidal neuron synapse were reduced by acute ethanol (20 or 60 mM). In contrast, acute ethanol enhanced the fEPSP and PS in hippocampal slices from IL-6 tg mice. Long-term synaptic plasticity of the fEPSP (i.e., LTP) showed the expected dose-dependent reduction by acute ethanol in non-tg hippocampal slices, whereas LTP in the IL-6 tg hippocampal slices was resistant to this depressive effect of acute ethanol. Consistent with altered effects of acute ethanol on synaptic function in the IL-6 tg mice, EEG recordings showed a higher level of CNS activity in the IL-6 tg mice than in the non-tg mice during the period of withdrawal from an acute high dose of ethanol. These results suggest a potential role for neuroadaptive effects of ethanol-induced astrocyte production of IL-6 as a mediator or modulator of the actions of ethanol on the CNS, including

  3. Effect of Methylphenidate on Retention and Retrieval of Passive Avoidance Memory in Young and Aged Mice

    Directory of Open Access Journals (Sweden)

    Arzi

    2014-10-01

    Full Text Available Background Several studies showed that dopamine and norepinephrine improve retention and retrieval of memory. Methylphenidate is an enhancer of dopamine and norepinephrine in brain. Objectives In the present study, the effect of methylphenidate was evaluated on retention and retrieval of memory in young and aged mice using passive avoidance apparatus. Materials and Methods Animals were divided into groups (n = 8 as follows: test groups received electric shock plus methylphenidate (2.5, 5 and 10mg kg-1, i. P., control group received electric shock plus normal saline and blank group received only electric shock. In all groups, step-down latency for both retention and retrieval test of memory was measured. Methylphenidate was administered immediately after receiving electric shock in the retention test, but methylphenidate was administered 23.5 hours after receiving electric shock in the retrieval test. Results The mean of step-down latency on day 4 was significantly higher compared to day 2 (P < 0.05 in all young and aged groups of mice. The best response was attained with 5 mg/kg of methylphenidate. In memory retention test, the mean of step-down latency in young groups that received 2.5 and 5 mg/kg methylphenidate was significantly longer(P < 0.05 than aged groups. However, this difference was not significant in memory retrieval test. Conclusions Methylphenidate may improve memory retention and retrieval.

  4. Female mice deficient in alpha-fetoprotein show female-typical neural responses to conspecific-derived pheromones.

    Directory of Open Access Journals (Sweden)

    Olivier Brock

    Full Text Available The neural mechanisms controlling sexual behavior are sexually differentiated by the perinatal actions of sex steroid hormones. We recently observed using female mice deficient in alpha-fetoprotein (AFP-KO and which lack the protective actions of AFP against maternal estradiol, that exposure to prenatal estradiol completely defeminized the potential to show lordosis behavior in adulthood. Furthermore, AFP-KO females failed to show any male-directed mate preferences following treatment with estradiol and progesterone, indicating a reduced sexual motivation to seek out the male. In the present study, we asked whether neural responses to male- and female-derived odors are also affected in AFP-KO female mice. Therefore, we compared patterns of Fos, the protein product of the immediate early gene, c-fos, commonly used as a marker of neuronal activation, between wild-type (WT and AFP-KO female mice following exposure to male or estrous female urine. We also tested WT males to confirm the previously observed sex differences in neural responses to male urinary odors. Interestingly, AFP-KO females showed normal, female-like Fos responses, i.e. exposure to urinary odors from male but not estrous female mice induced equivalent levels of Fos protein in the accessory olfactory pathways (e.g. the medial part of the preoptic nucleus, the bed nucleus of the stria terminalis, the amygdala, and the lateral part of the ventromedial hypothalamic nucleus as well as in the main olfactory pathways (e.g. the piriform cortex and the anterior cortical amygdaloid nucleus, as WT females. By contrast, WT males did not show any significant induction of Fos protein in these brain areas upon exposure to either male or estrous female urinary odors. These results thus suggest that prenatal estradiol is not involved in the sexual differentiation of neural Fos responses to male-derived odors.

  5. A Valepotriate Fraction of Valeriana glechomifolia Shows Sedative and Anxiolytic Properties and Impairs Recognition But Not Aversive Memory in Mice

    Directory of Open Access Journals (Sweden)

    Natasha Maurmann

    2011-01-01

    Full Text Available Plants of the genus Valeriana (Valerianaceae are used in traditional medicine as a mild sedative, antispasmodic and tranquilizer in many countries. This study was undertaken to explore the neurobehavioral effects of systemic administration of a valepotriate extract fraction of known quantitative composition of Valeriana glechomifolia (endemic of southern Brazil in mice. Adult animals were treated with a single intraperitoneal injection of valepotriate fraction (VF in the concentrations of 1, 3 or 10 mg kg-1, or with vehicle in the pre-training period before each behavioral test. During the exploration of an open field, mice treated with 10 mg kg-1 of VF showed reduced locomotion and exploratory behavior. Although overall habituation sessions for locomotion and exploratory behavior among vehicle control and doses of VF were not affected, comparison between open-field and habituation sessions within each treatment showed that VF administration at 1 and 10 mg kg-1 impaired habituation. In the elevated plus-maze test, mice treated with VF (10 mg kg-1 showed a significant increase in the percentage of time spent in the open arms without significant effects in the number of total arm entries. VF at 3 mg kg-1 produced an impairment of novel-object recognition memory. In contrast, VF did not affect fear-related memory assessed in an inhibitory avoidance task. The results indicate that VF can have sedative effects and affect behavioral parameters related to recognition memory.

  6. Development of a novel pink-eyed dilution mouse model showing progressive darkening of the eyes and coat hair with aging.

    Science.gov (United States)

    Ishikawa, Akira; Sugiyama, Makoto; Hondo, Eiichi; Kinoshita, Keiji; Yamagishi, Yuki

    2015-01-01

    Oca2(p-cas) (oculocutaneous albinism II; pink-eyed dilution castaneus) is a coat color mutant gene on mouse chromosome 7 that arose spontaneously in wild Mus musculus castaneus mice. Mice homozygous for Oca2(p-cas) usually exhibit pink eyes and gray coat hair on the non-agouti genetic background, and this ordinary phenotype remains unchanged throughout life. During breeding of a mixed strain carrying this gene on the C57BL/6J background, we discovered a novel spontaneous mutation that causes darkening of the eyes and coat hair with aging. In this study, we developed a novel mouse model showing this unique phenotype. Gross observations revealed that the pink eyes and gray coat hair of the novel mutant young mice became progressively darker in color by approximately 3 months after birth. Light and transmission-electron microscopic observations revealed a marked increase in melanin pigmentation of coat hair shafts and choroid of the eye in the novel mice compared to that in the ordinary mice. Sequence analysis of Oca2(p-cas) revealed a 4.1-kb deletion involving exons 15 and 16 of its wild-type gene. However, there was no sequence difference between the two types of mutant mice. Mating experiments suggested that the novel mutant phenotype was not inherited in a simple fashion, due to incomplete penetrance. The novel spontaneous mutant mouse is the first example of progressive hair darkening animals and is an essential animal model for understanding of the regulation mechanisms of melanin biosynthesis with aging. PMID:25739360

  7. Ischemic stroke induces gut permeability and enhances bacterial translocation leading to sepsis in aged mice

    Science.gov (United States)

    Verma, Rajkumar; Venna, Venugopal R.; Liu, Fudong; Chauhan, Anjali; Koellhoffer, Edward; Patel, Anita; Ricker, Austin; Maas, Kendra; Graf, Joerg; McCullough, Louise D.

    2016-01-01

    Aging is an important risk factor for post-stroke infection, which accounts for a large proportion of stroke-associated mortality. Despite this, studies evaluating post-stroke infection rates in aged animal models are limited. In addition, few studies have assessed gut microbes as a potential source of infection following stroke. Therefore we investigated the effects of age and the role of bacterial translocation from the gut in post-stroke infection in young (8-12 weeks) and aged (18-20 months) C57Bl/6 male mice following transient middle cerebral artery occlusion (MCAO) or sham surgery. Gut permeability was examined and peripheral organs were assessed for the presence of gut-derived bacteria following stroke. Furthermore, sickness parameters and components of innate and adaptive immunity were examined. We found that while stroke induced gut permeability and bacterial translocation in both young and aged mice, only young mice were able to resolve infection. Bacterial species seeding peripheral organs also differed between young (Escherichia) and aged (Enterobacter) mice. Consequently, aged mice developed a septic response marked by persistent and exacerbated hypothermia, weight loss, and immune dysfunction compared to young mice following stroke. PMID:27115295

  8. Longevity and tumour incidence in mice exposed to fast neutrons at different ages

    International Nuclear Information System (INIS)

    Experiments are under way in the authors' laboratory to observe both neoplastic and non-neoplastic late effects in mice irradiated with fission neutrons and X-rays at three different ages. Analysis of data from over 2800 animals is in progress and a preliminary evaluation can be made on the survival and the pathology at spontaneous death of mice irradiated in utero and at 3 months of age. Single doses of 250kV X-rays or of attenuated fission neutrons obtained in the biological channel of the experimental fast reactor RSV TAPIRO of the Casaccia Centre were given to male BC3F1 mice of 3 months of age and to pregnant females on day 17.5 post coitum. Both male and female offspring of the latter group were followed to spontaneous death, along with appropriate untreated controls. As for the 3 month old irradiated animals their mean survival time was decreased by X-rays, the dose-effect relationship being compatible with a linear fitting. Fission neutrons proved to be more efficient than X-rays in the induction of life shortening, but the shape of the dose-effect relationship did not fit a linear model because efficiency is higher at low than at high neutron doses. Reticulum cell sarcoma (RCS) was decreased by increasing X-ray and neutron doses, the latter being more efficient. The final incidences of all other neoplasms, regardless of tumour type and site, indicate that neutrons are more efficient than X-rays in tumour induction at low and intermediate doses. As for prenatally irradiated mice, no detectable effect on mean lifespan was observed for either type of radiation. A low final frequency of RCS was seen after irradiation at all dose levels of both types of radiation. The incidence of all other tumours was practically unchanged in male mice irradiated as foetuses with X-rays, but a significant excess was found after neutron irradiation, showing a frequency peak in the range of 0.27-0.45Gy. Similar results were obtained after irradiation of foetal females. (author)

  9. Circadian rhythms of body temperature and locomotor activity in aging BALB/c mice: early and late life span predictors.

    Science.gov (United States)

    Basso, Andrea; Del Bello, Giovanna; Piacenza, Francesco; Giacconi, Robertina; Costarelli, Laura; Malavolta, Marco

    2016-08-01

    Impairment of one or more parameters of circadian rhythms (CR) of body temperature (BT) and locomotor activity (LMA) are considered among the hallmarks of mammalian aging. These alterations are frequently used as markers for imminent death in laboratory mice. However, there are still contradictory data for particular strains and it is also uncertain which changes might predict senescence changes later in life, including the force of mortality. In the present paper we use telemetry to study LMA and CR of BT during aging of BALB/c mice. At our knowledge this is the first time that CR of BT and LMA are investigated in this strain in a range of age covering the whole lifespan, from young adult up to very old age. CR of BT was analyzed with a cosine model using a cross sectional approach and follow-up measurements. The results show that BT, LMA, amplitude, goodness-of-fit (GoF) to circadian cycle of temperature decrease with different shapes during chronological age. Moreover, we found that the % change of amplitude and BT in early life (5-19 months) can predict the remaining lifespan of the mice. Later in life (22-32 months), best predictors are single measurements of LMA and GoF. The results of this study also offer potential measures to rapidly identifying freely unrestrained mice with the worst longitudinal outcome and against which existing or novel biomarkers and treatments may be assessed. PMID:26820297

  10. Joint dysfunction and functional decline in middle age myostatin null mice.

    Science.gov (United States)

    Guo, Wen; Miller, Andrew D; Pencina, Karol; Wong, Siu; Lee, Amanda; Yee, Michael; Toraldo, Gianluca; Jasuja, Ravi; Bhasin, Shalender

    2016-02-01

    Since its discovery as a potent inhibitor for muscle development, myostatin has been actively pursued as a drug target for age- and disease-related muscle loss. However, potential adverse effects of long-term myostatin deficiency have not been thoroughly investigated. We report herein that male myostatin null mice (mstn(-/-)), in spite of their greater muscle mass compared to wild-type (wt) mice, displayed more significant functional decline from young (3-6months) to middle age (12-15months) than age-matched wt mice, measured as gripping strength and treadmill endurance. Mstn(-/-) mice displayed markedly restricted ankle mobility and degenerative changes of the ankle joints, including disorganization of bone, tendon and peri-articular connective tissue, as well as synovial thickening with inflammatory cell infiltration. Messenger RNA expression of several pro-osteogenic genes was higher in the Achilles tendon-bone insertion in mstn(-/-) mice than wt mice, even at the neonatal age. At middle age, higher plasma concentrations of growth factors characteristic of excessive bone remodeling were found in mstn(-/-) mice than wt controls. These data collectively indicate that myostatin may play an important role in maintaining ankle and wrist joint health, possibly through negative regulation of the pro-osteogenic WNT/BMP pathway. PMID:26549246

  11. Propeptide-mediated inhibition of myostatin increases muscle mass through inhibiting proteolytic pathways in aged mice.

    Science.gov (United States)

    Collins-Hooper, Henry; Sartori, Roberta; Macharia, Raymond; Visanuvimol, Korntip; Foster, Keith; Matsakas, Antonios; Flasskamp, Hannah; Ray, Steve; Dash, Philip R; Sandri, Marco; Patel, Ketan

    2014-09-01

    Mammalian aging is accompanied by a progressive loss of skeletal muscle, a process called sarcopenia. Myostatin, a secreted member of the transforming growth factor-β family of signaling molecules, has been shown to be a potent inhibitor of muscle growth. Here, we examined whether muscle growth could be promoted in aged animals by antagonizing the activity of myostatin through the neutralizing activity of the myostatin propeptide. We show that a single injection of an AAV8 virus expressing the myostatin propeptide induced an increase in whole body weights and all muscles examined within 7 weeks of treatment. Our cellular studies demonstrate that muscle enlargement was due to selective fiber type hypertrophy, which was accompanied by a shift toward a glycolytic phenotype. Our molecular investigations elucidate the mechanism underpinning muscle hypertrophy by showing a decrease in the expression of key genes that control ubiquitin-mediated protein breakdown. Most importantly, we show that the hypertrophic muscle that develops as a consequence of myostatin propeptide in aged mice has normal contractile properties. We suggest that attenuating myostatin signaling could be a very attractive strategy to halt and possibly reverse age-related muscle loss. PMID:24414825

  12. Age Dependence of Immunity Induced by a Candidate Universal Influenza Vaccine in Mice.

    Science.gov (United States)

    García, Mayra; Misplon, Julia A; Price, Graeme E; Lo, Chia-Yun; Epstein, Suzanne L

    2016-01-01

    Influenza has a major impact on the elderly due to increased susceptibility to infection with age and poor response to current vaccines. We have studied universal influenza vaccine candidates based on influenza A nucleoprotein and matrix 2 (A/NP+M2). Long-lasting protection against influenza virus strains of divergent subtypes is induced, especially with mucosal immunization. Here, we tested universal vaccination in BALB/c mice of different ages. Vaccination used intramuscular DNA priming to A/NP+M2 followed by intranasal (i.n.) boosting with recombinant adenoviruses (rAd) expressing the same antigens, or only A/NP+M2-rAd given i.n. Antigen-specific systemic antibody responses were induced in young, middle-aged, and elderly mice (2, 11-17, and 20 months old, respectively), but decreased with age. Antibody responses in bronchoalveolar lavage (BAL) were detected only in young mice. Antigen-specific T cell responses were seen in young and middle-aged but not elderly mice. A/NP+M2 vaccination by the two regimens above protected against stringent challenge in young and middle-aged mice, but not in elderly mice. However, mice vaccinated with A/NP-rAd or A/M2-rAd during their youth were partially protected against challenge 16 months later when they were elderly. In addition, a regimen of two doses of A/NP+M2-rAd given i.n. one month apart beginning in old age protected elderly mice against stringent challenge. This study highlights the potential benefit of cross-protective vaccines through middle age, and suggests that their performance might be enhanced in elderly individuals who had been exposed to influenza antigens early in life, as most humans have been, or by a two-dose rAd regimen given later in life. PMID:27055234

  13. Age Dependence of Immunity Induced by a Candidate Universal Influenza Vaccine in Mice

    Science.gov (United States)

    García, Mayra; Misplon, Julia A.; Price, Graeme E.; Lo, Chia-Yun; Epstein, Suzanne L.

    2016-01-01

    Influenza has a major impact on the elderly due to increased susceptibility to infection with age and poor response to current vaccines. We have studied universal influenza vaccine candidates based on influenza A nucleoprotein and matrix 2 (A/NP+M2). Long-lasting protection against influenza virus strains of divergent subtypes is induced, especially with mucosal immunization. Here, we tested universal vaccination in BALB/c mice of different ages. Vaccination used intramuscular DNA priming to A/NP+M2 followed by intranasal (i.n.) boosting with recombinant adenoviruses (rAd) expressing the same antigens, or only A/NP+M2-rAd given i.n. Antigen-specific systemic antibody responses were induced in young, middle-aged, and elderly mice (2, 11–17, and 20 months old, respectively), but decreased with age. Antibody responses in bronchoalveolar lavage (BAL) were detected only in young mice. Antigen-specific T cell responses were seen in young and middle-aged but not elderly mice. A/NP+M2 vaccination by the two regimens above protected against stringent challenge in young and middle-aged mice, but not in elderly mice. However, mice vaccinated with A/NP-rAd or A/M2-rAd during their youth were partially protected against challenge 16 months later when they were elderly. In addition, a regimen of two doses of A/NP+M2-rAd given i.n. one month apart beginning in old age protected elderly mice against stringent challenge. This study highlights the potential benefit of cross-protective vaccines through middle age, and suggests that their performance might be enhanced in elderly individuals who had been exposed to influenza antigens early in life, as most humans have been, or by a two-dose rAd regimen given later in life. PMID:27055234

  14. Reduced IGF-1 Signaling Delays Age-associated Proteotoxicity in Mice

    OpenAIRE

    Cohen, Ehud; Paulsson, Johan F.; Blinder, Pablo; Burstyn-Cohen, Tal; Du, Deguo; Estepa, Gabriela; Adame, Anthony; Pham, Hang M.; Holzenberger, Martin; Kelly, Jeffery W.; Masliah, Eliezer; Dillin, Andrew

    2009-01-01

    The Insulin/IGF signaling pathway (IIS) is a prominent regulator of aging of worms, flies, mice and likely humans. Delayed aging by IIS reduction protects the nematode, C. elegans, from toxicity associated with the aggregation of the Alzheimer's disease linked human peptide, Aβ. We reduced IGF signaling in Alzheimer's model mice and discovered that these animals are protected from the Alzheimer's-like disease symptoms including reduced behavioral impairment, neruoinflammation, neuronal and sy...

  15. An adjuvanted respiratory syncytial virus fusion protein induces protection in aged BALB/c mice

    Directory of Open Access Journals (Sweden)

    Cherukuri Anu

    2012-10-01

    Full Text Available Abstract Background Respiratory Syncytial Virus (RSV causes significant disease in the elderly, in part, because immunosenescence impairs protective immune responses to infection in this population. Despite previous and current efforts, there is no RSV vaccine currently licensed in infants or elderly adults. Adjuvanted RSV subunit vaccines have the potential to boost waning immune responses and reduce the burden of RSV disease in the elderly population. Results We used an aged BALB/c mouse model to evaluate immune responses to RSV Fusion (F protein in the absence and presence of an alum adjuvant. We demonstrate that aged BALB/c mice immunized with alum-adjuvanted RSV F protein had significantly reduced lung viral titers at day 4 following challenge with wild-type (wt RSV. Serum neutralizing antibody titers measured on day 27 correlated with protection in both young and aged vaccinated mice, although the magnitude of antibody titers was lower in aged mice. Unlike young mice, in aged mice, alum-adjuvanted RSV F did not induce lung TH2-type cytokines or eosinophil infiltration compared to non-adjuvanted F protein following wt RSV challenge. Conclusion Our studies demonstrate that neutralizing anti-RSV antibody titers correlate with protection in both young and aged BALB/c mice vaccinated with RSV F protein vaccines. The F + alum formulation mediated greater protection compared to the non-adjuvanted F protein in both young and aged mice. However, while alum can boost F-specific antibody responses in aged mice, it does not completely overcome the reduced ability of a senescent immune system to respond to the RSV F antigen. Thus, our data suggest that a stronger adjuvant may be required for the prevention of RSV disease in immunosenescent populations, to achieve the appropriate balance of protective neutralizing antibodies and effective TH1-type cytokine response along with minimal lung immunopathology.

  16. Lung vitamin E transport processes are affected by both age and environmental oxidants in mice

    International Nuclear Information System (INIS)

    Despite the physiological importance of alpha-tocopherol (AT), the molecular mechanisms involved in maintaining cellular and tissue tocopherol levels remain to be fully characterized. Scavenger receptor B1 (SRB1), one of a large family of scavenger receptors, has been shown to facilitate AT transfer from HDL to peripheral tissues via apo A-1-mediated processes and to be important in the delivery of AT to the lung cells. In the present studies the effects of age and two environmental oxidants ozone (O3) (0.25 ppm 6 h/day) and cigarette smoke (CS) (60 mg/m3 6 h/day) for 4 days on selected aspects of AT transport in murine lung tissues were assessed. While AT levels were 25% higher (p 3 or CS at the doses used had no effect. Gene expression levels, determined by RT-PCR of AT transport protein (ATTP), SRB1, CD36, ATP binding cassette 3 (ABCA3) and ABCA1 and protein levels, determined by Western blots for SRB1, ATTP and ABCA1 were assessed. Aged mouse lung showed a lower levels of ATTP, ABCA3 and SRB1 and a higher level CD36 and ABCA1. Acute exposure to either O3 or CS induced declines in ATTP and SRB1 in both aged and young mice lung. CD36 increased in both young and aged mice lung upon exposure to O3 and CS. These findings suggest that both age and environmental oxidant exposure affect pathways related to lung AT homeostasis and do so in a way that favors declines in lung AT. However, given the approach taken, the effects cannot be traced to changes in these pathways or AT content in any specific lung associated cell type and thus highlight the need for further follow-up studies looking at specific lung associated cell types

  17. Influence of dose and age of radiation exposure on attributable risk in mice

    International Nuclear Information System (INIS)

    The present study was aimed to clarify influence of the dose and age of radiation exposure on attributable risk, relative cumulative hazard and expression pattern of the lethal diseases. The attributable risk, relative cumulative hazard and excess cumulative hazard were estimated with the age-specific mortalities. Experimental data using female B6C3F1 mice were made subject of analysis. In this experiment mice were irradiated at day 14, 17 or 18 prenatal age or day 0, 7, 35, 105, 240 or 365 postnatal age with doses ranging from 0.95 to 5.7 Gy of 137Cs γ-rays and were allowed to live out their entire life spans under a specific pathogen free condition. Among mice irradiated at day 0 postnatal period the attributable risk and relative cumulative hazard were 38 % and 1.61, respectively; whereas, shortening of the mean life span was 7 %. Shape of dose-response relationship for the attributable risk was downward concave and that for the relative cumulative hazard was upward concave. The relative cumulative hazards in mice irradiated during neonatal or juvenile period were apparently higher than that irradiated during adulthood. Latent period for expression of radiation-induced lethal diseases in mice irradiated during the prenatal or early postnatal period was longer than that in mice exposed during adult period. Susceptibility of mice in the late fetal period to induction of late-occurring lethal diseases was lower than neonatal mice and was almost similar to young adult mice. The relative cumulative hazard did not increase with statistically significant difference when mice were irradiated at day 14 prenatal age with 0.95 Gy. (author)

  18. Mitochondrial DNA modifies cognition in interaction with the nuclear genome and age in mice.

    Science.gov (United States)

    Roubertoux, Pierre L; Sluyter, Frans; Carlier, Michèle; Marcet, Brice; Maarouf-Veray, Fatima; Chérif, Chabane; Marican, Charlotte; Arrechi, Patricia; Godin, Fabienne; Jamon, Marc; Verrier, Bernard; Cohen-Salmon, Charles

    2003-09-01

    Several lines of evidence indicate an association between mitochondrial DNA (mtDNA) and the functioning of the nervous system. As neuronal development and structure as well as axonal and synaptic activity involve mitochondrial genes, it is not surprising that most mtDNA diseases are associated with brain disorders. Only one study has suggested an association between mtDNA and cognition, however. Here we provide direct evidence of mtDNA involvement in cognitive functioning. Total substitution of mtDNA was achieved by 20 repeated backcrosses in NZB/BlNJ (N) and CBA/H (H) mice with different mtDNA origins. All 13 mitochondrial genes were expressed in the brains of the congenic quartet. In interaction with nuclear DNA (nDNA), mtDNA modified learning, exploration, sensory development and the anatomy of the brain. The effects of mtDNA substitution persisted with age, increasing in magnitude as the mice got older. We observed different effects with input of mtDNA from N versus H mice, varying according to the phenotypes. Exchanges of mtDNA may produce phenotypes outside the range of scores observed in the original mitochondrial and nuclear combinations. These findings show that mitochondrial polymorphisms are not as neutral as was previously believed. PMID:12923532

  19. Sox4 Links Tumor Suppression to Accelerated Aging in Mice by Modulating Stem Cell Activation

    Directory of Open Access Journals (Sweden)

    Miguel Foronda

    2014-07-01

    Full Text Available Sox4 expression is restricted in mammals to embryonic structures and some adult tissues, such as lymphoid organs, pancreas, intestine, and skin. During embryogenesis, Sox4 regulates mesenchymal and neural progenitor survival, as well as lymphocyte and myeloid differentiation, and contributes to pancreas, bone, and heart development. Aberrant Sox4 expression is linked to malignant transformation and metastasis in several types of cancer. To understand the role of Sox4 in the adult organism, we first generated mice with reduced whole-body Sox4 expression. These mice display accelerated aging and reduced cancer incidence. To specifically address a role for Sox4 in adult stem cells, we conditionally deleted Sox4 (Sox4cKO in stratified epithelia. Sox4cKO mice show increased skin stem cell quiescence and resistance to chemical carcinogenesis concomitantly with downregulation of cell cycle, DNA repair, and activated hair follicle stem cell pathways. Altogether, these findings highlight the importance of Sox4 in regulating adult tissue homeostasis and cancer.

  20. Inflammatory insult during pregnancy accelerates age-related behavioral and neurobiochemical changes in CD-1 mice.

    Science.gov (United States)

    Li, Xue-Yan; Wang, Fang; Chen, Gui-Hai; Li, Xue-Wei; Yang, Qi-Gang; Cao, Lei; Yan, Wen-Wen

    2016-06-01

    Data shows that inflammation during pregnancy significantly exerts a long-term influence on offspring, such as increasing the risk of adult cognition decline in animals. However, it is unclear whether gestational inflammation affects the neurobehavioral and neurobiochemical outcomes in the mother-self during aging. In this study, pregnant CD-1 mice intraperitoneally received lipopolysaccharide (LPS) in two doses (25 and 50 g/kg, respectively) or normal saline daily during gestational days 15-17. At the age of 15 months, a battery of behavioral tasks was employed to evaluate their species-typical behaviors, sensorimotor ability, anxiety levels, and spatial learning and memory abilities. An immunohistochemical method was utilized preliminarily to detect neurobiochemical indicators consisting of amyloid-β, phosphorylated tau, presynaptic proteins synaptotagmin-1 and syntaxin-1, glial fibrillary acidic protein (GFAP), and histone-4 acetylation on the K8 site (H4K8ac). The behavioral results showed that LPS exposure during pregnancy exacerbated a decline in 15-month-old CD-1 mice's abilities to nest, their sensorimotor and spatial learning and memory capabilities, and increased their anxiety levels. The neurobiochemical results indicated that gestational LPS exposure also intensified age-related hippocampal changes, including increased amyloid-β42, phosphorylated tau, synaptotagmin-1 and GFAP, and decreased syntaxin-1 and H4K8ac. Our results suggested that the inflammatory insult during pregnancy could be an important risk factor for the development of Alzheimer's disease, and the H4K8 acetylation might play an important role in the underlying mechanism. This study offers a perspective for improving strategies that support healthy development and successful aging. PMID:27194408

  1. Age-dependent changes in lipid peroxide levels in peripheral organs, but not in brain, in senescence-accelerated mice.

    Science.gov (United States)

    Matsugo, S; Kitagawa, T; Minami, S; Esashi, Y; Oomura, Y; Tokumaru, S; Kojo, S; Matsushima, K; Sasaki, K

    2000-01-01

    The tissue concentration of lipid peroxides was determined in the brain, heart, liver, lung and kidney of accelerated senescence-prone (SAMP-8) and -resistant (SAMR-1) mice at 3, 6 and 9 months of age by a method involving chemical derivatization and high performance liquid chromatography. The level of lipid peroxides in the brain did not show an age-dependent change, but at each age the brain level of lipid peroxides was significantly higher in SAMP-8 than in SAMR-1. In contrast, the lipid peroxide levels in the peripheral organs showed increases with aging in both strains, and they were significantly higher in SAMP-8 than in SAMR-1 at both 3 and 6 months of age (except at 3 months of age in the kidney). These results suggest that increased oxidative stress in the brain and peripheral organs is a cause of the senescence-related degeneration and impairments seen in SAMP-8. PMID:10643812

  2. Estradiol to aged female or male mice improves learning in inhibitory avoidance and water maze tasks

    OpenAIRE

    Frye, Cheryl A.; Rhodes, Madeline E; Dudek, Bruce

    2005-01-01

    Although 17β-Estradiol (E2) improves cognitive performance of aged female mice, its mnemonic effects when administered post-training to aged male mice have not been examined. E2 (10 µg, SC) or oil vehicle was administered to intact, 24-month-old female or male congenic (primarily C57BL/6 background) mice immediately after training in the inhibitory avoidance or water maze tasks. Following behavioral testing, effects of 1 or 24 h of E2 exposure on hippocampal levels of E2 and brain-derived neu...

  3. Age-Related Deterioration of Rod Vision in Mice

    OpenAIRE

    Kolesnikov, Alexander V.; Fan, Jie; Crouch, Rosalie K.; Kefalov, Vladimir J.

    2010-01-01

    Even in healthy individuals, aging leads to deterioration in visual acuity, contrast sensitivity, visual field, and dark adaptation. Little is known about the neural mechanisms that drive the age-related changes of the retina and more specifically of photoreceptors. According to one hypothesis, the age-related deterioration in rod function is due to the limited availability of 11-cis-retinal for rod pigment formation. To determine how aging affects rod photoreceptors and to test the retinoid ...

  4. β - Alanine protects mice from memory deficits induced by ageing, scopolamine, diazepam and ethanol

    Directory of Open Access Journals (Sweden)

    Dhingra D

    2006-01-01

    Full Text Available The present study was undertaken to investigate the effects of β-alanine (a glycine agonist, on learning and memory in mice. β-alanine (5, 10, 20 and 40 mg/kg i.p. was administered for 6 successive days, to young (3 months old and aged-mice (16 months old. The learning and memory parameters were assessed, using elevated plus-maze and passive-avoidance apparatus. The effect of β-alanine (20 mg/kg for 6 days on locomotor function of young and aged mice, was studied using photoactometer, to rule out the increase in locomotor performance of mice. β-alanine at both the doses (10 and 20 mg/kg, significantly improved learning and memory of young- and aged- mice. β-alanine also reversed scopolamine (0.4 mg/kg i.p., ethanol (1.0 g/kg i.p. and diazepam (1.0 mg/kg i.p. -induced amnesia in young mice. There was no significant effect of β-alanine on the locomotor activity of both young and aged mice. The probable underlying mechanism of the memory-enhancing effect of β-alanine appears to be related to its antioxidant, anti-amyloid and procholinergic activities.

  5. Colitic scid mice fed Lactobacillus spp. show an ameliorated gut histopathology and an altered cytokine profile by local T cells

    DEFF Research Database (Denmark)

    Møller, Peter Lange; Pærregaard, Anders; Gad, Monika;

    2005-01-01

    Scid mice transplanted with CD4 T blast cells develop colitis. We investigated if the disease was influenced in colitic mice treated with antibiotic and fed Lactobacillus spp.......Scid mice transplanted with CD4 T blast cells develop colitis. We investigated if the disease was influenced in colitic mice treated with antibiotic and fed Lactobacillus spp....

  6. Global view of transcriptome in the brains of aged NR2B transgenic mice*****

    Institute of Scientific and Technical Information of China (English)

    Chunxia Li; Men Su; Huimin Wang; Yinghe Hu

    2013-01-01

    NR2B subunits are involved in regulating aging, in particular, age-related learning and memory deficits. We examined 19-month-old NR2B transgenic mice and their littermate controls. First, we detected expression of the NR2B subunit gene, Grin2b, in the neocortex of transgenic mice using real-time PCR. Next, we used microarrays to examine differences in neocortical gene expression. Pathway and signal-net analyses identified multiple pathways altered in the transgenic mice, in-cluding the P53, Jak-STAT, Wnt, and Notch pathways, as wel as regulation of the actin cytoskeleton and neuroactive ligand-receptor interactions. Further signal-net analysis highlighted the P53 and insulin-like growth factor pathways as key regulatory pathways. Our results provide new insight into understanding the molecular mechanisms of NR2B regulated age-related memory storage, normal organismal aging and age-related disease.

  7. Complement factor H deficiency results in decreased neuroretinal expression of Cd59a in aged mice

    DEFF Research Database (Denmark)

    Faber, Carsten; Williams, Jennifer; Juel, Helene Bæk; Greenwood, John; Nissen, Mogens Holst; Moss, Stephen E.

    2012-01-01

    changes in the function of CFH influence development of AMD are unclear, we examined ocular complement expression as a consequence of age in control and CFH null mutant mice. Methods. Gene expression in neuroretinas and RPE/choroid from young and aged WT and Cfh−/− C57BL/6J mice was analyzed by...... microarrays. Expression of a wide range of complement genes was compared with expression in liver. Results. An age-associated increased expression of complement, particularly C1q, C3, and factor B, in the RPE/choroid coincided with increased expression of the negative regulators Cfh and Cd59a in the...... neuroretina. Young mice deficient in CFH expressed Cd59a similar to WT, but failed to upregulate Cd59a expression with age. Hepatic expression of Cd59a increased with age regardless of Cfh genotype. Conclusions. While the connection between CFH deficiency and failure to upregulate CD59a remains unknown, these...

  8. Running rescues a fear-based contextual discrimination deficit in aged mice

    OpenAIRE

    Wu, Melody V; Luna, Victor M.; Hen, René

    2015-01-01

    Normal aging and exercise exert extensive, often opposing, effects on the dentate gyrus (DG) of the hippocampus altering volume, synaptic function, and behaviors. The DG is especially important for behaviors requiring pattern separation—a cognitive process that enables animals to differentiate between highly similar contextual experiences. To determine how age and exercise modulate pattern separation in an aversive setting, young, aged, and aged mice provided with a running wheel were assayed...

  9. Characteristics of spinal microglia in aged and obese mice: potential contributions to impaired sensory behavior

    OpenAIRE

    Lee, Seunghwan; Wu, YaSi; Shi, Xiang Qun; Zhang, Ji

    2015-01-01

    Background Both aging and obesity have been recognized widely as health conditions that profoundly affect individuals, families and the society. Aged and obese people often report altered pain responses while underlying mechanisms have not been fully elucidated. We aim to understand whether spinal microglia could potentially contribute to altered sensory behavior in aged and obese population. Results In this study, we monitored pain behavior in adult (6 months) and aged (17 months) mice fed w...

  10. Treadmill Exercise Attenuates Retinal Oxidative Stress in Naturally-Aged Mice: An Immunohistochemical Study

    OpenAIRE

    Chan-Sik Kim; Sok Park; Yoonseok Chun; Wook Song; Hee-Jae Kim; Junghyun Kim

    2015-01-01

    In the retina, a number of degenerative diseases, including glaucoma, diabetic retinopathy, and age-related macular degeneration, may occur as a result of aging. Oxidative damage is believed to contribute to the pathogenesis of aging as well as to age-related retinal disease. Although physiological exercise has been shown to reduce oxidative stress in rats and mice, it is not known whether it has a similar effect in retinal tissues. The aim of this study was to evaluate retinal oxidative str...

  11. Short-term Treatment of Daumone Improves Hepatic Inflammation in Aged Mice

    OpenAIRE

    Park, Jong Hee; Ha, Hunjoo

    2015-01-01

    Chronic inflammation has been proposed as one of the main molecular mechanisms of aging and age-related diseases. Although evidence in humans is limited, short-term calorie restriction (CR) has been shown to have anti-inflammatory effects in aged experimental animals. We reported on the long-term treatment of daumone, a synthetic pheromone secreted by Caenorhabditis elegans in an energy deficient environment, extends the life-span and attenuates liver injury in aged mice. The present study ex...

  12. Comparison of mice with accelerated aging caused by distinct mechanisms.

    Science.gov (United States)

    Gurkar, Aditi U; Niedernhofer, Laura J

    2015-08-01

    Aging is the primary risk factor for numerous chronic, debilitating diseases. These diseases impact quality of life of the elderly and consume a large portion of health care costs. The cost of age-related diseases will only increase as the world's population continues to live longer. Thus it would be advantageous to consider aging itself as a therapeutic target, potentially stemming multiple age-related diseases simultaneously. While logical, this is extremely challenging as the molecular mechanisms that drive aging are still unknown. Furthermore, clinical trials to treat aging are impractical. Even in preclinical models, testing interventions to extend healthspan in old age are lengthy and therefore costly. One approach to expedite aging studies is to take advantage of mouse strains that are engineered to age rapidly. These strains are genetically and phenotypically quite diverse. This review aims to offer a comparison of several of these strains to highlight their relative strengths and weaknesses as models of mammalian and more specifically human aging. Additionally, careful identification of commonalities among the strains may lead to the identification of fundamental pathways of aging. PMID:25617508

  13. Suppressing an anti-inflammatory cytokine reveals a strong age-dependent survival cost in mice.

    Directory of Open Access Journals (Sweden)

    Virginia Belloni

    Full Text Available BACKGROUND: The central paradigm of ecological immunology postulates that selection acts on immunity as to minimize its cost/benefit ratio. Costs of immunity may arise because the energetic requirements of the immune response divert resources that are no longer available for other vital functions. In addition to these resource-based costs, mis-directed or over-reacting immune responses can be particularly harmful for the host. In spite of the potential importance of immunopathology, most studies dealing with the evolution of the immune response have neglected such non resource-based costs. To keep the immune response under control, hosts have evolved regulatory pathways that should be considered when studying the target of the selection pressures acting on immunity. Indeed, variation in regulation may strongly modulate the negative outcome of immune activation, with potentially important fitness consequences. METHODOLOGY/PRINCIPAL FINDINGS: Here, we experimentally assessed the survival costs of reduced immune regulation by inhibiting an anti-inflammatory cytokine (IL-10 with anti-IL-10 receptor antibodies (anti-IL-10R in mice that were either exposed to a mild inflammation or kept as control. The experiment was performed on young (3 months and old (15 months individuals, as to further assess the age-dependent cost of suppressing immune regulation. IL-10 inhibition induced high mortality in old mice exposed to the mild inflammatory insult, whereas no mortality was observed in young mice. However, young mice experienced a transitory lost in body mass when injected with the anti-IL-10R antibodies, showing that the treatment was to a lesser extent also costly for young individuals. CONCLUSIONS: These results suggest a major role of immune regulation that deserves attention when investigating the evolution of immunity, and indicate that the capacity to down-regulate the inflammatory response is crucial for late survival and longevity.

  14. Mutation types and aging differently affect revertant fiber expansion in dystrophic mdx and mdx52 mice.

    Directory of Open Access Journals (Sweden)

    Yusuke Echigoya

    Full Text Available Duchenne muscular dystrophy (DMD, one of the most common and lethal genetic disorders, and the mdx mouse myopathies are caused by a lack of dystrophin protein. These dystrophic muscles contain sporadic clusters of dystrophin-expressing revertant fibers (RFs, as detected by immunohistochemistry. RFs are known to arise from muscle precursor cells with spontaneous exon skipping (alternative splicing and clonally expand in size with increasing age through the process of muscle degeneration/regeneration. The expansion of revertant clusters is thought to represent the cumulative history of muscle regeneration and proliferation of such precursor cells. However, the precise mechanisms by which RFs arise and expand are poorly understood. Here, to test the effects of mutation types and aging on RF expansion and muscle regeneration, we examined the number of RFs in mdx mice (containing a nonsense mutation in exon 23 and mdx52 mice (containing deletion mutation of exon 52 with the same C57BL/6 background at 2, 6, 12, and 18months of age. Mdx mice displayed a significantly higher number of RFs compared to mdx52 mice in all age groups, suggesting that revertant fiber expansion largely depends on the type of mutation and/or location in the gene. A significant increase in the expression and clustering levels of RFs was found beginning at 6months of age in mdx mice compared with mdx52 mice. In contrast to the significant expansion of RFs with increasing age, the number of centrally nucleated fibers and embryonic myosin heavy chain-positive fibers (indicative of cumulative and current muscle regeneration, respectively decreased with age in both mouse strains. These results suggest that mutation types and aging differently affect revertant fiber expansion in mdx and mdx52 mice.

  15. Age-Related Hearing Loss in Mn-SOD Heterozygous Knockout Mice

    Directory of Open Access Journals (Sweden)

    Makoto Kinoshita

    2013-01-01

    Full Text Available Age-related hearing loss (AHL reduces the quality of life for many elderly individuals. Manganese superoxide dismutase (Mn-SOD, one of the antioxidant enzymes acting within the mitochondria, plays a crucial role in scavenging reactive oxygen species (ROS. To determine whether reduction in Mn-SOD accelerates AHL, we evaluated auditory function in Mn-SOD heterozygous knockout (HET mice and their littermate wild-type (WT C57BL/6 mice by means of auditory brainstem response (ABR. Mean ABR thresholds were significantly increased at 16 months when compared to those at 4 months in both WT and HET mice, but they did not significantly differ between them at either age. The extent of hair cell loss, spiral ganglion cell density, and thickness of the stria vascularis also did not differ between WT and HET mice at either age. At 16 months, immunoreactivity of 8-hydroxydeoxyguanosine was significantly greater in the SGC and SV in HET mice compared to WT mice, but that of 4-hydroxynonenal did not differ between them. These findings suggest that, although decrease of Mn-SOD by half may increase oxidative stress in the cochlea to some extent, it may not be sufficient to accelerate age-related cochlear damage under physiological aging process.

  16. Mitochondrial DNA deletion and aging induced by low dose rate of radiation in mice

    International Nuclear Information System (INIS)

    Mitochondrial DNA (mtDNA) is a closed circular DNA molecule and more than 100 copies are present in a cell. Deletion mutation of mtDNA accumulates with aging and can be a suitable marker for estimating biological effects on radiation-induced mutation in mice. The mice life span study in the Institute for Environmental Sciences suggests that low dose rate of radiation might accelerate aging in mice prolongly irradiated by 137Cs γ-rays (20 mGy/day for 400 days). To know the relationships between low dose rate irradiation, aging and mutation, we observed deletion mutations of mtDNA from mice irradiated by 137Cs γ-rays (20 mGy/day) for different dates. The real-time fluorescence PCR method was sensitive enough to determine the relative amount of deletion in several tissues. Age-dependent accumulations of deletion mutations were observed in aged mice (250-700 days). However, a significant increase of deletion mutation related to accumulated dose was not detected in 137Cs γ-ray irradiated mice for 4-12 Gy. These data suggest that the effect of the low dose rate irradiation on mtDNA is within a background level. (author)

  17. Altered left ventricular performance in aging physically active mice with an ankle sprain injury.

    Science.gov (United States)

    Turner, Michael J; Guderian, Sophie; Wikstrom, Erik A; Huot, Joshua R; Peck, Bailey D; Arthur, Susan T; Marino, Joseph S; Hubbard-Turner, Tricia

    2016-02-01

    We assessed the impact of differing physical activity levels throughout the lifespan, using a musculoskeletal injury model, on the age-related changes in left ventricular (LV) parameters in active mice. Forty male mice (CBA/J) were randomly placed into one of three running wheel groups (transected CFL group, transected ATFL/CFL group, SHAM group) or a SHAM Sedentary group (SHAMSED). Before surgery and every 6 weeks after surgery, LV parameters were measured under 2.5 % isoflurane inhalation. Group effects for daily distance run was significantly greater for the SHAM and lesser for the ATLF/CFL mice (p = 0.013) with distance run decreasing with age for all mice (p < 0.0001). Beginning at 6 months of age, interaction (group × age) was noted with LV posterior wall thickness-to-radius ratios (h/r) where h/r increased with age in the ATFL/CFL and SHAMSED mice while the SHAM and CFL mice exhibited decreased h/r with age (p = 0.0002). Passive filling velocity (E wave) was significantly greater in the SHAM mice and lowest for the ATFL/CFL and SHAMSED mice (p < 0.0001) beginning at 9 months of age. Active filling velocity (A wave) was not different between groups (p = 0.10). Passive-to-active filling velocity ratio (E/A ratio) was different between groups (p < 0.0001), with higher ratios for the SHAM mice and lower ratios for the ATFL/CFL and SHAMSED mice in response to physical activity beginning at 9 months of age. Passive-to-active filling velocity ratio decreased with age (p < 0.0001). Regular physical activity throughout the lifespan improved LV structure, passive filling velocity, and E/A ratio by 6 to 9 months of age and attenuated any negative alterations throughout the second half of life. The diastolic filling differences were found to be significantly related to the amount of activity performed by 9 months and at the end of the lifespan. PMID:26803818

  18. Experimental induction of type 2 diabetes in aging-accelerated mice triggered Alzheimer-like pathology and memory deficits.

    Science.gov (United States)

    Mehla, Jogender; Chauhan, Balwantsinh C; Chauhan, Neelima B

    2014-01-01

    Alzheimer's disease (AD) is an age-dependent neurodegenerative disease constituting ~95% of late-onset non-familial/sporadic AD, and only ~5% accounting for early-onset familial AD. Availability of a pertinent model representing sporadic AD is essential for testing candidate therapies. Emerging evidence indicates a causal link between diabetes and AD. People with diabetes are >1.5-fold more likely to develop AD. Senescence-accelerated mouse model (SAMP8) of accelerated aging displays many features occurring early in AD. Given the role played by diabetes in the pre-disposition of AD, and the utility of SAMP8 non-transgenic mouse model of accelerated aging, we examined if high fat diet-induced experimental type 2 diabetes in SAMP8 mice will trigger pathological aging of the brain. Results showed that compared to non-diabetic SAMP8 mice, diabetic SAMP8 mice exhibited increased cerebral amyloid-β, dysregulated tau-phosphorylating glycogen synthase kinase 3β, reduced synaptophysin immunoreactivity, and displayed memory deficits, indicating Alzheimer-like changes. High fat diet-induced type 2 diabetic SAMP8 mice may represent the metabolic model of AD. PMID:24121970

  19. A higher oxidative status accelerates senescence and aggravates age-dependent disorders in SAMP strains of mice.

    Science.gov (United States)

    Hosokawa, Masanori

    2002-11-01

    The SAM strain of mice is actually a group of related inbred strains consisting of series of SAMP (accelerated senescence-prone, short-lived) and SAMR (accelerated senescence-resistant, longer-lived) strains. Comparing with the SAMR strains, the SAMP strains of mice show a more accelerated senescence process, shorter lifespan, and an earlier onset and more rapid progress of age-associated pathological phenotypes similar to several geriatric disorders observed in humans, including senile osteoporosis, degenerative joint disease, age-related deficits in learning and memory, olfactory bulb and forebrain atrophy, presbycusis and retinal atrophy, senile amyloidosis, immunosenescence, senile lungs, and diffuse medial thickening of the aorta. The higher oxidative stress observed in the SAMP strains of mice are partly caused by mitochondrial dysfunction, and may be one cause of the senescence acceleration and age-dependent alterations in cell structure and function, including neuronal cell degeneration. This senescence acceleration is also observed during senescence/crisis in cultures of isolated fibroblast-like cells from SAMP strains of mice, and was associated with a hyperoxidative status. These observations suggest that the SAM strains are useful tools in the attempt to understand the mechanisms of age-dependent degeneration of cells and tissues, and their aggravation, and to develop clinical interventions. PMID:12470893

  20. A mild impairment of mitochondrial electron transport has sex-specific effects on lifespan and aging in mice.

    Directory of Open Access Journals (Sweden)

    Bryan G Hughes

    Full Text Available Impairments of various aspects of mitochondrial function have been associated with increased lifespan in various model organisms ranging from Caenorhabditis elegans to mice. For example, disruption of the function of the 'Rieske' iron-sulfur protein (RISP of complex III of the mitochondrial electron transport chain can result in increased lifespan in the nematode worm C. elegans. However, the mechanisms by which impaired mitochondrial function affects aging remain under investigation, including whether or not they require decreased electron transport. We have generated knock-in mice with a loss-of-function Risp mutation that is homozygous lethal. However, heterozygotes (Risp(+/P224S were viable and had decreased levels of RISP protein and complex III enzymatic activity. This decrease was sufficient to impair mitochondrial respiration and to decrease overall metabolic rate in males, but not females. These defects did not appear to exert an overtly deleterious effect on the health of the mutants, since young Risp(+/P224S mice are outwardly normal, with unaffected performance and fertility. Furthermore, biomarkers of oxidative stress were unaffected in both young and aged animals. Despite this, the average lifespan of male Risp(+/P224S mice was shortened and aged Risp(+/P224S males showed signs of more rapidly deteriorating health. In spite of these differences, analysis of Gompertz mortality parameters showed that Risp heterozygosity decreased the rate of increase of mortality with age and increased the intrinsic vulnerability to death in both sexes. However, the intrinsic vulnerability was increased more dramatically in males, which resulted in their shortened lifespan. For females, the slower acceleration of age-dependent mortality results in significantly increased survival of Risp(+/P224S mice in the second half of lifespan. These results demonstrate that even relatively small perturbations of the mitochondrial electron transport chain can

  1. Effects of Aging on Spermatogenesis, Sperm Maturation and Fertility in Mice

    Institute of Scientific and Technical Information of China (English)

    Qiu-ju CHEN; Wei-jie ZHU; Jing LI

    2006-01-01

    Objective To investigate effects of aging on spermatogenesis in testis, sperm maturation in epididymis, and fertility in mice.Methods Testicular specimens, caput epididymal sperm and cauda epididymal sperm were obtained from Kuming mice (18-month aged group, n=15; 6-month young group as control, n=15). The testicular histological examinations and quantitative evaluations on spermatogenesis were performed. Sperm parameters including sperm density, sperm viability, sperm motility, and normal morphological rate were assessed. The fertilization rate and embryo development were measured by in vitro fertilization and embryo culture.Results The histological changes of testes in aged mice were mainly seminiferous tubule atrophy and hypospermatogenesis. In aged testes, a significant decline was found in the numbers of round spermatids and elongated spermatids per Sertoli cell (P<0.01). Sperm density, sperm motility and normal morphological rate in caput epididymis and cauda epididymis in aged mice significantly decreased (P<0. 05). The fertilization rate and embryo development of aged group were lower than those in the control(P< 0.01).Conclusions Spermatogenesis and sperm functions could be maintained in the aging male. However, aging affects spermatogenesis and sperm maturation, which leads to lower the quality of sperm, including sperm fertilizing capacity. The development of embryo from aging sperm would have more abnormalities.

  2. Paraquat induces selective dopaminergic nigrostriatal degeneration in aging C57BL/6 mice

    Institute of Scientific and Technical Information of China (English)

    LI Xia; YIN Jun; CHENG Chun-mei; SUN Jin-lai; LI Zheng; WU Ying-liang

    2005-01-01

    Background Paraquat (PQ; 1,1'-dimethyl-4,4'-bipyridinium), a widely used herbicide that is structurally similar to the known dopaminergic neurotoxicant MPTP (1-methyl-1,2,3,6-tetrahydropyridine), has been suggested as a potential etiologic factor for the development of Parkinson's disease (PD). Aging is an accepted risk factor for idiopathic Parkinson's disease. The aim of this study was to test the hypothesis that paraquat could induce PD-like nigrostriatal dopaminergic degeneration in aging C57BL/6 mice.Methods Senile male C57BL/6 mice were intraperitoneally injected with either saline or PQ at 2-day intervals for a total of 10 doses. Locomotor activity and performance on the pole test were measured 7 days after the last injection and animals were sacrificed one day later. Level of dopamine (DA) and its metabolites levels in the striatum were measured by high-performance liquid chromatography with an electrochemical detector (HPLC-ECD), and numbers of tyrosine hydroxylase (TH) positive neurons were estimated using immunohistochemistry.Results Locomotor activities were significantly decreased and the behavioral performance on the pole test were significantly impaired in the PQ treated group. Level of DA and its metabolites levels in the striatum were declined by 8 days after the last injection. Immunohistochemical analyses showed that PQ was associated with a reduction in numbers of tyrosine hydroxylase positive neurons.Conclusions Long-term repeated exposes to PQ can selectively impair the nigrostriatal dopaminergic system of senile mice, suggesting that PQ could play an important role in the pathogenesis of Parkinson's disease (PD). Our results also validate a novel model of PD induced by exposure to a toxic environmental agent.

  3. [Effect of flavonoids from Sophora flavescens in aging mice induced by D-galactos].

    Science.gov (United States)

    Fan, Hong-yan; Gu, Rao-sheng; Ren, Kuang; Wang, Yan-chun; Yao, Zhen; Shen, Nan; Liu, Shi-bing

    2015-11-01

    To investigate the effect of flavonoids from Sophora flavescens in aging mice induced by D-galactose and its mechanism. Totally 60 mice were randomly divided into six groups: the control group, the model group, the piracetam group (positive control group) and flavonoids from S. flavescens low, medium and high doses groups. Except for the control group, all of the rest groups were subcutaneously injected with D-galactose (160 mg x kg(-1)) for successively 30 days to establish the sub-acute senescent model. Meanwhile, flavonoids from S. flavescens low, medium and high doses groups were respectively administered with 150, 300 and 600 mg xkg-('1)of flavonoids from S. flavescens for 30 days. The learning and memory abilities of mice were determined by avoiding darkness ex-eriment and jumping stair experiment. The contents of malondialdehyde (MDA) tumor necrosis factor-aα NF-aα the activities of superoxide dismutase (SOD) monoamine oxidase-B (MAO-B) Na'(+)K'(+)-ATPase and Ca2(+ )-ATPase in the brain of mice were deter-ined respectively after the behavioral experiments. The activity of lactic dehydrogenase ( DH) in blood serum was also determined and analyzed by microscope after HE staining to observe the changes in hippocampal organizational structure. Compared with the model group, flavonoids from S. favescens medium and high doses groups showed significantly increases in the latency of avoiding darkness and jumping stair experiments; flavonoids from S. fllvescens low, medium and high doses groups and the piracetam group showed de-reases in the numbers of errors in avoiding darkness experiment; the flavonoids from S. flavescens high dose group and the piracetam group showed reduction- n the number of errors in jumping stair experiment (P memory ability of senescent mice induced by D-galactose. Its mechanism may be correlated with the enhancement of anti-oxidative actions by lowering TNF-aαcontent, which results in the stability of cell membrane and the reduction in

  4. The development of autoimmune features in aging mice is closely associated with alterations of the peripheral CD4⁺ T-cell compartment.

    Science.gov (United States)

    Nusser, Anja; Nuber, Natko; Wirz, Oliver F; Rolink, Hannie; Andersson, Jan; Rolink, Antonius

    2014-10-01

    Some signs of potential autoimmunity, such as the appearance of antinuclear antibodies (ANAs) become prevalent with age. In most cases, elderly people with ANAs remain healthy. Here, we investigated whether the same holds true for inbred strains of mice. Indeed, we show that most mice of the C57BL/6 (B6) strain spontaneously produced IgG ANA at 8-12 months of age, showed IgM deposition in kidneys and lymphocyte infiltrates in submandibular salivary glands. Despite all of this, the mice remained healthy. ANA production is likely CD4(+) T-cell dependent, since old (40-50 weeks of age) B6 mice deficient for MHC class II do not produce IgG ANAs. BM chimeras showed that ANA production was not determined by age-related changes in radiosensitive, hematopoietic progenitor cells, and that the CD4(+) T cells that promote ANA production were radioresistant. Thymectomy of B6 mice at 5 weeks of age led to premature alterations in T-cell homeostasis and ANA production, by 15 weeks of age, similar to that in old mice. Our findings suggest that a disturbed T-cell homeostasis may drive the onset of some autoimmune features. PMID:25044476

  5. Evaluation of Effect of Oleuropein on Skin Wound Healing in Aged Male Balb/c Mice

    Directory of Open Access Journals (Sweden)

    Fereshteh Mehraein

    2014-03-01

    Full Text Available Objective: Olive oil and olive leaf extract are used for treatment of skin diseases and wounds in Iran. The main component of olive leaf extract is Oleuropein. This research is focused on the effects of Oleuropein on skin wound healing in aged male Balb/c mice. Materials and Methods: In this experimental study, Oleuropein was provided by Razi Herbal Medicine Institute, Lorestan, Iran. Twenty four male Balb/c mice, 16 months of age, were divided equally into control and experimental groups. Under ether anesthesia, the hairs on the back of neck of all groups were shaved and a 1 cm long full-thickness incision was made. The incision was then left un-sutured. The experimental group received intradermal injections with a daily single dose of 50 mg/kg Oleuropein for a total period of 7 days. The control group received only distilled water. On days 3 and 7 after making the incision and injections, mice were sacrificed, and the skin around incision area was dissected and stained by hematoxylin and eosin (H&E and Van Gieson’s methods for tissue analysis. In addition, western blot analysis was carried out to evaluate the level of vascular endothelial growth factor (VEGF protein expression. The statistical analysis was performed using SPSS (SPSS Inc., Chicago, USA. The t test was applied to assess the significance of changes between control and experimental groups. Results: Oleuropein not only reduced cell infiltration in the wound site on days 3 and 7 post incision, but also a significant increase in collagen fiber deposition and more advanced re- epithelialization were observed (p<0.05 in the experimental group as compared to the control group. The difference of hair follicles was not significant between the two groups at the same period of time. Furthermore, western blot analysis showed an increased in VEGF protein level from samples collected on days 3 and 7 post-incision of experimental group as compared to the control group (p<0.05. Conclusion

  6. Types and rate of cataract development in mice irradiated at different ages

    International Nuclear Information System (INIS)

    The effect of age on the development of radiation cataract has been investigated in an inbred A strain of mice and, as a result, the patterns of age dependence and senile mice cataract development were obtained. In general, the lenses of mice 1 to 3 days old were the most sensitive to radiation; the maximum resistance was noted in 5-day-old mice, and from this age up to 3 to 7 weeks of life there was a period of increasing sensitivity. In older animals the lens sensitivity tends to level off. The early stages of cataract occurred in all irradiated groups at a younger age than in the control group, but the late stages occurred in irradiated groups at the same age as the senile cataract occurred in the control group. Two types of cataract were observed. One was typical for young irradiated mice 1 to 5 days of age and the other was typical for all remaining irradiated groups and for a control group. Also, an attempt was made to correlate the obtained results with the cell kinetics in normal lens epithelium

  7. Homeostatic imbalance between apoptosis and cell renewal in the liver of premature aging Xpd mice.

    Directory of Open Access Journals (Sweden)

    Jung Yoon Park

    Full Text Available Unrepaired or misrepaired DNA damage has been implicated as a causal factor in cancer and aging. Xpd(TTD mice, harboring defects in nucleotide excision repair and transcription due to a mutation in the Xpd gene (R722W, display severe symptoms of premature aging but have a reduced incidence of cancer. To gain further insight into the molecular basis of the mutant-specific manifestation of age-related phenotypes, we used comparative microarray analysis of young and old female livers to discover gene expression signatures distinguishing Xpd(TTD mice from their age-matched wild type controls. We found a transcription signature of increased apoptosis in the Xpd(TTD mice, which was confirmed by in situ immunohistochemical analysis and found to be accompanied by increased proliferation. However, apoptosis rate exceeded the rate of proliferation, resulting in homeostatic imbalance. Interestingly, a metabolic response signature was observed involving decreased energy metabolism and reduced IGF-1 signaling, a major modulator of life span. We conclude that while the increased apoptotic response to endogenous DNA damage contributes to the accelerated aging phenotypes and the reduced cancer incidence observed in the Xpd(TTD mice, the signature of reduced energy metabolism is likely to reflect a compensatory adjustment to limit the increased genotoxic stress in these mutants. These results support a general model for premature aging in DNA repair deficient mice based on cellular responses to DNA damage that impair normal tissue homeostasis.

  8. The mouse as a model for understanding chronic diseases of aging: the histopathologic basis of aging in inbred mice

    Directory of Open Access Journals (Sweden)

    David Harrison

    2011-06-01

    Full Text Available Inbred mice provide a unique tool to study aging populations because of the genetic homogeneity within an inbred strain, their short life span, and the tools for analysis which are available. A large-scale longitudinal and cross-sectional aging study was conducted on 30 inbred strains to determine, using histopathology, the type and diversity of diseases mice develop as they age. These data provide tools that when linked with modern in silico genetic mapping tools, can begin to unravel the complex genetics of many of the common chronic diseases associated with aging in humans and other mammals. In addition, novel disease models were discovered in some strains, such as rhabdomyosarcoma in old A/J mice, to diseases affecting many but not all strains including pseudoxanthoma elasticum, pulmonary adenoma, alopecia areata, and many others. This extensive data set is now available online and provides a useful tool to help better understand strain-specific background diseases that can complicate interpretation of genetically engineered mice and other manipulatable mouse studies that utilize these strains.

  9. CD-1 Mice Show Individual Differences in Nicotine Preference in a Modified Two-Bottle Oral Self-Administration Model

    Directory of Open Access Journals (Sweden)

    MingDLi

    2012-03-01

    Full Text Available Genetic epidemiology reveals significant contributions of genetics to smoking addiction. However, such study is underpowered because of the many potential confounding variables. These issues can be compensated for by a proper animal model. In the current study, we used non-sibling CD-1 mice to increase the genetic variation and evaluated nicotine preference in a modified two-bottle oral self-administration model. Animals were first given free access to two bottles, one filled with nicotine dissolved in 2% saccharin and the other with saccharin only. At this stage, the majority of animals avoided the nicotine solution with small individual differences. However, after four days of exposure to 5% saccharin in the drinking water, the ratio of nicotine consumption to total liquid consumption was significantly increased, and about 40% animals showed a nicotine preference. There were striking individual differences in nicotine consumption, with a range of 0 to 100% of total liquid consumption. Nicotine preference after 5% saccharin treatment remained elevated throughout the 28 days of experiment. The enhanced ratio of nicotine consumption and individual differences were observed at different concentrations of nicotine (10 to 80 µg/ml and in both adolescents and adults. Although liquid consumption during the four days of 5% saccharin induction was decreased by about 30%, comparable liquid restriction alone for four days did not induce nicotine preference. The long-lasting nicotine preference was not correlated with nicotine consumption before the induction, 5% saccharin consumption, or weight gain during the induction. Together, this study showed a long-lasting nicotine preference in CD-1 mice, which was induced by a short-term high concentration of saccharin in the drinking water. We observed significant individual differences in nicotine consumption. Given the nature and heterogeneity of CD-1 mice, such striking individual differences indicate that

  10. Longitudinal Attentional Engagement Rescues Mice from Age-Related Cognitive Declines and Cognitive Inflexibility

    Science.gov (United States)

    Matzel, Louis D.; Light, Kenneth R.; Wass, Christopher; Colas-Zelin, Danielle; Denman-Brice, Alexander; Waddel, Adam C.; Kolata, Stefan

    2011-01-01

    Learning, attentional, and perseverative deficits are characteristic of cognitive aging. In this study, genetically diverse CD-1 mice underwent longitudinal training in a task asserted to tax working memory capacity and its dependence on selective attention. Beginning at 3 mo of age, animals were trained for 12 d to perform in a dual radial-arm…

  11. p21 both attenuates and drives senescence and aging in BubR1 progeroid mice.

    NARCIS (Netherlands)

    Baker, D.J.; Weaver, R.L.; Deursen, J.M.A. van

    2013-01-01

    BubR1 insufficiency occurs with natural aging and induces progeroid phenotypes in both mice and children with mosaic variegated aneuploidy syndrome. In response to BubR1 insufficiency, skeletal muscle, fat, and lens tissue engage p19(Arf) to attenuate senescence and age-related deterioration. Here,

  12. CpG Improves Influenza Vaccine Efficacy in Young Adult but Not Aged Mice.

    Science.gov (United States)

    Ramirez, Alejandro; Co, Mary; Mathew, Anuja

    2016-01-01

    Several studies have shown a reduced efficacy of influenza vaccines in the elderly compared to young adults. In this study, we evaluated the immunogenicity and protective efficacy of a commercially available inactivated influenza vaccine (Fluzone®) in young adult and aged mice. C57/BL6 mice were administered a single or double immunization of Fluzone® with or without CpG and challenged intranasally with H1N1 A/California/09 virus. A double immunization of Fluzone® adjuvanted with CpG elicited the highest level of protection in young adult mice which was associated with increases in influenza specific IgG, elevated HAI titres, reduced viral titres and lung inflammation. In contrast, the vaccine schedule which provided fully protective immunity in young adult mice conferred limited protection in aged mice. Antigen presenting cells from aged mice were found to be less responsive to in vitro stimulation by Fluzone and CpG which may partially explain this result. Our data are supportive of studies that have shown limited effectiveness of influenza vaccines in the elderly and provide important information relevant to the design of more immunogenic vaccines in this age group. PMID:26934728

  13. Dynamic studies of positron-emitting putative tumor marker 132Cs in mice show differential tumor and regional uptake

    International Nuclear Information System (INIS)

    Positron-emitting 132Cs (t1/2 = 6.47 days) was generated from stable 133CsCl via the 133Cs (p,pn) 132Cs reaction. BALB/c mice, bearing implanted MT296 mammary tumors, were given 4.6 mEq kg-1 of 132CsCl via a single intraperitoneal injection. Postinjection uptake of 132Cs into body regions was monitored in vivo with external detectors. Positron emission from the tumor region was continuously greater than that from the head, the numerical ratio of mean emission intensities being fourfold at 10 min postinjection. Tissues excised from these mice postmortem showed sequence of relative tissue cesium uptake rates to be kidney 1.8, small intestine 1.7, tumor 1.0, skin 0.75, liver 0.75, skeletal muscle 0.4, and brain 0.28. Comparative studies with multiple injections of stable cesium and rubidium showed this sequence to be ion-specific. These observations suggest that positron-emitting isotopes of cesium could provide useful markers for tumors of several tissues

  14. Pregnane X receptor knockout mice display aging-dependent wearing of articular cartilage.

    Directory of Open Access Journals (Sweden)

    Kotaro Azuma

    Full Text Available Steroid and xenobiotic receptor (SXR and its murine ortholog, pregnane X receptor (PXR, are nuclear receptors that are expressed at high levels in the liver and the intestine where they function as xenobiotic sensors that induce expression of genes involved in detoxification and drug excretion. Recent evidence showed that SXR and PXR are also expressed in bone tissue where they mediate bone metabolism. Here we report that systemic deletion of PXR results in aging-dependent wearing of articular cartilage of knee joints. Histomorphometrical analysis showed remarkable reduction of width and an enlarged gap between femoral and tibial articular cartilage in PXR knockout mice. We hypothesized that genes induced by SXR in chondrocytes have a protective effect on articular cartilage and identified Fam20a (family with sequence similarity 20a as an SXR-dependent gene induced by the known SXR ligands, rifampicin and vitamin K2. Lastly, we demonstrated the biological significance of Fam20a expression in chondrocytes by evaluating osteoarthritis-related gene expression of primary articular chondrocytes. Consistent with epidemiological findings, our results indicate that SXR/PXR protects against aging-dependent wearing of articular cartilage and that ligands for SXR/PXR have potential role in preventing osteoarthritis caused by aging.

  15. Pregnane X receptor knockout mice display aging-dependent wearing of articular cartilage.

    Science.gov (United States)

    Azuma, Kotaro; Casey, Stephanie C; Urano, Tomohiko; Horie-Inoue, Kuniko; Ouchi, Yasuyoshi; Blumberg, Bruce; Inoue, Satoshi

    2015-01-01

    Steroid and xenobiotic receptor (SXR) and its murine ortholog, pregnane X receptor (PXR), are nuclear receptors that are expressed at high levels in the liver and the intestine where they function as xenobiotic sensors that induce expression of genes involved in detoxification and drug excretion. Recent evidence showed that SXR and PXR are also expressed in bone tissue where they mediate bone metabolism. Here we report that systemic deletion of PXR results in aging-dependent wearing of articular cartilage of knee joints. Histomorphometrical analysis showed remarkable reduction of width and an enlarged gap between femoral and tibial articular cartilage in PXR knockout mice. We hypothesized that genes induced by SXR in chondrocytes have a protective effect on articular cartilage and identified Fam20a (family with sequence similarity 20a) as an SXR-dependent gene induced by the known SXR ligands, rifampicin and vitamin K2. Lastly, we demonstrated the biological significance of Fam20a expression in chondrocytes by evaluating osteoarthritis-related gene expression of primary articular chondrocytes. Consistent with epidemiological findings, our results indicate that SXR/PXR protects against aging-dependent wearing of articular cartilage and that ligands for SXR/PXR have potential role in preventing osteoarthritis caused by aging. PMID:25749104

  16. Mice lacking thyroid hormone receptor Beta show enhanced apoptosis and delayed liver commitment for proliferation after partial hepatectomy.

    Directory of Open Access Journals (Sweden)

    Raquel López-Fontal

    Full Text Available BACKGROUND: The role of thyroid hormones and their receptors (TR during liver regeneration after partial hepatectomy (PH was studied using genetic and pharmacologic approaches. Roles in liver regeneration have been suggested for T3, but there is no clear evidence distinguishing the contribution of increased amounts of T3 from the modulation by unoccupied TRs. METHODOLOGY/PRINCIPAL FINDINGS: Mice lacking TRalpha1/TRbeta or TRbeta alone fully regenerated liver mass after PH, but showed delayed commitment to the initial round of hepatocyte proliferation and transient but intense apoptosis at 48h post-PH, affecting approximately 30% of the remaining hepatocytes. Pharmacologically induced hypothyroidism yielded similar results. Loss of TR activity was associated with enhanced nitrosative stress in the liver remnant, due to an increase in the activity of the nitric oxide synthase (NOS 2 and 3, caused by a transient decrease in the concentration of asymmetric dimethylarginine (ADMA, a potent NOS inhibitor. This decrease in the ADMA levels was due to the presence of a higher activity of dimethylarginineaminohydrolase-1 (DDAH-1 in the regenerating liver of animals lacking TRalpha1/TRbeta or TRbeta. DDAH-1 expression and activity was paralleled by the activity of FXR, a transcription factor involved in liver regeneration and up-regulated in the absence of TR. CONCLUSIONS/SIGNIFICANCE: We report that TRs are not required for liver regeneration; however, hypothyroid mice and TRbeta- or TRalpha1/TRbeta-deficient mice exhibit a delay in the restoration of liver mass, suggesting a specific role for TRbeta in liver regeneration. Altered regenerative responses are related with a delay in the expression of cyclins D1 and E, and the occurrence of liver apoptosis in the absence of activated TRbeta that can be prevented by administration of NOS inhibitors. Taken together, these results indicate that TRbeta contributes significantly to the rapid initial round of

  17. Trigeminal ganglion neurons of mice show intracellular chloride accumulation and chloride-dependent amplification of capsaicin-induced responses.

    Directory of Open Access Journals (Sweden)

    Nicole Schöbel

    Full Text Available Intracellular Cl(- concentrations ([Cl(-](i of sensory neurons regulate signal transmission and signal amplification. In dorsal root ganglion (DRG and olfactory sensory neurons (OSNs, Cl(- is accumulated by the Na(+-K(+-2Cl(- cotransporter 1 (NKCC1, resulting in a [Cl(-](i above electrochemical equilibrium and a depolarizing Cl(- efflux upon Cl(- channel opening. Here, we investigate the [Cl(-](i and function of Cl(- in primary sensory neurons of trigeminal ganglia (TG of wild type (WT and NKCC1(-/- mice using pharmacological and imaging approaches, patch-clamping, as well as behavioral testing. The [Cl(-](i of WT TG neurons indicated active NKCC1-dependent Cl(- accumulation. Gamma-aminobutyric acid (GABA(A receptor activation induced a reduction of [Cl(-](i as well as Ca(2+ transients in a corresponding fraction of TG neurons. Ca(2+ transients were sensitive to inhibition of NKCC1 and voltage-gated Ca(2+ channels (VGCCs. Ca(2+ responses induced by capsaicin, a prototypical stimulus of transient receptor potential vanilloid subfamily member-1 (TRPV1 were diminished in NKCC1(-/- TG neurons, but elevated under conditions of a lowered [Cl(-](o suggesting a Cl(--dependent amplification of capsaicin-induced responses. Using next generation sequencing (NGS, we found expression of different Ca(2+-activated Cl(- channels (CaCCs in TGs of mice. Pharmacological inhibition of CaCCs reduced the amplitude of capsaicin-induced responses of TG neurons in Ca(2+ imaging and electrophysiological recordings. In a behavioral paradigm, NKCC1(-/- mice showed less avoidance of the aversive stimulus capsaicin. In summary, our results strongly argue for a Ca(2+-activated Cl(--dependent signal amplification mechanism in TG neurons that requires intracellular Cl(- accumulation by NKCC1 and the activation of CaCCs.

  18. The synthetic thyroid hormone, levothyroxine, protects cholinergic neurons in the hippocampus of naturally aged mice

    Institute of Scientific and Technical Information of China (English)

    Ailing Fu; Rumei Zhou; Xingran Xu

    2014-01-01

    The thyroid hormones, triiodothyronine and thyroxine, play important roles in cognitive func-tion during the mammalian lifespan. However, thyroid hormones have not yet been used as a therapeutic agent for normal age-related cognitive deficits. In this study, CD-1 mice (aged 24 months) were intraperitoneally injected with levothyroxine (L-T4;1.6μg/kg per day) for 3 consecutive months. Our findings revealed a significant improvement in hippocampal cyto-skeletal rearrangement of actin and an increase in serum hormone levels of L-T4-treated aged mice. Furthermore, the survival rate of these mice was dramatically increased from 60%to 93.3%. The Morris water maze task indicated that L-T4 restored impaired spatial memory in aged mice. Furthermore, level of choline acetyltransferase, acetylcholine, and superoxide dismutase were in-creased in these mice, thus suggesting that a possible mechanism by which L-T4 reversed cognitive impairment was caused by increased activity of these markers. Overall, supplement of low-dosage L-T4 may be a potential therapeutic strategy for normal age-related cognitive deifcits.

  19. Premature skin aging features rescued by inhibition of NADPH oxidase activity in XPC-deficient mice.

    Science.gov (United States)

    Hosseini, Mohsen; Mahfouf, Walid; Serrano-Sanchez, Martin; Raad, Houssam; Harfouche, Ghida; Bonneu, Marc; Claverol, Stephane; Mazurier, Frederic; Rossignol, Rodrigue; Taieb, Alain; Rezvani, Hamid Reza

    2015-04-01

    Xeroderma pigmentosum type C (XP-C) is characterized mostly by a predisposition to skin cancers and accelerated photoaging, but little is known about premature skin aging in this disease. By comparing young and old mice, we found that the level of progerin and p16(INK4a) expression, β-galactosidase activity, and reactive oxygen species, which increase with age, were higher in young Xpc(-/-) mice than in young Xpc(+/+) ones. The expression level of mitochondrial complexes and mitochondrial functions in the skin of young Xpc(-/-) was as low as in control aged Xpc(+/+)animals. Furthermore, the metabolic profile in young Xpc(-/-) mice resembled that found in aged Xpc(+/+) mice. Furthermore, premature skin aging features in young Xpc(-/-) mice were mostly rescued by inhibition of nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1) activity by using a NOX1 peptide inhibitor, suggesting that the continuous oxidative stress due to overactivation of NOX1 has a causative role in the underlying pathophysiology. PMID:25437426

  20. Sustained beta-cell dysfunction but normalized islet mass in aged thrombospondin-1 deficient mice.

    Directory of Open Access Journals (Sweden)

    Carl Johan Drott

    Full Text Available Pancreatic islet endothelial cells have in recent years been shown to support beta-cell mass and function by paracrine interactions. Recently, we identified an islets endothelial-specific glycoprotein, thrombospondin-1 (TSP-1, that showed to be of importance for islet angiogenesis and beta-cell function in young mice. The present study aimed to investigate long-term consequences for islet morphology and beta-cell function of TSP-1 deficiency. Islet and beta-cell mass were observed increased at 10-12 weeks of age in TSP-1 deficient mice, but were normalized before 16 weeks of age when compared to wild-type controls. Islet vascularity was normal in 10-12 and 16-week-old TSP-1 deficient animals, whereas islets of one-year-old animals lacking TSP-1 were hypervascular. Beta-cell dysfunction in TSP-1 deficient animals was present at similar magnitudes between 10-12 and 52 weeks of age, as evaluated by glucose tolerance tests. The insulin secretion capacity in vivo of islets in one-year-old TSP-1 deficient animals was only ∼15% of that in wild-type animals. Using a transplantation model, we reconstituted TSP-1 in adult TSP-deficient islets. In contrast to neonatal TSP-1 deficient islets that we previously reported to regain function after TSP-1 reconstitution, adult islets failed to recover. We conclude that TSP-1 deficiency in islets causes changing vascular and endocrine morphological alterations postnatally, but is coupled to a chronic beta-cell dysfunction. The beta-cell dysfunction induced by TSP-1 deficiency is irreversible if not substituted early in life.

  1. Ageing and the humoral immune response in mice

    International Nuclear Information System (INIS)

    The study presented in this thesis is concerned with changes in the humoral immune system as a function of age in different inbred mouse strains. Their capacity to develop humoral immune responses to experimentally given thymus-dependent and thymus-independent antigens under various conditions is compared. Furthermore, experiments employing thymus transplantation and thymic humoral factors which are directed at the restoration of the diminished T cell functions in old age are reported. (Auth.)

  2. Altered connexin 43 expression underlies age-dependent decrease of regulatory T cell suppressor function in nonobese diabetic mice.

    Science.gov (United States)

    Kuczma, Michal; Wang, Cong-Yi; Ignatowicz, Leszek; Gourdie, Robert; Kraj, Piotr

    2015-06-01

    Type 1 diabetes is one of the most extensively studied autoimmune diseases, but the cellular and molecular mechanisms leading to T cell-mediated destruction of insulin-producing β cells are still not well understood. In this study, we show that regulatory T cells (T(regs)) in NOD mice undergo age-dependent loss of suppressor functions exacerbated by the decreased ability of activated effector T cells to upregulate Foxp3 and generate T(regs) in the peripheral organs. This age-dependent loss is associated with reduced intercellular communication mediated by gap junctions, which is caused by impaired upregulation and decreased expression of connexin 43. Regulatory functions can be corrected, even in T cells isolated from aged, diabetic mice, by a synergistic activity of retinoic acid, TGF-β, and IL-2, which enhance connexin 43 and Foxp3 expression in T(regs) and restore the ability of conventional CD4(+) T cells to upregulate Foxp3 and generate peripherally derived T(regs). Moreover, we demonstrate that suppression mediated by T(regs) from diabetic mice is enhanced by a novel reagent, which facilitates gap junction aggregation. In summary, our report identifies gap junction-mediated intercellular communication as an important component of the T(reg) suppression mechanism compromised in NOD mice and suggests how T(reg) mediated immune regulation can be improved. PMID:25911751

  3. Sex effects of Interleukin-6 deficiency on neuroinflammation in aged C57Bl/6 mice

    OpenAIRE

    Miller, VM; Lawrence, DA; Coccaro, GA; Mondal, TK; Andrews, K; Dreiem, A; Seegal, RF

    2010-01-01

    High levels of Interleukin-6 (IL-6) are associated with an increased risk of dementia in the elderly and can increase neuroinflammation in mice. Dementia is more frequent in females, and IL-6 is regulated by estrogen, suggesting elevated IL-6 levels may contribute to neuroinflammation and dementia particularly in women. Therefore we hypothesized that IL-6 deficient (−/−) female mice would have lower aging-related neuroinflammation than wild type (WT). We quantified neuroinflammatory markers w...

  4. Comprehensive behavioral analysis of Ox1r-/- mice showed implication of orexin receptor-1 in mood, anxiety and social behavior

    Directory of Open Access Journals (Sweden)

    Md Golam Abbas

    2015-12-01

    Full Text Available Neuropeptides orexin A and orexin B, which are exclusively produced by neurons in the lateral hypothalamic area, play an important role in the regulation of a wide range of behaviors and homeostatic processes, including regulation of sleep/wakefulness states and energy homeostasis. The orexin system has close anatomical and functional relationships with systems that regulate the autonomic nervous system, emotion, mood, the reward system and sleep/wakefulness states. Recent pharmacological studies using selective antagonists have suggested that orexin receptor-1 (OX1R is involved in physiological processes that regulate emotion, the reward system and autonomic nervous system. Here, we examined Ox1r-/- mice with a comprehensive behavioral test battery to screen additional OX1R functions. Ox1r-/- mice showed increased anxiety-like behavior, altered depression-like behavior, slightly decreased spontaneous locomotor activity, reduced social interaction, increased startle response and decreased prepulse inhibition. These results suggest that OX1R plays roles in social behaviour and sensory motor gating in addition to roles in mood and anxiety.

  5. Atf3 mutant mice show reduced axon regeneration and impaired regeneration-associated gene induction after peripheral nerve injury.

    Science.gov (United States)

    Gey, Manuel; Wanner, Renate; Schilling, Corinna; Pedro, Maria T; Sinske, Daniela; Knöll, Bernd

    2016-08-01

    Axon injury in the peripheral nervous system (PNS) induces a regeneration-associated gene (RAG) response. Atf3 (activating transcription factor 3) is such a RAG and ATF3's transcriptional activity might induce 'effector' RAGs (e.g. small proline rich protein 1a (Sprr1a), Galanin (Gal), growth-associated protein 43 (Gap43)) facilitating peripheral axon regeneration. We provide a first analysis of Atf3 mouse mutants in peripheral nerve regeneration. In Atf3 mutant mice, facial nerve regeneration and neurite outgrowth of adult ATF3-deficient primary dorsal root ganglia neurons was decreased. Using genome-wide transcriptomics, we identified a neuropeptide-encoding RAG cluster (vasoactive intestinal peptide (Vip), Ngf, Grp, Gal, Pacap) regulated by ATF3. Exogenous administration of neuropeptides enhanced neurite growth of Atf3 mutant mice suggesting that these molecules might be effector RAGs of ATF3's pro-regenerative function. In addition to the induction of growth-promoting molecules, we present data that ATF3 suppresses growth-inhibiting molecules such as chemokine (C-C motif) ligand 2. In summary, we show a pro-regenerative ATF3 function during PNS nerve regeneration involving transcriptional activation of a neuropeptide-encoding RAG cluster. ATF3 is a general injury-inducible factor, therefore ATF3-mediated mechanisms identified herein might apply to other cell and injury types. PMID:27581653

  6. Atf3 mutant mice show reduced axon regeneration and impaired regeneration-associated gene induction after peripheral nerve injury

    Science.gov (United States)

    Gey, Manuel; Wanner, Renate; Schilling, Corinna; Pedro, Maria T.; Sinske, Daniela

    2016-01-01

    Axon injury in the peripheral nervous system (PNS) induces a regeneration-associated gene (RAG) response. Atf3 (activating transcription factor 3) is such a RAG and ATF3's transcriptional activity might induce ‘effector’ RAGs (e.g. small proline rich protein 1a (Sprr1a), Galanin (Gal), growth-associated protein 43 (Gap43)) facilitating peripheral axon regeneration. We provide a first analysis of Atf3 mouse mutants in peripheral nerve regeneration. In Atf3 mutant mice, facial nerve regeneration and neurite outgrowth of adult ATF3-deficient primary dorsal root ganglia neurons was decreased. Using genome-wide transcriptomics, we identified a neuropeptide-encoding RAG cluster (vasoactive intestinal peptide (Vip), Ngf, Grp, Gal, Pacap) regulated by ATF3. Exogenous administration of neuropeptides enhanced neurite growth of Atf3 mutant mice suggesting that these molecules might be effector RAGs of ATF3's pro-regenerative function. In addition to the induction of growth-promoting molecules, we present data that ATF3 suppresses growth-inhibiting molecules such as chemokine (C-C motif) ligand 2. In summary, we show a pro-regenerative ATF3 function during PNS nerve regeneration involving transcriptional activation of a neuropeptide-encoding RAG cluster. ATF3 is a general injury-inducible factor, therefore ATF3-mediated mechanisms identified herein might apply to other cell and injury types. PMID:27581653

  7. Moderate exercise prevents neurodegeneration in D-galactose-induced aging mice

    Institute of Scientific and Technical Information of China (English)

    Li Li; Meng Xu; Bo Shen; Man Li; Qian Gao; Shou-gang Wei

    2016-01-01

    D-galactose has been widely used in aging research because of its efifcacy in inducing senescence and accelerating aging in animal models. The present study investigated the beneifts of exercise for preventing neurodegeneration, such as synaptic plasticity, spatial learning and memory abilities, in mouse models of aging. D-galactose-induced aging mice were administered daily subcutaneous injections of D-ga-lactose at the base of the neck for 10 consecutive weeks. Then, the mice were subjected to exercise training by running on a treadmill for 6 days a week. Shortened escape latency in a Morris water maze test indicated that exercise improved learning and memory in aging mice. The ameliorative changes were likely induced by an upregulation of Bcl-2 and brain-derived neurotrophic factor, the repression of apop-tosis factors such as Fas and Bax, and an increase in the activity of glucose transporters-1 and 4. The data suggest moderate exercise may retard or inhibit neurodegeneration in D-galactose-induced aging mice.

  8. Polysaccharide Extracted from Laminaria japonica Delays Intrinsic Skin Aging in Mice

    Science.gov (United States)

    Hu, Longyuan; Tan, Jia; Yang, Xiaomei; Tan, Haitao; Xu, Xiaozhen; You, Manhang; Qin, Wu; Huang, Liangzhao; Li, Siqi; Mo, Manqiu; Wei, Huifen; Li, Jing; Tan, Jiyong

    2016-01-01

    This study aimed to determine the effect of topically applied Laminaria polysaccharide (LP) on skin aging. We applied ointment containing LP (10, 25, and 50 μg/g) or vitamin E (10 μg/g) to the dorsal skin of aging mice for 12 months and young control mice for 4 weeks. Electron microscopy analysis of skin samples revealed that LP increased dermal thickness and skin collagen content. Tissue inhibitor of metalloprotease- (TIMP-) 1 expression was upregulated while that of matrix metalloproteinase- (MMP-) 1 was downregulated in skin tissue of LP-treated as compared to untreated aging mice. Additionally, phosphorylation of c-Jun N-terminal kinase (JNK) and p38 was higher in aging skin than in young skin, while LP treatment suppressed phospho-JNK expression. LP application also enhanced the expression of antioxidative enzymes in skin tissue, causing a decrease in malondialdehyde levels and increases in superoxide dismutase, catalase, and glutathione peroxidase levels relative to those in untreated aging mice. These results indicate that LP inhibits MMP-1 expression by preventing oxidative stress and JNK phosphorylation, thereby delaying skin collagen breakdown during aging. PMID:27143987

  9. Moderate exercise prevents neurodegeneration in D-galactose-induced aging mice.

    Science.gov (United States)

    Li, Li; Xu, Meng; Shen, Bo; Li, Man; Gao, Qian; Wei, Shou-Gang

    2016-05-01

    D-galactose has been widely used in aging research because of its efficacy in inducing senescence and accelerating aging in animal models. The present study investigated the benefits of exercise for preventing neurodegeneration, such as synaptic plasticity, spatial learning and memory abilities, in mouse models of aging. D-galactose-induced aging mice were administered daily subcutaneous injections of D-galactose at the base of the neck for 10 consecutive weeks. Then, the mice were subjected to exercise training by running on a treadmill for 6 days a week. Shortened escape latency in a Morris water maze test indicated that exercise improved learning and memory in aging mice. The ameliorative changes were likely induced by an upregulation of Bcl-2 and brain-derived neurotrophic factor, the repression of apoptosis factors such as Fas and Bax, and an increase in the activity of glucose transporters-1 and 4. The data suggest moderate exercise may retard or inhibit neurodegeneration in D-galactose-induced aging mice. PMID:27335566

  10. Changes with age in swimming performance of X-irradiated mice

    International Nuclear Information System (INIS)

    The time required to swim 250 cm was determined once weekly for the entire life of fifteen pairs of male dd/K mice. The irradiated group was exposed to a single 224 rad of X-rays at 20 weeks of age. Median survival time (ST50) for the control was 88.9 weeks and that for the irradiated group was 77.4 weeks, and both regression lines relating to death rate and age were parallel. The swimming ability of control mice began to decrease when the mice were 40 weeks of age, after which there was a gradual reduction with age at 0.00646/day. In the irradiated group, the swimming ability decreased from seven weeks after irradiation. The time of 50% reduction of swimming speed (TRS50) for the control was 78.9 weeks and that for the irradiated group was 66.3 weeks, and the slopes of the regression lines relating reduction rate and age were similar. Differences between ST50 and TRS50 were 10 weeks in the control and 11 weeks in the irradiated group, respectively. These results indicate that there is no basic difference in the reduction in swimming ability between control and irradiated mice. The X-irradiation may simply mean that the reduction in the swimming ability is displaced to an earlier time with no alteration in the rate of reduction, and that the earlier appearance in the irradiated group is related to premature aging as induced by irradiation. (author)

  11. Berberine alleviates postoperative cognitive dysfunction by suppressing neuroinflammation in aged mice.

    Science.gov (United States)

    Zhang, Zhijie; Li, Xiuhua; Li, Fayin; An, Lijun

    2016-09-01

    Postoperative cognitive dysfunction (POCD) is a significant cause of morbidity after surgery, especially for the elderly. Accumulating evidence has demonstrated that neuroinflammation plays a key role in the pathogenesis of POCD. Thus, we hypothesized that berberine, an isoquinoline alkaloid with anti-inflammatory effects, could improve surgery-induced cognitive impairment. Twenty-month-old male C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to mimic the clinical human abdominal surgery. For the interventional studies, mice received berberine (10mg/kg) or vehicle intraperitoneally. For the in vitro study, we examined the effects of berberine on lipopolysaccharide (LPS)-induced inflammatory mediators by cultured BV2 cells. Behavioral tests, expressions of IBA1, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 were performed at the indicated time points. In the present study, we showed that surgery impaired the contextual fear memory, as evidenced by the significantly decreased freezing time to the context. This behavioral change coincided with marked increases in IBA1, TNF-α, IL-1β, and IL-6 in the prefrontal cortex and hippocampus only at 24h but not 7 d after surgery. In BV2 cells, LPS induced significantly increased TNF-α and IL-1β expressions. Notably, berberine treatment rescued surgery-induced cognitive impairment and inhibited the release of IBA1, IL-1β, and IL-6 in the hippocampus. In line with the in vivo study, berberine treatment suppressed LPS-stimulated production of TNF-α and IL-1β in BV2 cells. In conclusion, our study suggests that berberine could alleviate POCD by suppressing neuroinflammation in aged mice. PMID:27376853

  12. Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit

    Institute of Scientific and Technical Information of China (English)

    Hongkai Wang; Chengren Li; Hanzhi Wang; Feng Mei; Zhi Liu; Hai-Ying Shen; Lan Xiao

    2013-01-01

    Schizophrenia is a mental disease that mainly affects young individuals (15 to 35 years old) but its etiology remains largely undefined.Recently,accumulating evidence indicated that demyelination and/or dysfunction of oligodendrocytes is an important feature of its pathogenesis.We hypothesized that the vulnerability of young individuals to demyelination may contribute to the onset of schizophrenia.In the present study,three different age cohorts of mice,i.e.juvenile (3 weeks),young-adult (6 weeks) and middle-aged (8months),were subjected to a 6-week diet containing 0.2% cuprizone (CPZ) to create an animal model of acute demyelination.Then,age-related vulnerability to CPZ-induced demyelination,behavioral outcomes,and myelination-related molecular biological changes were assessed.We demonstrated:(1) CPZ treatment led to more severe demyelination in juvenile and young-adult mice than in middle-aged mice in the corpus callosum,a region closely associated with the pathophysiology of schizophrenia; (2)the higher levels of demyelination in juvenile and young-adult mice were correlated with a greater reduction of myelin basic protein,more loss of CC-1-positive mature oligodendrocytes,and higher levels of astrocyte activation; and (3) CPZ treatment resulted in a more prominent exploratory behavior deficit in juvenile and young-adult mice than in middle-aged mice.Together,our data demonstrate an age-related vulnerability to demyelination with a concurrent behavioral deficit,providing supporting evidence for better understanding the susceptibility of the young to the onset of schizophrenia.

  13. Galanin 3 receptor-deficient mice show no alteration in the oxazolone-induced contact dermatitis phenotype.

    Science.gov (United States)

    Botz, Bálint; Brunner, Susanne M; Kemény, Ágnes; Pintér, Erika; McDougall, Jason J; Kofler, Barbara; Helyes, Zsuzsanna

    2016-09-01

    Allergic contact dermatitis (ACD) is an inflammatory skin disease induced by allergen exposure and characterized by erythema, oedema and immune cell infiltration. The sensory peptide galanin (GAL) and its three receptors (GAL1-3 ) are involved in regulating inflammation. As GAL and its receptors are expressed in human and murine skin and GAL expression is increased in oxazolone-induced contact allergy, it could play a role in dermatitis. As GAL reduces neurogenic plasma extravasation in the mouse skin via GAL3 activation, the role of GAL3 in the oxazolone-induced dermatitis model was explored. Following topical challenge with oxazolone, GAL3 gene-deficient mice showed a trend towards reduced ear thickness. Plasma extravasation and neutrophil infiltration increased considerably upon oxazolone challenge in both GAL3 knockout animals and wild-type controls without any observable effect of the gene deletion. We conclude that a lack of GAL3 does not influence oxazolone-induced ACD. PMID:27121264

  14. Bone marrow from Balb/c mice radiocontaminated with 241Am in utero shows a deficient in vitro haemopoiesis

    International Nuclear Information System (INIS)

    Radiation damage from 241Am to bone marrow cells was manifest in long-term bone marrow cultures (LTC) from offspring of mice radiocontaminated at 14th day of gestation (119, 479, 803, 1754 kBq 241Am kg). Offspring were reared by their own contaminated mother for 3 weeks postnatal. LTC from these offspring were less able to support in vitro CFC proliferation than control LTC. This radiation damage persisted 71 weeks after radiocontamination in utero. Damage was observed at lower doses if 241Am contamination occurred at foetal rather than adult ages. Radiation damage was observed only using LTC. After culturing LTC in 25% FCS and recharging the stromal adherent layer with bone marrow cell suspensions originating either from control offspring or from offspring contaminated with 241Am in utero evidence was found that the proliferation capacity of haemopoietic cells was diminished. However, the nature of effects on the stromal elements is currently somewhat equivocal. Following in utero contamination stromal adherent cells appeared to support better production of in vitro CFC. (author)

  15. Like cognitive function, decision making across the life span shows profound age-related changes

    OpenAIRE

    Tymula, Agnieszka; Rosenberg Belmaker, Lior A.; Ruderman, Lital; Paul W Glimcher; Levy, Ifat

    2013-01-01

    Although largely unstudied, behavioral changes in decision making across the life span have implications for problems associated with poor decision making at different life stages, such as careless driving in adolescents and disadvantageous medical or financial decision making in older adults. We examine age-based differences in individual decision-making characteristics—choice consistency, rationality, and preferences for known and unknown risks—in 12- to 90-y-olds. We found that even the he...

  16. Nitrite Treatment Rescues Cardiac Dysfunction in Aged Mice Treated with Conjugated Linoleic Acid

    OpenAIRE

    Piell, Kellianne M.; Kelm, Natia Qipshidze; Caroway, Megan P.; Aman, Masarath; Cole, Marsha P.

    2014-01-01

    Conjugated linoleic acid (cLA) is a commercially available weight loss supplement that is not currently regulated by the FDA. Numerous studies suggest that cLA mediates protection in diseases including cancer, diabetes, atherosclerosis, immune function, and obesity. Based upon these reports, it was hypothesized that supplementation of cLA would improve heart function in aged wild-type (WT) mice. At 10 months of age, mice were treated with cLA, nitrite, or the combination of the two. Echocardi...

  17. Age-dependent effects of UCP2 deficiency on experimental acute pancreatitis in mice.

    Directory of Open Access Journals (Sweden)

    Sarah Müller

    Full Text Available Reactive oxygen species (ROS have been implicated in the pathogenesis of acute pancreatitis (AP for many years but experimental evidence is still limited. Uncoupling protein 2 (UCP2-deficient mice are an accepted model of age-related oxidative stress. Here, we have analysed how UCP2 deficiency affects the severity of experimental AP in young and older mice (3 and 12 months old, respectively triggered by up to 7 injections of the secretagogue cerulein (50 μg/kg body weight at hourly intervals. Disease severity was assessed at time points from 3 hours to 7 days based on pancreatic histopathology, serum levels of alpha-amylase, intrapancreatic trypsin activation and levels of myeloperoxidase (MPO in lung and pancreatic tissue. Furthermore, in vitro studies with pancreatic acini were performed. At an age of 3 months, UCP2-/- mice and wild-type (WT C57BL/6 mice were virtually indistinguishable with respect to disease severity. In contrast, 12 months old UCP2-/- mice developed a more severe pancreatic damage than WT mice at late time points after the induction of AP (24 h and 7 days, respectively, suggesting retarded regeneration. Furthermore, a higher peak level of alpha-amylase activity and gradually increased MPO levels in pancreatic and lung tissue were observed in UCP2-/- mice. Interestingly, intrapancreatic trypsin activities (in vivo studies and intraacinar trypsin and elastase activation in response to cerulein treatment (in vitro studies were not enhanced but even diminished in the knockout strain. Finally, UCP2-/- mice displayed a diminished ratio of reduced and oxidized glutathione in serum but no increased ROS levels in pancreatic acini. Together, our data indicate an aggravating effect of UCP2 deficiency on the severity of experimental AP in older but not in young mice. We suggest that increased severity of AP in 12 months old UCP2-/- is caused by an imbalanced inflammatory response but is unrelated to acinar cell functions.

  18. FES Training in Aging: interim results show statistically significant improvements in mobility and muscle fiber size

    Directory of Open Access Journals (Sweden)

    Helmut Kern

    2012-03-01

    Full Text Available Aging is a multifactorial process that is characterized by decline in muscle mass and performance. Several factors, including reduced exercise, poor nutrition and modified hormonal metabolism, are responsible for changes in the rates of protein synthesis and degradation that drive skeletal muscle mass reduction with a consequent decline of force generation and mobility functional performances. Seniors with normal life style were enrolled: two groups in Vienna (n=32 and two groups in Bratislava: (n=19. All subjects were healthy and declared not to have any specific physical/disease problems. The two Vienna groups of seniors exercised for 10 weeks with two different types of training (leg press at the hospital or home-based functional electrical stimulation, h-b FES. Demografic data (age, height and weight were recorded before and after the training period and before and after the training period the patients were submitted to mobility functional analyses and muscle biopsies. The mobility functional analyses were: 1. gait speed (10m test fastest speed, in m/s; 2. time which the subject needed to rise from a chair for five times (5x Chair-Rise, in s; 3. Timed –Up-Go- Test, in s; 4. Stair-Test, in s; 5. isometric measurement of quadriceps force (Torque/kg, in Nm/kg; and 6. Dynamic Balance in mm. Preliminary analyses of muscle biopsies from quadriceps in some of the Vienna and Bratislava patients present morphometric results consistent with their functional behaviors. The statistically significant improvements in functional testings here reported demonstrates the effectiveness of h-b FES, and strongly support h-b FES, as a safe home-based method to improve contractility and performances of ageing muscles.

  19. Mathematical modeling of left ventricular dimensional changes in mice during aging

    Directory of Open Access Journals (Sweden)

    Yang Tianyi

    2012-12-01

    Full Text Available Abstract Cardiac aging is characterized by diastolic dysfunction of the left ventricle (LV, which is due in part to increased LV wall stiffness. In the diastolic phase, myocytes are relaxed and extracellular matrix (ECM is a critical determinant to the changes of LV wall stiffness. To evaluate the effects of ECM composition on cardiac aging, we developed a mathematical model to predict LV dimension and wall stiffness changes in aging mice by integrating mechanical laws and our experimental results. We measured LV dimension, wall thickness, LV mass, and collagen content for wild type (WT C57/BL6J mice of ages ranging from 7.3 months to those of 34.0 months. The model was established using the thick wall theory and stretch-induced tissue growth to an isotropic and homogeneous elastic composite with mixed constituents. The initial conditions of the simulation were set based on the data from the young mice. Matlab simulations of this mathematical model demonstrated that the model captured the major features of LV remodeling with age and closely approximated experimental results. Specifically, the temporal progression of the LV interior and exterior dimensions demonstrated the same trend and order-of-magnitude change as our experimental results. In conclusion, we present here a validated mathematical model of cardiac aging that applies the thick-wall theory and stretch-induced tissue growth to LV remodeling with age.

  20. Effects of aging on time course of neovascularization-related gene expression following acute hindlimb ischemia in mice

    Institute of Scientific and Technical Information of China (English)

    WANG Jin-song; LIU Xia; XUE Zhen-yi; Lee Alderman; Justin U. Tilan; Remi Adenika; Stephen E. Epstein; Mary Susan Burnett

    2011-01-01

    Background Molecular analysis of neovascularization related genes by time course in response to ischemia has not been described in the context of aging. We aimed to provide a progressively deeper understanding of how aging compromises neovascularization.Methods Young (3-month) and old (18-month) C57BI mice were subjected to left hindlimb ischemia. Necrosis score was evaluated in calf muscles. Calf muscles,peripheral blood,bone marrow were harvested at different time points. The expressions of matrix metalloproteiniase-9 (MMPg),endothelial nitric oxide synthase (eNOS),vascular endothelial growth factor (VEGF),stromal derived growth factor-1 (SDF1),hypoxia inducible factor-1α (HIF1α),VEGF receptor-1(Fit1),VEGF receptor-2 (Flk1),angiopoietin-1 (Ang1),CD133,CD26 were detected by RT-PCR or Western blotting.White blood cells were counted in the peripheral blood. Gene expression data were compared by two-way analysis of variance.Results MMP9,HIF-1α and SDF-1 were more upregulated during acute ischemia in old vs. young mice,reflecting increased ischemia in aging mice. However VEGF and eNOS exhibited lower expression in old vs. young mice,despite greater ischemia intensity. Ang1 and Flk1 showed similar expression in old vs. young mice. MMP9 peaked earlier in peripheral blood in young vs. old mice. Concurrent decreasing CD26 and increasing CD133 expression in aging bonemarrow suggest aging impairs progenitor cell mobilization,Conclusions Our results indicate that a complex array of defects occur with aging that interfere with optimal neovascularization. These include potential impaired mobilization of progenitor cells to ischemic tissue,decreased levels of eNOS and VEGF and delayed responses to ischemia.ZLEr. WANG Jin-song,Division of Vascular Surgery,the First Affiliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong 510080,China (Tel:86-20-87333440.Fax:86-20-87333242. Email:wangjs@mail.sysu.edu.cn)This work was supported by NIH RO1 HL085003-01A2,NNSF30100179.

  1. Age-Dependent Defects of Regulatory B Cells in Wiskott-Aldrich Syndrome Gene Knockout Mice.

    Directory of Open Access Journals (Sweden)

    Tadafumi Yokoyama

    Full Text Available The Wiskott-Aldrich syndrome (WAS is a rare X-linked primary immunodeficiency characterized by recurrent infections, thrombocytopenia, eczema, and high incidence of malignancy and autoimmunity. The cellular mechanisms underlying autoimmune complications in WAS have been extensively studied; however, they remain incompletely defined. We investigated the characteristics of IL-10-producing CD19+CD1dhighCD5+ B cells (CD1dhighCD5+ Breg obtained from Was gene knockout (WKO mice and found that their numbers were significantly lower in these mice compared to wild type (WT controls. Moreover, we found a significant age-dependent reduction of the percentage of IL-10-expressing cells in WKO CD1dhighCD5+ Breg cells as compared to age-matched WT control mice. CD1dhighCD5+ Breg cells from older WKO mice did not suppress the in vitro production of inflammatory cytokines from activated CD4+ T cells. Interestingly, CD1dhighCD5+ Breg cells from older WKO mice displayed a basal activated phenotype which may prevent normal cellular responses, among which is the expression of IL-10. These defects may contribute to the susceptibility to autoimmunity with age in patients with WAS.

  2. Combined administration of cerebrolysin and donepezil induces plastic changes in prefrontal cortex in aged mice.

    Science.gov (United States)

    Alcántara-González, Faviola; Mendoza-Perez, Claudia Rebeca; Zaragoza, Néstor; Juarez, Ismael; Arroyo-García, Luis Enrique; Gamboa, Citlalli; De La Cruz, Fidel; Zamudio, Sergio; Garcia-Dolores, Fernando; Flores, Gonzalo

    2012-11-01

    Cerebrolysin (Cbl) shows neurotrophic and neuroprotective properties while donepezil (Dnp) is a potent acetylcholinesterase (AChE) inhibitor, both drugs are prescribed for Alzheimer's disease (AD) treatment. Previous studies have shown that the Dnp and Cbl administered separately, modify dendritic morphology of neurons in the prefrontal cortex and hippocampus in senile rodents. Since the deficit of neurotrophic factor activity is implicated in the degeneration of cholinergic neurons of basal forebrain, a combination therapy of Dnp and Cbl has been tested recently in Alzheimer's patients. However, the plastic changes that may underlie this combined treatment have not yet been explored. We present here the effect of the combined administration of Cbl and Dnp on dendritic morphology in brain regions related to learning and memory in aged mice. The Golgi-Cox staining protocol and Sholl analysis were used for studying dendritic changes. Cbl and Dnp were administrated daily for 2 months to 9-months-old mice. Locomotor activity was assessed, as well as the dendritic morphology of neurons in several limbic regions was analyzed. Results showed that Cbl and Dnp induced an increase in locomotor activity without synergistic effect. The Cbl or Dnp treatment modified the dendritic morphology of neurons from prefrontal cortex (PFC), dorsal hippocampus (DH), dentate gyrus (DG), and the shell of nucleus accumbens (NAcc). These changes show an increase in the total dendritic length and spine density, resulting in an improvement of dendritic arborization. Prominently, a synergistic effect of Cbl and Dnp was observed on branching order and total dendritic length of pyramidal neurons from PFC. These results suggest that Dnp and Cbl may induce plastic changes in a manner independent of each other, but could enhance their effect in target cells from PFC. PMID:22826038

  3. The Cardioprotective Effect of Vitamin E (Alpha-Tocopherol Is Strongly Related to Age and Gender in Mice.

    Directory of Open Access Journals (Sweden)

    Xiao-Xia Hu

    Full Text Available Vitamin E (VitE only prevented cardiovascular diseases in some patients and the mechanisms remain unknown. VitE levels can be affected by aging and gender. We hypothesize that age and gender can influence VitE's cardioprotective effect. Mice were divided into 4 groups according to age and gender, and each group of mice were divided into a control group and a VitE group. The mice were administered water or VitE for 21 days; Afterward, the cardiac function and myocardial infarct size and cardiomyocyte apoptosis were measured after myocardial ischemia reperfusion(MI/R. VitE may significantly improved cardiac function in young male mice and aged female mice by enhancing ERK1/2 activity and reducing JNK activity. Enhanced expression of HSP90 and Bcl-2 were also seen in young male mice. No changes in cardiac function and cardiac proteins were detected in aged male mice and VitE was even liked to exert a reverse effect in cardiac function in young mice by enhancing JNK activity and reducing Bcl-2 expression. Those effects were in accordance with the changes of myocardial infarction size and cardiomyocyte apoptosis in each group of mice. VitE may reduce MI/R injury by inhibiting cardiomyocyte apoptosis in young male mice and aged female mice but not in aged male mice. VitE was possibly harmful for young female mice, shown as increased cardiomyocyte apoptosis after MI/R. Thus, we speculated that the efficacy of VitE in cardiac protection was associated with age and gender.

  4. The Cardioprotective Effect of Vitamin E (Alpha-Tocopherol) Is Strongly Related to Age and Gender in Mice

    Science.gov (United States)

    Li, Yan; Lin, Ze-Bang; Liu, Xiang; Wang, Jing-Feng; Chen, Yang-Xin; Wang, Zhi-Ping; Zhang, Xi; Ou, Zhi-Jun; Ou, Jing-Song

    2015-01-01

    Vitamin E (VitE) only prevented cardiovascular diseases in some patients and the mechanisms remain unknown. VitE levels can be affected by aging and gender. We hypothesize that age and gender can influence VitE’s cardioprotective effect. Mice were divided into 4 groups according to age and gender, and each group of mice were divided into a control group and a VitE group. The mice were administered water or VitE for 21 days; Afterward, the cardiac function and myocardial infarct size and cardiomyocyte apoptosis were measured after myocardial ischemia reperfusion(MI/R). VitE may significantly improved cardiac function in young male mice and aged female mice by enhancing ERK1/2 activity and reducing JNK activity. Enhanced expression of HSP90 and Bcl-2 were also seen in young male mice. No changes in cardiac function and cardiac proteins were detected in aged male mice and VitE was even liked to exert a reverse effect in cardiac function in young mice by enhancing JNK activity and reducing Bcl-2 expression. Those effects were in accordance with the changes of myocardial infarction size and cardiomyocyte apoptosis in each group of mice. VitE may reduce MI/R injury by inhibiting cardiomyocyte apoptosis in young male mice and aged female mice but not in aged male mice. VitE was possibly harmful for young female mice, shown as increased cardiomyocyte apoptosis after MI/R. Thus, we speculated that the efficacy of VitE in cardiac protection was associated with age and gender. PMID:26331272

  5. Diabetes exacerbates amyloid and neurovascular pathology in aging-accelerated mice

    OpenAIRE

    Currais, Antonio; Prior, Marguerite; Lo, David; Jolivalt, Corinne; Schubert, David; Maher, Pamela

    2012-01-01

    Mounting evidence supports a link between diabetes, cognitive dysfunction and aging. However, the physiological mechanisms by which diabetes impacts brain function and cognition are not fully understood. To determine how diabetes contributes to cognitive dysfunction and age-associated pathology, we used streptozotocin to induce type 1 diabetes (T1D) in senescence-accelerated prone 8 (SAMP8) and senescence-resistant 1 (SAMR1) mice. Contextual fear conditioning demonstrated that T1D resulted in...

  6. Content of stromal precursor cells in heterotopic transplants of bone marrow in CBA mice of various ages.

    Science.gov (United States)

    Gorskaya, Yu F; Kuralesova, A I; Shuklina, E Yu; Nesterenko, V G

    2002-02-01

    Efficiency of colony formation of stromal precursor cells in cultured bone marrow transplants from old (24 month) CBA mice implanted to young (2-month-old) mice almost 3-fold surpassed that in cultured transplants implanted to old recipients. The content of nucleated cells in bone marrow transplants from senescence accelerated mice SAMP increased more than 2-fold, if SAMR mice with normal aging rate were used as the recipients instead of SAMP mice. Bone marrow taken from old and young CBA mice endured the same number of transplantations if the recipient mice were of the same age (5 month). It was concluded that stromal tissue considerably changes with age and is under strict control of the body. PMID:12432868

  7. Effect of Mitochondrial Transplantation from Cumulus Granular Cells to the Early Embryos of Aged Mice

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Objective To assess the role of mitochondria in the early embryonic development of ageing mice.Methods Mitochondria isolated from cumulus granular cells of aged mice were microinjected into oocytes or zygotes of aged mice. In the setting of oocyte injection, mitochondria were transferred via intracytoplasmic sperm injection (ICSI+MIT), and ICSI without mitochondrial transfer. In the setting of zygote injection, mitochondria were directly microinjected into fertilized oocytes (MIT), and those injected with buffer alone (mock injection) or not injected (uninjected) served as controls.Results Although the rates of oocyte cleavage between ICSI and ICSI+MIT groups were not statistically different (P>0.05), the rate of blastocyst in the ICSI+MIT group was significantly higher than that in ICSI group (P<0.05). Although both the cleavage and blastocyst rates of mock injection group were significantly lower than those of uninjected group (P<0.05), likely due to mechanical damages of the cells by microinjection, the decrease of these rates was prevented by mitochondrial transfer. After mitochondrial transfer, the rates of both cleavage and blastocyst were significantly improved over the mock-injection group (P<0.05).Conclusion Mitochondrial transplantation can improve the developmental potential of early embryos of aged mice.

  8. Characteristics of bone marrow-derived endothelial progenitor cells in aged mice

    International Nuclear Information System (INIS)

    Evidence for dysfunction of endothelial repair in aged mice was sought by studying the pattern of induced differentiation, quantity, and function of bone marrow-derived endothelial progenitor cells (EPCs) in aged mice. The CD117-positive stem cell population was separated from bone marrow by magnetic activated cell-sorting system (MACS), and EPCs were defined by demonstrating the expression of CD117+CD34+Flk-1+ by flow cytometry. After 7 days of culture, the number of clones formed was counted, and proliferation and migration of EPCs were analyzed by MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay and modified Boyden chamber assay. The results demonstrated that compared to the control group, the quantity of bone marrow-derived CD117+ stem cells and EPCs, as well as the proliferation, migration, the number of clones formed, and phagocytotic function of EPCs were significantly reduced in aged mice. There were no significant differences in the morphology and induced differentiation pattern of EPCs between the aged mouse group and the control group. Authors suggest that the dysfunction of EPCs may serve as a surrogate parameter of vascular function in old mice

  9. Middle age has a significant impact on gene expression during skin wound healing in male mice.

    Science.gov (United States)

    Yanai, Hagai; Lumenta, David Benjamin; Vierlinger, Klemens; Hofner, Manuela; Kitzinger, Hugo-Benito; Kamolz, Lars-Peter; Nöhammer, Christa; Chilosi, Marco; Fraifeld, Vadim E

    2016-08-01

    The vast majority of research on the impact of age on skin wound healing (WH) compares old animals to young ones. The middle age is often ignored in biogerontological research despite the fact that many functions that decline in an age-dependent manner have starting points in mid-life. With this in mind, we examined gene expression patterns during skin WH in late middle-aged versus young adult male mice, using the head and back punch models. The rationale behind this study was that the impact of age would first be detectable at the transcriptional level. We pinpointed several pathways which were over-activated in the middle-aged mice, both in the intact skin and during WH. Among them were various metabolic, immune-inflammatory and growth-promoting pathways. These transcriptional changes were much more pronounced in the head than in the back. In summary, the middle age has a significant impact on gene expression in intact and healing skin. It seems that the head punch model is more sensitive to the effect of age than the back model, and we suggest that it should be more widely applied in aging research on wound healing. PMID:27241672

  10. Brain morphometry shows effects of long-term musical practice in middle-aged keyboard players

    Directory of Open Access Journals (Sweden)

    HannaGärtner

    2013-09-01

    Musicians showed a significantly better symmetric motor performance as well as a greater capability of controlling hand independence than controls. Structural MRI-data revealed significant volumetric differences between the brains of keyboard players, who practiced intensively and controls in right sensorimotor areas and the corticospinal tract as well as in the entorhinal cortex and the left superior parietal lobule. Moreover, they showed also larger volumes in a comparable set of regions than the less intensively practicing musicians. The structural changes in the sensory and motor systems correspond well to the behavioral results, and can be interpreted in terms of plasticity as a result of intensive motor training. Areas of the superior parietal lobule and the entorhinal cortex might be enlarged in musicians due to their special skills in sight-playing and memorizing of scores. In conclusion, intensive and specific musical training seems to have an impact on brain structure, not only during the sensitive period of childhood but throughout life.

  11. High preservation of CpG cytosine methylation patterns at imprinted gene loci in liver and brain of aged mice.

    Directory of Open Access Journals (Sweden)

    Silvia Gravina

    Full Text Available A gradual loss of the correct patterning of 5-methyl cytosine marks in gene promoter regions has been implicated in aging and age-related diseases, most notably cancer. While a number of studies have examined DNA methylation in aging, there is no consensus on the magnitude of the effects, particularly at imprinted loci. Imprinted genes are likely candidate to undergo age-related changes because of their demonstrated plasticity in utero, for example, in response to environmental cues. Here we quantitatively analyzed a total of 100 individual CpG sites in promoter regions of 11 imprinted and non-imprinted genes in liver and cerebral cortex of young and old mice using mass spectrometry. The results indicate a remarkably high preservation of methylation marks during the aging process in both organs. To test if increased genotoxic stress associated with premature aging would destabilize DNA methylation we analyzed two DNA repair defective mouse models showing a host of premature aging symptoms in liver and brain. However, also in these animals, at the end of their life span, we found a similarly high preservation of DNA methylation marks. We conclude that patterns of DNA methylation in gene promoters of imprinted genes are surprisingly stable over time in normal, postmitotic tissues and that the multiple documented changes with age are likely to involve exceptions to this pattern, possibly associated with specific cellular responses to age-related changes other than genotoxic stress.

  12. Behavioral responses to and brain distribution of morphine in mature adult and aged mice

    International Nuclear Information System (INIS)

    Mature adult (3-6 mo old) and aged (2 yr old) male ICR mice were injected with 10 to 100 mg/kg morphine, s.c. The ED50 values for running behavior (as measured using Stoelting activity monitors and having each mouse serve as its own control) representing 5 times control activity was approximately 7.5 mg/kg for aged mice and approximately 17.5 mg/kg for the mature adults. The ED50 values for analgesia 1 hr after morphine administration using the tail-flick method (max. response time = 8 sec) were approx. 70 mg/kg for the aged mice and 15 mg/kg for the mature adults. One hour after injecting 3H-morphine at doses of 30 and 100 mg/kg, 0.13 and 0.14% of the doses appeared in brains of aged and mature adult mice, respectively. Regional distribution of the morphine was the same for both age groups. Expressed as percent of total brain morphine, it was as follows: cortex, 30%; midbrain, 18%; cerebellum, 17%; medulla, 12%; pons, 9%; striatum, 8% and periaqueductal gray, 6%. Expressed as g morphine/g tissue for the 2 doses, the distribution was; periaqueductal gray, 30 and 80; striatum, 9 and 34; medulla, 6 and 20 pons; 5 and 19; cerebellum, 4 and 13; midbrain 2.5 and 8.5 and cortex, 2 and 8. These results suggest that the differences in response to morphine by the two age groups were due to age-related differences in opioid receptor populations and/or affinities

  13. Behavioral responses to and brain distribution of morphine in mature adult and aged mice

    Energy Technology Data Exchange (ETDEWEB)

    Burton, C.K.; Ho, I.K.; Hoskins, B.

    1986-03-01

    Mature adult (3-6 mo old) and aged (2 yr old) male ICR mice were injected with 10 to 100 mg/kg morphine, s.c. The ED50 values for running behavior (as measured using Stoelting activity monitors and having each mouse serve as its own control) representing 5 times control activity was approximately 7.5 mg/kg for aged mice and approximately 17.5 mg/kg for the mature adults. The ED50 values for analgesia 1 hr after morphine administration using the tail-flick method (max. response time = 8 sec) were approx. 70 mg/kg for the aged mice and 15 mg/kg for the mature adults. One hour after injecting /sup 3/H-morphine at doses of 30 and 100 mg/kg, 0.13 and 0.14% of the doses appeared in brains of aged and mature adult mice, respectively. Regional distribution of the morphine was the same for both age groups. Expressed as percent of total brain morphine, it was as follows: cortex, 30%; midbrain, 18%; cerebellum, 17%; medulla, 12%; pons, 9%; striatum, 8% and periaqueductal gray, 6%. Expressed as g morphine/g tissue for the 2 doses, the distribution was; periaqueductal gray, 30 and 80; striatum, 9 and 34; medulla, 6 and 20 pons; 5 and 19; cerebellum, 4 and 13; midbrain 2.5 and 8.5 and cortex, 2 and 8. These results suggest that the differences in response to morphine by the two age groups were due to age-related differences in opioid receptor populations and/or affinities.

  14. Acetaminophen hepatotoxicity in mice: Effect of age, frailty and exposure type.

    Science.gov (United States)

    Kane, Alice E; Mitchell, Sarah J; Mach, John; Huizer-Pajkos, Aniko; McKenzie, Catriona; Jones, Brett; Cogger, Victoria; Le Couteur, David G; de Cabo, Rafael; Hilmer, Sarah N

    2016-01-01

    Acetaminophen is a commonly used analgesic that can cause severe hepatotoxicity in overdose. Despite old age and frailty being associated with extensive and long-term utilization of acetaminophen and a high prevalence of adverse drug reactions, there is limited information on the risks of toxicity from acetaminophen in old age and frailty. This study aimed to assess changes in the risk and mechanisms of hepatotoxicity from acute, chronic and sub-acute acetaminophen exposure with old age and frailty in mice. Young and old male C57BL/6 mice were exposed to either acute (300 mg/kg via oral gavage), chronic (100 mg/kg/day in diet for six weeks) or sub-acute (250 mg/kg, t.i.d., for three days) acetaminophen, or saline control. Pre-dosing mice were scored for the mouse clinical frailty index, and after dosing serum and liver tissue were collected for assessment of toxicity and mechanisms. There were no differences with old age or frailty in the degree of hepatotoxicity induced by acute, chronic or subacute acetaminophen exposure as assessed by serum liver enzymes and histology. Age-related changes in the acetaminophen toxicity pathways included increased liver GSH concentrations, increased NQO1 activity and an increased pro- and anti-inflammatory response to acetaminophen in old age. Frailty-related changes included a negative correlation between frailty index and serum protein, albumin and ALP concentrations for some mouse groups. In conclusion, although there were changes in some pathways that would be expected to influence susceptibility to acetaminophen toxicity, there was no overall increase in acetaminophen hepatotoxicity with old age or frailty in mice. PMID:26615879

  15. Investigation and identification of etiologies involved in the development of acquired hydronephrosis in aged laboratory mice with the use of high-frequency ultrasound imaging

    Directory of Open Access Journals (Sweden)

    Danielle A. Springer

    2014-08-01

    Full Text Available Laboratory mice develop naturally occurring lesions that affect biomedical research. Hydronephrosis is a recognized pathologic abnormality of the mouse kidney. Acquired hydronephrosis can affect any mouse, as it is caused by any naturally occurring disease that impairs free urine flow. Many etiologies leading to this condition are of particular significance to aging mice. Non-invasive ultrasound imaging detects renal pelvic dilation, renal enlargement, and parenchymal loss for pre-mortem identification of this condition. High-frequency ultrasound transducers produce high-resolution images of small structures, ideal for detecting organ pathology in mice. Using a 40 MHz linear array transducer, we obtained high-resolution images of a diversity of pathologic lesions occurring within the abdomen of seven geriatric mice with acquired hydronephrosis that enabled a determination of the underlying etiology. Etiologies diagnosed from the imaging results include pyelonephritis, neoplasia, urolithiasis, mouse urologic syndrome, and spontaneous hydronephrosis, and were confirmed at necropsy. A retrospective review of abdominal scans from an additional 149 aging mice shows that the most common etiologies associated with acquired hydronephrosis are mouse urologic syndrome and abdominal neoplasia. This report highlights the utility of high-frequency ultrasound for surveying research mice for age-related pathology, and is the first comprehensive report of multiple cases of acquired hydronephrosis in mice.

  16. Single administration of a novel γ-secretase modulator ameliorates cognitive dysfunction in aged C57BL/6J mice.

    Science.gov (United States)

    Hayama, Tatsuya; Murakami, Koji; Watanabe, Tomomichi; Maeda, Ryota; Kamata, Makoto; Kondo, Shinichi

    2016-02-15

    Mutations in presenilin 1 (PS1) and presenilin 2 (PS2) are known to cause early onset of Alzheimer's disease (AD). These proteins comprise the catalytic domain of γ-secretase, which catalyzes the cleavage of β-amyloid (Aβ) from amyloid precursor protein (APP). In recent reports, PS1 and PS2 were linked to the modulation of intracellular calcium ion (Ca(2+)) dynamics, a key regulator of synaptic function. Ca(2+) dysregulation and synaptic dysfunction are leading hypothesis of cognitive dysfunctions during aging and AD progression. Accordingly, manipulations of presenilins by small molecules may have therapeutic potential for the treatment of cognitive dysfunction. In an accompanying report, we showed that chronic treatment with compound-1, a novel γ-secretase modulator (GSM), reduced Aβ production and ameliorated cognitive dysfunction in Tg2576 APP transgenic mice. Accordingly, in the present study we showed that single oral administration of compound-1 at 1 and 3mg/kg ameliorated cognitive dysfunction in aged non-transgenic mice. Moreover, compound-1 enhanced synaptic plasticity in hippocampal slices from aged C57BL/6J mice and increased messenger RNA (mRNA) expression of the immediate early gene c-fos, which has been shown to be related to synaptic plasticity in vivo. Finally, compound-1 modulated Ca(2+) signals through PS1 in mouse embryonic fibroblast cells. Taken together, compound-1 ameliorates both Aβ pathology and age-related cognitive dysfunctions. Hence, compound-1 may have potential as an early intervention for the cognitive declines that are commonly diagnosed in aged subjects, such as mild cognitive impairment (MCI) and prodromal AD. PMID:26707406

  17. Age-related changes in the motricity of the inbred mice strains 129/sv and C57BL/6j.

    Science.gov (United States)

    Serradj, Najet; Jamon, Marc

    2007-02-12

    The development of motor skills was studied at different stages in the life of the mouse, focusing on three key aspects of motor development: early rhythmic motor activities prior to the acquisition of quadruped locomotion, motor skills in young adults, and the effect of aging on motor skills. The age-related development pattern was analysed and compared in two strains of major importance for genomic studies (C57Bl6/j and 129/sv). Early rhythmic air-stepping activities by l-dopa injected mice showed similar overall development in both strains; differences were observed with greater beating frequency and less inter-limb coordination in 129/sv, suggesting that 129/sv had a different maturation process. Performance on the rotarod by young adult C57Bl6/j gradually improved between 1 and 3 months, but then declined with age; performance on the treadmill also declined with an age-related increase in fatigability. Overall performance by 129/sv mice was lower than C57Bl6/j, and the age-related pattern of change was different, with 129/sv having relatively stable performance over time. Inter-strain differences and their possible causes, in particular the role of dopaminergic pathways, are discussed together with repercussions affecting mutant phenotyping procedures. PMID:17126421

  18. Age-Dependent Decrease in Chaperone Activity Impairs MANF Expression, Leading to Purkinje Cell Degeneration in Inducible SCA17 Mice

    Science.gov (United States)

    Yang, Su; Huang, Shanshan; Gaertig, Marta A.; Li, Xiao-Jiang; Li, Shihua

    2016-01-01

    SUMMARY Although protein-misfolding-mediated neurodegenerative diseases have been linked to aging, how aging contributes to selective neurodegeneration remains unclear. We established spinocerebellar ataxia 17 (SCA17) knockin mice that inducibly express one copy of mutant TATA box binding protein (TBP) at different ages by tamoxifen-mediated Cre recombination. We find that more mutant TBP accumulates in older mouse and that this accumulation correlates with age-related decreases in Hsc70 and chaperone activity. Consistently, older SCA17 mice experienced earlier neurological symptom onset and more severe Purkinje cell degeneration. Mutant TBP shows decreased association with XBP1s, resulting in the reduced transcription of mesencephalic astrocyte-derived neurotrophic factor (MANF), which is enriched in Purkinje cells. Expression of Hsc70 improves the TBP-XBP1s interaction and MANF transcription, and overexpression of MANF ameliorates mutant TBP-mediated Purkinje cell degeneration via protein kinase C (PKC)-dependent signaling. These findings suggest that the age-related decline in chaperone activity affects polyglutamine protein function that is important for the viability of specific types of neurons. PMID:24462098

  19. Clustered epitopes within a new poly-epitopic HIV-1 DNA vaccine shows immunogenicity in BALB/c mice.

    Science.gov (United States)

    Jafarpour, Nazli; Memarnejadian, Arash; Aghasadeghi, Mohammad Reza; Kohram, Fatemeh; Aghababa, Haniyeh; Khoramabadi, Nima; Mahdavi, Mehdi

    2014-08-01

    Despite a huge number of studies towards vaccine development against human immunodeficiency virus-1, no effective vaccine has been approved yet. Thus, new vaccines should be provided with new formulations. Herein, a new DNA vaccine candidate encoding conserved and immunogenic epitopes from HIV-1 antigens of tat, pol, gag and env is designed and constructed. After bioinformatics analyses to find the best epitopes and their tandem, nucleotide sequence corresponding to the designed multiepitope was synthesized and cloned into pcDNA3.1+ vector. Expression of pcDNA3.1-tat/pol/gag/env plasmid was evaluated in HEK293T cells by RT-PCR and western-blotting. Seven groups of BALB/c mice were intramuscularly immunized three times either with 50, 100, 200 µg of plasmid in 2-week intervals or with similar doses of insert-free plasmid. Two weeks after the last injection, proliferation of T cells and secretion of IL4 and IFN-γ cytokines were evaluated using Brdu and ELISA methods, respectively. Results showed the proper expression of the plasmid in protein and mRNA levels. Moreover, the designed multiepitope plasmid was capable of induction of both proliferation responses as well as IFN-γ and IL-4 cytokine production in a considerable level compared to the control groups. Overall, our primary data warranted further detailed studies on the potency of this vaccine. PMID:24842263

  20. Age-dependent postoperative cognitive impairment and Alzheimer-related neuropathology in mice

    Science.gov (United States)

    Xu, Zhipeng; Dong, Yuanlin; Wang, Hui; Culley, Deborah J.; Marcantonio, Edward R.; Crosby, Gregory; Tanzi, Rudolph E.; Zhang, Yiying; Xie, Zhongcong

    2014-01-01

    Post-operative cognitive dysfunction (POCD) is associated with increased cost of care, morbidity, and mortality. However, its pathogenesis remains largely to be determined. Specifically, it is unknown why elderly patients are more likely to develop POCD and whether POCD is dependent on general anesthesia. We therefore set out to investigate the effects of peripheral surgery on the cognition and Alzheimer-related neuropathology in mice with different ages. Abdominal surgery under local anesthesia was established in the mice. The surgery induced post-operative elevation in brain β-amyloid (Aβ) levels and cognitive impairment in the 18 month-old wild-type and 9 month-old Alzheimer's disease transgenic mice, but not the 9 month-old wild-type mice. The Aβ accumulation likely resulted from elevation of beta-site amyloid precursor protein cleaving enzyme and phosphorylated eukaryotic translation initiation factor 2α. γ-Secretase inhibitor compound E ameliorated the surgery-induced brain Aβ accumulation and cognitive impairment in the 18 month-old mice. These data suggested that the peripheral surgery was able to induce cognitive impairment independent of general anesthesia, and that the combination of peripheral surgery with aging- or Alzheimer gene mutation-associated Aβ accumulation was needed for the POCD to occur. These findings would likely promote more research to investigate the pathogenesis of POCD.

  1. Heme oxygenase-1 regulates the immune response to influenza virus infection and vaccination in aged mice.

    Science.gov (United States)

    Cummins, Nathan W; Weaver, Eric A; May, Shannon M; Croatt, Anthony J; Foreman, Oded; Kennedy, Richard B; Poland, Gregory A; Barry, Michael A; Nath, Karl A; Badley, Andrew D

    2012-07-01

    Underlying mechanisms of individual variation in severity of influenza infection and response to vaccination are poorly understood. We investigated the effect of reduced heme oxygenase-1 (HO-1) expression on vaccine response and outcome of influenza infection. HO-1-deficient and wild-type (WT) mice (kingdom, Animalia; phylum, Chordata; genus/species, Mus musculus) were infected with influenza virus A/PR/8/34 with or without prior vaccination with an adenoviral-based influenza vaccine. A genome-wide association study evaluated the expression of single-nucleotide polymorphisms (SNPs) in the HO-1 gene and the response to influenza vaccination in healthy humans. HO-1-deficient mice had decreased survival after influenza infection compared to WT mice (median survival 5.5 vs. 6.5 d, P=0.016). HO-1-deficient mice had impaired production of antibody following influenza vaccination compared to WT mice (mean antibody titer 869 vs. 1698, P=0.02). One SNP in HO-1 and one SNP in the constitutively expressed isoform HO-2 were independently associated with decreased antibody production after influenza vaccination in healthy human volunteers (P=0.017 and 0.014, respectively). HO-1 deficient mice were paired with sex- and age-matched WT controls. HO-1 affects the immune response to both influenza infection and vaccination, suggesting that therapeutic induction of HO-1 expression may represent a novel adjuvant to enhance influenza vaccine effectiveness. PMID:22490782

  2. In Vivo Antioxidant and Anti-Skin-Aging Activities of Ethyl Acetate Extraction from Idesia polycarpa Defatted Fruit Residue in Aging Mice Induced by D-Galactose

    Directory of Open Access Journals (Sweden)

    Yang Ye

    2014-01-01

    Full Text Available Two different concentrations of D-galactose (D-gal induced organism and skin aging in Kunming mice were used to examine comprehensively the antioxidant and antiaging activities of ethyl acetate extraction (EAE from Idesia polycarpa defatted fruit residue for the first time. The oxygen radical absorbance capacity (ORAC of EAE was 13.09 ± 0.11 μmol Trolox equivalents (TE/mg, which showed EAE had great in vitro free radical scavenging and antioxidant activity. Biochemical indexes and morphological analysis of all tested tissues showed that EAE could effectively improve the total antioxidant capacity (T-AOC of the antioxidant defense system of the aging mice, enhance the activities of superoxide dismutase (SOD, catalase (CAT, and glutathione peroxidase (GSH-Px of tissues and serum, increase glutathione (GSH content and decrease the malondialdehyde (MDA content, and maintain the skin collagen, elastin, and moisture content. Meanwhile, EAE could effectively attenuate the morphological damage in brain, liver, kidney, and skin induced by D-gal and its effect was not less than that of the well-known L-ascorbic acid (VC and α-tocopherol (VE. Overall, EAE is a potent natural antiaging agent with great antioxidant activity, which can be developed as a new medicine and cosmetic for the treatment of age-related conditions.

  3. Transcriptome composition of the preoptic area in mid-age and escitalopram treatment in male mice.

    Science.gov (United States)

    Moriya, Shogo; Soga, Tomoko; Wong, Dutt Way; Parhar, Ishwar S

    2016-05-27

    The decrease in serotonergic neurotransmission during aging can increase the risk of neuropsychiatric diseases such as depression in elderly population and decline the reproductive system. Therefore, it is important to understand the age-associated molecular mechanisms of brain aging. In this study, the effect of aging and chronic escitalopram (antidepressant) treatment to admit mice was investigated by comparing transcriptomes in the preoptic area (POA) which is a key nucleus for reproduction. In the mid-aged brain, the immune system-related genes were increased and hormone response-related genes were decreased. In the escitalopram treated brains, transcription-, granule cell proliferation- and vasoconstriction-related genes were increased and olfactory receptors were decreased. Since homeostasis and neuroprotection-related genes were altered in both of mid-age and escitalopram treatment, these genes could be important for serotonin related physiologies in the POA. PMID:27113202

  4. Gender-Divergent Profile of Bile Acid Homeostasis during Aging of Mice

    OpenAIRE

    Fu, Zidong Donna; Csanaky, Iván L.; Klaassen, Curtis D.

    2012-01-01

    Aging is a physiological process with a progressive decline of adaptation and functional capacity of the body. Bile acids (BAs) have been recognized as signaling molecules regulating the homeostasis of glucose, lipid, and energy. The current study characterizes the age-related changes of individual BA concentrations by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) in serum and liver of male and female C57BL/6 mice from 3 to 27 months of age. Total BA concentrat...

  5. L-DOPA Reverses Motor Deficits Associated with Normal Aging in Mice

    OpenAIRE

    Allen, Erika; Carlson, Kirsten M.; Zigmond, Michael J.; Cavanaugh, Jane E.

    2010-01-01

    We wished to determine whether L-DOPA, a common treatment for the motor deficits in Parkinson's disease, could also reverse the motor deficits that occur during aging. We assessed motor performance in young (2-3 months) and old (20-21 months) male C57BL/6 mice using the challenge beam and cylinder tests. Prior to testing, mice were treated with L-DOPA or vehicle. Following testing, striatal tissue was analyzed for phenotypic markers of dopamine neurons: dopamine, dopamine transporter, and tyr...

  6. Liver Fatty Acid Binding Protein Gene Ablation Enhances Age-Dependent Weight Gain in Male Mice

    OpenAIRE

    Martin, Gregory G.; Atshaves, Barbara P.; McIntosh, Avery L.; Payne, H. Ross; Mackie, John T.; Kier, Ann B.; Schroeder, Friedhelm

    2008-01-01

    Although studies performed in vitro and with transfected cells in culture suggest a role for liver fatty acid binding protein (L-FABP) in regulating fatty acid oxidation and fat deposition, the physiological significance of this possibility is not completely clear. To begin to address this question, the effect of L-FABP gene ablation on phenotype of standard rodent chow-fed male mice was examined with increasing age up to 18 mo. While young (2-3 mo) L-FABP null mice displayed no visually obvi...

  7. In Vivo Antioxidant and Anti-Skin-Aging Activities of Ethyl Acetate Extraction from Idesia polycarpa Defatted Fruit Residue in Aging Mice Induced by D-Galactose

    OpenAIRE

    Yang Ye; Ran-ran Jia; Lin Tang; Fang Chen

    2014-01-01

    Two different concentrations of D-galactose (D-gal) induced organism and skin aging in Kunming mice were used to examine comprehensively the antioxidant and antiaging activities of ethyl acetate extraction (EAE) from Idesia polycarpa defatted fruit residue for the first time. The oxygen radical absorbance capacity (ORAC) of EAE was 13.09 ± 0.11  μ mol Trolox equivalents (TE)/mg, which showed EAE had great in vitro free radical scavenging and antioxidant activity. Biochemical indexes and morph...

  8. Absence of collagen XVIII in mice causes age-related insufficiency in retinal pigment epithelium proteostasis.

    Science.gov (United States)

    Kivinen, Niko; Felszeghy, Szabolcs; Kinnunen, Aino I; Setälä, Niko; Aikio, Mari; Kinnunen, Kati; Sironen, Reijo; Pihlajaniemi, Taina; Kauppinen, Anu; Kaarniranta, Kai

    2016-08-01

    Collagen XVIII has the structural properties of both collagen and proteoglycan. It has been found at the basement membrane/stromal interface where it is thought to mediate their attachment. Endostatin, a proteolytic fragment from collagen XVIII C-terminal end has been reported to possess anti-angiogenic properties. Age-related vision loss in collagen XVIII mutant mice has been accompanied with a pathological accumulation of deposits under the retinal pigment epithelium (RPE). We have recently demonstrated that impaired proteasomal and autophagy clearance are associated with the pathogenesis of age-related macular degeneration. This study examined the staining levels of proteasomal and autophagy markers in the RPE of different ages of the Col18a1 (-/-) mice. Eyes from 3, 6-7, 10-13 and 18 months old mice were enucleated and embedded in paraffin according to the routine protocol. Sequential 5 μm-thick parasagittal samples were immunostained for proteasome and autophagy markers ubiquitin (ub), SQSTM1/p62 and beclin-1. The levels of immunopositivity in the RPE cells were evaluated by confocal microscopy. Collagen XVIII knock-out mice had undergone age-related RPE degeneration accompanied by an accumulation of drusen-like deposits. Ub protein conjugate staining was prominent in both RPE cytoplasm and extracellular space whereas SQSTM1/p62 and beclin-1 stainings were clearly present in the basal part of RPE cell cytoplasm in the Col18a1 (-/-) mice. SQSTM1/p62 displayed mild extracellular space staining. Disturbed proteostasis regulated by collagen XVIII might be responsible for the RPE degeneration, increased protein aggregation, ultimately leading to choroidal neovascularization. PMID:27125427

  9. Inhibition of Advanced Glycation End Products (AGEs Accumulation by Pyridoxamine Modulates Glomerular and Mesangial Cell Estrogen Receptor α Expression in Aged Female Mice.

    Directory of Open Access Journals (Sweden)

    Simone Pereira-Simon

    Full Text Available Age-related increases in oxidant stress (OS play a role in regulation of estrogen receptor (ER expression in the kidneys. In this study, we establish that in vivo 17β-estradiol (E2 replacement can no longer upregulate glomerular ER expression by 21 months of age in female mice (anestrous. We hypothesized that advanced glycation end product (AGE accumulation, an important source of oxidant stress, contributes to these glomerular ER expression alterations. We treated 19-month old ovariectomized female mice with pyridoxamine (Pyr, a potent AGE inhibitor, in the presence or absence of E2 replacement. Glomerular ERα mRNA expression was upregulated in mice treated with both Pyr and E2 replacement and TGFβ mRNA expression decreased compared to controls. Histological sections of kidneys demonstrated decreased type IV collagen deposition in mice receiving Pyr and E2 compared to placebo control mice. In addition, anti-AGE defenses Sirtuin1 (SIRT1 and advanced glycation receptor 1 (AGER1 were also upregulated in glomeruli following treatment with Pyr and E2. Mesangial cells isolated from all groups of mice demonstrated similar ERα, SIRT1, and AGER1 expression changes to those of whole glomeruli. To demonstrate that AGE accumulation contributes to the observed age-related changes in the glomeruli of aged female mice, we treated mesangial cells from young female mice with AGE-BSA and found similar downregulation of ERα, SIRT1, and AGER1 expression. These results suggest that inhibition of intracellular AGE accumulation with pyridoxamine may protect glomeruli against age-related oxidant stress by preventing an increase of TGFβ production and by regulation of the estrogen receptor.

  10. A validated age-related normative model for male total testosterone shows increasing variance but no decline after age 40 years.

    Science.gov (United States)

    Kelsey, Thomas W; Li, Lucy Q; Mitchell, Rod T; Whelan, Ashley; Anderson, Richard A; Wallace, W Hamish B

    2014-01-01

    The diagnosis of hypogonadism in human males includes identification of low serum testosterone levels, and hence there is an underlying assumption that normal ranges of testosterone for the healthy population are known for all ages. However, to our knowledge, no such reference model exists in the literature, and hence the availability of an applicable biochemical reference range would be helpful for the clinical assessment of hypogonadal men. In this study, using model selection and validation analysis of data identified and extracted from thirteen studies, we derive and validate a normative model of total testosterone across the lifespan in healthy men. We show that total testosterone peaks [mean (2.5-97.5 percentile)] at 15.4 (7.2-31.1) nmol/L at an average age of 19 years, and falls in the average case [mean (2.5-97.5 percentile)] to 13.0 (6.6-25.3) nmol/L by age 40 years, but we find no evidence for a further fall in mean total testosterone with increasing age through to old age. However we do show that there is an increased variation in total testosterone levels with advancing age after age 40 years. This model provides the age related reference ranges needed to support research and clinical decision making in males who have symptoms that may be due to hypogonadism. PMID:25295520

  11. Mice Abundant in Muricholic Bile Acids Show Resistance to Dietary Induced Steatosis, Weight Gain, and to Impaired Glucose Metabolism.

    Directory of Open Access Journals (Sweden)

    Ylva Bonde

    Full Text Available High endogenous production of, or treatment with muricholic bile acids, strongly reduces the absorption of cholesterol. Mice abundant in muricholic bile acids may therefore display an increased resistance against dietary induced weight gain, steatosis, and glucose intolerance due to an anticipated general reduction in lipid absorption. To test this hypothesis, mice deficient in steroid 12-alpha hydroxylase (Cyp8b1-/- and therefore abundant in muricholic acids were monitored for 11 weeks while fed a high fat diet. Food intake and body and liver weights were determined, and lipids in liver, serum and feces were measured. Further, responses during oral glucose and intraperitoneal insulin tolerance tests were evaluated. On the high fat diet, Cyp8b1-/- mice displayed less weight gain compared to wildtype littermates (Cyp8b1+/+. In addition, liver enlargement with steatosis and increases in serum LDL-cholesterol were strongly attenuated in Cyp8b1-/- mice on high fat diet. Fecal excretion of cholesterol was increased and there was a strong trend for doubled fecal excretion of free fatty acids, while excretion of triglycerides was unaltered, indicating dampened lipid absorption. On high fat diet, Cyp8b1-/- mice also presented lower serum glucose levels in response to oral glucose gavage or to intraperitoneal insulin injection compared to Cyp8b1+/+. In conclusion, following exposure to a high fat diet, Cyp8b1-/- mice are more resistant against weight gain, steatosis, and to glucose intolerance than Cyp8b1+/+ mice. Reduced lipid absorption may in part explain these findings. Overall, the results suggest that muricholic bile acids may be beneficial against the metabolic syndrome.

  12. β2-Adrenergic receptor ablation modulates hepatic lipid accumulation and glucose tolerance in aging mice.

    Science.gov (United States)

    Shi, Yun; Shu, Zhen-Ju; Xue, Xiaoling; Yeh, Chih-Ko; Katz, Michael S; Kamat, Amrita

    2016-06-01

    Catecholamines acting through β-adrenergic receptors (β1-, β2-, β3-AR subtypes) modulate important biological responses in various tissues. Our previous studies suggest a role for increased hepatic β-AR-mediated signaling during aging as a mediator of hepatic steatosis, liver glucose output, and insulin resistance in rodents. In the current study, we have utilized β2-AR knockout (KO) and wildtype (WT) control mice to define further the role of β2-AR signaling during aging on lipid and glucose metabolism. Our results demonstrate for the first time that age-related increases in hepatic triglyceride accumulation and body weight are attenuated upon β2-AR ablation. Although no differences in plasma triglyceride, non-esterified fatty acids or insulin levels were detected between old WT and KO animals, an age-associated increase in hepatic expression of lipid homeostasis regulator Cidea was significantly reduced in old KO mice. Interestingly, we also observed a shift from reduced glucose tolerance in young adult KO animals to significantly improved glucose tolerance in old KO when compared to age-matched WT mice. These results provide evidence for an important role played by β2-ARs in the regulation of lipid and glucose metabolism during aging. The effect of β2-AR ablation on caloric intake during aging is currently not known and requires investigation. Future studies are also warranted to delineate the β2-AR-mediated mechanisms involved in the control of lipid and glucose homeostasis, especially in the context of a growing aging population. PMID:26952573

  13. Dietary polyphenol supplementation prevents alterations of spatial navigation in middle-aged mice

    Directory of Open Access Journals (Sweden)

    Julien eBensalem

    2016-02-01

    Full Text Available Spatial learning and memory deficits associated with hippocampal synaptic plasticity impairments are commonly observed during aging. Besides, the beneficial role of dietary polyphenols has been suggested as potential functional food candidates to prevent this memory decline. Indeed, polyphenols could potentiate the signaling pathways of synaptic plasticity underlying learning and memory. In this study, spatial learning deficits of middle-aged mice were first highlighted and characterized according to navigation patterns in the Morris water maze task. An eight-week polyphenol-enriched diet, containing a polyphenol-rich extract from grape and blueberry (PEGB (from the Neurophenols Consortium with high contents of flavonoids, stilbenes and phenolic acids, was then successful in reversing these age-induced effects. The use of spatial strategies was indeed delayed with aging whereas a polyphenol supplementation could promote the occurrence of spatial strategies. These behavioral results were associated with neurobiological changes: while the expression of hippocampal CaMKII mRNA levels was reduced in middle-aged animals, the polyphenol-enriched diet could rescue them. Besides, an increased expression of NGF mRNA levels was also observed in supplemented adult and middle-aged mice. Thus these data suggest that supplementation with polyphenols could be an efficient nutritional way to prevent age-induced cognitive decline.

  14. Comparison of catalase immunoreactivity in the hippocampus between young, adult and aged mice and rats.

    Science.gov (United States)

    Ahn, Ji Hyeon; Chen, Bai Hui; Shin, Bich-Na; Lee, Tae-Kyeong; Cho, Jeong Hwi; Kim, In Hye; Park, Joon Ha; Lee, Jae-Chul; Tae, Hyun-Jin; Lee, Choong-Hyun; Won, Moo-Ho; Lee, Yun Lyul; Choi, Soo Young; Hong, Seongkweon

    2016-07-01

    Catalase (CAT) is an important antioxidant enzyme and is crucial in modulating synaptic plasticity in the brain. In this study, CAT expression as well as neuronal distribution was compared in the hippocampus among young, adult and aged mice and rats. Male ICR mice and Sprague Dawley rats were used at postnatal month (PM) 1, PM 6 and PM 24 as the young, adult and aged groups, respectively (n=14/group). CAT expression was examined by immunohistochemistry and western blot analysis. In addition, neuronal distribution was examined by NeuN immunohistochemistry. In the present study, the mean number of NeuN‑immunoreactive neurons was marginally decreased in mouse and rat hippocampi during aging, although this change was not identified to be significantly different. However, CAT immunoreactivity was significantly increased in pyramidal and granule neurons in the adult mouse and rat hippocampi and was significantly decreased in the aged mouse and rat hippocampi compared with that in the young animals. CAT protein levels in the hippocampus were also lowest in the aged mouse and rat hippocampus. These results indicate that CAT expression is significantly decreased in the hippocampi of aged animals and decreased CAT expression may be closely associated with aging. PMID:27221506

  15. Experimental febrile seizures induce age-dependent structural plasticity and improve memory in mice.

    Science.gov (United States)

    Tao, K; Ichikawa, J; Matsuki, N; Ikegaya, Y; Koyama, R

    2016-03-24

    Population-based studies have demonstrated that children with a history of febrile seizure (FS) perform better than age-matched controls at hippocampus-dependent memory tasks. Here, we report that FSs induce two distinct structural reorganizations in the hippocampus and bidirectionally modify future learning abilities in an age-dependent manner. Compared with age-matched controls, adult mice that had experienced experimental FSs induced by hyperthermia (HT) on postnatal day 14 (P14-HT) performed better in a cognitive task that requires dentate granule cells (DGCs). The enhanced memory performance correlated with an FS-induced persistent increase in the density of large mossy fiber terminals (LMTs) of the DGCs. The memory enhancement was not observed in mice that had experienced HT-induced seizures at P11 which exhibited abnormally located DGCs in addition to the increased LMT density. The ectopic DGCs of the P11-HT mice were abolished by the diuretic bumetanide, and this pharmacological treatment unveiled the masked memory enhancement. Thus, this work provides a novel basis for age-dependent structural plasticity in which FSs influence future brain function. PMID:26794590

  16. Restoration of the immune functions in aged mice by supplementation with a new herbal composition, HemoHIM.

    Science.gov (United States)

    Park, Hae-Ran; Jo, Sung-Kee; Jung, Uhee; Yee, Sung-Tae

    2008-01-01

    The effect of a new herbal composition, HemoHIM, on immune functions was examined in aged mice, in which various immune responses had been impaired. The composition HemoHIM was prepared by adding the ethanol-insoluble fraction to the total water extract of a mixture of three edible herbs, Angelica Radix, Cnidium Rhizoma and Paeonia Radix. Supplementation to the aged mice with HemoHIM restored the proliferative response and cytokine production of splenocytes with a response to ConA. Also, HemoHIM recovered the NK cell activity which had been impaired in the aged mice. Meanwhile aging is known to reduce the Th1-like function, but not the Th2-like function, resulting in a Th1/Th2 imbalance. HemoHIM restored the Th1/Th2 balance in the aged mice through enhanced IFN-gamma and IgG2a production, and conversely a reduced IL-4 and IgG1 production. It was found that one factor for the Th1/Th2 imbalance in the aged mice was a lower production of IL-12p70. However, HemoHIM restored the IL-12p70 production in the aged mice. These results suggested that HemoHIM was effective for the restoration of impaired immune functions of the aged mice and therefore could be a good recommendation for immune restoration in elderly humans. PMID:17705143

  17. Mice with targeted Slc4a10 gene disruption have small brain ventricles and show reduced neuronal excitability

    OpenAIRE

    Jacobs, Stefan; Ruusuvuori, Eva; Sipilä, Sampsa T; Haapanen, Aleksi; Damkier, Helle H.; Kurth, Ingo; Hentschke, Moritz; Schweizer, Michaela; Rudhard, York; Laatikainen, Linda M.; Tyynelä, Jaana; Praetorius, Jeppe; Voipio, Juha; Hübner, Christian A

    2007-01-01

    Members of the SLC4 bicarbonate transporter family are involved in solute transport and pH homeostasis. Here we report that disrupting the Slc4a10 gene, which encodes the Na+-coupled Cl−–HCO3− exchanger Slc4a10 (NCBE), drastically reduces brain ventricle volume and protects against fatal epileptic seizures in mice. In choroid plexus epithelial cells, Slc4a10 localizes to the basolateral membrane. These cells displayed a diminished recovery from an acid load in KO mice. Slc4a10 also was expres...

  18. Reactive Oxygen Species Limit the Ability of Bone Marrow Stromal Cells to Support Hematopoietic Reconstitution in Aging Mice

    Science.gov (United States)

    Khatri, Rahul; Krishnan, Shyam; Roy, Sushmita; Chattopadhyay, Saborni; Kumar, Vikash

    2016-01-01

    Aging of organ and abnormal tissue regeneration are recurrent problems in physiological and pathophysiological conditions. This is most crucial in case of high-turnover tissues, like bone marrow (BM). Using reciprocal transplantation experiments in mouse, we have shown that self-renewal potential of hematopoietic stem and progenitor cells (HSPCs) and BM cellularity are markedly influenced with the age of the recipient mice rather than donor mice. Moreover, accumulation of excessive reactive oxygen species (ROS) in BM stromal cells compared to HSPC compartment, in time-dependent manner, suggests that oxidative stress is involved in suppression of BM cellularity by affecting microenvironment in aged mice. Treatment of these mice with a polyphenolic antioxidant curcumin is found to partially quench ROS, thereby rescues stromal cells from oxidative stress-dependent cellular injury. This rejuvenation of stromal cells significantly improves hematopoietic reconstitution in 18-month-old mice compared to age control mice. In conclusion, this study implicates the role of ROS in perturbation of stromal cell function upon aging, which in turn affects BM's reconstitution ability in aged mice. Thus, a rejuvenation therapy using curcumin, before HSPC transplantation, is found to be an efficient strategy for successful marrow reconstitution in older mice. PMID:27140293

  19. Effect of Cistanche Desertica Polysaccharides on Learning and Memory Functions and Ultrastructure of Cerebral Neurons in Experimental Aging Mice

    Institute of Scientific and Technical Information of China (English)

    孙云; 邓杨梅; 王德俊; 沈春锋; 刘晓梅; 张洪泉

    2001-01-01

    To observe the effects of Cistanche desertica polysaccharides (CDP) on the learning and memory functions and cerebral ultrastructure in experimental aging mice. Methods: CDP was administrated intragastrically 50 or 100 mg/kg per day for 64 successive days to experimental aging model mice induced by D-galactose, then the learning and memory functions of mice were estimated by step-down test and Y-maze test; organelles of brain tissue and cerebral ultrastructure were observed by transmission electron microscope and physical strength was determined by swimming test. Results: CDP could obviously enhance the learning and memory functions (P<0.01) and prolong the swimming time (P<0.05), decrease the number of lipofuscin and slow down the degeneration of mitochondria in neurons(P<0.05), and improve the degeneration of cerebral ultra-structure in aging mice. Conclusion: CDP could improve the impaired physiological function and alleviate cerebral morphological change in experimental aging mice.

  20. Aged mice have increased inflammatory monocyte concentration and altered expression of cell-surface functional receptors

    Indian Academy of Sciences (India)

    Kelley Strohacker; Whitney L Breslin; Katie C Carpenter; Brian K McFarlin

    2012-03-01

    The expression of monocyte cell-surface receptors represents one index of immune dysfunction, which is common with aging. Although mouse models of aging are prevalent, monocyte subset assessment is rare. Our purpose was to compare cell receptor expression on classic (CD115+/Gr-1high) and non-classic (CD115+/Gr-1low) monocytes from 80- or 20-week-old CD-1 mice. Three-colour flow cytometry was used to determine the concentration of monocyte subsets and their respective cell-surface expression of TLR2, TLR4, CD80, CD86, MHC II and CD54. These receptors were selected because they have been previously associated with altered monocyte function. Data were analysed with independent -tests; significance was set at < 0.05. Old mice had a greater concentration of both classic (258%, =0.003) and non-classic (70%, =0.026) monocytes. The classic : non-classic monocyte ratio doubled in old as compared with that in young mice (=0.006), indicating a pro-inflammatory shift. TLR4 ($\\downarrow$27%, =0.001) and CD80 ($\\downarrow$37%, =0.004) were decreased on classic monocytes from old as compared with those from young mice. TLR2 ($\\uparrow$24%, =0.002) and MHCII ($\\downarrow$21%, =0.026) were altered on non-classic monocytes from old as compared with those from young mice. The increased classic : non-classic monocyte ratio combined with changes in the cell-surface receptor expression on both monocyte subsets is indicative of immune dysfunction, which may increase age-associated disease risk.

  1. BubR1 Insufficiency Impairs Liver Regeneration in Aged Mice after Hepatectomy through Intercalated Disc Abnormality.

    Science.gov (United States)

    Ikawa-Yoshida, Ayae; Matsumoto, Takuya; Okano, Shinji; Aoyagi, Yukihiko; Matsubara, Yutaka; Furuyama, Tadashi; Nakatsu, Yoshimichi; Tsuzuki, Teruhisa; Onimaru, Mitsuho; Ohkusa, Tomoko; Nomura, Masatoshi; Maehara, Yoshihiko

    2016-01-01

    A delay in liver regeneration after partial hepatectomy (PHx) leads to acute liver injury, and such delays are frequently observed in aged patients. BubR1 (budding uninhibited by benzimidazole-related 1) controls chromosome mitotic segregation through the spindle assembly checkpoint, and BubR1 down-regulation promotes aging-associated phenotypes. In this study we investigated the effects of BubR1 insufficiency on liver regeneration in mice. Low-BubR1-expressing mutant (BubR1(L/L)) mice had a delayed recovery of the liver weight-to-body weight ratio and increased liver deviation enzyme levels after PHx. Microscopic observation of BubR1(L/L) mouse liver showed an increased number of necrotic hepatocytes and intercalated disc anomalies, resulting in widened inter-hepatocyte and perisinusoidal spaces, smaller hepatocytes and early-stage microvilli atrophy. Up-regulation of desmocollin-1 (DSC1) was observed in wild-type, but not BubR1(L/L), mice after PHx. In addition, knockdown of BubR1 expression caused down-regulation of DSC1 in a human keratinocyte cell line. BubR1 insufficiency results in the impaired liver regeneration through weakened microstructural adaptation against PHx, enhanced transient liver failure and delayed hepatocyte proliferation. Thus, our data suggest that a reduction in BubR1 levels causes failure of liver regeneration through the DSC1 abnormality. PMID:27561386

  2. Aging in mice reduces the ability to sustain sleep/wake states.

    Directory of Open Access Journals (Sweden)

    Mathieu E Wimmer

    Full Text Available One of the most significant problems facing older individuals is difficulty staying asleep at night and awake during the day. Understanding the mechanisms by which the regulation of sleep/wake goes awry with age is a critical step in identifying novel therapeutic strategies to improve quality of life for the elderly. We measured wake, non-rapid eye movement (NREM and rapid-eye movement (REM sleep in young (2-4 months-old and aged (22-24 months-old C57BL6/NIA mice. We used both conventional measures (i.e., bout number and bout duration and an innovative spike-and-slab statistical approach to characterize age-related fragmentation of sleep/wake. The short (spike and long (slab components of the spike-and-slab mixture model capture the distribution of bouts for each behavioral state in mice. Using this novel analytical approach, we found that aged animals are less able to sustain long episodes of wakefulness or NREM sleep. Additionally, spectral analysis of EEG recordings revealed that aging slows theta peak frequency, a correlate of arousal. These combined analyses provide a window into the mechanisms underlying the destabilization of long periods of sleep and wake and reduced vigilance that develop with aging.

  3. Interaction between diazepam and hippocampal corticosterone after acute stress: impact on memory in middle-aged mice

    Directory of Open Access Journals (Sweden)

    Daniel eBeracochea

    2011-04-01

    Full Text Available Benzodiazepines (BDZ are widely prescribed in the treatment of anxiety disorders associated to aging. Interestingly, whereas a reciprocal interaction between the GABAergic system and HPA axis has been evidenced, there is to our knowledge no direct evaluation of the impact of BDZ on both hippocampus (HPC corticosterone concentrations and HPC-dependent memory in stressed middle-aged subjects. We showed previously that an acute stress induced in middle-aged mice severe memory impairments in a hippocampus-dependent task, and increased in parallel hippocampus corticosterone concentrations, as compared to non stressed middle-aged controls (Tronche et al., 2010. Based on these findings, the aims of the present study were to evidence the impact of diazepam (a positive allosteric modulator of the GABA-A receptor on HPC glucocorticoids concentrations and in parallel on HPC-dependent memory in acutely stressed middle-aged mice.Microdialysis experiments showed an interaction between diazepam doses and corticosterone concentrations into the HPC. From 0.25 mg/kg to 0.5 mg/kg, diazepam dose-dependently reduces intra-HPC corticosterone concentrations and in parallel, dose-dependently increased hippocampal-dependent memory performance. In contrast, the highest (1.0mg/kg diazepam dose induces a reduction in HPC corticosterone concentration, which was of greater magnitude as compared to the two other diazepam doses, but however decreased the hippocampal-dependent memory performance. In summary, our study provides first evidence that diazepam restores in stressed middle-aged animals the hippocampus-dependent response, in relation with HPC corticosterone concentrations. Overall, our data illustrate how stress and benzodiazepines could modulate cognitive functions depending on hippocampus activity.

  4. Recovery of immune competence following sublethal X irradiation of young and old mice: a model for studying age-related loss of immunologic homeostasis

    International Nuclear Information System (INIS)

    Age-related alteration in lymphohematopoietic homeostasis was assessed kinetically by determining immunologic and stem-cell regenerating capacities of young (5-7 months), middle-aged (13 months), and old (23-24 months) C3H and C57BL/6 mice following their exposure to 500 R. Immunologic activities were based on the ability of spleen cells to respond to sheep erythrocytes, phytohemagglutinin, and bacterial lipopolysaccharide. Stem-cell activity was based on the ability of splenic and bone marrow cells to form colonies in vivo. Reflective of age-related homeostatic imbalance was alteration in the (a) time of recovery, (b) rate of regeneration, and (c) capacity of the regenerating system to overshoot the preirradition steady-state level. Most of the immunologic parameters showed a delay in the time of recovery in old mice. In contrast, the time of recovery of stem cells in old mice was equal to or faster than that in young mice. Furthermore, the magnitude of regeneration of stem cells was greater in old than young mice. These results suggest that recovery of immunologic activities in old mice is delayed partly because of the inability of their stem cells to rapidly generate immunocompetent progenies

  5. Early Signs of Pathological Cognitive Aging in Mice Lacking High-Affinity Nicotinic Receptors

    OpenAIRE

    Konsolaki, Eleni; Tsakanikas, Panagiotis; Polissidis, Alexia V.; Stamatakis, Antonios; Skaliora, Irini

    2016-01-01

    In order to address pathological cognitive decline effectively, it is critical to adopt early preventive measures in individuals considered at risk. It is therefore essential to develop approaches that identify such individuals before the onset of irreversible dementia. A deficient cholinergic system has been consistently implicated as one of the main factors associated with a heightened vulnerability to the aging process. In the present study we used mice lacking high affinity nicotinic rece...

  6. Early maternal separation impacts cognitive flexibility at the age of first independence in mice.

    Science.gov (United States)

    Thomas, A Wren; Caporale, Natalia; Wu, Claudia; Wilbrecht, Linda

    2016-04-01

    Early life adversity is associated with increased risk for mental and physical health problems, including substance abuse. Changes in neural development caused by early life insults could cause or complicate these conditions. Maternal separation (MS) is a model of early adversity for rodents. Clear effects of MS have been shown on behavioral flexibility in rats, but studies of effects of MS on cognition in mice have been mixed. We hypothesized that previous studies focused on adult mice may have overlooked a developmental transition point when juvenile mice exhibit greater flexibility in reversal learning. Here, using a 4-choice reversal learning task we find that early MS leads to decreased flexibility in post-weaning juvenile mice, but no significant effects in adults. In a further study of voluntary ethanol consumption, we found that adult mice that had experienced MS showed greater cumulative 20% ethanol consumption in an intermittent access paradigm compared to controls. Our data confirm that the MS paradigm can reduce cognitive flexibility in mice and may enhance risk for substance abuse. We discuss possible interpretations of these data as stress-related impairment or adaptive earlier maturation in response to an adverse environment. PMID:26531108

  7. Minocycline attenuates post-operative cognitive impairment in aged mice by inhibiting microglia activation.

    Science.gov (United States)

    Wang, Hui-Lin; Liu, Hua; Xue, Zhang-Gang; Liao, Qing-Wu; Fang, Hao

    2016-09-01

    Although it is known that isoflurane exposure or surgery leads to post-operative cognitive dysfunction in aged rodents, there are few clinical interventions and treatments available to prevent this disorder. Minocycline (MINO) produces neuroprotection from several neurodegenerative diseases and various experimental animal models. Therefore, we set out to investigate the effects of MINO pre-treatment on isoflurane or surgery induced cognitive impairment in aged mice by assessing the hippocampal-dependent spatial memory performance using the Morris water maze task. Hippocampal tissues were isolated from mice and evaluated by Western blot analysis, immunofluorescence procedures and protein array system. Our results elucidate that MINO down-regulated the isoflurane-induced and surgery-induced enhancement in the protein levels of pro-inflammatory cytokine tumour necrosis factor alpha, interleukin (IL)-1β, interferon-γ and microglia marker Iba-1, and up-regulated protein levels of the anti-inflammatory cytokine IL-4 and IL-10. These findings suggest that pre-treatment with MINO attenuated isoflurane or surgery induced cognitive impairment by inhibiting the overactivation of microglia in aged mice. PMID:27061744

  8. Aged mice display an altered pulmonary host response to Francisella tularensis live vaccine strain (LVS) infections

    OpenAIRE

    CA, Mares; SS, Ojeda; Q., Li; EG, Morris; JJ, Coalson; JM, Teale

    2009-01-01

    Aging is a complex phenomenon that has been shown to affect many organ systems including the innate and adaptive immune systems. The current study was designed to examine the potential effect of immunosenescence on the pulmonary immune response using a Francisella tularensis live vaccine strain (LVS) inhalation infection model. F. tularensis is a gram-negative intracellular pathogen that can cause a severe pneumonia.In this study both young (8-12 week old) and aged (20-24 month old) mice were...

  9. Lifelong vitamin E intake retards age-associated decline of spatial learning ability in apoE-deficient mice

    OpenAIRE

    McDonald, Shelley R.; Forster, Michael J.

    2005-01-01

    The potential for lifelong vitamin E supplementation to delay age-associated cognitive decline was tested in apoE-deficient and wild-type C57BL/6 mice. Beginning at eight weeks of age, the mice were maintained on a control diet or diets supplemented with dl-α-tocopheryl acetate yielding approximate daily intakes of either 20 or 200 mg/kg body weight. When 6 or 18 months of age, cognitive functioning of the mice was assessed using swim maze and discriminated avoidance testing procedures. For t...

  10. The Cardioprotective Effect of Vitamin E (Alpha-Tocopherol) Is Strongly Related to Age and Gender in Mice

    OpenAIRE

    Hu, Xiao-Xia; Fu, Li; Li, Yan; Lin, Ze-Bang; Liu, Xiang; Wang, Jing-Feng; Chen, Yang-xin; Wang, Zhi-Ping; Zhang, Xi; Ou, Zhi-Jun; Ou, Jing-Song

    2015-01-01

    Vitamin E (VitE) only prevented cardiovascular diseases in some patients and the mechanisms remain unknown. VitE levels can be affected by aging and gender. We hypothesize that age and gender can influence VitE’s cardioprotective effect. Mice were divided into 4 groups according to age and gender, and each group of mice were divided into a control group and a VitE group. The mice were administered water or VitE for 21 days; Afterward, the cardiac function and myocardial infarct size and cardi...

  11. Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice.

    Science.gov (United States)

    Mitchell, Sarah J; Madrigal-Matute, Julio; Scheibye-Knudsen, Morten; Fang, Evandro; Aon, Miguel; González-Reyes, José A; Cortassa, Sonia; Kaushik, Susmita; Gonzalez-Freire, Marta; Patel, Bindi; Wahl, Devin; Ali, Ahmed; Calvo-Rubio, Miguel; Burón, María I; Guiterrez, Vincent; Ward, Theresa M; Palacios, Hector H; Cai, Huan; Frederick, David W; Hine, Christopher; Broeskamp, Filomena; Habering, Lukas; Dawson, John; Beasley, T Mark; Wan, Junxiang; Ikeno, Yuji; Hubbard, Gene; Becker, Kevin G; Zhang, Yongqing; Bohr, Vilhelm A; Longo, Dan L; Navas, Placido; Ferrucci, Luigi; Sinclair, David A; Cohen, Pinchas; Egan, Josephine M; Mitchell, James R; Baur, Joseph A; Allison, David B; Anson, R Michael; Villalba, José M; Madeo, Frank; Cuervo, Ana Maria; Pearson, Kevin J; Ingram, Donald K; Bernier, Michel; de Cabo, Rafael

    2016-06-14

    Calorie restriction (CR) is the most robust non-genetic intervention to delay aging. However, there are a number of emerging experimental variables that alter CR responses. We investigated the role of sex, strain, and level of CR on health and survival in mice. CR did not always correlate with lifespan extension, although it consistently improved health across strains and sexes. Transcriptional and metabolomics changes driven by CR in liver indicated anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. CR prevented age-associated decline in the liver proteostasis network while increasing mitochondrial number, preserving mitochondrial ultrastructure and function with age. Abrogation of mitochondrial function negated life-prolonging effects of CR in yeast and worms. Our data illustrate the complexity of CR in the context of aging, with a clear separation of outcomes related to health and survival, highlighting complexities of translation of CR into human interventions. PMID:27304509

  12. Effects of velvet antler polypeptide on sexual behavior and testosterone synthesis in aging male mice

    Science.gov (United States)

    Zang, Zhi-Jun; Tang, Hong-Feng; Tuo, Ying; Xing, Wei-Jie; Ji, Su-Yun; Gao, Yong; Deng, Chun-Hua

    2016-01-01

    Twenty-four-month-old male C57BL/6 mice with low serum testosterone levels were used as a late-onset hypogonadism (LOH) animal model for examining the effects of velvet antler polypeptide (VAP) on sexual function and testosterone synthesis. These mice received VAP for 5 consecutive weeks by daily gavage at doses of 100, 200, or 300 mg kg−1 body weight per day (n = 10 mice per dose). Control animals (n = 10) received the same weight-based volume of vehicle. Sexual behavior and testosterone levels in serum and interstitial tissue of testis were measured after the last administration of VAP. Furthermore, to investigate the mechanisms of how VAP affects sexual behavior and testosterone synthesis in vivo, the expression of steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), and 3β-hydroxysteroid dehydrogenase (3β-HSD) in Leydig cells was also measured by immunofluorescence staining and quantitative real-time PCR. As a result, VAP produced a significant improvement in the sexual function of these aging male mice. Serum testosterone level and intratesticular testosterone (ITT) concentration also increased in the VAP-treated groups. The expression of StAR, P450scc, and 3β-HSD was also found to be enhanced in the VAP-treated groups compared with the control group. Our results suggested that VAP was effective in improving sexual function in aging male mice. The effect of velvet antler on sexual function was due to the increased expression of several rate-limiting enzymes of testosterone synthesis (StAR, P450scc, and 3β-HSD) and the following promotion of testosterone synthesis in vivo. PMID:26608944

  13. Age related retention and dose burden after injection of 224Ra and 227Th in mice

    International Nuclear Information System (INIS)

    Incorporation of 224Ra in different aged female NMRI mice was investigated. The retention in skeleton (long bones) decreased continuously with age and remained constant after an age of about 10 months (decrease of percentage uptake from 50 to 25%). Rather similar conditions were found for the retention of 227Th, but with a somewhat smaller decrease (45 to 35%). These skeletal doses are often based on the values of femur concentration. In the case of mice, however, most bone tumours occur in the lumbar vertebrae, where the retention does not vary much with age. In contrast to the skeleton the retention of 224Ra was increased with age in the spleen, reaching concentrations even higher than that in the skeleton of old animals. It was remarkable that radium was retained in the spleen in this high concentration only when it was injected directly (as 224Ra) but much less, when it was given indirectly i.e. as the daughter nuclide 223Ra of its parent 227Th. If equal skeletal doses for different aged animals are to be intended, the reduced retention in the higher age has to be taken into account. Since dosage is mostly related to body weight (for instance Bq per kilogram) the resulting skeletal dose will be too small if the body weight and skeletal weight would be proportional. Since by the growth of fat tissue the body weight normally increases more than skeletal weight (after an age of a few months), the lowered retention might be more or less corrected for by relating to body weight. 3 refs.; 3 figs

  14. The sensitivity of female NMRI mice of different ages for osteosarcoma induction with 227thorium

    International Nuclear Information System (INIS)

    The effect of age on osteosarcoma induction after incorporation of the short-lived alpha-emitter 227Th was studied in 12 month old and young (1 month and 3 month old) female NMRI mice. Injection of 1 μCi/kg 227Th in 1 month or 12 month old mice induced osteosarcomas with a similar incidence in both groups (21% and 16%, maximum corrected cumulative incidence 32% and 43%). The osteosarcoma appearance time in the older animals was shorter and there was no significant difference in the age at appearance of osteosarcomas in the two groups. After injection of 5 μCi/kg 227Th the maximum corrected cumulative osteosarcoma incidence was considerably lower in the older group (10%) than in the younger group (61%) despite the fact that there were 32 survivors in the older group at the time of appearance of the last osteosarcoma. Incorporation of 2x1 μCi/kg 227Th at the age of 12 months and 14 months or 3 months and 5 months induced osteosarcoma with a similar maximum corrected cumulative osteosarcoma incidence (62% and 68% respectively). The mean osteosarcoma appearance time after the first incorporation was shorter in the older age group than in the younger age group but osteosarcomas still appeared overall at a younger age in the younger age group. The mean osteosarcoma appearance time after the first incorporation following fractionation of the internal irradiation period, by injection of 1 μCi/kg at the age of 3 months and 12 months, was significantly longer than in either the 3-months/5-months group or the 12-months /14-months group. (orig.)

  15. Enzyme-treated Asparagus officinalis extract shows neuroprotective effects and attenuates cognitive impairment in senescence-accelerated mice.

    Science.gov (United States)

    Sakurai, Takuya; Ito, Tomohiro; Wakame, Koji; Kitadate, Kentaro; Arai, Takashi; Ogasawara, Junetsu; Kizaki, Takako; Sato, Shogo; Ishibashi, Yoshinaga; Fujiwara, Tomonori; Akagawa, Kimio; Ishida, Hitoshi; Ohno, Hideki

    2014-01-01

    Increases in the number of patients with dementia involving Alzheimer's disease (AD) are seen as a grave public health problem. In neurodegenerative disorders involving AD, biological stresses, such as oxidative and inflammatory stress, induce neural cell damage. Asparagus (Asparagus officinalis) is a popular vegetable, and an extract prepared from this reportedly possesses various beneficial biological activities. In the present study, we investigated the effects of enzyme-treated asparagus extract (ETAS) on neuronal cells and early cognitive impairment of senescence-accelerated mouse prone 8 (SAMP8) mice. The expression of mRNAs for factors that exert cytoprotective and anti-apoptotic functions, such as heat-shock protein 70 and heme oxygenase-1, was upregulated in NG108-15 neuronal cells by treatment with ETAS. Moreover, when release of lactate dehydrogenase from damaged NG108-15 cells was increased for cells cultured in medium containing either the nitric oxide donor sodium nitroprusside or the hypoxia mimic reagent cobalt chloride, ETAS significantly attenuated this cell damage. Also, when contextual fear memory, which is considered to be a hippocampus-dependent memory, was significantly impaired in SAMP8 mice, ETAS attenuated the cognitive impairment. These results suggest that ETAS produces cytoprotective effects in neuronal cells and attenuates the effects on the cognitive impairment of SAMP8 mice. PMID:24660475

  16. Evaluation of Diagnostic Methods for Myocoptes musculinus According to Age and Treatment Status of Mice (Mus musculus)

    OpenAIRE

    Rice, Kelly A; Albacarys, Lauren K; Pate, Kelly A. Metcalf; Perkins, Cheryl; Henderson, Kenneth S; Watson, Julie

    2013-01-01

    Detecting and controlling murine fur mites continues to be challenging. Here we compared the efficacy of fur-pluck, cage PCR, and fur PCR testing of mice naturally infested with Myocoptes musculinus and make recommendations regarding the application of these diagnostic strategies in aged or treated mice. We compared all 3 diagnostic methods in groups of infested and noninfested control mice over time. For fur plucks, we used a scoring system to quantitatively compare mite infestations across ...

  17. Accelerated ovarian aging in mice by treatment of busulfan and cyclophosphamide

    Institute of Scientific and Technical Information of China (English)

    Yan JIANG; Jing ZHAO; Hui-jing QI; Xiao-lin LI; Shi-rong ZHANG; Daniel W.SONG; Chi-yang YU

    2013-01-01

    Busulfan/cyclophosphamide (Bu/Cy) conditioning regimen has been widely used to treat cancer patients,while their effects on major internal organs in females are not fully understood.We treated female mice with Bu/Cy,and examined the histopathology of major internal organs on Day 30 after the treatment.The results show that Bu/Cy treatment affected the ovaries most extensively,while it had less effect on the spleen,lungs,and kidneys,and no effect on the heart,liver,stomach,and pancreas.To better understand the effect of Bu/Cy on the ovaries,we counted follicles,and determined the levels of ovarian steroids.The Bu/Cy-treated mice showed a reduction of primordial and primary follicles (P<0.01) on Day 30 and a marked loss of follicles at all developmental stages (P<0.01) on Day 60.Plasma levels of estradiol and progesterone in Bu/Cy-treated mice decreased by 43.9% and 61.4%,respectively.Thus,there was a gradual process of follicle loss and low estradiol in Bu/Cy-treated mice; this is a profile similar to what is found in women with premature ovarian failure (POF).The Bu/Cy-treated mice may serve as a useful animal model to study the dynamics of follicle loss in women undergoing POF.

  18. The antioxidant effect of astaxanthin is higher in young mice than aged: a region specific study on brain.

    Science.gov (United States)

    Al-Amin, Md Mamun; Akhter, Samiha; Hasan, Ahmed Tasdid; Alam, Tanzir; Nageeb Hasan, S M; Saifullah, A R M; Shohel, Mohammad

    2015-10-01

    Astaxanthin is a potential antioxidant which shows neuroprotective property. We aimed to investigate the age-dependent and region-specific antioxidant effects of astaxanthin in mice brain. Animals were divided into 4 groups; treatment young (3 months, n = 6) (AY), treatment old (16 months, n = 6) (AO), placebo young (3 months, n = 6) (PY) and placebo old (16 months, n = 6) (PO) groups. Treatment group was given astaxanthin (2 mg/kg/day, body weight), and placebo group was given 100 μl of 0.9% normal saline orally to the healthy Swiss albino mice for 4 weeks. The level of non-enzymatic oxidative markers namely malondialdehyde (MDA); nitric oxide (NO); advanced protein oxidation product (APOP); glutathione (GSH) and the activity of enzymatic antioxidants i.e.; catalase (CAT) and superoxide dismutase (SOD) were determined from the isolated brain regions. Treatment with astaxanthin significantly (p Astaxanthin markedly (p astaxanthin is age-dependent, higher in young in compared to the aged brain. PMID:26116165

  19. Age influence on mice lung tissue response to [i]Aspergillus fumigatus[/i] chronic exposure

    Directory of Open Access Journals (Sweden)

    Marta Kinga Lemieszek

    2015-02-01

    Full Text Available [b]Introduction and objective[/b]. Exposure to conidia of [i]Aspergillus fumigatus[/i] was described as a causative factor of a number of the respiratory system diseases, including asthma, chronic eosinophilic pneumonia, hypersensitivity pneumonitis and bronchopulmonary aspergillosis. The study investigates the effects of the repeated exposure to [i]A. fumigatus[/i] in mice pulmonary compartment. Our work tackles two, so far insufficiently addressed, important aspects of interaction between affected organism and[i] A. fumigatus[/i]: 1 recurrent character of exposure (characteristic for pathomechanism of the abovementioned disease states and 2 impact of aging, potentially important for the differentiation response to an antigen. [b]Materials and methods[/b]. In order to dissect alterations of the immune system involved with both aging and chronic exposure to [i]A. fumigatus[/i], we used 3- and 18-month-old C57BL/6J mice exposed to repeated[i] A. fumigatus[/i] inhalations for 7 and 28 days. Changes in lung tissue were monitored by histological and biochemical evaluation. Concentration of pro- and anti-inflammatory cytokines in lung homogenates was assessed by ELISA tests. [b]Results and conclusions. [/b]Our study demonstrated that chronic inflammation in pulmonary compartment, characterized by the significant increase of proinflammatory cytokines (IL1, IL6, IL10 levels, was the dominant feature of mice response to repeated [i]A. fumigatus[/i] inhalations. The pattern of cytokines’ profile in the course of exposure was similar in both age groups, however in old mice the growth of the cytokines’ levels was more pronounced (especially in case of IL1.

  20. A myostatin inhibitor (propeptide-Fc) increases muscle mass and muscle fiber size in aged mice but does not increase bone density or bone strength.

    Science.gov (United States)

    Arounleut, Phonepasong; Bialek, Peter; Liang, Li-Fang; Upadhyay, Sunil; Fulzele, Sadanand; Johnson, Maribeth; Elsalanty, Mohammed; Isales, Carlos M; Hamrick, Mark W

    2013-09-01

    Loss of muscle and bone mass with age are significant contributors to falls and fractures among the elderly. Myostatin deficiency is associated with increased muscle mass in mice, dogs, cows, sheep and humans, and mice lacking myostatin have been observed to show increased bone density in the limb, spine, and jaw. Transgenic overexpression of myostatin propeptide, which binds to and inhibits the active myostatin ligand, also increases muscle mass and bone density in mice. We therefore sought to test the hypothesis that in vivo inhibition of myostatin using an injectable myostatin propeptide (GDF8 propeptide-Fc) would increase both muscle mass and bone density in aged (24 mo) mice. Male mice were injected weekly (20 mg/kg body weight) with recombinant myostatin propeptide-Fc (PRO) or vehicle (VEH; saline) for four weeks. There was no difference in body weight between the two groups at the end of the treatment period, but PRO treatment significantly increased mass of the tibialis anterior muscle (+ 7%) and increased muscle fiber diameter of the extensor digitorum longus (+ 16%) and soleus (+ 6%) muscles compared to VEH treatment. Bone volume relative to total volume (BV/TV) of the femur calculated by microCT did not differ significantly between PRO- and VEH-treated mice, and ultimate force (Fu), stiffness (S), toughness (U) measured from three-point bending tests also did not differ significantly between groups. Histomorphometric assays also revealed no differences in bone formation or resorption in response to PRO treatment. These data suggest that while developmental perturbation of myostatin signaling through either gene knockout or transgenic inhibition may alter both muscle and bone mass in mice, pharmacological inhibition of myostatin in aged mice has a more pronounced effect on skeletal muscle than on bone. PMID:23832079

  1. CpG ODN Enhances Immunization Effects of Hepatitis B Vaccine in Aged Mice

    Institute of Scientific and Technical Information of China (English)

    WeibingQin; JianweiJiang; QiaoerChen; NingYang; YifengWang; XiangcaiWei; RuqiangOu

    2004-01-01

    Oligodeoxynucleotides (ODN) containing unmethylated CpG dinucleotides in contexts of unique sequence (CpG motifs) is active as adjuvant in induction of cellular and humoral immune responses in young mice. To date, there are only limited reports about effect of CpG ODN on immune responses against hepatitis B (HB) infection in aged mice. Our studies demonstrated there were significant increases in secreting of total anti-HB IgG, IgG1 and IgG2a, as well as of IL-12 and IFN-γ, when CpG ODNs were injected together with hepatitis B antigen in aged mice. Moreover, CpG ODN could stimulate proliferation of spleen lymphocytes in a dose-dependent manner. Taken together, the results we obtained indicate that the adding of CpG ODN into the vaccine antigen might be useful in development of more effective vaccination for inducing anti-HB virus responses in the elderly. Cellular & Molecular Immunology. 2004;1(2):148-152.

  2. CpG ODN Enhances Immunization Effects of Hepatitis B Vaccine in Aged Mice

    Institute of Scientific and Technical Information of China (English)

    Weibing Qin; Jianwei Jiang; Qiaoer Chen; Ning Yang; Yifeng Wang; Xiangcai Wei; Ruqiang Ou

    2004-01-01

    Oligodeoxynucleotides (ODN) containing unmethylated CpG dinucleotides in contexts of unique sequence (CpG motifs) is active as adjuvant in induction of cellular and humoral immune responses in young mice. To date, there are only limited reports about effect of CpG ODN on immune responses against hepatitis B (HB) infection in aged mice. Our studies demonstrated there were significant increases in secreting of total anti-HB IgG, IgG1 and IgG2a, as well as of IL-12 and IFN-γ, when CpG ODNs were injected together with hepatitis B antigen in aged mice. Moreover, CpG ODN could stimulate proliferation of spleen lymphocytes in a dose-dependent manner. Taken together, the results we obtained indicate that the adding of CpG ODN into the vaccine antigen might be useful in development of more effective vaccination for inducing anti-HB virus responses in the elderly.

  3. BDNF pathway is involved in the protective effects of SS-31 on isoflurane-induced cognitive deficits in aging mice.

    Science.gov (United States)

    Wu, Jing; Zhang, Mingqiang; Li, Huihui; Sun, Xiaoru; Hao, Shuangying; Ji, Muhuo; Yang, Jianjun; Li, Kuanyu

    2016-05-15

    Mitochondrial dysfunction has been linked to the earliest pathogenesis of isoflurane-induced cognitive impairments in developing or aging mammalian brain. However, its molecular mechanism is poorly understood and a pharmacologic treatment to rapidly reverse mitochondrial dysfunction is lacking. Fifteen-month-old male C57BL/6 mice were exposed to isoflurane for two hours following intraperitoneal administration of mitochondrion-targeted peptide SS-31 or vehicle with 30min interval. The hippocampus was immediately removed for biochemical assays and mitochondria isolation after inhalation. Behavioral tests were evaluated by the open field test and fear conditioning test 24h after the experiment. We showed that cognitive deficits induced by exposure of the aging mice to isoflurane were accompanied by mitochondrial dysfunction in hippocampus due to loss of the enzymatic activity of complex I. This loss resulted in the increase of reactive oxygen species production, decrease of ATP production and mitochondrial membrane potential, and opening of mitochondrial permeability transition pore. Further, we provided evidence that the BDNF signaling pathway was involved in this process to regulate synaptic plasticity-related proteins, for instance, downregulation of synapsin 1, PSD-95 and p-CREB, and upregulation of NR2A, NR2B, CaMKIIα and CaMKIIβ. Of note, the isoflurane-induced cognitive deficits were rescued by SS-31 through reversal of mitochondrial dysfunction, which facilitated the regulation of BDNF signaling including the expression reversal of aforementioned important synaptic-signaling proteins in aging mice. Our data demonstrate that reversing mitochondrial dysfunction by SS-31 enhances BDNF signaling pathway and synaptic plasticity, and provides protective effects on cognitive function, thereby support the notion that SS-31 may have therapeutic benefits for elderly humans undertaking anesthesia. PMID:26944333

  4. Comparative gene expression and phenotype analyses of skeletal muscle from aged wild-type and PAPP-A-deficient mice.

    Science.gov (United States)

    Conover, Cheryl A; Bale, Laurie K; Nair, K Sreekumaran

    2016-07-01

    Mice deficient in pregnancy-associated plasma protein-A (PAPP-A) have extended lifespan associated with decreased incidence and severity of degenerative diseases of age, such as cardiomyopathy and nephropathy. In this study, the effect of PAPP-A deficiency on aging skeletal muscle was investigated. Whole-genome expression profiling was performed on soleus muscles from 18-month-old wild-type (WT) and PAPP-A knock-out (KO) mice of the same sex and from the same litter ('womb-mates') to identify potential mechanisms of skeletal muscle aging and its retardation in PAPP-A deficiency. Top genes regulated in PAPP-A KO compared to WT muscle were associated with increased muscle function, increased metabolism, in particular lipid metabolism, and decreased stress. Fiber cross-sectional area was significantly increased in solei from PAPP-A KO mice. In vitro contractility experiments indicated increased specific force and decreased fatigue in solei from PAPP-A KO mice. Intrinsic mitochondrial oxidative capacity was significantly increased in skeletal muscle of aged PAPP-A KO compared to WT mice. Moreover, 18-month-old PAPP-A KO mice exhibited significantly enhanced endurance running on a treadmill. Thus, PAPP-A deficiency in mice is associated with indices of healthy skeletal muscle function with age. PMID:27086066

  5. Age-Dependent Neuroimmune Modulation of IGF-1R in the Traumatic Mice

    Directory of Open Access Journals (Sweden)

    Zhao Hui

    2012-05-01

    Full Text Available Abstract Background Age-dependent neuroimmune modulation following traumatic stress is accompanied by discordant upregulation of Fyn signaling in the frontal cortex, but the mechanistic details of the potential cellular behavior regarding IGF-1R/Fyn have not been established. Methods Trans-synaptic IGF-1R signaling during the traumatic stress was comparably examined in wild type, Fyn (−/− and MOR (−/− mice. Techniques included primary neuron culture, in vitro kinase activity, immunoprecipitation, Western Blot, sucrose discontinuous centrifugation. Besides that, [3 H] incorporation was used to assay lymphocyte proliferation and NK cell activity. Results We demonstrate robust upregulation of synaptic Fyn activity following traumatic stress, with higher amplitude in 2-month mice than that in 1-year counterpart. We also established that the increased Fyn signaling is accompanied by its molecular connection with IGF-1R within the synaptic zone. Detained analysis using Fyn (−/− and MOR (−/− mice reveal that IGF-1R/Fyn signaling is governed to a large extent by mu opioid receptor (MOR, and with age-dependent manner; these signaling cascades played a central role in the modulation of lymphocyte proliferation and NK cell activity. Conclusions Our data argued for a pivotal role of synaptic IGF-1R/Fyn signaling controlled by MOR downstream signaling cascades were crucial for the age-dependent neuroimmune modulation following traumatic stress. The result here might present a new quality of synaptic cellular communication governing the stress like events and have significant potential for the development of therapeutic approaches designed to minimize the heightened vulnerability during aging.

  6. n-3 polyunsaturated fatty acids supplementation enhances hippocampal functionality in aged mice

    Directory of Open Access Journals (Sweden)

    Debora eCutuli

    2014-08-01

    Full Text Available As major components of neuronal membranes, omega-3 polyunsaturated acids (n-3 PUFA exhibit a wide range of regulatory functions, modulating from synaptic plasticity to neuroinflammation, from oxidative stress to neuroprotection. Recent human and animal studies indicated the n-3 PUFA neuroprotective properties in aging, with a clear negative correlation between n-3 PUFA levels and hippocampal deficits. The present multidimensional study was aimed at associating cognition, hippocampal neurogenesis, volume, neurodegeneration and metabolic correlates to verify n-3 PUFA neuroprotective effects in aging. To this aim 19 month-old mice were given n-3 PUFA mixture, or olive oil or no dietary supplement for 8 weeks during which hippocampal-dependent mnesic functions were tested. At the end of behavioral testing morphological and metabolic correlates were analyzed. n-3 PUFA supplemented aged mice exhibited better object recognition memory, spatial and localizatory memory, and aversive response retention, without modifications in anxiety levels in comparison to controls. These improved hippocampal cognitive functions occurred in the context of an enhanced cellular plasticity and a reduced neurodegeneration. In fact, n-3 PUFA supplementation increased hippocampal neurogenesis and dendritic arborization of newborn neurons, volume, neuronal density and microglial cell number, while it decreased apoptosis, astrocytosis and lipofuscin accumulation in the hippocampus. The increased levels of some metabolic correlates (blood Acetyl-L-Carnitine and brain n-3 PUFA concentrations found in n-3 PUFA supplemented mice also pointed towards an effective neuroprotection.On the basis of the present results n-3 PUFA supplementation appears to be a useful tool in health promotion and cognitive decline prevention during aging.

  7. Post activation depression of the Ia EPSP in motoneurones is reduced in both aged mice and in the G127X SOD1 model of Amyotrophic lateral sclerosis

    DEFF Research Database (Denmark)

    Hedegaard, Anne; Lehnhoff, Janna; Moldovan, Mihai;

    2014-01-01

    Post Activation Depression (PActD) is a long lasting depression of Ia afferent EPSPs in response to repetitive activation. This is of clinical relevance given its consistent reduction across a range of spastic disorders. We used in vivo intracellular recording in mice to explore changes in PActD in...... both normal aging and in the neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). We used both wild type (WT) C57BL/6J mice and the G127X SOD1 transgenic model of ALS (Jonsson et al 2004)Mice were anaesthetized with Hypnorm (0.315mg/mL fentanyl-citrate +10mg/mL fluanisone), Midazolam (5mg...... and both PS G127X (P<0.0001) and S G127X (P<0.05) mice but no significant difference between PS and S G127X mice.Our result validate the use of mice models to study PActD and show that it is reduced in both normal aging (without spasticity) and in ALS (a disorder with spasticity) questioning a direct...

  8. Blocking glucocorticoid receptors at adolescent age prevents enhanced freezing between repeated cue-exposures after conditioned fear in adult mice raised under chronic early life stress.

    Science.gov (United States)

    Arp, J Marit; Ter Horst, Judith P; Loi, Manila; den Blaauwen, Jan; Bangert, Eline; Fernández, Guillén; Joëls, Marian; Oitzl, Melly S; Krugers, Harm J

    2016-09-01

    Early life adversity can have long-lasting impact on learning and memory processes and increase the risk to develop stress-related psychopathologies later in life. In this study we investigated (i) how chronic early life stress (ELS) - elicited by limited nesting and bedding material from postnatal day 2 to 9 - affects conditioned fear in adult mice and (ii) whether these effects can be prevented by blocking glucocorticoid receptors (GRs) at adolescent age. In adult male and female mice, ELS did not affect freezing behavior to the first tone 24h after training in an auditory fear-conditioning paradigm. Exposure to repeated tones 24h after training also resulted in comparable freezing behavior in ELS and control mice, both in males and females. However, male (but not female) ELS compared to control mice showed significantly more freezing behavior between the tone-exposures, i.e. during the cue-off periods. Intraperitoneal administration of the GR antagonist RU38486 during adolescence (on postnatal days 28-30) fully prevented enhanced freezing behavior during the cue-off period in adult ELS males. Western blot analysis revealed no effects of ELS on hippocampal expression of glucocorticoid receptors, neither at postnatal day 28 nor at adult age, when mice were behaviorally tested. We conclude that ELS enhances freezing behavior in adult mice in a potentially safe context after cue-exposure, which can be normalized by brief blockade of glucocorticoid receptors during the critical developmental window of adolescence. PMID:27246249

  9. Vulnerability to nicotine self-administration in adolescent mice correlates with age-specific expression of α4* nicotinic receptors.

    Science.gov (United States)

    Renda, Anthony; Penty, Nora; Komal, Pragya; Nashmi, Raad

    2016-09-01

    The majority of smokers begin during adolescence, a developmental period with a high susceptibility to substance abuse. Adolescents are affected differently by nicotine compared to adults, with adolescents being more vulnerable to nicotine's rewarding properties. It is unknown if the age-dependent molecular composition of a younger brain contributes to a heightened susceptibility to nicotine addiction. Nicotine, the principle pharmacological component of tobacco, binds and activates nicotinic acetylcholine receptors (nAChRs) in the brain. The most prevalent is the widely expressed α4-containing (α4*) subtype which mediates reward and is strongly implicated in nicotine dependence. Exposing different age groups of mice, postnatal day (P) 44-86 days old, to a two bottle-choice oral nicotine self-administration paradigm for five days yielded age-specific consumption levels. Nicotine self-administration was elevated in the P44 group, peaked at P54-60 and was drastically lower in the P66 through P86 groups. We also quantified α4* nAChR expression via spectral confocal imaging of brain slices from α4YFP knock-in mice, in which the α4 nAChR subunit is tagged with a yellow fluorescent protein. Quantitative fluorescence revealed age-specific α4* nAChR expression in dopaminergic and GABAergic neurons of the ventral tegmental area. Receptor expression showed a strong positive correlation with daily nicotine dose, suggesting that α4* nAChR expression levels are age-specific and may contribute to the propensity to self-administer nicotine. PMID:27102349

  10. Pannexin-1 Deficient Mice Have an Increased Susceptibility for Atrial Fibrillation and Show a QT-Prolongation Phenotype

    Directory of Open Access Journals (Sweden)

    Stella Petric

    2016-02-01

    Full Text Available Background/Aims: Pannexin-1 (Panx1 is an ATP release channel that is ubiquitously expressed and coupled to several ligand-gated receptors. In isolated cardiac myocytes, Panx1 forms large conductance channels that can be activated by Ca2+ release from the sarcoplasmic reticulum. Here we characterized the electrophysiological function of these channels in the heart in vivo, taking recourse to mice with Panx1 ablation. Methods: Cardiac phenotyping of Panx1 knock-out mice (Panx1-/- was performed by employing a molecular, cellular and functional approach, including echocardiography, surface and telemetric ECG recordings with QT analysis, physical stress testing and quantification of heart rate variability. In addition, an in vivo electrophysiological study entailed programmed electrical stimulation using an intracardiac octapolar catheter. Results: Panx1 deficiency results in a higher incidence of AV-block, delayed ventricular depolarisation, significant prolongation of QT- and rate corrected QT-interval and a higher incidence of atrial fibrillation after intraatrial burst stimulation. Conclusion: Panx1 seems to play an important role in murine cardiac electrophysiology and warrants further consideration in the context of hereditary forms of atrial fibrillation.

  11. Aging impairs hippocampus-dependent long-term memory for object location in mice

    OpenAIRE

    Wimmer, Mathieu; Hernandez, Pepe; Blackwell, Jennifer; Abel, Ted

    2011-01-01

    The decline in cognitive function that accompanies normal aging has a negative impact on the quality of life of the elderly and their families. Studies in humans and rodents show that spatial navigation and other hippocampus-dependent functions are particularly vulnerable to the deleterious effects of aging. However, reduced motor activity and alterations in the stress response that accompany normal aging can hinder the ability to study certain cognitive behaviors in aged animals. In an attem...

  12. Influence of prolonged dietary consumption of zeolites on a survival rate and intestine response in mice different age after irradiation

    International Nuclear Information System (INIS)

    Effect of long-term dietary consumption of zeolites on the structural-functional status of adherent mucous layers of digestive tract in mice of different age is studied as well as zeolites effect on the survival and mean life span in irradiation mice. Mice were exposed to whole-body acute irradiation at 4 Gy dose. RUM-17 X-ray apparatus was used for exposure. It is shown that the zeolites increase the survival and mean life span in mice following irradiation. Shivirtuin caused more expressed effect than that of pegasin

  13. Influence of age and sex on the spontaneous DNA damage detected by micronucleus test and comet assay in mice peripheral blood cells.

    Science.gov (United States)

    Heuser, Vanina Dahlström; de Andrade, Vanessa Moraes; Peres, Alessandra; Gomes de Macedo Braga, Luisa Maria; Bogo Chies, José Arthur

    2008-10-01

    We have investigated the normal variations in basal DNA damage detected by Comet assay in leukocytes and micronucleated erythrocytes (MNE) using the Micronucleus test (MN) in peripheral blood cells from 45 female and male mice from different age groups (newborns, 3.5, 12, and 104 weeks) to clarify age and sex-related changes. Comparison of basal DNA damage detected by Comet assay showed significantly increased values in 104 weeks old mice in relation to the other ages (P < or = 0.01), and newborn mice showed higher values in MNE frequency when compared to all the other groups (P < or = 0.01). A positive correlation was observed between Damage Frequency (r =0.382, P = 0.010) and Damage Index (r = 0.640, P < 0.001) and age. Age was also correlated with the ratio of polychromatic erythrocytes/normachromatic erythrocytes (PCE/NCE) (r = -0.473, P = 0.001), and the MNE frequency was positively correlated with the ratio of PCE/NCE (r = 0.454, P = 0.002). These results suggest an age-related slow down of DNA repair efficiency of DNA damage and/or DNA damage accumulation. Furthermore, data on the spontaneous MNE frequency indicate that the reticuloendothelial system matures with age, and there is a close relationship between erythropoiesis and micronucleus induction in erythrocytes. The influence of sex in the parameters analyzed was less clear. In conclusion, age seems to influence in basal DNA damage and should be considered in genotoxicity studies using mice. Finally, comparisons between assays must be made with care when different cells are compared (e.g. leukocytes and erythrocytes), as found with the Comet assay and MN test. PMID:18675925

  14. Age and sex dependence in tumorigenesis in mice by continuous low-dose-rate gamma-ray whole-body irradiation

    International Nuclear Information System (INIS)

    We investigated the dependency of sex and age in mice in the induction of neoplasms by gamma-rays from cesium-137 at a low dose rate of 0.375Gy/22h/day. Thymic lymphomas occurred significantly at the same incidence in both sexes, and more frequently when younger mice were exposed to radiation. Strain C57BL/6J mice were divided into 8 groups, which were whole-body irradiated with a total dose of 39Gy for 105 days each. The exposure was begun at 28 days of age (male:AM1, female:AF1), and then stepwise increasing the starting age by 105 days, i.e., from 133 days (AM2 and AF2), from 238 days (AM3 and AF3), and from 343 days (AM4 and AF4), respectively. Unirradiated mice served as control (UM and UF). The incidence of thymic lymphomas was about 60 % in AM1, AM2, AF1 and AF2, 40 % in AM3 and AF3 and 20 % in AF4 and AF4, demonstrating no sex dependency, but a distinct age dependency, for lymphomogenesis. It was proven that mice showed a tendency to become less susceptible to radiation induced thymic lymphoma with increasing age. Concomitantly, life-shortening also was caused, and the greater the degree of life-shortening was, the younger the mice were the start of exposure. Life-shortening was attributed to thymic lymphoma, and hemorrhage and infectious diseases due to the depletion of bone marrow cells. (author)

  15. Hyperactive mTOR signals in the proopiomelanocortin-expressing hippocampal neurons cause age-dependent epilepsy and premature death in mice

    Science.gov (United States)

    Matsushita, Yuki; Sakai, Yasunari; Shimmura, Mitsunori; Shigeto, Hiroshi; Nishio, Miki; Akamine, Satoshi; Sanefuji, Masafumi; Ishizaki, Yoshito; Torisu, Hiroyuki; Nakabeppu, Yusaku; Suzuki, Akira; Takada, Hidetoshi; Hara, Toshiro

    2016-01-01

    Epilepsy is a frequent comorbidity in patients with focal cortical dysplasia (FCD). Recent studies utilizing massive sequencing data identified subsets of genes that are associated with epilepsy and FCD. AKT and mTOR-related signals have been recently implicated in the pathogenic processes of epilepsy and FCD. To clarify the functional roles of the AKT-mTOR pathway in the hippocampal neurons, we generated conditional knockout mice harboring the deletion of Pten (Pten-cKO) in Proopiomelanocortin-expressing neurons. The Pten-cKO mice developed normally until 8 weeks of age, then presented generalized seizures at 8–10 weeks of age. Video-monitored electroencephalograms detected paroxysmal discharges emerging from the cerebral cortex and hippocampus. These mice showed progressive hypertrophy of the dentate gyrus (DG) with increased expressions of excitatory synaptic markers (Psd95, Shank3 and Homer). In contrast, the expression of inhibitory neurons (Gad67) was decreased at 6–8 weeks of age. Immunofluorescence studies revealed the abnormal sprouting of mossy fibers in the DG of the Pten-cKO mice prior to the onset of seizures. The treatment of these mice with an mTOR inhibitor rapamycin successfully prevented the development of seizures and reversed these molecular phenotypes. These data indicate that the mTOR pathway regulates hippocampal excitability in the postnatal brain. PMID:26961412

  16. Premature aging phenotype in mice lacking high affinity nicotinic receptors: region specific changes in layer V pyramidal cell morphology

    Directory of Open Access Journals (Sweden)

    Eleni Konsolaki

    2014-02-01

    Full Text Available The mechanisms by which aging leads to alterations in brain structure and cognitive deficits are unclear. A central yet presently unresolved issue in aging research concerns the distinction between normal/successful aging, consisting of a moderate decline in cognitive performance, and pathological aging, manifested as mild cognitive impairment or full-blown neurodegeneration and dementia. In particular, it has been proposed that the age-related decline in cognitive abilities may be an age-related escalation of early-life cognitive limitations, rather than an abruptly emerging neuropathological process that occurs in old age (Elias et al., 2000; Small et al., 2000; Sarter and Bruno, 2004; Amieva et al., 2005; Tyas et al., 2007. In this scenario, early abnormalities or incompletely matured neural systems would interact with age-related processes to explain the cognitive decline in later ages. However this proposal remains controversial (Nilsson et al., 2009; Salthouse, 2009 and, to our knowledge, has not been explored at the morphological/structural level. Hence it is important to identify factors that may confer a predisposition to pathological aging and examine how they interact with the process of aging per se. One such factor is the integrity of the cholinergic system: cholinergic basal forebrain neurons and their projections to the cortex show increased vulnerability to aging (Fischer et al., 1987; Altavista et al., 1990; Casu et al., 2002 and cognitive decline is associated with selective loss of neuronal nicotinic acetylcholine receptor (nAChR function (Hellstrom-Lindahl and Court, 2000; Schliebs and Arendt, 2011. In this respect, animals with specific cholinergic deficits are important tools for understanding the neurobiology of successful aging. One such animal model is the β2-/- mouse, in which the gene encoding the β2 subunit of the nAChR is genetically deleted (Picciotto et al., 1995. Aged β2-/- mice have been proposed as a model of

  17. Effects of Saikokaryukotsuboreito on Spermatogenesis and Fertility in Aging Male Mice

    Science.gov (United States)

    Zang, Zhi-Jun; Ji, Su-Yun; Zhang, Ya-Nan; Gao, Yong; Zhang, Bin

    2016-01-01

    Background: Aspermia caused by exogenous testosterone limit its usage in late-onset hypogonadism (LOH) patients desiring fertility. Saikokaryukotsuboreito (SKRBT) is reported to improve serum testosterone and relieve LOH-related symptoms. However, it is unclear whether SKRBT affects fertility. We aimed to examine the effects of SKRBT on spermatogenesis and fertility in aging male mice. Methods: Thirty aging male mice were randomly assigned to three groups. Mice were orally administered with phosphate-buffer solution or SKRBT (300 mg/kg, daily) or received testosterone by subcutaneous injections (10 mg/kg, every 3 days). Thirty days later, each male mouse was mated with two female mice. All animals were sacrificed at the end of 90 days. Intratesticular testosterone (ITT) levels, quality of sperm, expression of synaptonemal complex protein 3 (SYCP3), and fertility were assayed. Results: In the SKRBT-treated group, ITT, quality of sperm, and expression of SYCP3 were all improved compared with the control group (ITT: 85.50 ± 12.31 ng/g vs. 74.10 ± 11.45 ng/g, P = 0.027; sperm number: [14.94 ± 4.63] × 106 cells/ml vs. [8.79 ± 4.38] × 106 cells/ml, P = 0.002; sperm motility: 43.16 ± 9.93% vs. 33.51 ± 6.98%, P = 0.015; the number of SYCP3-positive cells/tubule: 77.50 ± 11.01 ng/ml vs. 49.30 ± 8.73 ng/ml, P 0.05, respectively). In the testosterone-treated group, ITT, quality of sperm, and expression of SYCP3 were markedly lower than the control group (ITT: 59.00 ± 8.67, P = 0.005; sperm number: [4.34 ± 2.45] × 106 cells/ml, P = 0.018; sperm motility: 19.53 ± 7.69%, P = 0.001; the number of SYCP3-positive cells/tubule: 30.00 ± 11.28, P < 0.001; the percentage of SYCP3-positive tubules/section 71.98 ± 8.88%, P = 0.001; the expression of SYCP3 protein: 0.71 ± 0.09, P < 0.001), and fertility was also suppressed (P < 0.05, respectively). Conclusion: SKRBT had no adverse effect on fertility potential in aging male mice. PMID:26996482

  18. Dietary lactoferrin alleviates age-related lacrimal gland dysfunction in mice.

    Directory of Open Access Journals (Sweden)

    Motoko Kawashima

    Full Text Available BACKGROUND: Decrease in lacrimal gland secretory function is related to age-induced dry eye disease. Lactoferrin, the main glycoprotein component of tears, has multiple functions, including anti-inflammatory effects and the promotion of cell growth. We investigated how oral administration of lactoferrin affects age-related lacrimal dysfunction. METHODS AND FINDINGS: Twelve-month-old male C57BL/6Cr Slc mice were randomly divided into a control fed group and an oral lactoferrin treatment group. Tear function was measured at a 6-month time-point. After euthanasia, the lacrimal glands were subjected to histological examination with 8-hydroxy-2'-deoxyguanosine (8-OHdG antibodies, and serum concentrations of 8-OHdG and hexanoyl-lysine adduct (HEL were evaluated. Additionally, monocyte chemotactic protein-1(MCP-1 and tumor necrosis factor-α (TNF-α gene expression levels were determined by real-time PCR. The volume of tear secretion was significantly larger in the treated group than in the control. Lactoferrin administration reduced inflammatory cell infiltration and the MCP-1 and TNF-α expression levels. Serum concentrations of 8-OHdG and HEL in the lactoferrin group were lower than those in the control group and were associated with attenuated 8-OHdG immunostaining of the lacrimal glands. CONCLUSION: Oral lactoferrin administration preserves lacrimal gland function in aged mice by attenuating oxidative damage and suppressing subsequent gland inflammation.

  19. Apolipoprotein E4 causes age- and sex-dependent impairments of hilar GABAergic interneurons and learning and memory deficits in mice.

    Directory of Open Access Journals (Sweden)

    Laura Leung

    Full Text Available Apolipoprotein (apo E4 is the major genetic risk factor for Alzheimer's disease (AD. ApoE4 has sex-dependent effects, whereby the risk of developing AD is higher in apoE4-expressing females than males. However, the mechanism underlying the sex difference, in relation to apoE4, is unknown. Previous findings indicate that apoE4 causes age-dependent impairments of hilar GABAergic interneurons in female mice, leading to learning and memory deficits. Here, we investigate whether the detrimental effects of apoE4 on hilar GABAergic interneurons are sex-dependent using apoE knock-in (KI mice across different ages. We found that in female apoE-KI mice, there was an age-dependent depletion of hilar GABAergic interneurons, whereby GAD67- or somatostatin-positive--but not NPY- or parvalbumin-positive-interneuron loss was exacerbated by apoE4. Loss of these neuronal populations was correlated with the severity of spatial learning deficits at 16 months of age in female apoE4-KI mice; however, this effect was not observed in female apoE3-KI mice. In contrast, we found an increase in the numbers of hilar GABAergic interneurons with advancing age in male apoE-KI mice, regardless of apoE genotype. Moreover, male apoE-KI mice showed a consistent ratio of hilar inhibitory GABAergic interneurons to excitatory mossy cells approximating 1.5 that is independent of apoE genotype and age, whereas female apoE-KI mice exhibited an age-dependent decrease in this ratio, which was exacerbated by apoE4. Interestingly, there are no apoE genotype effects on GABAergic interneurons in the CA1 and CA3 subregions of the hippocampus as well as the entorhinal and auditory cortexes. These findings suggest that the sex-dependent effects of apoE4 on developing AD is in part attributable to inherent sex-based differences in the numbers of hilar GABAergic interneurons, which is further modulated by apoE genotype.

  20. Hyperbaric Oxygen Exposure Reduces Age-Related Decrease in Oxidative Capacity of the Tibialis Anterior Muscle in Mice

    Directory of Open Access Journals (Sweden)

    Takahiro Nishizaka

    2010-01-01

    Full Text Available The effects of exposure to hyperbaric oxygen on the oxidative capacity of the skeletal muscles in mice at different ages were investigated. We exposed 5-, 34-, 55-, and 88-week-old mice to 36% oxygen at 950 mmHg for 6 hours per day for 2 weeks. The activities of succinate dehydrogenase (SDH, which is a mitochondrial marker enzyme, of the tibialis anterior muscle in hyperbaric mice were compared with those in age-matched mice under normobaric conditions (21% oxygen at 760 mmHg. Furthermore, the SDH activities of type IIA and type IIB fibers in the muscle were determined using quantitative histochemical analysis. The SDH activity of the muscle in normobaric mice decreased with age. Similar results were observed in both type IIA and type IIB fibers in the muscle. The decrease in the SDH activity of the muscle was reduced in hyperbaric mice at 57 and 90 weeks. The decreased SDH activities of type IIA and type IIB fibers were reduced in hyperbaric mice at 90 weeks and at 57 and 90 weeks, respectively. We conclude that exposure to hyperbaric oxygen used in this study reduces the age-related decrease in the oxidative capacity of skeletal muscles.

  1. Ablation of neurogenesis attenuates recovery of motor function after focal cerebral ischemia in middle-aged mice.

    Directory of Open Access Journals (Sweden)

    Fen Sun

    Full Text Available Depletion of neurogenesis worsens functional outcome in young-adult mice after focal cerebral ischemia, but whether a similar effect occurs in older mice is unknown. Using middle-aged (12-month-old transgenic (DCX-TK((+ mice that express herpes simplex virus thymidine kinase (HSV-TK under control of the doublecortin (DCX promoter, we conditionally depleted DCX-positive cells in the subventricular zone (SVZ and hippocampus by treatment with ganciclovir (GCV for 14 days. Focal cerebral ischemia was induced by permanent occlusion of the middle cerebral artery (MCAO or occlusion of the distal segment of middle cerebral artery (dMCAO on day 14 of vehicle or GCV treatment and mice were killed 24 hr or 12 weeks later. Increased infarct volume or brain atrophy was found in GCV- compared to vehicle-treated middle-aged DCX-TK((+ mice, both 24 hr after MCAO and 12 weeks after dMCAO. More severe motor deficits were also observed in GCV-treated, middle-aged DCX-TK((+ transgenic mice at both time points. Our results indicate that ischemia-induced newborn neurons contribute to anatomical and functional outcome after experimental stroke in middle-aged mice.

  2. Palladium and platinum nanoparticles attenuate aging-like skin atrophy via antioxidant activity in mice.

    Directory of Open Access Journals (Sweden)

    Shuichi Shibuya

    Full Text Available Cu-Zn superoxide dismutase (Sod1 loss causes a redox imbalance as it leads to excess superoxide generation, which results in the appearance of various aging-related phenotypes, including skin atrophy. Noble metal nanoparticles, such as palladium (Pd and platinum (Pt nanoparticles, are considered to function as antioxidants due to their strong catalytic activity. In Japan, a mixture of Pd and Pt nanoparticles called PAPLAL has been used to treat chronic diseases over the past 60 years. In the present study, we investigated the protective effects of PAPLAL against aging-related skin pathologies in mice. Transdermal PAPLAL treatment reversed skin thinning associated with increased lipid peroxidation in Sod1-/- mice. Furthermore, PAPLAL normalized the gene expression levels of Col1a1, Mmp2, Has2, Tnf-α, Il-6, and p53 in the skin of the Sod1-/- mice. Pt nanoparticles exhibited marked SOD and catalase activity, while Pd nanoparticles only displayed weak SOD and catalase activity in vitro. Although the SOD and catalase activity of the Pt nanoparticles significantly declined after they had been oxidized in air, a mixture of Pd and Pt nanoparticles continued to exhibit SOD and catalase activity after oxidation. Importantly, a mixture of Pd and Pt nanoparticles with a molar ratio of 3 or 4 to 1 continued to exhibit SOD and catalase activity after oxidation, indicating that Pd nanoparticles prevent the oxidative deterioration of Pt nanoparticles. These findings indicate that PAPLAL stably suppresses intrinsic superoxide generation both in vivo and in vitro via SOD and catalase activity. PAPLAL is a potentially powerful tool for the treatment of aging-related skin diseases caused by oxidative damage.

  3. Artery Tertiary Lymphoid Organs Control Multilayered Territorialized Atherosclerosis B-Cell Responses in Aged ApoE−/− Mice

    Science.gov (United States)

    Srikakulapu, Prasad; Hu, Desheng; Yin, Changjun; Mohanta, Sarajo K.; Bontha, Sai Vineela; Peng, Li; Beer, Michael; Weber, Christian; McNamara, Coleen A.; Grassia, Gianluca; Maffia, Pasquale; Manz, Rudolf A.

    2016-01-01

    Objective— Explore aorta B-cell immunity in aged apolipoprotein E-deficient (ApoE−/−) mice. Approach and Results— Transcript maps, fluorescence-activated cell sorting, immunofluorescence analyses, cell transfers, and Ig-ELISPOT (enzyme-linked immunospot) assays showed multilayered atherosclerosis B-cell responses in artery tertiary lymphoid organs (ATLOs). Aging-associated aorta B-cell–related transcriptomes were identified, and transcript atlases revealed highly territorialized B-cell responses in ATLOs versus atherosclerotic lesions: ATLOs showed upregulation of bona fide B-cell genes, including Cd19, Ms4a1 (Cd20), Cd79a/b, and Ighm although intima plaques preferentially expressed molecules involved in non–B effector responses toward B-cell–derived mediators, that is, Fcgr3 (Cd16), Fcer1g (Cd23), and the C1q family. ATLOs promoted B-cell recruitment. ATLO B-2 B cells included naive, transitional, follicular, germinal center, switched IgG1+, IgA+, and IgE+ memory cells, plasmablasts, and long-lived plasma cells. ATLOs recruited large numbers of B-1 cells whose subtypes were skewed toward interleukin-10+ B-1b cells versus interleukin-10− B-1a cells. ATLO B-1 cells and plasma cells constitutively produced IgM and IgG and a fraction of plasma cells expressed interleukin-10. Moreover, ApoE−/− mice showed increased germinal center B cells in renal lymph nodes, IgM-producing plasma cells in the bone marrow, and higher IgM and anti–MDA-LDL (malondialdehyde-modified low-density lipoprotein) IgG serum titers. Conclusions— ATLOs orchestrate dichotomic, territorialized, and multilayered B-cell responses in the diseased aorta; germinal center reactions indicate generation of autoimmune B cells within the diseased arterial wall during aging. PMID:27102965

  4. Experimental Tityus serrulatus scorpion envenomation: age- and sex-related differences in symptoms and mortality in mice

    Directory of Open Access Journals (Sweden)

    Pucca MB

    2011-01-01

    Full Text Available Among the various methods for evaluating animal venom toxicity, the calculation of the median lethal dose (LD50 is the most widely used. Although different protocols can be used to calculate the LD50, the source of the venom and the method of extraction, as well as the strain, age, and sex of the animal model employed, should be taken into consideration. The objective of the present study was to evaluate the influence of sex and age on the toxicity of Tityus serrulatus scorpion venom in Swiss mice. Although the symptoms of envenomation were similar in male and female animals, female mice proved to be more resistant to the venom. In females, age had no impact on the susceptibility to scorpion envenomation. Male mice were more sensitive to T. serrulatus venom. Moreover, in males, age was an important parameter since sensitivity to the venom increased with age.

  5. Ageing Fxr Deficient Mice Develop Increased Energy Expenditure, Improved Glucose Control and Liver Damage Resembling NASH

    OpenAIRE

    Bjursell, Mikael; Wedin, Marianne; Admyre, Therése; Hermansson, Majlis; Böttcher, Gerhard; Göransson, Melker; Lindén, Daniel; Bamberg, Krister; Oscarsson, Jan; Bohlooly-Y, Mohammad

    2013-01-01

    Nuclear receptor subfamily 1, group H, member 4 (Nr1h4, FXR) is a bile acid activated nuclear receptor mainly expressed in the liver, intestine, kidney and adrenal glands. Upon activation, the primary function is to suppress cholesterol 7 alpha-hydroxylase (Cyp7a1), the rate-limiting enzyme in the classic or neutral bile acid synthesis pathway. In the present study, a novel Fxr deficient mouse line was created and studied with respect to metabolism and liver function in ageing mice fed chow d...

  6. Immunolocalization of nestin in pancreatic tissue of mice at different ages

    OpenAIRE

    Raj K Dorisetty, Sashi G Kiran, Malathi R Umrani, Sesikeran Boindala, Ramesh R Bhonde, Vijayalakshmi Venkatesan

    2008-01-01

    AIM: To localize nestin positive cells (NPC) in pancreatic tissue of mice of different ages.METHODS: Paraffin sections of 6-8 μm of fixed pancreatic samples were mounted on poly-L-lysine coated slides and used for Immunolocalization using appropriate primary antibodies (Nestin, Insulin, Glucagon), followed by addition of a fluorescently labeled secondary antibody. The antigen-antibody localization was captured using a confocal microscope (Leica SP 5 series).RESULTS: In 3-6 d pups, the NPC wer...

  7. Fractone-associated N-sulfated heparan sulfate shows reduced quantity in BTBR T+tf/J mice, a strong model of autism

    OpenAIRE

    Meyza, Ksenia Z.; Blanchard, D. Caroline; Pearson, Brandon L.; Pobbe, Roger L. H.; Blanchard, Robert J.

    2011-01-01

    BTBR T+tf/J (BTBR) mice show abnormal social, communicatory, and repetitive/stereotyped behaviors paralleling many of the symptoms of autism spectrum disorders. BTBR also show agenesis of the corpus callosum (CC) suggesting major perturbations of growth or guidance factors in the dorsal forebrain [1]. Heparan sulfate (HS) is a polysaccaride found in the brain and other animal tissues. It binds to a wide variety of ligands and through these ligands modulates a number of biological processes, i...

  8. Circulating biologically active oxidized phospholipids show on-going and increased oxidative stress in older male mice

    Directory of Open Access Journals (Sweden)

    Jinbo Liu

    2013-01-01

    Significance: Oxidatively modified phospholipids are increased in the circulation during common, mild oxidant stresses of aging, or in male compared to female animals. Turnover of these biologically active phospholipids by rapid transport into liver and kidney is unchanged, so circulating levels reflect continuously increased production.

  9. Elevation of Brain Magnesium Potentiates Neural Stem Cell Proliferation in the Hippocampus of Young and Aged Mice.

    Science.gov (United States)

    Jia, Shanshan; Liu, Yunpeng; Shi, Yang; Ma, Yihe; Hu, Yixin; Wang, Meiyan; Li, Xue

    2016-09-01

    In the adult brain, neural stem cells (NSCs) can self-renew and generate all neural lineage types, and they persist in the sub-granular zone (SGZ) of the hippocampus and the sub-ventricular zone (SVZ) of the cortex. Here, we show that dietary-supplemented - magnesium-L-threonate (MgT), a novel magnesium compound designed to elevate brain magnesium regulates the NSC pool in the adult hippocampus. We found that administration of both short- and long-term regimens of MgT, increased the number of hippocampal NSCs. We demonstrated that in young mice, dietary supplementation with MgT significantly enhanced NSC proliferation in the SGZ. Importantly, in aged mice that underwent long-term (12-month) supplementation with MgT, MgT did not deplete the hippocampal NSC reservoir but rather curtailed the age-associated decline in NSC proliferation. We further established an association between extracellular magnesium concentrations and NSC self-renewal in vitro by demonstrating that elevated Mg(2+) concentrations can maintain or increase the number of cultured hippocampal NSCs. Our study also suggests that key signaling pathways for cell growth and proliferation may be candidate targets for Mg(2+) 's effects on NSC self-renewal. J. Cell. Physiol. 231: 1903-1912, 2016. © 2016 Wiley Periodicals, Inc. PMID:26754806

  10. Adipose stem cells' antagonism in glycosylation of D-galactose-induced skin aging of nude mice and its skin recovery function.

    Science.gov (United States)

    Wang, Haiying; Wei, Shuyue; Xue, Xinxin; You, Yuntian; Ma, Qiang

    2016-09-01

    This study aims to discuss adipose stem cells' (ASCs) antagonism in glycosylation of D-galactose-induced skin aging of nude mice and its skin recovery function; the study also aims to explore a new mechanism of anti-aging to provide clinical anti-aging therapy with new thoughts and methods. We selected 40 healthy specific pathogen-free (SPF) nude mice and divided them randomly into four groups which were: blank control group; D-galactose + phosphate buffer saline (PBS) group; D-galactose + ASCs treatment group; and D-galactose + aminoguanidine (AG) group. Results showed that the superoxide dismutase (SOD) level of mice in the D-galactose-induced model group (87.15 ± 4.95 U/g) decreased significantly compared with that of control group (146.21 ± 4.76 U/g), while malonaldehyde (MDA) level of mice in D-galactose induced model group (11.12 ± 2.08 nmol/mg) increased significantly compared with that of control group (5.46 ± 2.05 nmol/mg) (P bioluminescence, and they survive for a short time in the skin after transplantation, which provides a basis for the application of ASC transplantation in clinical practices. Moreover, ASCs can control glycosylation level of D-galactose-induced skin aging of nude mice, reverse expression of aging-related biomarkers as well as restrain formation of advanced glycation end products, which are similar to the effects of AG inhibitors of advanced glycation end products. Thus, ASCs can prevent glycosylation-induced skin aging as well as recover functions of skin. PMID:26916459

  11. Cd59a deficiency in mice leads to preferential innate immune activation in the retinal pigment epithelium-choroid with age.

    Science.gov (United States)

    Herrmann, Philipp; Cowing, Jill A; Cristante, Enrico; Liyanage, Sidath E; Ribeiro, Joana; Duran, Yanai; Abelleira Hervas, Laura; Carvalho, Livia S; Bainbridge, James W B; Luhmann, Ulrich F O; Ali, Robin R

    2015-09-01

    Dysregulation of the complement system has been implicated in the pathogenesis of age-related macular degeneration. To investigate consequences of altered complement regulation in the eye with age, we examined Cd59a complement regulator deficient (Cd59a(-/-)) mice between 4 and 15 months. In vivo imaging revealed an increased age-related accumulation of autofluorescent spots in Cd59a(-/-) mice, a feature that reflects accumulation of subretinal macrophages and/or microglia. Despite this activation of myeloid cells in the eye, Cd59a(-/-) mice showed normal retinal histology and function as well as normal choroidal microvasculature. With age, they revealed increased expression of activators of the alternative complement pathway (C3, Cfb, Cfd), in particular in the retinal pigment epithelium (RPE)-choroid but less in the retina. This molecular response was not altered by moderately-enhanced light exposure. Cd59a deficiency therefore leads to a preferential age-related dysregulation of the complement system in the RPE-choroid, that alone or in combination with light as a trigger, is not sufficient to cause choroidal vascular changes or retinal degeneration and dysfunction. This data emphasizes the particular vulnerability of the RPE-choroidal complex to dysregulation of the alternative complement pathway during aging. PMID:26234657

  12. Bioinformatics and Microarray Analysis of miRNAs in Aged Female Mice Model Implied New Molecular Mechanisms for Impaired Fracture Healing

    Science.gov (United States)

    He, Bing; Zhang, Zong-Kang; Liu, Jin; He, Yi-Xin; Tang, Tao; Li, Jie; Guo, Bao-Sheng; Lu, Ai-Ping; Zhang, Bao-Ting; Zhang, Ge

    2016-01-01

    Impaired fracture healing in aged females is still a challenge in clinics. MicroRNAs (miRNAs) play important roles in fracture healing. This study aims to identify the miRNAs that potentially contribute to the impaired fracture healing in aged females. Transverse femoral shaft fractures were created in adult and aged female mice. At post-fracture 0-, 2- and 4-week, the fracture sites were scanned by micro computed tomography to confirm that the fracture healing was impaired in aged female mice and the fracture calluses were collected for miRNA microarray analysis. A total of 53 significantly differentially expressed miRNAs and 5438 miRNA-target gene interactions involved in bone fracture healing were identified. A novel scoring system was designed to analyze the miRNA contribution to impaired fracture healing (RCIFH). Using this method, 11 novel miRNAs were identified to impair fracture healing at 2- or 4-week post-fracture. Thereafter, function analysis of target genes was performed for miRNAs with high RCIFH values. The results showed that high RCIFH miRNAs in aged female mice might impair fracture healing not only by down-regulating angiogenesis-, chondrogenesis-, and osteogenesis-related pathways, but also by up-regulating osteoclastogenesis-related pathway, which implied the essential roles of these high RCIFH miRNAs in impaired fracture healing in aged females, and might promote the discovery of novel therapeutic strategies. PMID:27527150

  13. Age-dependent loss of cholinergic neurons in learning and memory-related brain regions and impaired learning in SAMP8 mice with trigeminal nerve damage.

    Science.gov (United States)

    He, Yifan; Zhu, Jihong; Huang, Fang; Qin, Liu; Fan, Wenguo; He, Hongwen

    2014-11-15

    The tooth belongs to the trigeminal sensory pathway. Dental damage has been associated with impairments in the central nervous system that may be mediated by injury to the trigeminal nerve. In the present study, we investigated the effects of damage to the inferior alveolar nerve, an important peripheral nerve in the trigeminal sensory pathway, on learning and memory behaviors and structural changes in related brain regions, in a mouse model of Alzheimer's disease. Inferior alveolar nerve transection or sham surgery was performed in middle-aged (4-month-old) or elderly (7-month-old) senescence-accelerated mouse prone 8 (SAMP8) mice. When the middle-aged mice reached 8 months (middle-aged group 1) or 11 months (middle-aged group 2), and the elderly group reached 11 months, step-down passive avoidance and Y-maze tests of learning and memory were performed, and the cholinergic system was examined in the hippocampus (Nissl staining and acetylcholinesterase histochemistry) and basal forebrain (choline acetyltransferase immunohistochemistry). In the elderly group, animals that underwent nerve transection had fewer pyramidal neurons in the hippocampal CA1 and CA3 regions, fewer cholinergic fibers in the CA1 and dentate gyrus, and fewer cholinergic neurons in the medial septal nucleus and vertical limb of the diagonal band, compared with sham-operated animals, as well as showing impairments in learning and memory. Conversely, no significant differences in histology or behavior were observed between middle-aged group 1 or group 2 transected mice and age-matched sham-operated mice. The present findings suggest that trigeminal nerve damage in old age, but not middle age, can induce degeneration of the septal-hippocampal cholinergic system and loss of hippocampal pyramidal neurons, and ultimately impair learning ability. Our results highlight the importance of active treatment of trigeminal nerve damage in elderly patients and those with Alzheimer's disease, and indicate that

  14. The retinoic acid receptor agonist Am80 increases hippocampal ADAM10 in aged SAMP8 mice.

    Science.gov (United States)

    Kitaoka, Kazuyoshi; Shimizu, Noriyuki; Ono, Koji; Chikahisa, Sachiko; Nakagomi, Madoka; Shudo, Koichi; Ishimura, Kazunori; Séi, Hiroyoshi; Yoshizaki, Kazuo

    2013-09-01

    The retinoic acid (RA, a vitamin A metabolite) receptor (RAR) is a transcription factor. Vitamin A/RA administration improves the Alzheimer's disease (AD)- and age-related attenuation of memory/learning in mouse models. Recently, a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) was identified as a key molecule in RA-mediated anti-AD mechanisms. We investigated the effect of chronic administration of the RAR agonist Am80 (tamibarotene) on ADAM10 expression in senescence-accelerated mice (SAMP8). Moreover, we estimated changes in the expression of the amyloid precursor protein (APP), amyloid beta (Aβ), and hairy/enhancer of split (Hes), which are mediated by ADAM10. Spatial working memory and the levels of a hippocampal proliferation marker (Ki67) were also assessed in these mice. ADAM10 mRNA and protein expression was significantly reduced in the hippocampus of 13-month-old SAMP8 mice; their expression improved significantly after Am80 administration. Further, after Am80 administration, the expression levels of Hes5 and Ki67 were restored and the deterioration of working memory was suppressed, whereas APP and Aβ levels remained unchanged. Our results suggest that Am80 administration effectively improves dementia by activating the hippocampal ADAM10-Notch-Hes5 proliferative pathway. PMID:23624141

  15. Environmental enrichment strengthens corticocortical interactions and reduces amyloid-β oligomers in aged mice.

    Science.gov (United States)

    Mainardi, Marco; Di Garbo, Angelo; Caleo, Matteo; Berardi, Nicoletta; Sale, Alessandro; Maffei, Lamberto

    2014-01-01

    Brain aging is characterized by global changes which are thought to underlie age-related cognitive decline. These include variations in brain activity and the progressive increase in the concentration of soluble amyloid-β (Aβ) oligomers, directly impairing synaptic function and plasticity even in the absence of any neurodegenerative disorder. Considering the high social impact of the decline in brain performance associated to aging, there is an urgent need to better understand how it can be prevented or contrasted. Lifestyle components, such as social interaction, motor exercise and cognitive activity, are thought to modulate brain physiology and its susceptibility to age-related pathologies. However, the precise functional and molecular factors that respond to environmental stimuli and might mediate their protective action again pathological aging still need to be clearly identified. To address this issue, we exploited environmental enrichment (EE), a reliable model for studying the effect of experience on the brain based on the enhancement of cognitive, social and motor experience, in aged wild-type mice. We analyzed the functional consequences of EE on aged brain physiology by performing in vivo local field potential (LFP) recordings with chronic implants. In addition, we also investigated changes induced by EE on molecular markers of neural plasticity and on the levels of soluble Aβ oligomers. We report that EE induced profound changes in the activity of the primary visual and auditory cortices and in their functional interaction. At the molecular level, EE enhanced plasticity by an upward shift of the cortical excitation/inhibition balance. In addition, EE reduced brain Aβ oligomers and increased synthesis of the Aβ-degrading enzyme neprilysin. Our findings strengthen the potential of EE procedures as a non-invasive paradigm for counteracting brain aging processes. PMID:24478697

  16. ENVIRONMENTAL ENRICHMENT STRENGTHENS CORTICOCORTICAL INTERACTIONS AND REDUCES AMYLOID-β OLIGOMERS IN AGED MICE

    Directory of Open Access Journals (Sweden)

    Marco eMainardi

    2014-01-01

    Full Text Available Brain aging is characterized by global changes which are thought to underlie age-related cognitive decline. These include variations in brain activity and the progressive increase in the concentration of soluble amyloid-β (Aβ oligomers, directly impairing synaptic function and plasticity even in the absence of any neurodegenerative disorder. Considering the high social impact of the decline in brain performance associated to aging, there is an urgent need to better understand how it can be prevented or contrasted. Lifestyle components, such as social interaction, motor exercise and cognitive activity, are thought to modulate brain physiology and its susceptibility to age-related pathologies. However, the precise functional and molecular factors that respond to environmental stimuli and might mediate their protective action again pathological aging still need to be clearly identified. To address this issue, we exploited environmental enrichment (EE, a reliable model for studying the effect of experience on the brain based on the enhancement of cognitive, social and motor experience, in aged wild-type mice. We analyzed the functional consequences of EE on aged brain physiology by performing in vivo local field potential (LFP recordings with chronic implants. In addition, we also investigated changes induced by EE on molecular markers of neural plasticity and on the levels of soluble Aβ oligomers. We report that EE induced profound changes in the activity of the primary visual and auditory cortices and in their functional interaction. At the molecular level, EE enhanced plasticity by an upward shift of the cortical excitation/inhibition balance. In addition, EE reduced brain Aβ oligomers and increased synthesis of the Aβ-degrading enzyme neprilysin. Our findings strengthen the potential of EE procedures as a non-invasive paradigm for counteracting brain aging processes.

  17. Age-related changes in the function and structure of the peripheral sensory pathway in mice.

    Science.gov (United States)

    Canta, Annalisa; Chiorazzi, Alessia; Carozzi, Valentina Alda; Meregalli, Cristina; Oggioni, Norberto; Bossi, Mario; Rodriguez-Menendez, Virginia; Avezza, Federica; Crippa, Luca; Lombardi, Raffaella; de Vito, Giuseppe; Piazza, Vincenzo; Cavaletti, Guido; Marmiroli, Paola

    2016-09-01

    This study is aimed at describing the changes occurring in the entire peripheral nervous system sensory pathway along a 2-year observation period in a cohort of C57BL/6 mice. The neurophysiological studies evidenced significant differences in the selected time points corresponding to childhood, young adulthood, adulthood, and aging (i.e., 1, 7, 15, and 25 months of age), with a parabolic course as function of time. The pathological assessment allowed to demonstrate signs of age-related changes since the age of 7 months, with a remarkable increase in both peripheral nerves and dorsal root ganglia at the subsequent time points. These changes were mainly in the myelin sheaths, as also confirmed by the Rotating-Polarization Coherent-Anti-stokes-Raman-scattering microscopy analysis. Evident changes were also present at the morphometric analysis performed on the peripheral nerves, dorsal root ganglia neurons, and skin biopsies. This extensive, multimodal characterization of the peripheral nervous system changes in aging provides the background for future mechanistic studies allowing the selection of the most appropriate time points and readouts according to the investigation aims. PMID:27459934

  18. Early signs of pathological cognitive aging in mice lacking high-affinity nicotinic receptors.

    Directory of Open Access Journals (Sweden)

    Eleni eKonsolaki

    2016-04-01

    Full Text Available In order to address pathological cognitive decline effectively, it is critical to adopt early preventive measures in individuals considered at risk. It is therefore essential to develop approaches that identify such individuals before the onset of irreversible dementia. Α deficient cholinergic system has been consistently implicated as one of the main factors associated with a heightened vulnerability to the aging process. In the present study we used mice lacking high affinity nicotinic receptors (β2-/-, which have been proposed as an animal model of accelerated/premature cognitive aging. Our aim was to identify behavioural signs that could serve as indicators or predictors of impending cognitive decline. We used test batteries in order to assess cognitive functions and additional tasks to investigate spontaneous behaviours, such as species-specific activities and exploration/locomotion in a novel environment. Our data confirm and extend the hypothesis that β2-/- animals exhibit age-related cognitive impairments, manifested in both spatial learning and recognition memory tasks. In addition, we reveal deficits in spontaneous behaviour and habituation processes earlier in life. To our knowledge, this is the first study to perform an extensive behavioural examination of an animal model of premature cognitive aging, and our results suggest that β2-nAChR dependent cognitive deterioration progressively evolves from initial subtle behavioural changes to global dementia due to the combined effect of the neuropathology and aging.

  19. SERCA2a gene transfer improves electrocardiographic performance in aged mdx mice

    Directory of Open Access Journals (Sweden)

    Hajjar Roger

    2011-08-01

    Full Text Available Abstract Background Cardiomyocyte calcium overloading has been implicated in the pathogenesis of Duchenne muscular dystrophy (DMD heart disease. The cardiac isoform of sarcoplasmic reticulum calcium ATPase (SERCA2a plays a major role in removing cytosolic calcium during heart muscle relaxation. Here, we tested the hypothesis that SERCA2a over-expression may mitigate electrocardiography (ECG abnormalities in old female mdx mice, a murine model of DMD cardiomyopathy. Methods 1 × 1012 viral genome particles/mouse of adeno-associated virus serotype-9 (AAV-9 SERCA2a vector was delivered to 12-m-old female mdx mice (N = 5 via a single bolus tail vein injection. AAV transduction and the ECG profile were examined eight months later. Results The vector genome was detected in the hearts of all AAV-injected mdx mice. Immunofluorescence staining and western blot confirmed SERCA2a over-expression in the mdx heart. Untreated mdx mice showed characteristic tachycardia, PR interval reduction and QT interval prolongation. AAV-9 SERCA2a treatment corrected these ECG abnormalities. Conclusions Our results suggest that AAV SERCA2a therapy may hold great promise in treating dystrophin-deficient heart disease.

  20. Enhanced inflammation in aged mice following infection with Streptococcus pneumoniae is associated with decreased IL-10 and augmented chemokine production.

    Science.gov (United States)

    Williams, Andrew E; José, Ricardo J; Brown, Jeremy S; Chambers, Rachel C

    2015-03-15

    Streptococcus pneumoniae is the most common cause of severe pneumonia in the elderly. However, the impact of aging on the innate inflammatory response to pneumococci is poorly defined. We compared the innate immune response in old vs. young adult mice following infection with S. pneumoniae. The accumulation of neutrophils recovered from bronchoalveolar lavage fluid and lung homogenates was increased in aged compared with young adult mice, although bacterial outgrowth was similar in both age groups, as were markers of microvascular leak. Aged mice had similar levels of IL-1β, TNF, IFN-γ, IL-17, and granulocyte colony-stimulating factor following S. pneumoniae infection, compared with young mice, but increased levels of the chemokines CXCL9, CXCL12, CCL3, CCL4, CCL5, CCL11, and CCL17. Moreover, levels of IL-10 were significantly lower in aged animals. Neutralization of IL-10 in infected young mice was associated with increased neutrophil recruitment but no decrease in bacterial outgrowth. Furthermore, IL-10 neutralization resulted in increased levels of CCL3, CCL5, and CXCL10. We conclude that aging is associated with enhanced inflammatory responses following S. pneumoniae infection as a result of a compromised immunomodulatory cytokine response. PMID:25595646

  1. Adult but Not Aged C57BL/6 Male Mice Are Capable of Using Geometry for Orientation

    Science.gov (United States)

    Schachner, Melitta; Morellini, Fabio; Fellini, Laetitia

    2006-01-01

    Geometry, e.g., the shape of the environment, can be used by numerous animal species to orientate, but data concerning the mouse are lacking. We addressed the question of whether mice are capable of using geometry for navigating. To test whether aging could affect searching strategies, we compared adult (3- to 5-mo old) and aged (20- to 21-mo old)…

  2. B Cell Production of Both OPG and RANKL is Significantly Increased in Aged Mice

    OpenAIRE

    Li, Yan; Terauchi, Masakazu; Vikulina, Tatyana; Roser-Page, Susanne; Weitzmann, M.N.

    2014-01-01

    Aging is a risk factor for osteoclastic bone loss and bone fracture. Receptor activator of NF-κB ligand (RANKL) is the key effector cytokine for osteoclastogenesis and bone resorption, and is moderated by its decoy receptor osteoprotegerin (OPG). The development of an inflammatory environment during aging leads to increased bone resorption and loss of bone mineral density (BMD). Interestingly, animal and clinical studies show that OPG is actually increased in aging but fails to fully compensa...

  3. Early Signs of Pathological Cognitive Aging in Mice Lacking High-Affinity Nicotinic Receptors.

    Science.gov (United States)

    Konsolaki, Eleni; Tsakanikas, Panagiotis; Polissidis, Alexia V; Stamatakis, Antonios; Skaliora, Irini

    2016-01-01

    In order to address pathological cognitive decline effectively, it is critical to adopt early preventive measures in individuals considered at risk. It is therefore essential to develop approaches that identify such individuals before the onset of irreversible dementia. A deficient cholinergic system has been consistently implicated as one of the main factors associated with a heightened vulnerability to the aging process. In the present study we used mice lacking high affinity nicotinic receptors (β2-/-), which have been proposed as an animal model of accelerated/premature cognitive aging. Our aim was to identify behavioral signs that could serve as indicators or predictors of impending cognitive decline. We used test batteries in order to assess cognitive functions and additional tasks to investigate spontaneous behaviors, such as species-specific activities and exploration/locomotion in a novel environment. Our data confirm the hypothesis that β2-/- animals exhibit age-related cognitive impairments in spatial learning. In addition, they document age-related deficits in other areas, such as recognition memory, burrowing and nesting building, thereby extending the validity of this animal model for the study of pathological aging. Finally, our data reveal deficits in spontaneous behavior and habituation processes that precede the onset of cognitive decline and could therefore be useful as a non-invasive behavioral screen for identifying animals at risk. To our knowledge, this is the first study to perform an extensive behavioral assessment of an animal model of premature cognitive aging, and our results suggest that β2-nAChR dependent cognitive deterioration progressively evolves from initial subtle behavioral changes to global dementia due to the combined effect of the neuropathology and aging. PMID:27199738

  4. Enhanced humoral response to influenza vaccine in aged mice with a novel adjuvant, rOv-ASP-1.

    Science.gov (United States)

    Jiang, Jiu; Fisher, Erin M; Concannon, Mark; Lustigman, Sara; Shen, Hao; Murasko, Donna M

    2016-02-10

    Immunization is the best way to prevent seasonal epidemics and pandemics of influenza. There are two kinds of influenza vaccines available in the United States: an inactivated vaccine (TIV) and an attenuated vaccine; however, only TIV is approved for immunization of the elderly population. While the aged population has the highest rate of influenza vaccination, the protective efficacy is low as evidenced by elderly individuals having the highest mortality associated with influenza. Recently, we reported that an adjuvant derived from the helminth parasite Onchocerca volvulus, named O. volvulus activation-associated secreted protein-1 (Ov-ASP-1), can significantly enhance the protective efficacy of an inactivated vaccine (TIV) in young adult mice. In the current study, we examined whether this recombinant Ov-ASP-1 (rOv-ASP-1) can enhance the efficacy of TIV in aged mice as well. While primary immunization with TIV alone produced only a low level of influenza-specific antibodies (total IgG, IgG1, and IgG2c) in aged mice, the antibody levels were significantly increased after immunization with TIV+rOv-ASP-1. More importantly, the level of the total IgG in aged mice administered TIV+rOv-ASP-1 was comparable to that of young adult mice immunized with TIV alone. Co-administration of rOv-ASP-1 induced a low level of cross-reactive antibody and enhanced the protective efficacy of TIV in aged mice, reflected by significantly increased survival after challenge with a heterologous influenza virus. rOv-ASP-1 was also superior to the conventional adjuvant alum in inducing specific IgG after TIV immunization in aged mice, and in conferring protection after challenge. These results demonstrate that rOv-ASP-1 may serve as a potential adjuvant for influenza vaccine to improve the efficacy of protection in the elderly. PMID:26795365

  5. Long-term physical exercise retards trabecular bone loss in lumbar vertebrae of aging female mice

    Energy Technology Data Exchange (ETDEWEB)

    Silbermann, M.; Bar-Shira-Maymon, B.; Coleman, R.; Reznick, A.; Weisman, Y.; Steinhagen-Thiessen, E.; von der Mark, H.; von der Mark, K. (Rappaport Family Institute for Research in the Medical Sciences, Technion, Haifa (Israel))

    1990-02-01

    The present study examined the effect of long-term, moderate physical exercise on trabecular bone volume (TBV), calcium content, 3H-proline uptake, and the activities of alkaline and acid phosphatases in lumbar vertebrae of aging and senescent mice. It became apparent that if physical activity starts at an early stage of life, i.e., prior to middle age and is extended until old age, it exerts beneficial effects on trabecular bone mass and mineralization. Such a positive effect is not obtained if the training program is initiated after middle age. The training-induced reduction in bone loss was accompanied by a significant decrease in acid phosphatase activity whereas no changes took place with regard to the activity of alkaline phosphatase. Long-term physical exercise also enhanced the uptake of 3H-proline by lining cells along the bone trabecules. In spite of its moderate nature, the endured training program served as a stress factor for the involved animals, a fact that was manifested by an increase in the serum levels of corticosterone. Thus, it seems that whereas young animals respond favorably to such a stimulatory stress, older animals lose this ability of adaptation.

  6. Cerebellar nuclei neurons show only small excitatory responses to optogenetic olivary stimulation in transgenic mice: in vivo and in vitro studies

    Directory of Open Access Journals (Sweden)

    Huo eLu

    2016-03-01

    Full Text Available To study the olivary input to the cerebellar nuclei (CN we used optogenetic stimulation in transgenic mice expressing channelrhodopsin-2 (ChR2 in olivary neurons. We obtained in vivo extracellular Purkinje cell (PC and CN recordings in anesthetized mice while stimulating the contralateral inferior olive (IO with a blue laser (single pulse, 10 - 50 ms duration. Peri-stimulus histograms were constructed to show the spike rate changes after optical stimulation. Among 29 CN neurons recorded, 15 showed a decrease in spike rate of variable strength and duration, and only 1 showed a transient spiking response. These results suggest that direct olivary input to CN neurons is usually overridden by stronger Purkinje cell inhibition triggered by climbing fiber responses. To further investigate the direct input from the climbing fiber collaterals we also conducted whole cell recordings in brain slices, where we used local stimulation with blue light. Due to the expression of ChR2 in Purkinje cell axons as well as the IO in our transgenic line, strong inhibitory responses could be readily triggered with optical stimulation (13 of 15 neurons. After blocking this inhibition with GABAzine, only in 5 of 13 CN neurons weak excitatory responses were revealed. Therefore our in vitro results support the in vivo findings that the excitatory input to CN neurons from climbing fiber collaterals in adult mice is masked by the inhibition under normal conditions.

  7. Effects of Long-Term Rice Bran Extract Supplementation on Survival, Cognition and Brain Mitochondrial Function in Aged NMRI Mice.

    Science.gov (United States)

    Hagl, Stephanie; Asseburg, Heike; Heinrich, Martina; Sus, Nadine; Blumrich, Eva-Maria; Dringen, Ralf; Frank, Jan; Eckert, Gunter P

    2016-09-01

    Aging represents a major risk factor for the development of neurodegenerative diseases like Alzheimer's disease (AD). As mitochondrial dysfunction plays an important role in brain aging and occurs early in the development of AD, the prevention of mitochondrial dysfunction might help to slow brain aging and the development of neurodegenerative diseases. Rice bran extract (RBE) contains high concentrations of vitamin E congeners and γ-oryzanol. We have previously shown that RBE increased mitochondrial function and protected from mitochondrial dysfunction in vitro and in short-term in vivo feeding studies. To mimic the use of RBE as food additive, we have now investigated the effects of a long-term (6 months) feeding of RBE on survival, behavior and brain mitochondrial function in aged NMRI mice. RBE administration significantly increased survival and performance of aged NMRI mice in the passive avoidance and Y-maze test. Brain mitochondrial dysfunction found in aged mice was ameliorated after RBE administration. Furthermore, data from mRNA and protein expression studies revealed an up-regulation of mitochondrial proteins in RBE-fed mice, suggesting an increase in mitochondrial content which is mediated by a peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)-dependent mechanism. Our findings suggest that a long-term treatment with a nutraceutical containing RBE could be useful for slowing down brain aging and thereby delaying or even preventing AD. PMID:27350374

  8. Free-hand ultrasound guidance permits safe and efficient minimally invasive intrathymic injections in both young and aged mice.

    Science.gov (United States)

    Tuckett, Andrea Z; Zakrzewski, Johannes L; Li, Duan; van den Brink, Marcel R M; Thornton, Raymond H

    2015-04-01

    The goal of this study was to evaluate whether use of an aseptic free-hand approach to ultrasound-guided injection facilitates injection into the thymic gland in mice. We used this interventional radiology technique in young, aged and immunodeficient mice and found that the thymus was visible in all cases. The mean injection period was 8 seconds in young mice and 19 seconds in aged or immunodeficient mice. Injection accuracy was confirmed by intrathymic location of an injected dye or by in vivo bioluminescence imaging of injected luciferase-expressing cells. Accurate intrathymic injection was confirmed in 97% of cases. No major complications were observed. We conclude that an aseptic freehand technique for ultrasound-guided intrathymic injection is safe and accurate and reduces the time required for intrathymic injections. This method facilitates large-scale experiments and injection of individual thymic lobes and is clinically relevant. PMID:25701534

  9. Cytokine-producing microglia have an altered beta-amyloid load in aged APP/PS1 Tg mice

    DEFF Research Database (Denmark)

    Babcock, Alicia A; Ilkjær, Laura; Clausen, Bettina H;

    2015-01-01

    latter cytokines was generally increased in APP/PS1 Tg mice. Microglia that phagocytosed endogenously-produced Aβ were only observed in APP/PS1 Tg mice. Differences in phagocytic index and total Aβ load were observed in microglia with specific cytokine profiles. Both phagocytic index and total Aβ load...... mice, we confirmed that the majority of neocortical CD11b(+)(CD45(+)) microglia were resident cells (GFP(-)) in APP/PS1 Tg mice, even after selectively analysing CD11b(+)CD45(high) cells, which are typically considered to be infiltrating cells. Together, our data demonstrate that cytokine expression is...... selectively correlated with age and Aβ pathology, and is associated with an altered Aβ load in phagocytic microglia from APP/PS1 Tg mice. These findings have implications for understanding the regulation of microglial cytokine production and phagocytosis of Aβ in Alzheimer's disease....

  10. Age-dependent modifications of AMPA receptor subunit expression levels and related cognitive effects in 3xTg-AD mice

    Directory of Open Access Journals (Sweden)

    Pamela eCantanelli

    2014-08-01

    Full Text Available GluA1, GluA2, GluA3, and GluA4 are the constitutive subunits of AMPA receptors (AMPARs, the major mediators of fast excitatory transmission in the mammalian central nervous system. Most AMPARs are Ca2+-impermeable because of the presence of the GluA2 subunit. GluA2 mRNA undergoes an editing process that results in a Q to R substitution, a key factor in the regulation of AMPAR Ca2+-permeability. AMPARs lacking GluA2 or containing the unedited subunit are permeable to Ca2+ and Zn2+. The phenomenon physiologically modulates synaptic plasticity while, in pathologic conditions, leads to increased vulnerability to excitotoxic neuronal death. Given the importance of these subunits, we have therefore evaluated possible associations between changes in expression levels of AMPAR subunits and development of cognitive deficits in 3xTg-AD mice, a widely investigated transgenic mouse model of Alzheimer’s disease. With qRT-PCR, we assayed hippocampal mRNA expression levels of GluA1-4 subunits occurring in young [3 months of age (m.o.a.] and old (12 m.o.a Tg-AD mice and made comparisons with levels found in age-matched wild type (WT mice. Efficiency of GluA2 RNA editing was also analyzed. All animals were cognitively tested for short- and long-term spatial memory with the Morris Water Maze (MWM navigation task. 3xTg-AD mice showed age-dependent decreases of mRNA levels for all the AMPAR subunits, with the exception of GluA2. Editing remained fully efficient with aging in 3xTg-AD and WT mice. A one-to-one correlation analysis between MWM performances and GluA1-4 mRNA expression profiles showed negative correlations between GluA2 levels and MWM performances in young 3xTg-AD mice. On the contrary, positive correlations between GluA2 mRNA and MWM performances were found in young WT mice. Our data suggest that increases of AMPARs that contain GluA1, GluA3, and GluA4 subunits may help in maintaining cognition in pre-symptomatic 3xTg-AD mice.

  11. Effect of Diet and Age on Arterial Stiffening Due to Atherosclerosis in ApoE(-/-) Mice.

    Science.gov (United States)

    Cilla, M; Pérez, M M; Peña, E; Martínez, M A

    2016-07-01

    This work analyzes the progressive stiffening of the aorta due to atherosclerosis development of both ApoE(-/-) and C57BL/6J mice fed on a Western (n = 5) and a normal (n = 5) chow diet for the ApoE(-/-) group and on a normal chow diet (n = 5) for the C57BL/6J group. Sets of 5 animals from the three groups were killed after 10, 20, 30 and 40 weeks on their respective diets (corresponding to 17, 27, 37 and 47 weeks of age). Mechanical properties (inflation test and axial residual stress measurements) and histological properties were compared for both strains, ApoE(-/-) on the hyper-lipidic diet and both ApoE(-/-) and C57BL/6J on the normal diet, after the same period and after different periods of diet. The results indicated that the aorta stiffness in the ApoE(-/-) and C57BL/6J mice under normal diet remained approximately constant irrespective of their age. However, the arterial stiffness in the ApoE(-/-) on the hyper-lipidic diet increased over time. Statistical differences were found between the group after 10 weeks and the groups after 30 and 40 weeks of a hyper-lipidic diet. Comparing the hyper-lipidic and normal diet mice, statistical differences were also found between both diets in all cases after 40 weeks of diet, frequently after 30 weeks, and in some cases after 20 weeks. The early stages of lesion corresponded to the first 2 weeks of diet. Advanced lesions were found at 30 weeks and, finally, the aorta was completely damaged after 40 weeks of diet. In conclusion, we found substantial changes in the mechanical properties of the aorta walls of the ApoE(-/-) mice fed with the hyper-lipidic diet compared to the normal chow diet groups for both the ApoE(-/-) and C57BL/6J groups. These findings could serve as a reference for the study of changes in the arterial wall properties in cases of atherosclerosis. PMID:26502169

  12. Short-Term Long Chain Omega3 Diet Protects from Neuroinflammatory Processes and Memory Impairment in Aged Mice

    OpenAIRE

    Virginie F Labrousse; Nadjar, Agnès; Joffre, Corinne; Costes, Laurence; Aubert, Agnès; Grégoire, Stéphane; Bretillon, Lionel; Layé, Sophie

    2012-01-01

    Regular consumption of food enriched in omega3 polyunsaturated fatty acids (ω3 PUFAs) has been shown to reduce risk of cognitive decline in elderly, and possibly development of Alzheimer's disease. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are the most likely active components of ω3-rich PUFAs diets in the brain. We therefore hypothesized that exposing mice to a DHA and EPA enriched diet may reduce neuroinflammation and protect against memory impairment in aged mice. For this...

  13. Liver Fatty Acid Binding Protein Gene-Ablated Female Mice Exhibit Increased Age-Dependent Obesity123

    OpenAIRE

    Martin, Gregory G.; Atshaves, Barbara P.; McIntosh, Avery L.; Mackie, John T.; Kier, Ann B.; Schroeder, Friedhelm

    2008-01-01

    Previous work done in our laboratory suggested a role for liver fatty acid binding protein (L-FABP) in obesity that develops in aging female L-FABP gene-ablated (−/−) mice. To examine this possibility in more detail, cohorts of wild-type (+/+) and L-FABP (−/−) female mice were fed a standard low-fat nonpurified rodent diet for up to 18 mo. Various obesity-related parameters were examined including body weight and fat and lean tissue mass. Obesity in (−/−) mice was associated with increased ex...

  14. Ampicillin-Improved Glucose Tolerance in Diet-Induced Obese C57BL/6NTac Mice Is Age Dependent

    DEFF Research Database (Denmark)

    Rune, I.; Hansen, C. H. F.; Ellekilde, M.;

    2013-01-01

    different ages or not at all. We found that both diet and Ampicillin significantly changed the gut microbiota composition in the animals. Furthermore, there was a significant improvement in glucose tolerance in Ampicillin-treated, five-week-old mice compared to nontreated mice in the control group. At study...... high-fat diet mice, and a lower tolerogenic dendritic cell percentage was found both in relation to high-fat diet and late Ampicillin treatment. The results support our hypothesis that a "window" exists early in life in which an alteration of the gut microbiota affects glucose tolerance as well as...

  15. Adolescent mice show anxiety- and aggressive-like behavior and the reduction of long-term potentiation in mossy fiber-CA3 synapses after neonatal maternal separation.

    Science.gov (United States)

    Shin, S Y; Han, S H; Woo, R-S; Jang, S H; Min, S S

    2016-03-01

    Exposure to maternal separation (MS) during early life is an identified risk factor for emotional disorders such as anxiety and depression later in life. This study investigated the effects of neonatal MS on the behavior and long-term potentiation (LTP) as well as basic synaptic transmission at hippocampal CA3-CA1 and mossy fiber (MF)-CA3 synapses in adolescent mice for 19days. When mice were adolescents, we measured depression, learning, memory, anxious and aggressive behavior using the forced swimming test (FST), Y-maze, Morris water maze (MWM), elevated plus maze (EPM), three consecutive days of the open field test, the social interaction test, the tube-dominance test and the resident-intruder test. The results showed that there was no difference in FST, Y-maze, and MWM performance. However, MS mice showed more anxiety-like behavior in the EPM test and aggressive-like behavior in the tube-dominance and resident-intruder tests. In addition, the magnitude of LTP and release probability in the MF-CA3 synapses was reduced in the MS group but not in the CA3-CA1 synapse. Our results indicate that early life stress due to MS may induce anxiety- and aggressive-like behavior during adolescence, and these effects are associated with synaptic plasticity at the hippocampal MF-CA3 synapses. PMID:26733385

  16. Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice.

    Science.gov (United States)

    de Picciotto, Natalie E; Gano, Lindsey B; Johnson, Lawrence C; Martens, Christopher R; Sindler, Amy L; Mills, Kathryn F; Imai, Shin-Ichiro; Seals, Douglas R

    2016-06-01

    We tested the hypothesis that supplementation of nicotinamide mononucleotide (NMN), a key NAD(+) intermediate, increases arterial SIRT1 activity and reverses age-associated arterial dysfunction and oxidative stress. Old control mice (OC) had impaired carotid artery endothelium-dependent dilation (EDD) (60 ± 5% vs. 84 ± 2%), a measure of endothelial function, and nitric oxide (NO)-mediated EDD (37 ± 4% vs. 66 ± 6%), compared with young mice (YC). This age-associated impairment in EDD was restored in OC by the superoxide (O2-) scavenger TEMPOL (82 ± 7%). OC also had increased aortic pulse wave velocity (aPWV, 464 ± 31 cm s(-1) vs. 337 ± 3 cm s(-1) ) and elastic modulus (EM, 6407 ± 876 kPa vs. 3119 ± 471 kPa), measures of large elastic artery stiffness, compared with YC. OC had greater aortic O2- production (2.0 ± 0.1 vs. 1.0 ± 0.1 AU), nitrotyrosine abundance (a marker of oxidative stress), and collagen-I, and reduced elastin and vascular SIRT1 activity, measured by the acetylation status of the p65 subunit of NFκB, compared with YC. Supplementation with NMN in old mice restored EDD (86 ± 2%) and NO-mediated EDD (61 ± 5%), reduced aPWV (359 ± 14 cm s(-1) ) and EM (3694 ± 315 kPa), normalized O2- production (0.9 ± 0.1 AU), decreased nitrotyrosine, reversed collagen-I, increased elastin, and restored vascular SIRT1 activity. Acute NMN incubation in isolated aortas increased NAD(+) threefold and manganese superoxide dismutase (MnSOD) by 50%. NMN supplementation may represent a novel therapy to restore SIRT1 activity and reverse age-related arterial dysfunction by decreasing oxidative stress. PMID:26970090

  17. SGA children with moderate catch-up growth are showing the impaired insulin secretion at the age of 4.

    Directory of Open Access Journals (Sweden)

    Ivana Milovanovic

    Full Text Available BACKGROUND: Being born small for gestational age (SGA is a risk factor for later development of type 2 diabetes. The development of glucose tolerance disorders in adults involves insulin resistance and impaired insulin secretion. OBJECTIVE: To evaluate insulin secretion and insulin sensitivity in a 4-yr old cohort of SGA. METHODS: 85 children were prospectively followed from mid-gestation to 4 years of age. Fetal growth velocity (FGV was measured using ultrasound measurements. Body composition and hormonal profile were measured at birth, 1 and 4 years. RESULTS: 23 SGA babies had lower birth weight compared to 62 AGA (-1.9±0.3 vs. -0.6±0.8 z-score; p<0.0001 and they were thinner at birth (ponderal index 24.8±1.8 vs. 26.3±3.1 kg/m3; p = 0.01 and fat mass 11±2.6 vs. 12.9±3.1%; p = 0.01. No significant differences in other measured metabolic and hormonal parameters were observed between two groups at birth. SGA infants experienced an early catch-up growth in weight (mean gain of 1.1±0.6 SD during the first year of life. At 4 years, SGA children remain lighter than AGA, but with weight z-score in the normal range (-0.1±1.3 vs. 0.5±1.3 z-score; p = 0.05. No excess of fat mass was observed (19±4.8 vs. 19.7±4.1%; p = 0.45. 120-min plasma glucose was significantly higher (6.2±1.1 vs. 5.6±0.9 mmol/l; p = 0.006 and insulinogenic index was significantly lower (0.28±0.15 vs. 0.40±2.4; p = 0.02 in the SGA group at 4-yrs of life contrasting with a preserved insulin sensitivity (QUICKI 0.47±0.09 vs. 0.43±0.05; p = 0.06. CONCLUSION: SGA children with compensatory catch-up growth in first year of life show mild disturbances of glucose tolerance associated to a lower insulinogenic index at 4-yrs of age suggesting impairment of β-cell function.

  18. Viable RNaseH1 knockout mice show RNaseH1 is essential for R loop processing, mitochondrial and liver function.

    Science.gov (United States)

    Lima, Walt F; Murray, Heather M; Damle, Sagar S; Hart, Christopher E; Hung, Gene; De Hoyos, Cheryl Li; Liang, Xue-Hai; Crooke, Stanley T

    2016-06-20

    Viable constitutive and tamoxifen inducible liver-specific RNase H1 knockout mice that expressed no RNase H1 activity in hepatocytes showed increased R-loop levels and reduced mitochondrial encoded DNA and mRNA levels, suggesting impaired mitochondrial R-loop processing, transcription and mitochondrial DNA replication. These changes resulted in mitochondrial dysfunction with marked changes in mitochondrial fusion, fission, morphology and transcriptional changes reflective of mitochondrial damage and stress. Liver degeneration ensued, as indicated by apoptosis, fibrosis and increased transaminase levels. Antisense oligonucleotides (ASOs) designed to serve as substrates for RNase H1 were inactive in the hepatocytes from the RNase H1 knockout mice and in vivo, demonstrating that RNase H1 is necessary for the activity of DNA-like ASOs. During liver regeneration, a clone of hepatocytes that expressed RNase H1 developed and partially restored mitochondrial and liver function. PMID:27131367

  19. Effects of Saikokaryukotsuboreito on Spermatogenesis and Fertility in Aging Male Mice

    Institute of Scientific and Technical Information of China (English)

    Zhi-Jun Zang; Su-Yun Ji; Ya-Nan Zhang; Yong Gao; Bin Zhang

    2016-01-01

    Background:Aspermia caused by exogenous testosterone limit its usage in late-onset hypogonadism (LOH) patients desiring fertility.Saikokaryukotsuboreito (SKRBT) is reported to improve serum testosterone and relieve LOH-related symptoms.However,it is unclear whether SKRBT affects fertility.We aimed to examine the effects of SKRBT on spermatogenesis and fertility in aging male mice.Methods:Thirty aging male mice were randomly assigned to three groups.Mice were orally administered with phosphate-buffer solution or SKRBT (300 mg/kg,daily) or received testosterone by subcutaneous injections (10 mg/kg,every 3 days).Thirty days later,each male mouse was mated with two female mice.All animals were sacrificed at the end of 90 days.Intratesticular testosterone (ITT) levels,quality of sperm,expression of synaptonemal complex protein 3 (SYCP3),and fertility were assayed.Results:In the SKRBT-treated group,ITT,quality of sperm,and expression of SYCP3 were all improved compared with the control group (ITT:85.50± 12.31 ng/gvs.74.10± 11.45 ng/g,P=0.027;sperm number:[14.94± 4.63] × 106 cells/ml vs.[8.79±4.38] × 106 cells/ml,P =0.002;sperm motility:43.16 ± 9.93% vs.33.51 ± 6.98%,P =0.015;the number of SYCP3-positive cells/tubule:77.50 ± 11.01 ng/ml vs.49.30 ± 8.73 ng/ml,P < 0.001;the expression of SYCP3 protein:1.23 ± 0.09 vs.0.84 ± 0.10,P < 0.001),but fertility was not significantly changed (P > 0.05,respectively).In the testosterone-treated group,ITT,quality of sperm,and expression of SYCP3 were markedly lower than the control group (ITT:59.00 ± 8.67,P =0.005;sperm number:[4.34 ± 2.45] × l06 cells/ml,P =0.018;sperm motility:19.53 ± 7.69%,P =0.001;the number of SYCP3-positive cells/tubule:30.00 ± 11.28,P < 0.001;the percentage of SYCP3-positive tubules/section 71.98 ± 8.88%,P =0.001;the expression of SYCP3 protein:0.71 ± 0.09,P < 0.001),and fertility was also suppressed (P < 0.05,respectively).Conclusion:SKRBT had no adverse effect on fertility

  20. The Brewed Rice Vinegar Kurozu Increases HSPA1A Expression and Ameliorates Cognitive Dysfunction in Aged P8 Mice.

    Directory of Open Access Journals (Sweden)

    Hiroaki Kanouchi

    Full Text Available Kurozu is a traditional Japanese rice vinegar. During fermentation and aging of the Kurozu liquid in an earthenware jar over 1 year, a solid residue called Kurozu Moromi is produced. In the present study, we evaluated whether concentrated Kurozu or Kurozu Moromi could ameliorate cognitive dysfunction in the senescence-accelerated P8 mouse. Senescence-accelerated P8 mice were fed 0.25% (w/w concentrated Kurozu or 0.5% (w/w Kurozu Moromi for 4 or 25 weeks. Kurozu suppressed cognitive dysfunction and amyloid accumulation in the brain, while Kurozu Moromi showed a tendency to ameliorate cognitive dysfunction, but the effect was not significant. We hypothesize that concentrated Kurozu has an antioxidant effect; however, the level of lipid peroxidation in the brain did not differ in senescence-accelerated P8 mice. DNA microarray analysis indicated that concentrated Kurozu increased HSPA1A mRNA expression, a protein that prevents protein misfolding and aggregation. The increase in HSPA1A expression by Kurozu was confirmed using quantitative real-time PCR and immunoblotting methods. The suppression of amyloid accumulation by concentrated Kurozu may be associated with HSPA1A induction. However, concentrated Kurozu could not increase HSPA1A expression in mouse primary neurons, suggesting it may not directly affect neurons.

  1. Combined anti-inflammatory and anti-AGE drug treatments have a protective effect on intervertebral discs in mice with diabetes.

    Directory of Open Access Journals (Sweden)

    Svenja Illien-Junger

    Full Text Available OBJECTIVE: Diabetes and low back pain are debilitating diseases and modern epidemics. Diabetes and obesity are also highly correlated with intervertebral disc (IVD degeneration and back pain. Advanced-glycation-end-products (AGEs increase reactive-oxygen-species (ROS and inflammation, and are one cause for early development of diabetes mellitus. We hypothesize that diabetes results in accumulation of AGEs in spines and associated spinal pathology via increased catabolism. We present a mouse model showing that: 1 diabetes induces pathological changes to structure and composition of IVDs and vertebrae; 2 diabetes is associated with accumulation of AGEs, TNFα, and increased catabolism spinal structures; and 3 oral-treatments with a combination of anti-inflammatory and anti-AGE drugs mitigate these diabetes-induced degenerative changes to the spine. METHODS: Three age-matched groups of ROP-Os mice were compared: non-diabetic, diabetic (streptozotocin (STZ-induced, or diabetic mice treated with pentosan-polysulfate (anti-inflammatory and pyridoxamine (AGE-inhibitor. Mice were euthanized and vertebra-IVD segments were analyzed by μCT, histology and Immunohistochemistry. RESULTS: Diabetic mice exhibited several pathological changes including loss in IVD height, decreased vertebral bone mass, decreased glycosaminoglycan content and morphologically altered IVDs with focal deposition of tissues highly expressing TNFα, MMP-13 and ADAMTS-5. Accumulation of larger amounts of methylglyoxal suggested that AGE accumulation was associated with these diabetic degenerative changes. However, treatment prevented or reduced these pathological effects on vertebrae and IVD. CONCLUSION: This is the first study to demonstrate specific degenerative changes to nucleus pulposus (NP morphology and their association with AGE accumulation in a diabetic mouse model. Furthermore, this is the first study to demonstrate that oral-treatments can inhibit AGE-induced ROS and

  2. Atherosclerosis in aged mice over-expressing the reverse cholesterol transport genes

    Directory of Open Access Journals (Sweden)

    J.A. Berti

    2005-03-01

    Full Text Available We determined whether over-expression of one of the three genes involved in reverse cholesterol transport, apolipoprotein (apo AI, lecithin-cholesterol acyl transferase (LCAT and cholesteryl ester transfer protein (CETP, or of their combinations influenced the development of diet-induced atherosclerosis. Eight genotypic groups of mice were studied (AI, LCAT, CETP, LCAT/AI, CETP/AI, LCAT/CETP, LCAT/AI/CETP, and non-transgenic after four months on an atherogenic diet. The extent of atherosclerosis was assessed by morphometric analysis of lipid-stained areas in the aortic roots. The relative influence (R² of genotype, sex, total cholesterol, and its main sub-fraction levels on atherosclerotic lesion size was determined by multiple linear regression analysis. Whereas apo AI (R² = 0.22, P < 0.001 and CETP (R² = 0.13, P < 0.01 expression reduced lesion size, the LCAT (R² = 0.16, P < 0.005 and LCAT/AI (R² = 0.13, P < 0.003 genotypes had the opposite effect. Logistic regression analysis revealed that the risk of developing atherosclerotic lesions greater than the 50th percentile was 4.3-fold lower for the apo AI transgenic mice than for non-transgenic mice, and was 3.0-fold lower for male than for female mice. These results show that apo AI overexpression decreased the risk of developing large atherosclerotic lesions but was not sufficient to reduce the atherogenic effect of LCAT when both transgenes were co-expressed. On the other hand, CETP expression was sufficient to eliminate the deleterious effect of LCAT and LCAT/AI overexpression. Therefore, increasing each step of the reverse cholesterol transport per se does not necessarily imply protection against atherosclerosis while CETP expression can change specific athero genic scenarios.

  3. Do long-lived mutant and calorie-restricted mice share common anti-aging mechanisms?—a pathological point of view

    OpenAIRE

    Ikeno, Yuji; Lew, Christie M.; Cortez, Lisa A.; Webb, Celeste R.; Lee, Shuko; Gene B Hubbard

    2006-01-01

    Rodent models are an invaluable resource for studying the mechanism of mammalian aging. In recent years, the availability of transgenic and knockout mouse models has facilitated the study of potential mechanisms of aging. Since 1996, aging studies with several long-lived mutant mice have been conducted. Studies with the long-lived mutant mice, Ames and Snell dwarf, and growth hormone receptor/binding protein knockout mice, are currently providing important clues regarding the role of the grow...

  4. Age-and diet-dependent requirement of DJ-1 for glucose homeostasis in mice with implications for human type 2 diabetes

    Institute of Scientific and Technical Information of China (English)

    Deepak Jain; Ruchi Jain; Daniel Eberhard; Jan Eglinger; Marco Bugliani; Lorenzo Piemonti; Piero Marchetti; Eckhard Lammert

    2012-01-01

    Elderly patients often suffer from multiple age-related diseases.Here we show that the expression of DJ-1,an antioxidant protein with reduced expression in the central nervous system of patients with Parkinson's disease,is reduced in pancreatic islets of patients with type 2 diabetes mellitus (T2DM).In contrast,under non-diabetic conditions,DJ-1 expression increases in mouse and human islets during aging.In mouse islets,we show that DJ-1 prevents an increase in reactive oxygen species levels as the mice age.This antioxidant function preserves mitochondrial integrity and physiology,prerequisites for glucose-stimulated insulin secretion.Accordingly,DJ-1-deficient mice develop glucose intolerance and reduced β cell area as they age or gain weight.Our data suggest that DJ-1 is more generally involved in age-and lifestyle-related human diseases and show for the first time that DJ-1 plays a key role in glucose homeostasis and might serve as a novel drug target for T2DM.

  5. Ischemic postconditioning confers cardioprotection and prevents reduction of Trx-1 in young mice, but not in middle-aged and old mice.

    Science.gov (United States)

    Perez, Virginia; D Annunzio, Verónica; Mazo, Tamara; Marchini, Timoteo; Caceres, Lourdes; Evelson, Pablo; Gelpi, Ricardo J

    2016-04-01

    Thioredoxin-1 (Trx-1) is part of an antioxidant system that maintains the cell redox homeostasis but their role on ischemic postconditioning (PostC) is unknown. The aim of this work was to determine whether Trx-1 participates in the cardioprotective mechanism of PostC in young, middle-aged, and old mice. Male FVB young (Y: 3 month-old), middle-aged (MA: 12 month-old), and old (O: 20 month-old) mice were used. Langendorff-perfused hearts were subjected to 30 min of ischemia and 120 min of reperfusion (I/R group). After ischemia, we performed 6 cycles of R/I (10 s each) followed by 120 min of reperfusion (PostC group). We measured the infarct size (triphenyltetrazolium); Trx-1, total and phosphorylated Akt, and GSK3β expression (Western blot); and the GSH/GSSG ratio (HPLC). PostC reduced the infarct size in young mice (I/R-Y: 52.3 ± 2.4 vs. PostC-Y: 40.0 ± 1.9, p aged and old mice groups. Trx-1 expression decreased after I/R, and the PostC prevented the protein degradation in young animals (I/R-Y: 1.05 ± 0.1 vs. PostC-Y: 0.52 ± .0.07, p aged and old groups. Cytosolic Akt and GSK3β phosphorylation increased in the PostC compared with the I/R group only in young animals. Our results suggest that PostC prevents Trx-1 degradation, decreasing oxidative stress and allowing the activation of Akt and GSK3β to exert its cardioprotective effect. This protection mechanism is not activated in middle-aged and old animals. PMID:26932791

  6. Intermittent fasting favored the resolution of Salmonella typhimurium infection in middle-aged BALB/c mice.

    Science.gov (United States)

    Campos-Rodríguez, Rafael; Godínez-Victoria, Marycarmen; Reyna-Garfias, Humberto; Arciniega-Martínez, Ivonne Maciel; Reséndiz-Albor, Aldo Arturo; Abarca-Rojano, Edgar; Cruz-Hernández, Teresita Rocío; Drago-Serrano, Maria Elisa

    2016-02-01

    Intermittent fasting (IF) reportedly increases resistance and intestinal IgA response to Salmonella typhimurium infection in mature mice. The aim of this study was to explore the effect of aging on the aforementioned improved immune response found with IF. Middle-aged male BALB/c mice were submitted to IF or ad libitum (AL) feeding for 40 weeks and then orally infected with S. typhimurium. Thereafter, infected animals were all fed AL (to maximize their viability) until sacrifice on day 7 or 14 post-infection. We evaluated body weight, bacterial load (in feces, Peyer's patches, spleen and liver), total and specific intestinal IgA, lamina propria IgA+ plasma cells, plasma corticosterone, and messenger RNA (mRNA) expression of α-chain, J-chain, and the polymeric immunoglobulin receptor (pIgR) in liver and intestinal mucosa. In comparison with the infected AL counterpart, the infected IF group (long-term IF followed by post-infection AL feeding) generally had lower intestinal and systemic bacterial loads as well as higher total IgA on both post-infection days. Both infected groups showed no differences in corticosterone levels, body weight, or food and caloric intake. The increase in intestinal IgA was associated with enhanced pIgR mRNA expression in the intestine (day 7) and liver. Thus, to maintain body weight and caloric intake, IF elicited metabolic signals that possibly induced the increased hepatic and intestinal pIgR mRNA expression found. The increase in IgA probably resulted from intestinal IgA transcytosis via pIgR. This IgA response along with phagocyte-induced killing of bacteria in systemic organs (not measured) may explain the resolution of the S. typhimurium infection. PMID:26798034

  7. Effects of Omega-3 Fatty Acid Supplementation on Cognitive Functions and Neural Substrates: A Voxel-Based Morphometry Study in Aged Mice.

    Science.gov (United States)

    Cutuli, Debora; Pagani, Marco; Caporali, Paola; Galbusera, Alberto; Laricchiuta, Daniela; Foti, Francesca; Neri, Cristina; Spalletta, Gianfranco; Caltagirone, Carlo; Petrosini, Laura; Gozzi, Alessandro

    2016-01-01

    Human and experimental studies have revealed putative neuroprotective and pro-cognitive effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) in aging, evidencing positive correlations between peripheral n-3 PUFA levels and regional grey matter (GM) volume, as well as negative correlations between dietary n-3 PUFA levels and cognitive deficits. We recently showed that n-3 PUFA supplemented aged mice exhibit better hippocampal-dependent mnesic functions, along with enhanced cellular plasticity and reduced neurodegeneration, thus supporting a role of n-3 PUFA supplementation in preventing cognitive decline during aging. To corroborate these initial results and develop new evidence on the effects of n-3 PUFA supplementation on brain substrates at macro-scale level, here we expanded behavioral analyses to the emotional domain (anxiety and coping skills), and carried out a fine-grained regional GM volumetric mapping by using high-resolution MRI-based voxel-based morphometry. The behavioral effects of 8 week n-3 PUFA supplementation were measured on cognitive (discriminative, spatial and social) and emotional (anxiety and coping) abilities of aged (19 month-old at the onset of study) C57B6/J mice. n-3 PUFA supplemented mice showed better mnesic performances as well as increased active coping skills. Importantly, these effects were associated with enlarged regional hippocampal, retrosplenial and prefrontal GM volumes, and with increased post mortem n-3 PUFA brain levels. These findings indicate that increased dietary n-3 PUFA intake in normal aging can improve fronto-hippocampal GM structure and function, an effect present also when the supplementation starts at late age. Our data are consistent with a protective role of n-3 PUFA supplementation in counteracting cognitive decline, emotional dysfunctions and brain atrophy. PMID:26973513

  8. Influence of age and ways of treatment in the parasitemia in mice infected with Trypanosoma cruzi treated with high potency biotherapy

    Directory of Open Access Journals (Sweden)

    Silvana Marques de Araujo

    2011-09-01

    Full Text Available Introduction: The infection of mice by Trypanosoma cruzi is well known, making this a good model for understanding the effect of highly diluted medications. Mice of different ages show different responses to biotherapic T. cruzi [1]. Other data from our laboratory using biotherapic treatment at low potencies show that long lasting treatment has a better effect in mice infected with T. cruzi. However, the use of high potency biotherapics in mice of different ages infected with T. cruzi has not been analysed yet. Aim: To evaluate the effect of different ways of treatment using biotherapic 200 DH T. cruzi in the evolution of the curve of parasitemia of mice of different ages infected with T. cruzi. Materials and methods: A blind randomized controlled trial was performed using 107 swiss male mice, aged 28, 35 and 56 days, divided into groups: CONTROL(C – mice aged 28(C28, 38(C38 and 56(C56 days, treated with 7% water-alcohol solution diluted with water (1mL/100mL; ONE DAY(OD – mice aged 28(OD28, 38(OD38 and 56(OD56 days, treated with highly diluted medication 200 DH T. cruzi in a single dose, diluted in water (10mL/100mL; EVERY DAY(ED – mice aged 28(ED28, 38(ED38 and 56(ED56 days, treated with highly diluted medication 200DH T.cruzi until the end of the experiment, diluted in water(1mL/100mL. Amber bottle was used and the water was changed every two days. The groups were infected with strain Y-T. cruzi, intraperitoneal,1400 blood trypomastigotes. Medicines were handled according to the Brazilian Homeopathic Pharmacopoeia [2], with microbiological testing according to RDC n° 67 and in vivo biological risk. We compared the parasitemia curve and total parasitemia, determined daily counting of the parasites [3], obtained using the tests Kruskal-Wallis and Wald-Wolfowitz, Statistica 8.0, 5% significance. Approved by the Ethics Committee for Animal Experimentation/ UEM - 030/2008. Results

  9. Measures of Healthspan as Indices of Aging in Mice-A Recommendation.

    Science.gov (United States)

    Richardson, Arlan; Fischer, Kathleen E; Speakman, John R; de Cabo, Rafael; Mitchell, Sarah J; Peterson, Charlotte A; Rabinovitch, Peter; Chiao, Ying A; Taffet, George; Miller, Richard A; Rentería, René C; Bower, James; Ingram, Donald K; Ladiges, Warren C; Ikeno, Yuji; Sierra, Felipe; Austad, Steven N

    2016-04-01

    Over the past decade, a large number of discoveries have shown that interventions (genetic, pharmacological, and nutritional) increase the lifespan of invertebrates and laboratory rodents. Therefore, the possibility of developing antiaging interventions for humans has gone from a dream to a reality. However, it has also become apparent that we need more information than just lifespan to evaluate the translational potential of any proposed antiaging intervention to humans. Information is needed on how an intervention alters the "healthspan" of an animal, that is, how the physiological functions that change with age are altered. In this report, we describe the utility and the limitations of assays in mice currently available for measuring a wide range of physiological functions that potentially impact quality of life. We encourage investigators and reviewers alike to expect at minimum an overall assessment of health in several domains across several ages before an intervention is labeled as "increasing healthspan." In addition, it is important that investigators indicate any tests in which the treated group did worse or did not differ statistically from controls because overall health is a complex phenotype, and no intervention discovered to date improves every aspect of health. Finally, we strongly recommend that functional measurements be performed in both males and females so that sex differences in the rate of functional decline in different domains are taken into consideration. PMID:26297941

  10. Interleukin 1 receptor antagonist knockout mice show enhanced microglial activation and neuronal damage induced by intracerebroventricular infusion of human β-amyloid

    Directory of Open Access Journals (Sweden)

    Watterson D Martin

    2005-06-01

    Full Text Available Abstract Background Interleukin 1 (IL-1 is a key mediator of immune responses in health and disease. Although classically the function of IL-1 has been studied in the systemic immune system, research in the past decade has revealed analogous roles in the CNS where the cytokine can contribute to the neuroinflammation and neuropathology seen in a number of neurodegenerative diseases. In Alzheimer's disease (AD, for example, pre-clinical and clinical studies have implicated IL-1 in the progression of a pathologic, glia-mediated pro-inflammatory state in the CNS. The glia-driven neuroinflammation can lead to neuronal damage, which, in turn, stimulates further glia activation, potentially propagating a detrimental cycle that contributes to progression of pathology. A prediction of this neuroinflammation hypothesis is that increased IL-1 signaling in vivo would correlate with increased severity of AD-relevant neuroinflammation and neuronal damage. Methods To test the hypothesis that increased IL-1 signaling predisposes animals to beta-amyloid (Aβ-induced damage, we used IL-1 receptor antagonist Knock-Out (IL1raKO and wild-type (WT littermate mice in a model that involves intracerebroventricular infusion of human oligomeric Aβ1–42. This model mimics many features of AD, including robust neuroinflammation, Aβ plaques, synaptic damage and neuronal loss in the hippocampus. IL1raKO and WT mice were infused with Aβ for 28 days, sacrificed at 42 days, and hippocampal endpoints analyzed. Results IL1raKO mice showed increased vulnerability to Aβ-induced neuropathology relative to their WT counterparts. Specifically, IL1raKO mice exhibited increased mortality, enhanced microglial activation and neuroinflammation, and more pronounced loss of synaptic markers. Interestingly, Aβ-induced astrocyte responses were not significantly different between WT and IL1raKO mice, suggesting that enhanced IL-1 signaling predominately affects microglia. Conclusion Our

  11. 55P0110, a Novel Synthetic Compound Developed from a Plant Derived Backbone Structure, Shows Promising Anti-Hyperglycaemic Activity in Mice.

    Science.gov (United States)

    Brunmair, Barbara; Lehner, Zsuzsanna; Stadlbauer, Karin; Adorjan, Immanuel; Frobel, Klaus; Scherer, Thomas; Luger, Anton; Bauer, Leonhardt; Fürnsinn, Clemens

    2015-01-01

    Starting off with a structure derived from the natural compound multiflorine, a derivatisation program aimed at the discovery and initial characterisation of novel compounds with antidiabetic potential. Design and discovery of the structures was guided by oral bioactivities obtained in oral glucose tolerance tests in mice. 55P0110, one among several new compounds with distinct anti-hyperglycaemic activity, was further examined to characterise its pharmacology and mode of action. Whereas a single oral dose of 55P0110 did not affect basal glycaemia, it markedly improved the glucose tolerance of healthy and diabetic mice (peak blood glucose in glucose tolerance test, mmol/l: healthy mice with 90 mg/kg 55P0110, 17.0 ± 1.2 vs. 10.1 ± 1.1; diabetic mice with 180 mg/kg 55P0110, 23.1 ± 0.9 vs. 11.1 ± 1.4; pgliclazide (16 mg/kg) distinctly increased the circulating insulin-per-glucose ratio under basal conditions, 55P0110 (90 mg/kg) lacked such an effect (30 min. after dosing, nmol/mol: vehicle, 2.49 ± 0.27; 55P0110, 2.99 ± 0.35; gliclazide, 8.97 ± 0.49; pgliclazide). Under an exogenous glucose challenge, however, 55P0110 increased this ratio to the same extent as gliclazide (20 min. after glucose feeding: vehicle, 2.53 ± 0.41; 55P0110, 3.80 ± 0.46; gliclazide, 3.99 ± 0.26; p<0.05 each vs. vehicle). By augmenting the glucose stimulated increase in plasma insulin, 55P0110 thus shows distinct anti-hyperglycaemic action in combination with low risk for fasting hypoglycaemia in mice. In summary, we have discovered a novel class of fully synthetic substituted quinazolidines with an attractive pharmacological profile that recommends the structures for further evaluation as candidates for the treatment of diabetes mellitus. PMID:25973898

  12. Aging Exacerbates Depressive-like Behavior in Mice in Response to Activation of the Peripheral Innate Immune System

    OpenAIRE

    Godbout, Jonathan P.; Moreau, Maïté; Lestage, Jacques; Chen, Jing; Sparkman, Nathan L; O’Connor, Jason; Castanon, Nathalie; Kelley, Keith W.; Dantzer, Robert; Johnson, Rodney W.

    2007-01-01

    Exposure to peripheral infections may be permissive to cognitive and behavioral complications in the elderly. We have reported that peripheral stimulation of the innate immune system with lipopolysaccharide (LPS) causes an exaggerated neuroinflammatory response and prolonged sickness behavior in aged BALB/c mice. Because LPS also causes depressive behavior, the purpose of this study was to determine whether aging is associated with an exacerbated depressive-like response. We confirmed that LP...

  13. Exercise does not enhance aged bone's impaired response to artificial loading in C57Bl/6 mice

    OpenAIRE

    Meakin, Lee B.; Udeh, Chinedu; Galea, Gabriel L.; Lanyon, Lance E.; Price, Joanna S.

    2015-01-01

    Bones adapt their structure to their loading environment and so ensure that they become, and are maintained, sufficiently strong to withstand the loads to which they are habituated. The effectiveness of this process declines with age and bones become fragile fracturing with less force. This effect in humans also occurs in mice which experience age-related bone loss and reduced adaptation to loading. Exercise engenders many systemic and local muscular physiological responses as well as engende...

  14. Early Shifts of Brain Metabolism by Caloric Restriction Preserve White Matter Integrity and Long-Term Memory in Aging Mice

    OpenAIRE

    Janet eGuo; Vikas eBakshi; Ai-Ling eLin

    2015-01-01

    Preservation of brain integrity with age is highly associated with lifespan determination. Caloric restriction (CR) has been shown to increase longevity and healthspan in various species; however, its effects on preserving living brain functions in aging remain largely unexplored. In the study, we used multimodal, non-invasive neuroimaging (PET/MRI/MRS) to determine in vivo brain glucose metabolism, energy metabolites, and white matter structural integrity in young and old mice fed with eithe...

  15. Age-dependent separation of class-specific suppressor cells in thymus of SJL/J mice

    International Nuclear Information System (INIS)

    The thymus of SJL/J mice of age 3-6 weeks has been previously shown to contain suppressor cells that inhibit the antibody response of lymph node cells to SRBC. The effect of these suppressor cells disappears as the animals age (24 weeks or more). The authors find that these aged animals acquire thymic suppressor cells which suppress the generation of cytotoxic T-cells both in vitro and in vivo. Although such suppressors are not present in the thymuses of young SJL/J mice, suppression can be induced by treatment with estrogen and progesterone. The differentiation of functionally different suppressor cell populations in thymus may be affected by both age and horomonal status. Lymph node cells were mixed with γ-irradiated spleen cells in a culture medium. Varying numbers of thymocytes were added and after 4-5 days incubation the number of cytotoxic T-cells was assayed using a 51Cr-release assay. Antibody formation in vivo was tested in γ-irradiated mice. The graft versus host reaction was tested in X-irradiated mice. (Auth.)

  16. Temporal fate mapping reveals age-linked heterogeneity in naive T lymphocytes in mice.

    Science.gov (United States)

    Hogan, Thea; Gossel, Graeme; Yates, Andrew J; Seddon, Benedict

    2015-12-15

    Understanding how our T-cell compartments are maintained requires knowledge of their population dynamics, which are typically quantified over days to weeks using the administration of labels incorporated into the DNA of dividing cells. These studies present snapshots of homeostatic dynamics and have suggested that lymphocyte populations are heterogeneous with respect to rates of division and/or death, although resolving the details of such heterogeneity is problematic. Here we present a method of studying the population dynamics of T cells in mice over timescales of months to years that reveals heterogeneity in rates of division and death with respect to the age of the host at the time of thymic export. We use the transplant conditioning drug busulfan to ablate hematopoetic stem cells in young mice but leave the peripheral lymphocyte compartments intact. Following their reconstitution with congenically labeled (donor) bone marrow, we followed the dilution of peripheral host T cells by donor-derived lymphocytes for a year after treatment. Describing these kinetics with mathematical models, we estimate rates of thymic production, division and death of naive CD4 and CD8 T cells. Population-averaged estimates of mean lifetimes are consistent with earlier studies, but we find the strongest support for a model in which both naive T-cell pools contain kinetically distinct subpopulations of older host-derived cells with self-renewing capacity that are resistant to displacement by naive donor lymphocytes. We speculate that these incumbent cells are conditioned or selected for increased fitness through homeostatic expansion into the lymphopenic neonatal environment. PMID:26607449

  17. Antigens of worms and eggs showed a differentiated detection of specific IgG according to the time of Schistosoma mansoni infection in mice

    Directory of Open Access Journals (Sweden)

    Rafaella Fortini Queiroz Grenfell

    2012-08-01

    Full Text Available INTRODUCTION: The correlation between the immunological assay and the antibody titer can offer a tool for the experimental analysis of different phases of the disease. METHODS: Two simple immunological assays for Schistosoma mansoni in mice sera samples based on specific IgG detection for worms soluble antigens and eggs soluble antigens were standardized and evaluated in our laboratory. Fifty mice were used in negative and positive groups and the results obtained by enzyme-linked immunosorbent assays (ELISA assays were compared with the number of worms counted and the IgG titers at different times of infection. RESULTS: Data showed that ELISA using adult worm antigens (ELISA-SWAP presented a satisfactory correlation between the absorbance value of IgG titers and the individual number of worms counted after perfusion technique (R²=0.62. In addition, ELISA-SWAP differentially detected positive samples with 30 and 60 days post infection (p=0.011 and 0.003, respectively, whereas ELISA using egg antigens (ELISA-SEA detected samples after 140 days (p=0.03. CONCLUSIONS: These data show that the use of different antigens in immunological methods can be used as potential tools for the analysis of the chronological evolution of S. mansoni infection in murine schistosomiasis. Correlations with human schistosomiasis are discussed.

  18. Age-related changes in behavior in C57BL/6J mice from young adulthood to middle age

    OpenAIRE

    Shoji, Hirotaka; Takao, Keizo; Hattori, Satoko; Miyakawa, Tsuyoshi

    2016-01-01

    Background Aging is considered to be associated with progressive changes in the brain and its associated sensory, motor, and cognitive functions. A large number of studies comparing young and aged animals have reported differences in various behaviors between age-cohorts, indicating behavioral dysfunctions related to aging. However, relatively little is known about behavioral changes from young adulthood to middle age, and the effect of age on behavior during the early stages of life remains ...

  19. N-Acetylmannosamine improves sleep-wake quality in middle-aged mice: relevance to autonomic nervous function.

    Science.gov (United States)

    Kuwahara, Masayoshi; Ito, Koichi; Hayakawa, Koji; Yagi, Shintaro; Shiota, Kunio

    2015-01-01

    Aging is associated with a variety of physiological changes originating peripherally and centrally, including within the autonomic nervous system. Sleep-wake disturbances constitute reliable hallmarks of aging in several animal species and humans. Recent studies have been interested in N-acetylmannosamine (ManNAc) a potential therapeutic agent for improving quality of life, as well as preventing age-related cognitive decline. In this study, ManNAc (5.0 mg/ml) was administered in the drinking water of middle-aged male C57BL/6J mice (55 weeks old) for 7 days. Mice were housed under a 12:12 h light:dark cycle at 23-24 °C. We evaluated bio-behavioral activity using electrocardiogram, body temperature and locomotor activity recorded by an implanted telemetry transmitter. To estimate sleep-wake profile, surface electroencephalogram and electromyogram leads connected to a telemetry transmitter were also implanted in mice. Autonomic nervous activity was evaluated using power spectral analysis of heart rate variability. ManNAc-treated mice spent more time in a wakeful state and less time in slow wave sleep during the dark phase. Parasympathetic nervous activity was increased following ManNAc treatment, then the sympatho-vagal balance was shifted predominance of parasympathetic nervous system. Furthermore, improvement in sleep-wake pattern was associated with increased parasympathetic nervous activity. These results suggest that ManNAc treatment can improve bio-behavioral activity and sleep-wake quality in middle-aged mice. This may have implications for improving sleep patterns in elderly humans. PMID:25443216

  20. Phenotypes of Aging Postovulatory Oocytes After Somatic Cell Nuclear Transfer in Mice.

    Science.gov (United States)

    Lee, Ah Reum; Shimoike, Takashi; Wakayama, Teruhiko; Kishigami, Satoshi

    2016-06-01

    Oocytes rapidly lose their developmental potential after ovulation, termed postovulatory oocyte aging, and often exhibit characteristic phenotypes, such as cytofragmentation, abnormal spindle shapes, and chromosome misalignments. Here, we reconstructed mouse oocytes using somatic cell nuclear transfer (SCNT) to reveal the effect of somatic cell-derived nuclei on oocyte physiology during aging. Normal oocytes started undergoing cytofragmentation 24 hours after oocyte collection; however, this occurred earlier in SCNT oocytes and was more severe at 48 hours, suggesting that the transferred somatic cell nuclei affected oocyte physiology. We found no difference in the status of acetylated α-tubulin (Ac-Tub) and α-tubulin (Tub) between normal and SCNT aging oocytes, but unlike normal oocytes, aging SCNT oocytes did not have astral microtubules. Interestingly, aging SCNT oocytes displayed more severely scattered chromosomes or irregularly shaped spindles. Observations of the microfilaments showed that, in normal oocytes, there was a clear actin ring beneath the plasma membrane and condensed microfilaments around the spindle (the actin cap) at 0 hours, and the actin filaments started degenerating at 1 hour, becoming completely disrupted and distributed to the cytoplasm at 24 hours. By contrast, in SCNT oocytes, an actin cap formed around the transplanted nuclei within 1 hour of SCNT, which was still present at 24 hours. Thus, SCNT oocytes age in a similar but distinct way, suggesting that they not only contain nuclei with abnormal epigenetics but are also physiologically different. PMID:27253626

  1. "Teacher, I Showed Her How to Do That!": Teaching Early-Years Children through Mixed-Age Play

    Science.gov (United States)

    Doherty, Andrea

    2012-01-01

    The principle of mixed-age play was first encountered in "Golden Key" schools in Moscow, where the schools were originally set up and organised (and continue to be so) in accordance with the work of Vygotsky. Vygotsky said that children can learn through imitation, or "emulation" as it has come to be known. Children observe someone more competent…

  2. Resistance to age-dependent thymic atrophy in long-lived mice that are deficient in pregnancy-associated plasma protein A

    OpenAIRE

    Vallejo, Abbe N.; Joshua J Michel; Bale, Laurie K.; Lemster, Bonnie H.; Borghesi, Lisa; Conover, Cheryl A.

    2009-01-01

    Pregnancy-associated plasma protein A (PAPPA) is a metalloproteinase that controls the tissue availability of insulin-like growth factor (IGF). Homozygous deletion of PAPPA in mice leads to lifespan extension. Since immune function is an important determinant of individual fitness, we examined the natural immune ecology of PAPPA−/− mice and their wild-type littermates reared under specific pathogen-free condition with aging. Whereas wild-type mice exhibit classic age-dependent thymic atrophy,...

  3. Aging changes of macromolecular synthesis in the digestive organs of mice as revealed by microscopic radioautography and X-ray microanalysis

    Energy Technology Data Exchange (ETDEWEB)

    Nagata, Tetsuji [Shinshu Univ., Matsumoto (Japan). School of Medicine. Dept. of Anatomy and Cell Biology]. E-mail: nagatas@po.cnet.ne.jp

    2002-07-01

    For the purpose of elucidating the aging changes of macromolecular synthesis such as DNA, RNA, proteins, glycoproteins, glycides and lipids in various organ systems of experimental animals, we have studied the digestive organs of aging mice and rats as a series of systematic studies using light and electron microscopic radioautography after incorporations with macromolecular precursors. The experimental animals mainly used were ddY strain mice at various aging groups from embryo to postnatal days 1 and 3, weeks 1 and 2, months 1, 2, 6, 12 up to 2 year senescent stages as well as several groups of adult Wistar rats. The animals were injected with such macromolecular precursors as {sup 3}H - thymidine for DNA, {sup 3}H-uridine for RNA, {sup 3}H-leucine and {sup 3}H proline for proteins, {sup 35}SO{sub 4} for glycoproteins, {sup 3} H-glucosamine for glucides and {sup 3}H-glycerol for lipids. The results demonstrated that these precursors were incorporated into various cell types in the oral cavity, the salivary glands, the esophagus, the stomach, the small and large intestines, the liver and the pancreas at various ages from perinatal to juvenile, mature and senescent stages, showing specific patterns of macromolecular synthesis. It is concluded that these specific patterns of macromolecular synthesis in respective cell types demonstrated the organ specificity of aging of animals. (author)

  4. Ghrelin is produced in taste cells and ghrelin receptor null mice show reduced taste responsivity to salty (NaCl and sour (citric acid tastants.

    Directory of Open Access Journals (Sweden)

    Yu-Kyong Shin

    Full Text Available BACKGROUND: The gustatory system plays a critical role in determining food preferences, food intake and energy balance. The exact mechanisms that fine tune taste sensitivity are currently poorly defined, but it is clear that numerous factors such as efferent input and specific signal transduction cascades are involved. METHODOLOGY/PRINCIPAL FINDINGS: Using immunohistochemical analyses, we show that ghrelin, a hormone classically considered to be an appetite-regulating hormone, is present within the taste buds of the tongue. Prepro-ghrelin, prohormone convertase 1/3 (PC 1/3, ghrelin, its cognate receptor (GHSR, and ghrelin-O-acyltransferase (GOAT , the enzyme that activates ghrelin are expressed in Type I, II, III and IV taste cells of mouse taste buds. In addition, ghrelin and GHSR co-localize in the same taste cells, suggesting that ghrelin works in an autocrine manner in taste cells. To determine a role for ghrelin in modifying taste perception, we performed taste behavioral tests using GHSR null mice. GHSR null mice exhibited significantly reduced taste responsivity to sour (citric acid and salty (sodium chloride tastants. CONCLUSIONS/SIGNIFICANCE: These findings suggest that ghrelin plays a local modulatory role in determining taste bud signaling and function and could be a novel mechanism for the modulation of salty and sour taste responsivity.

  5. T-type calcium channel Cav3.2 deficient mice show elevated anxiety, impaired memory and reduced sensitivity to psychostimulants.

    Science.gov (United States)

    Gangarossa, Giuseppe; Laffray, Sophie; Bourinet, Emmanuel; Valjent, Emmanuel

    2014-01-01

    The fine-tuning of neuronal excitability relies on a tight control of Ca(2+) homeostasis. The low voltage-activated (LVA) T-type calcium channels (Cav3.1, Cav3.2 and Cav3.3 isoforms) play a critical role in regulating these processes. Despite their wide expression throughout the central nervous system, the implication of T-type Cav3.2 isoform in brain functions is still poorly characterized. Here, we investigate the effect of genetic ablation of this isoform in affective disorders, including anxiety, cognitive functions as well as sensitivity to drugs of abuse. Using a wide range of behavioral assays we show that genetic ablation of the cacna1h gene results in an anxiety-like phenotype, whereas novelty-induced locomotor activity is unaffected. Deletion of the T-type channel Cav3.2 also triggers impairment of hippocampus-dependent recognition memories. Acute and sensitized hyperlocomotion induced by d-amphetamine and cocaine are dramatically reduced in T-type Cav3.2 deficient mice. In addition, the administration of the T-type blocker TTA-A2 prevented the expression of locomotor sensitization observed in wildtype mice. In conclusion, our data reveal that physiological activity of this specific Ca(2+) channel is required for affective and cognitive behaviors. Moreover, our work highlights the interest of T-type channel blockers as therapeutic strategies to reverse drug-associated alterations. PMID:24672455

  6. T-type calcium channel Cav3.2 deficient mice show elevated anxiety, impaired memory and reduced sensitivity to psychostimulants.

    Directory of Open Access Journals (Sweden)

    Giuseppe Gangarossa

    2014-03-01

    Full Text Available The fine-tuning of neuronal excitability relies on a tight control of Ca2+ homeostasis. The low voltage-activated T-type calcium channels (Cav3.1, Cav3.2 and Cav3.3 isoforms play a critical role in regulating these processes. Despite their wide expression throughout the central nervous system, the implication of T-type Cav3.2 isoform in brain functions is still poorly characterized. Here we investigate the effect of genetic ablation of this isoform in affective disorders, including anxiety, cognitive functions as well as sensitivity to drugs of abuse. Using a wide range of behavioral assays we show that genetic ablation of the cacna1h gene results in an anxiety-like phenotype, whereas novelty-induced locomotor activity is unaffected. Deletion of the T-type channel Cav3.2 also triggers impairment of hippocampus-dependent recognition memories. Acute and sensitized hyperlocomotion induced by d-amphetamine and cocaine are dramatically reduced in T-type Cav3.2 deficient mice. In addition, the administration of the T-type blocker TTA-A2 prevented the expression of locomotor sensitization observed in wildtype mice. In conclusion, our data reveal that physiological activity of this specific Ca2+ channel is required for affective and cognitive behaviors. Moreover, our work highlights the interest of T-type channel blockers as therapeutic strategies to reverse drug-associated alterations.

  7. Use of senescence-accelerated mouse model in bleomycin-induced lung injury suggests that bone marrow-derived cells can alter the outcome of lung injury in aged mice.

    Science.gov (United States)

    Xu, Jianguo; Gonzalez, Edilson T; Iyer, Smita S; Mac, Valerie; Mora, Ana L; Sutliff, Roy L; Reed, Alana; Brigham, Kenneth L; Kelly, Patricia; Rojas, Mauricio

    2009-07-01

    The incidence of pulmonary fibrosis increases with age. Studies from our group have implicated circulating progenitor cells, termed fibrocytes, in lung fibrosis. In this study, we investigate whether the preceding determinants of inflammation and fibrosis were augmented with aging. We compared responses to intratracheal bleomycin in senescence-accelerated prone mice (SAMP), with responses in age-matched control senescence-accelerated resistant mice (SAMR). SAMP mice demonstrated an exaggerated inflammatory response as evidenced by lung histology. Bleomycin-induced fibrosis was significantly higher in SAMP mice compared with SAMR controls. Consistent with fibrotic changes in the lung, SAMP mice expressed higher levels of transforming growth factor-beta1 in the lung. Furthermore, SAMP mice showed higher numbers of fibrocytes and higher levels of stromal cell-derived factor-1 in the peripheral blood. This study provides the novel observation that apart from increases in inflammatory and fibrotic factors in response to injury, the increased mobilization of fibrocytes may be involved in age-related susceptibility to lung fibrosis. PMID:19359440

  8. Aorta of young and middle-aged heterozygous familial hypercholesterolemia patients shows no functional or morphological impairment assessed by MRI

    Directory of Open Access Journals (Sweden)

    Sami Soljanlahti

    2008-09-01

    Full Text Available Sami Soljanlahti1, Taina Autti1, Alpo F Vuorio2, Pekka Keto1, Hannu Turtola3, Kirsi Lauerma11Helsinki Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland; 2Division of Internal Medicine, Department of Medicine, University of Helsinki, Helsinki, Finland; 3Department of Internal Medicine, North Karelia Central Hospital, Joensuu, FinlandAbstract: In familial hypercholesterolemia (FH the level of LDL cholesterol is 2–3 times that of the normal population and leads to accelerated atherosclerosis. Improved care for risk factors has decreased cardiovascular mortality of these patients. We studied subclinical atherosclerotic changes with morphologic and functional aortic magnetic resonance imaging (MRI in FH patients under the age of 50. 39 DNA test-verified heterozygous FH-North Karelia patients, aged 6–48, 28 of them treated with statins, and 25 healthy controls, aged 12 to 50, underwent aortic MRI, carotid ultrasound (US, and risk-factor assessment. No differences in any of the morphologic or functional aortic parameters appeared between patients and controls. Age and gender were independent predictors of the majority of the morphologic and functional measures. Carotid intima-media thickness assessed by US was greater in patients (0.57 mm ± 0.13 vs 0.48 ± 0.13 mm, p = 0.005 as was cholesterol-years score (243 ± 122 vs 137 ± 74, p < 0.001. Patients had thicker intima-media of the common carotid artery and higher cholesterol burden as indicated by their cholesterol-years score. Despite this, no differences existed in morphologic or functional aortic parameters assessed with MRI. The improved care of cardiovascular risk factors, especially statin treatment, may protect the aorta of FH patients. However, larger confirmatory studies are needed.Keywords: MRI, ultrasound, atherosclerosis, aorta, familial hypercholesterolemia

  9. Depression-like behavior of aged male and female mice is ameliorated with administration of testosterone or its metabolites

    OpenAIRE

    Frye, Cheryl A.; Walf, Alicia A.

    2009-01-01

    There may be a role of age-related decline in androgen production and/or its metabolism for late-onset depression disorders of men and women. Thus, the antidepressant-like effects of testosterone (T) and its metabolites are of interest. Given that these androgens have disparate mechanisms of action, it is important to begin to characterize and compare their effects in an aged animal model. We hypothesized that there would be sex differences in depression behavior of aged mice and that androge...

  10. Homeostatic Imbalance between Apoptosis and Cell Renewal in the Liver of Premature Aging XpdTTD Mice

    OpenAIRE

    Jung Yoon Park; Mi-Ook Cho; Shanique Leonard; Brent Calder; I Saira Mian; Woo Ho Kim; Susan Wijnhoven; Harry van Steeg; James Mitchell; van der Horst, Gijsbertus T. J.; Jan Hoeijmakers; Pinchas Cohen; Jan Vijg; Yousin Suh

    2008-01-01

    Unrepaired or misrepaired DNA damage has been implicated as a causal factor in cancer and aging. Xpd(TTD) mice, harboring defects in nucleotide excision repair and transcription due to a mutation in the Xpd gene (R722W), display severe symptoms of premature aging but have a reduced incidence of cancer. To gain further insight into the molecular basis of the mutant-specific manifestation of age-related phenotypes, we used comparative microarray analysis of young and old female livers to discov...

  11. Effects of Age and Parity on Mammary Gland Lesions and Progenitor Cells in the FVB/N-RC Mice

    OpenAIRE

    Raafat, Ahmed; Strizzi, Luigi; Lashin, Karim; Ginsburg, Erika; McCurdy, David; Salomon, David; Smith, Gilbert H.; Medina, Daniel; Callahan, Robert

    2012-01-01

    The FVB/N mouse strain is extensively used in the development of animal models for breast cancer research. Recently it has been reported that the aging FVB/N mice develop spontaneous mammary lesions and tumors accompanied with abnormalities in the pituitary glands. These observations have a great impact on the mouse models of human breast cancer. We have developed a population of inbred FVB/N mice (designated FVB/N-RC) that have been genetically isolated for 20 years. To study the effects of ...

  12. Age-dependent loss of cholinergic neurons in learning and memory-related brain regions and impaired learning in SAMP8 mice with trigeminal nerve damage

    Institute of Scientific and Technical Information of China (English)

    Yifan He; Jihong Zhu; Fang Huang; Liu Qin; Wenguo Fan; Hongwen He

    2014-01-01

    The tooth belongs to the trigeminal sensory pathway. Dental damage has been associated with impairments in the central nervous system that may be mediated by injury to the trigeminal nerve. In the present study, we investigated the effects of damage to the inferior alveolar nerve, an important peripheral nerve in the trigeminal sensory pathway, on learning and memory be-haviors and structural changes in related brain regions, in a mouse model of Alzheimer’s disease. Inferior alveolar nerve transection or sham surgery was performed in middle-aged (4-month-old) or elderly (7-month-old) senescence-accelerated mouse prone 8 (SAMP8) mice. When the middle-aged mice reached 8 months (middle-aged group 1) or 11 months (middle-aged group 2), and the elderly group reached 11 months, step-down passive avoidance and Y-maze tests of learn-ing and memory were performed, and the cholinergic system was examined in the hippocampus (Nissl staining and acetylcholinesterase histochemistry) and basal forebrain (choline acetyltrans-ferase immunohistochemistry). In the elderly group, animals that underwent nerve transection had fewer pyramidal neurons in the hippocampal CA1 and CA3 regions, fewer cholinergic ifbers in the CA1 and dentate gyrus, and fewer cholinergic neurons in the medial septal nucleus and vertical limb of the diagonal band, compared with sham-operated animals, as well as showing impairments in learning and memory. Conversely, no signiifcant differences in histology or be-havior were observed between middle-aged group 1 or group 2 transected mice and age-matched sham-operated mice. The present ifndings suggest that trigeminal nerve damage in old age, but not middle age, can induce degeneration of the septal-hippocampal cholinergic system and loss of hippocampal pyramidal neurons, and ultimately impair learning ability. Our results highlight the importance of active treatment of trigeminal nerve damage in elderly patients and those with Alzheimer’s disease, and

  13. Interleukin-21 administration to aged mice rejuvenates their peripheral T-cell pool by triggering de novo thymopoiesis.

    Science.gov (United States)

    Al-Chami, E; Tormo, A; Pasquin, S; Kanjarawi, R; Ziouani, S; Rafei, M

    2016-04-01

    The vaccination efficacy in the elderly is significantly reduced compared to younger populations due to thymic involution and age-related intrinsic changes affecting their naïve T-cell compartment. Interleukin (IL)-21 was recently shown to display thymostimulatory properties. Therefore, we hypothesized that its administration to ageing hosts may improve T-cell output and thus restore a competent peripheral T-cell compartment. Indeed, an increase in the production of recent thymic emigrants (RTEs) attributable to intrathymic expansion of early thymic progenitors (ETPs), double-negative (DN), and double-positive (DP) thymocytes as well as thymic epithelial cell (TEC) was observed in recombinant (r)IL-21-treated aged mice. In sharp contrast, no alterations in the frequency of bone marrow (BM)-derived progenitors were detected following rIL-21 administration. Enhanced production of naïve T cells improved the T-cell receptor (TCR) repertoire diversity and re-established a pool of T cells exhibiting higher levels of miR-181a and diminished amounts of the TCR-inhibiting phosphatases SHP-2 and DUSP5/6. As a result, stimulation of T cells derived from rIL-21-treated aged mice displayed enhanced activation of Lck, ZAP-70, and ERK, which ultimately boosted their IL-2 production, CD25 expression, and proliferation capabilities in comparison with T cells derived from control aged mice. Consequently, aged rIL-21-treated mice vaccinated using a tyrosinase-related protein 2 (Trp2)-derived peptide exhibited a substantial delay in B16 tumor growth and improved survival. The results of this study highlight the immunorestorative function of rIL-21 paving its use as a strategy for the re-establishment of effective immunity in the elderly. PMID:26762709

  14. Adverse effects of AMP-activated protein kinase alpha2-subunit deletion and high-fat diet on heart function and ischemic tolerance in aged female mice.

    Science.gov (United States)

    Slámová, K; Papoušek, F; Janovská, P; Kopecký, J; Kolář, F

    2016-03-14

    AMP-activated protein kinase (AMPK) plays a role in metabolic regulation under stress conditions, and inadequate AMPK signaling may be also involved in aging process. The aim was to find out whether AMPK alpha2-subunit deletion affects heart function and ischemic tolerance of adult and aged mice. AMPK alpha2(-/-) (KO) and wild type (WT) female mice were compared at the age of 6 and 18 months. KO mice exhibited subtle myocardial AMPK alpha2-subunit protein level, but no difference in AMPK alpha1-subunit was detected between the strains. Both alpha1- and alpha2-subunits of AMPK and their phosphorylation decreased with advanced age. Left ventricular fractional shortening was lower in KO than in WT mice of both age groups and this difference was maintained after high-fat feeding. Infarct size induced by global ischemia/reperfusion of isolated hearts was similar in both strains at 6 months of age. Aged WT but not KO mice exhibited improved ischemic tolerance compared with the younger group. High-fat feeding for 6 months during aging abolished the infarct size-reduction in WT without affecting KO animals; nevertheless, the extent of injury remained larger in KO mice. The results demonstrate that adverse effects of AMPK alpha2-subunit deletion and high-fat feeding on heart function and myocardial ischemic tolerance in aged female mice are not additive. PMID:26596312

  15. Exercise does not enhance aged bone's impaired response to artificial loading in C57Bl/6 mice.

    Science.gov (United States)

    Meakin, Lee B; Udeh, Chinedu; Galea, Gabriel L; Lanyon, Lance E; Price, Joanna S

    2015-12-01

    Bones adapt their structure to their loading environment and so ensure that they become, and are maintained, sufficiently strong to withstand the loads to which they are habituated. The effectiveness of this process declines with age and bones become fragile fracturing with less force. This effect in humans also occurs in mice which experience age-related bone loss and reduced adaptation to loading. Exercise engenders many systemic and local muscular physiological responses as well as engendering local bone strain. To investigate whether these physiological responses influence bones' adaptive responses to mechanical strain we examined whether a period of treadmill exercise influenced the adaptive response to an associated period of artificial loading in young adult (17-week) and old (19-month) mice. After treadmill acclimatization, mice were exercised for 30 min three times per week for two weeks. Three hours after each exercise period, right tibiae were subjected to 40 cycles of non-invasive axial loading engendering peak strain of 2250 με. In both young and aged mice exercise increased cross-sectional muscle area and serum sclerostin concentration. In young mice it also increased serum IGF1. Exercise did not affect bone's adaptation to loading in any measured parameter in young or aged bone. These data demonstrate that a level of exercise sufficient to cause systemic changes in serum, and adaptive changes in local musculature, has no effect on bone's response to loading 3h later. This study provides no support for the beneficial effects of exercise on bone in the elderly being mediated by systemic or local muscle-derived effects rather than local adaptation to altered mechanical strain. PMID:26142929

  16. Supplementation of selenium-enriched yeast attenuates age-dependent transcriptional changes of heart in mitochondrial DNA mutator mice

    Directory of Open Access Journals (Sweden)

    Rijin Xiao

    2014-03-01

    Full Text Available Background: Age is a major risk factor in developing heart diseases and has been associated with profound transcriptional changes in mammalian tissues. Low tissue selenium has recently been linked to several age-related diseases, including cardiovascular disease. This study investigated the global effects of age and dietary supplementation of selenium on heart transcriptional profiles in POLG mutator mice. Methods: Heart transcription profiles from young (2-month-old and old (13-month-old animals fed either a control diet or a diet supplemented with 1.0 mg selenium from seleniumenriched yeast (SP/kg diet were obtained and validated using microarray and real-time RTPCR techniques. Results: Aging led to significant transcriptional changes, where the expression of 1942 genes in old animals was changed by a fold change larger than 2.0, when compared to young animals. Age-regulated genes are associated with cardiovascular system development, immune and inflammatory response, and cellular oxidative stress response. Multiple genes linked with cardiomyocyte apoptosis, hypertrophy, and cardiac fibrosis, such as Myh7, Lcn2, Spp1, and Serpine1, were significantly up-regulated in old animals. SP supplementation also caused significant transcriptional changes in the heart, especially in old mice where many age-dependent transcriptional changes were totally or partially reversed by SP. Upstream regulator analysis further indicated that genes for Foxo1 and Foxo3, two transcriptional regulators involved in the regulation of cardiac muscle remodeling, were significantly activated by SP, suggesting that Foxo-mediated transcriptional activities play important roles in the anti-aging properties of SP. Functional Foods in Health and Disease 2014; 4(3:98- 119 Page 99 of 119 Conclusions: Results of this study indicate that SP supplementation attenuated age-related transcriptional changes in the heart of old POLG mice, which implies a potential clinical application of

  17. Phenobarbital and propiconazole toxicogenomic profiles in mice show major similarities consistent with the key role that constitutive androstane receptor (CAR) activation plays in their mode of action

    International Nuclear Information System (INIS)

    Toxicogenomics (TGx) is employed frequently to investigate underlying molecular mechanisms of the compound of interest and, thus, has become an aid to mode of action determination. However, the results and interpretation of a TGx dataset are influenced by the experimental design and methods of analysis employed. This article describes an evaluation and reanalysis, by two independent laboratories, of previously published TGx mouse liver microarray data for a triazole fungicide, propiconazole (PPZ), and the anticonvulsant drug phenobarbital (PB). Propiconazole produced an increase incidence of liver tumors in male CD-1 mice only at a dose that exceeded the maximum tolerated dose (2500 ppm). Firstly, we illustrate how experimental design differences between two in vivo studies with PPZ and PB may impact the comparisons of TGx results. Secondly, we demonstrate that different researchers using different pathway analysis tools can come to different conclusions on specific mechanistic pathways, even when using the same datasets. Finally, despite these differences the results across three different analyses also show a striking degree of similarity observed for PPZ and PB treated livers when the expression data are viewed as major signaling pathways and cell processes affected. Additional studies described here show that the postulated key event of hepatocellular proliferation was observed in CD-1 mice for both PPZ and PB, and that PPZ is also a potent activator of the mouse CAR nuclear receptor. Thus, with regard to the events which are hallmarks of CAR-induced effects that are key events in the mode of action (MOA) of mouse liver carcinogenesis with PB, PPZ-induced tumors can be viewed as being promoted by a similar PB-like CAR-dependent MOA

  18. Proteus mirabilis isolates of different origins do not show correlation with virulence attributes and can colonize the urinary tract of mice.

    Science.gov (United States)

    Sosa, Vanessa; Schlapp, Geraldine; Zunino, Pablo

    2006-07-01

    Proteus mirabilis has been described as an aetiological agent in a wide range of infections, playing an important role in urinary tract infections (UTIs). In this study, a collection of P. mirabilis isolates obtained from clinical and non-clinical sources was analysed in order to determine a possible correlation between origin, virulence factors and in vivo infectivity. Isolates were characterized in vitro, assessing several virulence properties that had been previously associated with P. mirabilis uropathogenicity. Swarming motility, urease production, growth in urine, outer-membrane protein patterns, ability to grow in the presence of different iron sources, haemolysin and haemagglutinin production, and the presence and expression of diverse fimbrial genes, were analysed. In order to evaluate the infectivity of the different isolates, the experimental ascending UTI model in mice was used. Additionally, the Dienes test and the enterobacterial repetitive intergenic consensus (ERIC)-PCR assay were performed to assess the genetic diversity of the isolates. The results of the present study did not show any correlation between distribution of the diverse potential urovirulence factors and isolate source. No significant correlation was observed between infectivity and the origin of the isolates, since they all similarly colonized the urinary tract of the challenged mice. Finally, all isolates showed unique ERIC-PCR patterns, indicating that the isolates were genetically diverse. The results obtained in this study suggest that the source of P. mirabilis strains cannot be correlated with pathogenic attributes, and that the distribution of virulence factors between isolates of different origins may correspond to the opportunistic nature of the organism. PMID:16804188

  19. Chronic pyruvate supplementation increases exploratory activity and brain energy reserves in young and middle-aged mice

    Directory of Open Access Journals (Sweden)

    Hennariikka eKoivisto

    2016-03-01

    Full Text Available Numerous studies have reported neuroprotective effects of pyruvate when given in systemic injections. Impaired glucose uptake and metabolism are found in Alzheimer's disease (AD and in AD mouse models. We tested whether dietary pyruvate supplementation is able to provide added energy supply to brain and thereby attenuate aging- or AD-related cognitive impairment. Mice received ~ 800 mg/kg/day Na-pyruvate in their chow for 2- 6 months. In middle-aged wild-type mice and in 6.5-month-old APP/PS1 mice, pyruvate facilitated spatial learning and increased exploration of a novel odor. However, in passive avoidance task for fear memory, the treatment group was clearly impaired. Independent of age, long-term pyruvate increased explorative behavior, which likely explains the paradoxical impairment in passive avoidance. We also assessed pyruvate effects on body weight, muscle force and endurance, and found no effects. Metabolic post-mortem assays revealed increased energy compounds in nuclear magnetic resonance spectroscopy as well as increased brain glycogen storages in the pyruvate group. Pyruvate supplementation may counteract aging-related behavioral impairment but its beneficial effect seems related to increased explorative activity rather than direct memory enhancement.

  20. E-cadherin expression and bromodeoxyuridine incorporation during development of ovarian inclusion cysts in age-matched breeder and incessantly ovulated CD-1 mice

    Directory of Open Access Journals (Sweden)

    Beaugié Clare R

    2007-04-01

    Full Text Available Abstract Background Female CD-1/Swiss Webster mice subjected to incessant ovulation for 8 months and 12-month breeder mice both developed ovarian inclusion cysts similar to serous cystadenomas. The majority of cysts appeared to be dilated rete ovarii tubules, but high ovulation number resulted in more cortical inclusion cysts. We hypothesized that comparison of inclusion cyst pathology in animals of the same age, but with differences in total lifetime ovulation number, might allow us to determine distinguishing characteristics of the two types of cyst. Methods Ovaries from breeder mice (BR or females subjected to incessant ovulation (IO were compared at 6-, 9- and 12-months of age. Ovaries were serially sectioned and cysts characterized with regard to location and histology, E-cadherin immunoreactivity and rates of BrdU incorporation. Results Inclusion cysts developed with age in BR and IO ovaries. The majority of cysts were connected to the ovarian hilus. Two cortical inclusion cysts were observed in ten IO ovaries and one in ten BR ovaries. Low or no E-cadherin immuno-staining was seen in the OSE of all mice studied. Conversely, strong membrane immuno-staining was observed in rete ovarii epithelial cells. Variable E-cadherin immunoreactivity was seen in cells of hilar inclusion cysts, with strong staining observed in cuboidal ciliated cells and little or no staining in flat epithelial cells. Two of the three cortical cysts contained papillae, which showed E-cadherin immuno-staining at the edge of cells. However hilar and cortical cysts were not distinguishable by morphology, cell type or E-cadherin immunoreactivity. BrdU incorporation in cyst cells (1.4% [95% CI: 1.0 to 2.1] was greater than in OSE (0.7% [95% CI: 0.4 to 1.2] and very few BrdU-labeled cells were observed in rete ovarii at any age. Incessant ovulation significantly increased BrdU incorporation in OSE of older animals. Conclusion These experiments confirm ovarian inclusion cysts

  1. Liver-specific Aquaporin 11 knockout mice show rapid vacuolization of the rough endoplasmic reticulum in periportal hepatocytes after amino acid feeding

    DEFF Research Database (Denmark)

    Rojek, Aleksandra; Füchtbauer, Ernst-Martin; Füchtbauer, Annette C.;

    2013-01-01

    Aquaporin 11 (AQP11) is a protein channel expressed intracellularly in multiple organs, yet its physiological function is unclear. Aqp11 knockout (KO) mice die early due to malfunction of the kidney, a result of hydropic degeneration of proximal tubule cells. Here we report the generation of liver......-specific Aqp11 KO mice, allowing us to study the role of AQP11 protein in liver of mice with normal kidney function. The unchallenged liver-specific Aqp11 KO mice have normal longevity, their livers appeared normal, and the plasma biochemistries revealed only a minor defect in lipid handling. Fasting of the...... mice (24 h) induced modest dilatation of the rough endoplasmic reticulum (RER) in the periportal hepatocytes. Refeeding with standard mouse chow induced rapid generation of large RER-derived vacuoles in Aqp11 KO mice hepatocytes. Similar effects were observed following oral administration of pure...

  2. Do long-lived mutant and calorie-restricted mice share common anti-aging mechanisms?--a pathological point of view.

    Science.gov (United States)

    Ikeno, Yuji; Lew, Christie M; Cortez, Lisa A; Webb, Celeste R; Lee, Shuko; Hubbard, Gene B

    2006-06-01

    Rodent models are an invaluable resource for studying the mechanism of mammalian aging. In recent years, the availability of transgenic and knockout mouse models has facilitated the study of potential mechanisms of aging. Since 1996, aging studies with several long-lived mutant mice have been conducted. Studies with the long-lived mutant mice, Ames and Snell dwarf, and growth hormone receptor/binding protein knockout mice, are currently providing important clues regarding the role of the growth hormone/insulin like growth factor-1 axis in the aging process. Interestingly, these studies demonstrate that these long-lived mutant mice have physiological characteristics that are similar to the effects of calorie restriction, which has been the most effective experimental manipulation capable of extending lifespan in various species. However, a question remains to be answered: do these long-lived mutant and calorie-restricted mice extend their lifespan through a common underlying mechanism? PMID:19943137

  3. Ageing and Chronic Administration of Serotonin-Selective Reuptake Inhibitor Citalopram Upregulate Sirt4 Gene Expression in the Preoptic Area of Male Mice

    Directory of Open Access Journals (Sweden)

    Wong eDutt Way

    2015-09-01

    Full Text Available Sexual dysfunction and cognitive deficits are markers of the ageing process. Mammalian sirtuins (SIRT, encoded by sirt 1-7 genes, are known as ageing molecules which are sensitive to serotonin (5-hydroxytryptamine, 5-HT. Whether the 5-HT system regulates SIRT in the preoptic area (POA, which could affect reproduction and cognition has not been examined. Therefore, this study was designed to examine the effects of citalopram (CIT, 10mg/kg for 4 weeks, wk, a potent selective-serotonin reuptake inhibitor and ageing on SIRT expression in the POA of male mice using real-time PCR and immunocytochemistry. Age-related increases of sirt1, sirt4, sirt5, and sirt7 mRNA levels were observed in the POA of 52 wk old mice. Furthermore, 4 wk of chronic CIT treatment started at 8 wk of age also increased sirt2 and sirt4 mRNA expression in the POA. Moreover, the number of SIRT4 immuno-reactive neurons increased with ageing in the medial septum area (12 wk = 1.00±0.15 vs 36 wk = 1.68±0.14 vs 52 wk = 1.54±0.11, p<0.05. In contrast, the number of sirt4-immunopositive cells did not show a statistically significant change with CIT treatment, suggesting that the increase in sirt4 mRNA levels may occur in cells in which sirt4 is already being expressed. Taken together, these studies suggest that CIT treatment and the process of ageing utilize the serotonergic system to up-regulate SIRT4 in the POA as a common pathway to deregulate social cognitive and reproductive functions.

  4. Lack of effect on the chromosomal non-disjunction in aged female mice after low dose x-irradiation

    International Nuclear Information System (INIS)

    Karyotypes were determined in 1064 embryos of aged C57/BL mothers. The virgin female mice were irradiated with 0, 4, 8 or 16 R of X-rays, respectively, and placed with young untreated males 5 days after irradiation. 10.5-days old embryos were recovered from the uterus. Aneuploid embryos classified as alive (heart beats observed at the dissection) were 1 monosomic in the control group (496 embryos) and 2 trisomics in the irradiated group (568 embryos). The number of aneuploid embryos classified as dead was 4 trisomic cases in the control group and 3 trisomics in the irradiated group. The data indicate that trisomic embryos are not uncommon in the mouse but are eliminated in post-implantation death. In contrast to the results of Yamamoto et al. the present data do not demonstrate an increased frequency of chromosome abnormalities in embryos of aged mice X-irradiated before mating as compared to non-irradiated ones

  5. Spatial learning and memory deficits in young adult mice exposed to a brief intense noise at postnatal age

    Institute of Scientific and Technical Information of China (English)

    Shan Tao; Lijie Liu; Lijuan Shi; Xiaowei Li; Pei Shen; Qingying Xun; Xiaojing Guo; Zhiping Yu; Jian Wang

    2015-01-01

    Noise pollution is a major hazardous factor to human health and is likely harmful for vulnerable groups such as pre-term infants under life-support system in an intensive care unit. Previous studies have suggested that noise exposure impairs children's learning ability and cognitive performance and cognitive functions in animal models in which the effect is mainly attributed to the oxidant stress of noise on the cognitive brain. The potential role of noise induced hearing loss (NIHL), rather than the oxidant stress, has also been indicated by a depression of neurogenesis in the hippocampus long after a brief noise exposure, which produces only a tentative oxidant stress. It is not clear if noise exposure and NIHL during early development exerts a long term impact on cognitive function and neurogenesis towards adulthood. In the present study, a brief noise exposure at high sound level was performed in neonatal C57BL/6J mice (15 days after birth) to produce a significant amount of permanent hearing loss as proved 2 months after the noise. At this age, the noise-exposed animals showed deteriorated spatial learning and memory abilities and a reduction of hippocampal neurogenesis as compared with the control. The averaged hearing threshold was found to be strongly correlated with the scores for spatial learning and memory. We consider the effects observed are largely due to the loss of hearing sensitivity, rather than the oxidant stress, due to the long interval between noise exposure and the observations.

  6. Isolation Housing Exacerbates Alzheimer’s Disease-Like Pathophysiology in Aged APP/PS1 Mice

    OpenAIRE

    Huang, Huang; Wang, Linmei; Cao, Min; Marshall, Charles; Gao, Junying; XIAO, NA; Hu, Gang; Xiao, Ming

    2015-01-01

    Background: Alzheimer’s disease is a neurodegenerative disease characterized by gradual declines in social, cognitive, and emotional functions, leading to a loss of expected social behavior. Social isolation has been shown to have adverse effects on individual development and growth as well as health and aging. Previous experiments have shown that social isolation causes an early onset of Alzheimer’s disease-like phenotypes in young APP695/PS1-dE9 transgenic mice. However, the interactions be...

  7. Age-related trends in gene expression in the chemosensory-nasal mucosae of senescence-accelerated mice.

    Science.gov (United States)

    Getchell, Thomas V; Peng, Xuejun; Stromberg, Arnold J; Chen, Kuey-Chu; Paul Green, C; Subhedar, Nishikant K; Shah, Dharmen S; Mattson, Mark P; Getchell, Marilyn L

    2003-04-01

    We have utilized high-density GeneChip oligonucleotide arrays to investigate the use of the senescence-accelerated mouse (SAM) as a biogerontological resource to identify patterns of gene expression in the chemosensory-nasal mucosa. Gene profiling in chronologically young and old mice of the senescence-resistant (SAMR) and senescence-prone (SAMP) strains revealed 133 known genes that were modulated by a three-fold or greater change either in one strain or the other or in both strains during aging. We also identified known genes in our study which based on their encoded proteins were identified as aging-related genes in the aging neocortex and cerebellum of mice as reported by Lee et al. (2000) [Nat. Genet. 25 (2000) 294]. Changes in gene profiles for chemosensory-related genes including olfactory and vomeronasal receptors, sensory transduction-associated proteins, and odor and pheromone transport molecules in the young SAMR and SAMP were compared with age-matched C57BL/6J mice. An analysis of known gene expression profiles suggests that changes in the expression of immune factor genes and genes associated with cell cycle progression and cell death were particularly prominent in the old SAM strains. A preliminary cellular validation study supported the dysregulation of cell cycle-related genes in the old SAM strains. The results of our initial study indicated that the use of the SAM models of aging could provide substantive information leading to a more fundamental understanding of the aging process in the chemosensory-nasal mucosa at the genomic, molecular, and cellular levels. PMID:12605961

  8. Structural, functional and molecular analysis of the effects of aging in the small intestine and colon of C57BL/6J mice

    Directory of Open Access Journals (Sweden)

    Steegenga Wilma T

    2012-08-01

    Full Text Available Abstract Background By regulating digestion and absorption of nutrients and providing a barrier against the external environment the intestine provides a crucial contribution to the maintenance of health. To what extent aging-related changes in the intestinal system contribute to the functional decline associated with aging is still under debate. Methods Young (4 M and old (21 M male C57BL/6J mice were fed a control low-fat (10E% or a high-fat diet (45E% for 2 weeks. During the intervention gross energy intake and energy excretion in the feces were measured. After sacrifice the small and large intestine were isolated and the small intestine was divided in three equal parts. Swiss rolls were prepared of each of the isolated segments for histological analysis and the luminal content was isolated to examine alterations in the microflora with 16S rRNA Q-PCR. Furthermore, mucosal scrapings were isolated from each segment to determine differential gene expression by microarray analysis and global DNA methylation by pyrosequencing. Results Digestible energy intake was similar between the two age groups on both the control and the high-fat diet. Microarray analysis on RNA from intestinal scrapings showed no marked changes in expression of genes involved in metabolic processes. Decreased expression of Cubilin was observed in the intestine of 21-month-old mice, which might contribute to aging-induced vitamin B12 deficiency. Furthermore, microarray data analysis revealed enhanced expression of a large number of genes involved in immune response and inflammation in the colon, but not in the small intestine of the 21-month-old mice. Aging-induced global hypomethylation was observed in the colon and the distal part of the small intestine, but not in the first two sections of the small intestine. Conclusion In 21-month old mice the most pronounced effects of aging were observed in the colon, whereas very few changes were observed in the small intestine.

  9. Effects of exercise and dietary epigallocatechin gallate and β-alanine on skeletal muscle in aged mice.

    Science.gov (United States)

    Pence, Brandt D; Gibbons, Trisha E; Bhattacharya, Tushar K; Mach, Houston; Ossyra, Jessica M; Petr, Geraldine; Martin, Stephen A; Wang, Lin; Rubakhin, Stanislav S; Sweedler, Jonathan V; McCusker, Robert H; Kelley, Keith W; Rhodes, Justin S; Johnson, Rodney W; Woods, Jeffrey A

    2016-02-01

    Aging leads to sarcopenia and loss of physical function. We examined whether voluntary wheel running, when combined with dietary supplementation with (-)-epigallocatechin-3-gallate (EGCG) and β-alanine (β-ALA), could improve muscle function and alter gene expression in the gastrocnemius of aged mice. Seventeen-month-old BALB/cByJ mice were given access to a running wheel or remained sedentary for 41 days while receiving either AIN-93M (standard feed) or AIN-93M containing 1.5 mg·kg(-1) EGCG and 3.43 mg·kg(-1) β-ALA. Mice underwent tests over 11 days from day 29 to day 39 of the study period, including muscle function testing (grip strength, treadmill exhaustive fatigue, rotarod). Following a rest day, mice were euthanized and gastrocnemii were collected for analysis of gene expression by quantitative PCR. Voluntary wheel running (VWR) improved rotarod and treadmill exhaustive fatigue performance and maintained grip strength in aged mice, while dietary intervention had no effect. VWR increased gastrocnemius expression of several genes, including those encoding interleukin-6 (Il6, p = 0.001), superoxide dismutase 1 (Sod1, p = 0.046), peroxisome proliferator-activated receptor gamma coactivator 1-α (Ppargc1a, p = 0.013), forkhead box protein O3 (Foxo3, p = 0.005), and brain-derived neurotrophic factor (Bdnf, p = 0.008), while reducing gastrocnemius levels of the lipid peroxidation marker 4-hydroxynonenal (p = 0.019). Dietary intervention alone increased gastrocnemius expression of Ppargc1a (p = 0.033) and genes encoding NAD-dependent protein deacetylase sirtuin-1 (Sirt1, p = 0.039), insulin-like growth factor I (Igf1, p = 0.003), and macrophage marker CD11b (Itgam, p = 0.016). Exercise and a diet containing β-ALA and EGCG differentially regulated gene expression in the gastrocnemius of aged mice, while VWR but not dietary intervention improved muscle function. We found no synergistic effects between dietary intervention and VWR. PMID:26761622

  10. Brain natriuretic peptide is a potent vasodilator in aged human microcirculation and shows a blunted response in heart failure patients

    DEFF Research Database (Denmark)

    Edvinsson, Marie-Louise; Uddman, Erik; Edvinsson, Lars; Andersson, Sven E

    2014-01-01

    BACKGROUND: Brain natriuretic peptide (BNP) is normally present in low levels in the circulation, but it is elevated in parallel with the degree of congestion in heart failure subjects (CHF). BNP has natriuretic effects and is a potent vasodilator. It is suggested that BNP could be a therapeutic...... vasodilator responses to ACh and to local heating were only somewhat attenuated in CHF patients. Thus, dilator capacity and nitric oxide signalling were not affected to the same extent as BNP-mediated dilation, indicating a specific downregulation of the latter response. CONCLUSIONS: The findings show for the...

  11. Impact of age on the cerebrovascular proteomes of wild-type and Tg-SwDI mice.

    Directory of Open Access Journals (Sweden)

    James L Searcy

    Full Text Available The structural integrity of cerebral vessels is compromised during ageing. Abnormal amyloid (Aβ deposition in the vasculature can accelerate age-related pathologies. The cerebrovascular response associated with ageing and microvascular Aβ deposition was defined using quantitative label-free shotgun proteomic analysis. Over 650 proteins were quantified in vessel-enriched fractions from the brains of 3 and 9 month-old wild-type (WT and Tg-SwDI mice. Sixty-five proteins were significantly increased in older WT animals and included several basement membrane proteins (nidogen-1, basement membrane-specific heparan sulfate proteoglycan core protein, laminin subunit gamma-1 precursor and collagen alpha-2(IV chain preproprotein. Twenty-four proteins were increased and twenty-one decreased in older Tg-SwDI mice. Of these, increases in Apolipoprotein E (APOE and high temperature requirement serine protease-1 (HTRA1 and decreases in spliceosome and RNA-binding proteins were the most prominent. Only six shared proteins were altered in both 9-month old WT and Tg-SwDI animals. The age-related proteomic response in the cerebrovasculature was distinctly different in the presence of microvascular Aβ deposition. Proteins found differentially expressed within the WT and Tg-SwDI animals give greater insight to the mechanisms behind age-related cerebrovascular dysfunction and pathologies and may provide novel therapeutic targets.

  12. Prevention of Neuromusculoskeletal Frailty in Slow-Aging Ames Dwarf Mice: Longitudinal Investigation of Interaction of Longevity Genes and Caloric Restriction

    OpenAIRE

    Arum, Oge; Rasche, Zachary Andrew; Rickman, Dustin John; Bartke, Andrzej

    2013-01-01

    Ames dwarf (Prop1 df/df ) mice are remarkably long-lived and exhibit many characteristics of delayed aging and extended healthspan. Caloric restriction (CR) has similar effects on healthspan and lifespan, and causes an extension of longevity in Ames dwarf mice. Our study objective was to determine whether Ames dwarfism or CR influence neuromusculoskeletal function in middle-aged (82 ± 12 weeks old) or old (128 ± 14 w.o.) mice. At the examined ages, strength was improved by dwarfism, CR, and d...

  13. Changes of regulatory T cells and FoxP3 gene expression in the aging process and its relationship with lung tumors in humans and mice

    Institute of Scientific and Technical Information of China (English)

    PAN Xu-dong; MAO Yan-qing; ZHU Li-jing; LI Jie; XIE Yan; WANG Ling; ZHANG Guang-bo

    2012-01-01

    Background Immunosuppressive regulatory T cells (Tregs) participate in tumor immune evasion and the number and suppressive function of Tregs change with the aging process,but it is not clear whether such change leads to a higher incidence of tumors in the elderly.To this end,we designed experiments to explore the changes of Tregs and the functional gene Forkhead box P3 (FoxP3) in the aging process and its relationship with lung tumors in humans and mice.Methods The percentage of CD4+CD25+CD127lowTregs and expression of FoxP3 mRNA were analyzed using flow cytometry (FCM) and real-time fluorescence-based quantitative polymerase chain reaction (FQ-PCR).Markers were analyzed in the peripheral blood (PB) of 65 elderly patients (age ≥65 years) with primary non-small cell lung cancer (NSCLC),20 younger patients (aged <55 years) with NSCLC,30 elderly healthy individuals and 30 young healthy individuals.Furthermore,we set up the Lewis lung cancer model with C57BL/6 female mice.Thirty-six mice were divided into a young healthy group,a middle-aged healthy group,an elderly healthy group,a young tumor group,a middle-aged tumor group,and an elderly tumor group.The percentage of CD4+CD25+FoxP3+ Tregs and the expression level of FoxP3mRNA in splenocytes were determined in the six groups.Results The percentage of peripheral CD4+CD25+CD127low Tregs and the expression of FoxP3 mRNA were significantly increased in elderly patients with NSCLC comparing with the other groups and in elderly healthy individuals compared with young healthy individuals.Further analysis showed that the percentage of CD4+CD25+CD127low Tregs and the expression of FoxP3 mRNA were closely associated with tumor node metastasis (TNM) staging in elderly patients with NSCLC.In the mouse model,the percentage of CD4+CD25+FoxP3+ Tregs and the expression of FoxP3 mRNA in splenocytes of the tumor groups were significantly higher than in the healthy groups,with the highest expression in the elderly tumor group.In the

  14. Photo-protective activity of pogostone against UV-induced skin premature aging in mice.

    Science.gov (United States)

    Wang, Xiu-Fen; Huang, Yan-Feng; Wang, Lan; Xu, Lie-Qiang; Yu, Xiu-Ting; Liu, Yu-Hong; Li, Cai-Lan; Zhan, Janis Ya-Xian; Su, Zi-Ren; Chen, Jian-Nan; Zeng, Hui-Fang

    2016-05-01

    Pogostone, a chemical constituent of patchouli oil, has been confirmed to possess favorable anti-inflammatory property. In the present study, we investigated the possible anti-photoaging potential of pogostone and the underlying mechanism against UV-induced skin damage in mice. The macroscopic and histopathological lesions were significantly ameliorated by pretreatment of pogostone as compared to the VC group. Furthermore, topical application of pogostone markedly increased the activities of the antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and observably decreased malonaldehyde (MDA) level. Analysis of inflammatory cytokines showed obvious down-regulation of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β) and cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) in the pogostone groups. In addition, pogostone pretreatment evidently inhibited the abnormal expression of matrix metalloproteinases (MMP-1 and MMP-3). Taken together, pogostone exhibited prominent photo-protective activity mainly by its antioxidative and anti-inflammatory properties, promising it as an effective alternative pharmaceutical therapy for photoaging. PMID:26929999

  15. Effect of Glycowithanolides on Fucose Content in Salivary Glands of Aged Mice

    Directory of Open Access Journals (Sweden)

    R. N. Mote

    2013-03-01

    Full Text Available Glycowithanolides (WSG is the extract of Withania somnifera leaves was tested to find its effect on fucose content in salivary glands of D-galactose(Dg stressed adult and old male mice (Mus musculus. Adult and old male mice were divided in to protective group and curative group. Both the groups were further divided into four batchesviz. 1st is the control batch received 0.5 ml 0.9 % saline per day for 20 and 40 days for protective and curative group respectively. Mice from 2nd, 3rd and 4th batches of protective group received 0.5 ml D-galactose (Dg, Dg+ centrophenoxine(CPH and D-galactose (Dg + (WSG respectively for 20 days. Mice from 2nd, 3rd and 4th batches of curative group received 0.5 ml D-galactose (Dg for 20 days then followed by 0.5ml saline, centrophenoxine and WSG alone for further 20 days respectively. Fucose content (μg/mg proteins in salivary glands was estimated. In Dgalactose stressed adult and old mice it was decreased significantly, but restored by the treatment of WSG andcentrophenoxine. The restoration was not exactly up to the normal level but was near to the normal level in adult. In D-galactose stressed old mice there was restoration in fucose content but it was not like that of adult. Restoration was significantly higher in WSG treatment. Thus WSG can be used as a powerful natural antioxidant andantistresser.

  16. Augmentation of primary influenza A virus-specific CD8+ T cell responses in aged mice through blockade of an immunoinhibitory pathway.

    Science.gov (United States)

    DiMenna, Lauren; Latimer, Brian; Parzych, Elizabeth; Haut, Larissa H; Töpfer, Katrin; Abdulla, Sarah; Yu, Hong; Manson, Brian; Giles-Davis, Wynetta; Zhou, Dongming; Lasaro, Marcio O; Ertl, Hildegund C J

    2010-05-15

    Immune responses diminish with age resulting in an increased susceptibility of the elderly to infectious agents and an inability to mount protective immune responses to vaccines. Immunosenescence affects multiple aspects of the immune system, including CD8(+) T cells, which control viral infections and are assumed to prevent the development of cancers. In this study, we tested if CD8(+) T cell responses in aged mice could be enhanced through a vaccine that concomitantly expresses Ag and a molecule that blocks an immunoinhibitory pathway. Specifically, we tested a vaccine based on a replication-defective chimpanzee-derived adenovirus vector expressing the nucleoprotein (NP) of influenza A virus as a fusion protein with the HSV type 1 glycoprotein D, which through binding to the herpes virus entry mediator, blocks the immunoinhibitory herpes virus entry mediator B and T lymphocyte attenuator/CD160 pathways. Our results show that the vaccine expressing a fusion protein of NP and glycoprotein D induces significantly higher NP-specific CD8(+) T cell responses in young and aged mice compared with the vaccine expressing NP only. PMID:20410485

  17. Brain natriuretic peptide is a potent vasodilator in aged human microcirculation and shows a blunted response in heart failure patients

    Science.gov (United States)

    Edvinsson, Marie-Louise; Uddman, Erik; Edvinsson, Lars; Andersson, Sven E.

    2014-01-01

    Background Brain natriuretic peptide (BNP) is normally present in low levels in the circulation, but it is elevated in parallel with the degree of congestion in heart failure subjects (CHF). BNP has natriuretic effects and is a potent vasodilator. It is suggested that BNP could be a therapeutic alternative in CHF. However, we postulated that the high levels of circulating BNP in CHF may downregulate the response of microvascular natriuretic receptors. This was tested by comparing 15 CHF patients (BNP > 3000 ng/L) with 10 matched, healthy controls. Methods Cutaneous microvascular blood flow in the forearm was measured by laser Doppler Flowmetry. Local heating (+44°C, 10 min) was used to evoke a maximum local dilator response. Results Non-invasive iontophoretic administration of either BNP or acetylcholine (ACh), a known endothelium-dependent dilator, elicited an increase in local flow. The nitric oxide synthase inhibitor, l-N-Arginine- methyl-ester (L-NAME), blocked the BNP response (in controls). Interestingly, responses to BNP in CHF patients were reduced to about one third of those seen in healthy controls (increase in flow: 251% in CHF vs. 908% in controls; P < 0.001). In contrast, the vasodilator responses to ACh and to local heating were only somewhat attenuated in CHF patients. Thus, dilator capacity and nitric oxide signalling were not affected to the same extent as BNP-mediated dilation, indicating a specific downregulation of the latter response. Conclusions The findings show for the first time that microvascular responses to BNP are markedly reduced in CHF patients. This is consistent with the hypothesis of BNP receptor function is downregulated in CHF. PMID:24748882

  18. Exercise intervention increases spontaneous locomotion but fails to attenuate dopaminergic system loss in a progressive MPTP model in aged mice.

    Science.gov (United States)

    Hood, Rebecca L; Liguore, William A; Moore, Cynthia; Pflibsen, Lacey; Meshul, Charles K

    2016-09-01

    While exercise is commonly recommended for PD patients to improve motor function, little is known about the disease-altering potential of exercise. Although others have demonstrated neuroprotective or neurorestorative effects of exercise in animal models of PD, the majority of these studies utilize young animals. In order to assess the effects of exercise intervention in a more clinically relevant model, we have subjected aged mice to progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioning and daily treadmill exercise, initiated early in the course of the disease. The MPTP model elicited a 55% reduction in striatal TH as measured by immunohistochemistry compared to sedentary controls, and exercise did not attenuate this loss in exercised MPTP animals. Furthermore, striatal TH and DAT loss, as assessed by western blotting, were not significantly impacted by treadmill exercise in MPTP-lesioned mice. We did find an increase in spontaneous locomotion in exercised mice that was not decreased by MPTP lesioning. This finding may be due, in part, to an increase in TH expression in the motor cortex in exercised MPTP mice. PMID:27350080

  19. Life span of C57 mice as influenced by radiation dose, dose rate, and age at exposure

    International Nuclear Information System (INIS)

    This study was designed to measure the life shortening of C57BL/6J male mice as a result of exposure to five external doses from 60Co gamma radiation delivered at six different dose rates. Total doses ranged from 20 to 1620 rad at exposure rates ranging from 0.7 to 36,000 R/day. The ages of the mice at exposure were newborn, 2, 6, or 15 months. Two replications were completed. Although death was the primary endpoint, we did perform gross necropsies. The life span findings are variable, but we found no consistent shortening compared to control life spans. Therefore, we cannot logically extrapolate life shortening to lower doses, from the data we have obtained. In general, the younger the animals were at the beginning of exposure, the longer their life spans were compared to those of controls. This relationship weakened at the higher doses and dose rates, as mice in these categories tended not to have significantly different life spans from controls. Using life span as a criterion, we find this study suggests that some threshold dosage may exist beyond which effects of external irradiation may be manifested. Up to this threshold, there is no shortening effect on life span compared to that of control mice. Our results are in general agreement with the results of other researchers investigating human and other animal life span effects on irradiation

  20. Age- and light-dependent development of localised retinal atrophy in CCL2(-/-CX3CR1(GFP/GFP mice.

    Directory of Open Access Journals (Sweden)

    Mei Chen

    Full Text Available Previous studies have shown that CCL2/CX3CR1 deficient mice on C57BL/6N background (with rd8 mutation have an early onset (6 weeks of spontaneous retinal degeneration. In this study, we generated CCL2(-/-CX3CR1(GFP/GFP mice on the C57BL/6J background. Retinal degeneration was not detected in CCL2(-/-CX3CR1(GFP/GFP mice younger than 6 months. Patches of whitish/yellowish fundus lesions were observed in 17∼60% of 12-month, and 30∼100% of 18-month CCL2(-/-CX3CR1(GFP/GFP mice. Fluorescein angiography revealed no choroidal neovascularisation in these mice. Patches of retinal pigment epithelium (RPE and photoreceptor damage were detected in 30% and 50% of 12- and 18-month CCL2(-/-CX3CR1(GFP/GFP mice respectively, but not in wild-type mice. All CCL2(-/-CX3CR1(GFP/GFP mice exposed to extra-light (∼800lux, 6 h/day, 6 months developed patches of retinal atrophy, and only 20-25% of WT mice which underwent the same light treatment developed atrophic lesions. In addition, synaptophysin expression was detected in the outer nucler layer (ONL of area related to photoreceptor loss in CCL2(-/-CX3CR1(GFP/GFP mice. Markedly increased rhodopsin but reduced cone arrestin expression was observed in retinal outer layers in aged CCL2(-/-CX3CR1(GFP/GFP mice. GABA expression was reduced in the inner retina of aged CCL2(-/-CX3CR1(GFP/GFP mice. Significantly increased Müller glial and microglial activation was observed in CCL2(-/-CX3CR1(GFP/GFP mice compared to age-matched WT mice. Macrophages from CCL2(-/-CX3CR1(GFP/GFP mice were less phagocytic, but expressed higher levels of iNOS, IL-1β, IL-12 and TNF-α under hypoxia conditions. Our results suggest that the deletions of CCL2 and CX3CR1 predispose mice to age- and light-mediated retinal damage. The CCL2/CX3CR1 deficient mouse may thus serve as a model for age-related atrophic degeneration of the RPE, including the dry type of macular degeneration, geographic atrophy.

  1. Artemether and Artesunate Show the Highest Efficacies in Rescuing Mice with Late-Stage Cerebral Malaria and Rapidly Decrease Leukocyte Accumulation in the Brain▿

    OpenAIRE

    Clemmer, L.; Martins, Y. C.; Zanini, G. M.; Frangos, J. A.; Carvalho, L. J. M.

    2011-01-01

    The murine model of cerebral malaria (ECM) caused by Plasmodium berghei ANKA (PbA) infection in susceptible mice has been extensively used for studies of pathogenesis and identification of potential targets for human CM therapeutics. However, the model has been seldom explored to evaluate adjunctive therapies for this malaria complication. A first step toward this goal is to define a treatment protocol with an effective antimalarial drug able to rescue mice presenting late-stage ECM. We evalu...

  2. Whole-Body Vibration Partially Reverses Aging-Induced Increases in Visceral Adiposity and Hepatic Lipid Storage in Mice

    Science.gov (United States)

    van Dijk, Theo H.; Havinga, Rick; van der Zee, Eddy A.; Groen, Albert K.; Reijngoud, Dirk-Jan; Bakker, Barbara M.; van Dijk, Gertjan

    2016-01-01

    At old age, humans generally have declining muscle mass and increased fat deposition, which can increase the risk of developing cardiometabolic diseases. While regular physical activity postpones these age-related derangements, this is not always possible in the elderly because of disabilities or risk of injury. Whole-body vibration (WBV) training may be considered as an alternative to physical activity particularly in the frail population. To explore this possibility, we characterized whole-body and organ-specific metabolic processes in 6-month and 25-month old mice, over a period of 14 weeks of WBV versus sham training. WBV training tended to increase blood glucose turnover rates and stimulated hepatic glycogen utilization during fasting irrespective of age. WBV was effective in reducing white fat mass and hepatic triglyceride content only in old but not in young mice and these reductions were related to upregulation of hepatic mitochondrial uncoupling of metabolism (assessed by high-resolution respirometry) and increased expression of uncoupling protein 2. Because these changes occurred independent of changes in food intake and whole-body metabolic rate (assessed by indirect calorimetry), the liver-specific effects of WBV may be a primary mechanism to improve metabolic health during aging, rather than that it is a consequence of alterations in energy balance. PMID:26886917

  3. Whole-Body Vibration Partially Reverses Aging-Induced Increases in Visceral Adiposity and Hepatic Lipid Storage in Mice.

    Directory of Open Access Journals (Sweden)

    Aaffien C Reijne

    Full Text Available At old age, humans generally have declining muscle mass and increased fat deposition, which can increase the risk of developing cardiometabolic diseases. While regular physical activity postpones these age-related derangements, this is not always possible in the elderly because of disabilities or risk of injury. Whole-body vibration (WBV training may be considered as an alternative to physical activity particularly in the frail population. To explore this possibility, we characterized whole-body and organ-specific metabolic processes in 6-month and 25-month old mice, over a period of 14 weeks of WBV versus sham training. WBV training tended to increase blood glucose turnover rates and stimulated hepatic glycogen utilization during fasting irrespective of age. WBV was effective in reducing white fat mass and hepatic triglyceride content only in old but not in young mice and these reductions were related to upregulation of hepatic mitochondrial uncoupling of metabolism (assessed by high-resolution respirometry and increased expression of uncoupling protein 2. Because these changes occurred independent of changes in food intake and whole-body metabolic rate (assessed by indirect calorimetry, the liver-specific effects of WBV may be a primary mechanism to improve metabolic health during aging, rather than that it is a consequence of alterations in energy balance.

  4. Biomarkers of aging, life span and spontaneous carcinogenesis in the wild type and HER-2 transgenic FVB/N female mice.

    Science.gov (United States)

    Panchenko, Andrey V; Popovich, Irina G; Trashkov, Alexandr P; Egormin, Peter A; Yurova, Maria N; Tyndyk, Margarita L; Gubareva, Ekaterina A; Artyukin, Ilia N; Vasiliev, Andrey G; Khaitsev, Nikolai V; Zabezhinski, Mark A; Anisimov, Vladimir N

    2016-04-01

    FVB/N wild type and transgenic HER-2/neu FVB/N female mice breed at N.N. Petrov Research Institute of Oncology were under observation until natural death without any special treatment. Age-related dynamics of body weight, food consumption and parameters of carbohydrate and lipid metabolism, level of nitric oxide, malonic dialdehyde, catalase, Cu, Zn-superoxide dismutase, vascular endothelial growth factor were studied in both mice strains. The parameters of life span and tumor pathology were studied as well. Cancer-prone transgenic HER-2/neu mice developed in 100 % multiple mammary adenocarcinomas and died before the age of 1 year. Forty tree percent of long-lived wild type mice survived the age of 2 years and 19 %-800 days. The total tumor incidence in wild type mice was 34 %. The age-associated changes in the level of serum IGF-1, glucose and insulin started much earlier in transgene HER-2/neu mice as compared with wild type FVB/N mice. It was suggested that transgenic HER-2/neu involves in initiation of malignization of mammary epithelial cells but also in acceleration of age-related hormonal and metabolic changes in turn promoting mammary carcinogenesis. PMID:26423570

  5. Estradiol-induced object memory consolidation in middle-aged female mice requires dorsal hippocampal ERK and PI3K activation

    OpenAIRE

    Fan, Lu; Zhao, Zaorui; Orr, Patrick T.; Chambers, Cassie H.; Michael C. Lewis; Frick, Karyn M.

    2010-01-01

    We previously demonstrated that dorsal hippocampal extracellular signal-regulated kinase (ERK) activation is necessary for 17β-estradiol (E2) to enhance novel object recognition in young ovariectomized mice (Fernandez et al., 2008). Here, we asked whether E2 has similar memory-enhancing effects in middle-aged and aged ovariectomized mice, and whether these effects depend on ERK and phosphatidylinositol 3-kinase (PI3K)/Akt activation. We first demonstrated that intracerebroventricular (ICV) E2...

  6. Anti-free radical, anti-oxidative ability and anti-fatigue effects of Huanshaodan An experiment of aging mice

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    BACKGROUND: In the theory of traditional Chinese medicine, aging is mainly thought renal deficiency caused renal failure, mainly involving decline of kidney-Yang and deficiency of kidney-essence.Huanshaodan, a Chinese traditional preparation for kidney-replenishing essence, was used to be the preparation for reinforcing renal deficiency and preventing aging for aged people.OBJECTIVE: To observe the effects of Huanshaodan on swimming durance and the abilities of catalase(CAT) in serum and monoamine oxidase-B (MAO-B) in brain tissue as well as in vitro anti-oxidative ability of aging mouse.DESIGN: A controlled animal experiment.SETTING: College of Basic Medicine, Hunan University of Traditional Chinese Medicine.MATERIALS: Fifty-four healthy NIH mice, aged 18 months old, of either gender, weighing (48.9 ± 5.4) g,and one SD male rat, aged 16 months old, weighing 51.7 g, were provided by Animal Experimental Center,Hunan University of Traditional Chinese Medicine. Thirty NIH mice were randomly chosen for swimming test, and divided into experimental group and control group, with 15 in each; The other 24 NIH mice were used for enzyme activity assay, and also divided into experimental group and control group, with 12 in each.SD rat was used for in vitro anti-oxidative ability test. Huanshaodan water decoction was composed of Cheqianzi, Wuweizi, Huaishan, Danggui, Huangbai, Shudi, Baizhi, Niuxi, Baishen, Tusizi, Buguzhi,Roucongrong and Heshouwu 13 Chinese herbs.METHODS: This study was carried out in the Second Laboratory, Department of Biochemistry, Hunan University of Traditional Chinese Medicine in June 2006. Swimming and enzyme activity assay: Mice in the two experimental groups were intragastrically administrated with 10 μ L/g Huanshaodan water decoction.Mice in the two control groups were intragastrically administrated with the same amount of normal saline.All the mice were intragastrically administrated for 5 days, and they were free to access to medicine in the

  7. Cellular and Physiological Effects of Dietary Supplementation with β-Hydroxy-β-Methylbutyrate (HMB and β-Alanine in Late Middle-Aged Mice.

    Directory of Open Access Journals (Sweden)

    Julian Vallejo

    Full Text Available There is growing evidence that severe decline of skeletal muscle mass and function with age may be mitigated by exercise and dietary supplementation with protein and amino acid ingredient technologies. The purposes of this study were to examine the effects of the leucine catabolite, beta-hydroxy-beta-methylbutyrate (HMB, in C2C12 myoblasts and myotubes, and to investigate the effects of dietary supplementation with HMB, the amino acid β-alanine and the combination thereof, on muscle contractility in a preclinical model of pre-sarcopenia. In C2C12 myotubes, HMB enhanced sarcoplasmic reticulum (SR calcium release beyond vehicle control in the presence of all SR agonists tested (KCl, P<0.01; caffeine, P = 0.03; ionomycin, P = 0.03. HMB also improved C2C12 myoblast viability (25 μM HMB, P = 0.03 and increased proliferation (25 μM HMB, P = 0.04; 125 μM HMB, P<0.01. Furthermore, an ex vivo muscle contractility study was performed on EDL and soleus muscle from 19 month old, male C57BL/6nTac mice. For 8 weeks, mice were fed control AIN-93M diet, diet with HMB, diet with β-alanine, or diet with HMB and β-alanine. In β-alanine fed mice, EDL muscle showed a 7% increase in maximum absolute force compared to the control diet (202 ± 3vs. 188± 5 mN, P = 0.02. At submaximal frequency of stimulation (20 Hz, EDL from mice fed HMB plus β-alanine showed an 11% increase in absolute force (88.6 ± 2.2 vs. 79.8 ± 2.4 mN, P = 0.025 and a 13% increase in specific force (12.2 ± 0.4 vs. 10.8 ± 0.4 N/cm2, P = 0.021. Also in EDL muscle, β-alanine increased the rate of force development at all frequencies tested (P<0.025, while HMB reduced the time to reach peak contractile force (TTP, with a significant effect at 80 Hz (P = 0.0156. In soleus muscle, all experimental diets were associated with a decrease in TTP, compared to control diet. Our findings highlight beneficial effects of HMB and β-alanine supplementation on skeletal muscle function in aging mice.

  8. Cellular and Physiological Effects of Dietary Supplementation with β-Hydroxy-β-Methylbutyrate (HMB) and β-Alanine in Late Middle-Aged Mice.

    Science.gov (United States)

    Vallejo, Julian; Spence, Madoka; Cheng, An-Lin; Brotto, Leticia; Edens, Neile K; Garvey, Sean M; Brotto, Marco

    2016-01-01

    There is growing evidence that severe decline of skeletal muscle mass and function with age may be mitigated by exercise and dietary supplementation with protein and amino acid ingredient technologies. The purposes of this study were to examine the effects of the leucine catabolite, beta-hydroxy-beta-methylbutyrate (HMB), in C2C12 myoblasts and myotubes, and to investigate the effects of dietary supplementation with HMB, the amino acid β-alanine and the combination thereof, on muscle contractility in a preclinical model of pre-sarcopenia. In C2C12 myotubes, HMB enhanced sarcoplasmic reticulum (SR) calcium release beyond vehicle control in the presence of all SR agonists tested (KCl, Pionomycin, P = 0.03). HMB also improved C2C12 myoblast viability (25 μM HMB, P = 0.03) and increased proliferation (25 μM HMB, P = 0.04; 125 μM HMB, P<0.01). Furthermore, an ex vivo muscle contractility study was performed on EDL and soleus muscle from 19 month old, male C57BL/6nTac mice. For 8 weeks, mice were fed control AIN-93M diet, diet with HMB, diet with β-alanine, or diet with HMB and β-alanine. In β-alanine fed mice, EDL muscle showed a 7% increase in maximum absolute force compared to the control diet (202 ± 3vs. 188± 5 mN, P = 0.02). At submaximal frequency of stimulation (20 Hz), EDL from mice fed HMB plus β-alanine showed an 11% increase in absolute force (88.6 ± 2.2 vs. 79.8 ± 2.4 mN, P = 0.025) and a 13% increase in specific force (12.2 ± 0.4 vs. 10.8 ± 0.4 N/cm2, P = 0.021). Also in EDL muscle, β-alanine increased the rate of force development at all frequencies tested (P<0.025), while HMB reduced the time to reach peak contractile force (TTP), with a significant effect at 80 Hz (P = 0.0156). In soleus muscle, all experimental diets were associated with a decrease in TTP, compared to control diet. Our findings highlight beneficial effects of HMB and β-alanine supplementation on skeletal muscle function in aging mice. PMID:26953693

  9. Transgenic overexpression of ADAM12 suppresses muscle regeneration and aggravates dystrophy in aged mdx mice

    DEFF Research Database (Denmark)

    Jørgensen, Louise Helskov; Jensen, Charlotte Harken; Wewer, Ulla M;

    2007-01-01

    ADAM12 could be a candidate for nonreplacement gene therapy of Duchenne muscular dystrophy. We therefore evaluated the long-term effect of ADAM12 overexpression in muscle. Surprisingly, we observed loss of skeletal muscle and accelerated fibrosis and adipogenesis in 1-year-old mdx mice transgenically......Muscular dystrophies are characterized by insufficient restoration and gradual replacement of the skeletal muscle by fat and connective tissue. ADAM12 has previously been shown to alleviate the pathology of young dystrophin-deficient mdx mice, a model for Duchenne muscular dystrophy. The observed...... regeneration as a possible factor in development of muscular dystrophy....

  10. Prevention of neuromusculoskeletal frailty in slow-aging ames dwarf mice: longitudinal investigation of interaction of longevity genes and caloric restriction.

    Directory of Open Access Journals (Sweden)

    Oge Arum

    Full Text Available Ames dwarf (Prop1 (df/df mice are remarkably long-lived and exhibit many characteristics of delayed aging and extended healthspan. Caloric restriction (CR has similar effects on healthspan and lifespan, and causes an extension of longevity in Ames dwarf mice. Our study objective was to determine whether Ames dwarfism or CR influence neuromusculoskeletal function in middle-aged (82 ± 12 weeks old or old (128 ± 14 w.o. mice. At the examined ages, strength was improved by dwarfism, CR, and dwarfism plus CR in male mice; balance/ motor coordination was improved by CR in old animals and in middle-aged females; and agility/ motor coordination was improved by a combination of dwarfism and CR in both genders of middle-aged mice and in old females. Therefore, extension of longevity by congenital hypopituitarism is associated with improved maintenance of the examined measures of strength, agility, and motor coordination, key elements of frailty during human aging, into advanced age. This study serves as a particularly important example of knowledge related to addressing aging-associated diseases and disorders that results from studies in long-lived mammals.

  11. Effect of sex and age on the frequency of tumors arising in non-linear mice exposed to total gamma irradiation

    International Nuclear Information System (INIS)

    The effect of sex and age of nonlinear mice on the frequency of tumours was studied. Nonlinear mice of the SHK colony of both sexes were gamma-irradiated with 137Cs. The histological material, frequency and time of tumour appearance were investigated in dependence on age. Single exposure accelerated the appearance of tumours of the hemopoietic tissue in females and lung and liver tumours in males. The irradiation increased the frequency of tumour appearance in females. The frequency of mammary gland tumours increased under irradiation of females of older age. Ovary tumours developed irrespective of mouse age by the time of irradiation. Average longevity reduced only in young females

  12. PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells

    OpenAIRE

    Latchman, Yvette E.; Liang, Spencer C.; Wu, Yin; Chernova, Tatyana; Sobel, Raymond A.; Klemm, Martina; Kuchroo, Vijay K.; Freeman, Gordon J; Sharpe, Arlene H.

    2004-01-01

    Both positive and negative regulatory roles have been suggested for the B7 family member PD-L1(B7-H1). PD-L1 is expressed on antigen-presenting cells (APCs), activated T cells, and a variety of tissues, but the functional significance of PD-L1 on each cell type is not yet clear. To dissect the functions of PD-L1 in vivo, we generated PD-L1-deficient (PD-L1–/–) mice. CD4+ and CD8+ T cell responses were markedly enhanced in PD-L1–/– mice compared with wild-type mice in vitro and in vivo. PD-L1–...

  13. In silico analysis of gene expression profiles in the olfactory mucosae of aging senescence-accelerated mice.

    Science.gov (United States)

    Getchell, Thomas V; Peng, Xuejun; Green, C Paul; Stromberg, Arnold J; Chen, Kuey-Chu; Mattson, Mark P; Getchell, Marilyn L

    2004-08-01

    We utilized high-density Affymetrix oligonucleotide arrays to investigate gene expression in the olfactory mucosae of near age-matched aging senescence-accelerated mice (SAM). The senescence-prone (SAMP) strain has a significantly shorter lifespan than does the senescence-resistant (SAMR) strain. To analyze our data, we applied biostatistical methods that included a correlation analysis to evaluate sources of methodologic and biological variability; a two-sided t-test to identify a subpopulation of Present genes with a biologically relevant P-value SAMRs (SAMR-Os, 12.5 months). Volcano plots related the variability in the mean hybridization signals as determined by the two-sided t-test to fold changes in gene expression. The genes were categorized into the six functional groups used previously in gene profiling experiments to identify candidate genes that may be relevant for senescence at the genomic and cellular levels in the aging mouse brain (Lee et al. [2000] Nat Genet 25:294-297) and in the olfactory mucosa (Getchell et al. [2003] Ageing Res Rev 2:211-243), which serves several functions that include chemosensory detection, immune barrier function, xenobiotic metabolism, and neurogenesis. Because SAMR-Os and SAMP-Os have substantially different median lifespans, we related the rate constant alpha in the Gompertz equation on aging to intrinsic as opposed to environmental mechanisms of senescence based on our analysis of genes modulated during aging in the olfactory mucosa. PMID:15248299

  14. Anti-aging effects of Piper cambodianum P. Fourn. extract on normal human dermal fibroblast cells and a wound-healing model in mice

    Directory of Open Access Journals (Sweden)

    Lee H

    2016-07-01

    that PPF-treated cells displayed dose-dependent increase in messenger RNA expression levels of collagen, elastin, and hyaluronan synthase-2 and decreased expression levels of matrix metalloproteinase-1 aging gene. PPF treatment led to decreased production of reactive oxygen species in cells subjected to ultraviolet irradiation. Furthermore, PPF extract showed positive wound-healing effects in mice.Conclusion: This study demonstrated the anti-aging and wound-healing effects of PPF extract. Therefore, PPF extract represents a promising new therapeutic agent for anti-aging and wound-healing treatments. Keywords: PPF extract, anti-aging, wound healing, antioxidant, ROS, normal human dermal fibroblasts

  15. Mice generated from tetraploid complementation competent iPS cells show similar developmental features as those from ES cells but are prone to tumorigenesis

    Institute of Scientific and Technical Information of China (English)

    Man Tong; Hua-Jun Wu; Zhi-Kun Li; Fanyi Zeng; Liu Wang; Xiu-Jie Wang; Jia-Hao Sha; Qi Zhou; Zhuo Lv; Lei Liu; Hui Zhu; Qin-Yuan Zheng; Xiao-Yang Zhao; Wei Li; Yi-Bo Wu; Hai-Jiang Zhang

    2011-01-01

    Dear Editor,Ever since the creation of induced pluripotent cells (iPSCs) from adult somatic cells by the ectopic expression of defined transcription factors [1,2],whether iPS cells are equivalent to embryonic stem cells (ESCs) in function and safety aspects has been a major concern regarding their potential applications.Previously,we and others have demonstrated that fully reprogrammed iPSCs were capable of producing full-term mice via the tetraploid complementation method [3-5],yet a thorough postnatal development evaluation of iPS mice is still lacking.

  16. Brevican-deficient mice display impaired hippocampal CA1 long-term potentiation but show no obvious deficits in learning and memory

    DEFF Research Database (Denmark)

    Brakebusch, Cord; Seidenbecher, Constanze I; Asztely, Fredrik;

    2002-01-01

    Brevican is a brain-specific proteoglycan which is found in specialized extracellular matrix structures called perineuronal nets. Brevican increases the invasiveness of glioma cells in vivo and has been suggested to play a role in central nervous system fiber tract development. To study the role of...... brevican in the development and function of the brain, we generated mice lacking a functional brevican gene. These mice are viable and fertile and have a normal life span. Brain anatomy was normal, although alterations in the expression of neurocan were detected. Perineuronal nets formed but appeared to be...

  17. Long term low dose rate irradiation causes recovery from type II diabetes and suppression of aging in type II diabetes-prone mice

    International Nuclear Information System (INIS)

    The effects of low dose rate gamma irradiation on model C57BL/KsJ-db/db mice with Type II diabetes mellitus was investigated. These mice develop Type II diabetes by 10 weeks of age, due to obesity, and are characterized by hyperinsulinemia. A group of 12 female 10-week old mice were irradiated at 0.65 mGy/hr in the low dose rate irradiation facility in the Low Dose Radiation Research Center. The urine glucose levels of all of the mice were strongly positive at the beginning of the irradiation. In the irradiated group, a decrease in the glucose level was observed in three mice, one in the 35th week, another in the 52nd week and the third in the 80th week. No recovery from the diabetes was observed in the 12 mice of non-irradiated control group. There was no systematic change of body weight or consumption of food and drinking water between the irradiated group and the non-irradiated group or between the recovered mice and the non-recovered mice. Survival was better in the irradiated group. The surviving fraction at the age of 90 weeks was 75 % in the irradiated group but only 40 % in the non-irradiated. A marked difference was also observed in the appearance of the coat hair, skin and tail. The irradiated group was in much better condition. Mortality was delayed and the healthy appearance was prolonged in the irradiated mice by about 20-30 weeks compared with the control mice. These results suggest that the low dose irradiation modified the condition of the diabetic mice, leading not only to recovery from diabetes, but also to suppression of the aging process

  18. Partial correction of the dwarf phenotype by non-viral transfer of the growth hormone gene in mice: Treatment age is critical.

    Science.gov (United States)

    Higuti, Eliza; Cecchi, Cláudia R; Oliveira, Nélio A J; Lima, Eliana R; Vieira, Daniel P; Aagaard, Lars; Jensen, Thomas G; Jorge, Alexander A L; Bartolini, Paolo; Peroni, Cibele N

    2016-02-01

    Non-viral transfer of the growth hormone gene to different muscles of immunodeficient dwarf (lit/scid) mice is under study with the objective of improving phenotypic correction via this particular gene therapy approach. Plasmid DNA was administered into the exposed quadriceps or non-exposed tibialis cranialis muscle of lit/scid mice followed by electroporation, monitoring several growth parameters. In a 6-month bioassay, 50μg DNA were injected three times into the quadriceps muscle of 80-day old mice. A 50% weight increase, with a catch-up growth of 21%, together with a 16% increase for nose-to-tail and tail lengths (catch-up=19-21%) and a 24-28% increase for femur length (catch-up=53-60%), were obtained. mIGF1 serum levels were ~7-fold higher than the basal levels for untreated mice, but still ~2-fold lower than in non-dwarf scid mice. Since treatment age was found to be particularly important in a second bioassay utilizing 40-day old mice, these pubertal mice were compared in a third bioassay with adult (80-day old) mice, all treated twice with 50μg DNA injected into each tibialis cranialis muscle, via a less invasive approach. mIGF1 concentrations at the same level as co-aged scid mice were obtained 15days after administration in pubertal mice. Catch-up growth, based on femur length (77%), nose-to-tail (36%) and tail length (39%) increases was 40 to 95% higher than those obtained upon treating adult mice. These data pave the way for the development of more effective pre-clinical assays in pubertal dwarf mice for the treatment of GH deficiency via plasmid-DNA muscular administration. PMID:26774398

  19. Atherosclerosis in aged mice over-expressing the reverse cholesterol transport genes

    OpenAIRE

    J.A. Berti; de Faria, E.C.; H.C.F. Oliveira

    2005-01-01

    We determined whether over-expression of one of the three genes involved in reverse cholesterol transport, apolipoprotein (apo) AI, lecithin-cholesterol acyl transferase (LCAT) and cholesteryl ester transfer protein (CETP), or of their combinations influenced the development of diet-induced atherosclerosis. Eight genotypic groups of mice were studied (AI, LCAT, CETP, LCAT/AI, CETP/AI, LCAT/CETP, LCAT/AI/CETP, and non-transgenic) after four months on an atherogenic diet. The extent of atherosc...

  20. Transgenic Overexpression of ADAM12 Suppresses Muscle Regeneration and Aggravates Dystrophy in Aged mdx Mice

    OpenAIRE

    Jørgensen, Louise Helskov; Jensen, Charlotte Harken; Wewer, Ulla M.; Schrøder, Henrik Daa

    2007-01-01

    Muscular dystrophies are characterized by insufficient restoration and gradual replacement of the skeletal muscle by fat and connective tissue. ADAM12 has previously been shown to alleviate the pathology of young dystrophin-deficient mdx mice, a model for Duchenne muscular dystrophy. The observed effect of ADAM12 was suggested to be mediated via a membrane-stabilizing up-regulation of utrophin, α7B integrin, and dystroglycans. Ectopic ADAM12 expression in normal mouse skeletal muscle also imp...

  1. Heme oxygenase-1 regulates the immune response to influenza virus infection and vaccination in aged mice

    OpenAIRE

    Cummins, Nathan W.; Weaver, Eric A.; May, Shannon M.; Croatt, Anthony J.; Foreman, Oded; Kennedy, Richard B.; Poland, Gregory A.; Michael A. Barry; Nath, Karl A.; Badley, Andrew D.

    2012-01-01

    Underlying mechanisms of individual variation in severity of influenza infection and response to vaccination are poorly understood. We investigated the effect of reduced heme oxygenase-1 (HO-1) expression on vaccine response and outcome of influenza infection. HO-1-deficient and wild-type (WT) mice (kingdom, Animalia; phylum, Chordata; genus/species, Mus musculus) were infected with influenza virus A/PR/8/34 with or without prior vaccination with an adenoviral-based influenza vaccine. A genom...

  2. [Information theory of ageing: studying the effect of bone marrow transplantation on the life span of mice].

    Science.gov (United States)

    Karnaukhov, A V; Karnaukhova, E V; Sergievich, L A; Karnaukhova, N A; Karnaukhova, N A; Bogdanenko, E V; Smirnov, A A; Manokhina, I A; Karnaukhov, V N

    2014-01-01

    In this paper the method of life span extension of multicellular organisms (human) using the reservation of stem cells followed by autotransplantation has been proposed. As the efficiency of this method results from the information theory of ageing, it is important to verify it experimentally testing the basic concepts of the theory. Taking it into consideration, the experiment on the bone marrow transplantation to old mice from young closely-related donors of the inbred line was carried out. It has been shown, that transplanted animals exhibited a survival advantage, a mean life span increased by 34% as compared to the control. This result not only demonstrates the efficiency of the proposed method for life span extension of multicellular organisms, but also confirms the basis of the information theory of ageing. PMID:25707248

  3. 17ß-Estradiol Regulates Histone Alterations Associated with Memory Consolidation and Increases "Bdnf" Promoter Acetylation in Middle-Aged Female Mice

    Science.gov (United States)

    Fortress, Ashley M.; Kim, Jaekyoon; Poole, Rachel L.; Gould, Thomas J.; Frick, Karyn M.

    2014-01-01

    Histone acetylation is essential for hippocampal memory formation in young adult rodents. Although dysfunctional histone acetylation has been associated with age-related memory decline in male rodents, little is known about whether histone acetylation is altered by aging in female rodents. In young female mice, the ability of 17ß-estradiol…

  4. Age-Related Declines in General Cognitive Abilities of Balb/C Mice and General Activity Are Associated with Disparities in Working Memory, Body Weight, and General Activity

    Science.gov (United States)

    Matzel, Louis D.; Grossman, Henya; Light, Kenneth; Townsend, David; Kolata, Stefan

    2008-01-01

    A defining characteristic of age-related cognitive decline is a deficit in general cognitive performance. Here we use a testing and analysis regimen that allows us to characterize the general learning abilities of young (3-5 mo old) and aged (19-21 mo old) male and female Balb/C mice. Animals' performance was assessed on a battery of seven diverse…

  5. Novel dual agonist peptide analogues derived from dogfish glucagon show promising in vitro insulin releasing actions and antihyperglycaemic activity in mice.

    Science.gov (United States)

    O'Harte, F P M; Ng, M T; Lynch, A M; Conlon, J M; Flatt, P R

    2016-08-15

    The antidiabetic potential of thirteen novel dogfish glucagon derived analogues were assessed in vitro and in acute in vivo studies. Stable peptide analogues enhanced insulin secretion from BRIN-BD11 β-cells (p 39) and [S2a]dogfish glucagon-Lys(30)-γ-glutamyl-PAL, were blocked (p 39) and (desHis(1)Pro(4)Glu(9))glucagon amide but not by (Pro(3))GIP, indicating lack of GIP receptor involvement. These analogues dose-dependently stimulated cAMP production in GLP-1 and glucagon (p diabetic mice and in wild-type C57BL/6J and GIPR-KO mice (p diabetes therapy, exerting beneficial metabolic effects via GLP-1 and glucagon receptors. PMID:27179756

  6. AMPK Agonist AICAR Improves Cognition and Motor Coordination in Young and Aged Mice

    Science.gov (United States)

    Kobilo, Tali; Guerrieri, Davide; Zhang, Yongqing; Collica, Sarah C.; Becker, Kevin G.; van Praag, Henriette

    2014-01-01

    Normal aging can result in a decline of memory and muscle function. Exercise may prevent or delay these changes. However, aging-associated frailty can preclude physical activity. In young sedentary animals, pharmacological activation of AMP-activated protein kinase (AMPK), a transcriptional regulator important for muscle physiology, enhanced…

  7. 55P0110, a Novel Synthetic Compound Developed from a Plant Derived Backbone Structure, Shows Promising Anti-Hyperglycaemic Activity in Mice

    OpenAIRE

    Brunmair, Barbara; Lehner, Zsuzsanna; Stadlbauer, Karin; Adorjan, Immanuel; Frobel, Klaus; Scherer, Thomas; Luger, Anton; Bauer, Leonhardt; Fürnsinn, Clemens

    2015-01-01

    Starting off with a structure derived from the natural compound multiflorine, a derivatisation program aimed at the discovery and initial characterisation of novel compounds with antidiabetic potential. Design and discovery of the structures was guided by oral bioactivities obtained in oral glucose tolerance tests in mice. 55P0110, one among several new compounds with distinct anti-hyperglycaemic activity, was further examined to characterise its pharmacology and mode of action. Whereas a sin...

  8. Swim-exercised mice show a decreased level of protein O-GlcNAcylation and expression of O-GlcNAc transferase in heart.

    Science.gov (United States)

    Belke, Darrell D

    2011-07-01

    Swim-training exercise in mice leads to cardiac remodeling associated with an improvement in contractile function. Protein O-linked N-acetylglucosamine (O-GlcNAcylation) is a posttranslational modification of serine and threonine residues capable of altering protein-protein interactions affecting gene transcription, cell signaling pathways, and general cell physiology. Increased levels of protein O-GlcNAcylation in the heart have been associated with pathological conditions such as diabetes, ischemia, and hypertrophic heart failure. In contrast, the impact of physiological exercise on protein O-GlcNAcylation in the heart is currently unknown. Swim-training exercise in mice was associated with the development of a physiological hypertrophy characterized by an improvement in contractile function relative to sedentary mice. General protein O-GlcNAcylation was significantly decreased in swim-exercised mice. This effect was mirrored in the level of O-GlcNAcylation of individual proteins such as SP1. The decrease in protein O-GlcNAcylation was associated with a decrease in the expression of O-GlcNAc transferase (OGT) and glutamine-fructose amidotransferase (GFAT) 2 mRNA. O-GlcNAcase (OGA) activity was actually lower in swim-trained than sedentary hearts, suggesting that it did not contribute to the decreased protein O-GlcNAcylation. Thus it appears that exercise-induced physiological hypertrophy is associated with a decrease in protein O-GlcNAcylation, which could potentially contribute to changes in gene expression and other physiological changes associated with exercise. PMID:21493720

  9. Suppressed retinal degeneration in aged wild type and APPswe/PS1ΔE9 mice by bone marrow transplantation.

    Directory of Open Access Journals (Sweden)

    Yue Yang

    Full Text Available Alzheimer's disease (AD is an age-related condition characterized by accumulation of neurotoxic amyloid β peptides (Aβ in brain and retina. Because bone marrow transplantation (BMT results in decreased cerebral Aβ in experimental AD, we hypothesized that BMT would mitigate retinal neurotoxicity through decreased retinal Aβ. To test this, we performed BMT in APPswe/PS1ΔE9 double transgenic mice using green fluorescent protein expressing wild type (wt mice as marrow donors. We first examined retinas from control, non-transplanted, aged AD mice and found a two-fold increase in microglia compared with wt mice, prominent inner retinal Aβ and paired helical filament-tau, and decreased retinal ganglion cell layer neurons. BMT resulted in near complete replacement of host retinal microglia with BMT-derived cells and normalized total AD retinal microglia to non-transplanted wt levels. Aβ and paired helical filament-tau were reduced (61.0% and 44.1% respectively in BMT-recipient AD mice, which had 20.8% more retinal ganglion cell layer neurons than non-transplanted AD controls. Interestingly, aged wt BMT recipients also had significantly more neurons (25.4% compared with non-transplanted aged wt controls. Quantitation of retinal ganglion cell layer neurons in young mice confirmed age-related retinal degeneration was mitigated by BMT. We found increased MHC class II expression in BMT-derived microglia and decreased oxidative damage in retinal ganglion cell layer neurons. Thus, BMT is neuroprotective in age-related as well as AD-related retinal degeneration, and may be a result of alterations in innate immune function and oxidative stress in BMT recipient mice.

  10. A comparative review of aging and B cell function in mice and humans

    OpenAIRE

    Scholz, Jean L.; Diaz, Alain; Riley, Richard L.; Cancro, Michael P.; Frasca, Daniela

    2013-01-01

    Immune system function declines with age. Here we review and compare age-associated changes in murine and human B cell pools and humoral immune responses. We summarize changes in B cell generation and homeostasis, as well as notable changes at the sub-cellular level; then discuss how these changes help to explain alterations in immune responses across the adult lifespan of the animal. In each section we compare and contrast findings in the mouse, arguably the best animal model of the aging im...

  11. Early-onset motor impairment and increased accumulation of phosphorylated α-synuclein in the motor cortex of normal aging mice are ameliorated by coenzyme Q.

    Science.gov (United States)

    Takahashi, Kazuhide; Ohsawa, Ikuroh; Shirasawa, Takuji; Takahashi, Mayumi

    2016-08-01

    Brain mitochondrial function declines with age; however, the accompanying behavioral and histological alterations that are characteristic of Parkinson's disease (PD) are poorly understood. We found that the mitochondrial oxygen consumption rate (OCR) and coenzyme Q (CoQ) content were reduced in aged (15-month-old) male mice compared to those in young (6-month-old) male mice. Concomitantly, motor functions, including the rate of movement and exploratory and voluntary motor activities, were significantly reduced in the aged mice compared to the young mice. In the motor cortex of the aged mouse brain, the accumulation of α-synuclein (α-syn) phosphorylated at serine129 (Ser129) significantly increased, and the level of vesicular glutamate transporter 1 (VGluT1) decreased compared with that in the young mouse brain. The administration of exogenous water-soluble CoQ10 to aged mice via drinking water restored the mitochondrial OCR, motor function, and phosphorylated α-syn and VGluT1 levels in the motor cortex. These results suggest that early-onset motor impairment and the increased accumulation of Ser129-phosphorylated α-syn in the motor cortex are ameliorated by the exogenous administration of CoQ10. PMID:27143639

  12. Protective Effects of Punica Granatum Seeds Extract Against Aging and Scopolamine Induced Cognitive Impairments in Mice

    OpenAIRE

    Kumar, Sokindra; Maheshwari, Kamal Kishore; Singh, Vijender

    2008-01-01

    Dementia is one of the age related mental problems and characteristic symptom of various neurodegenerative diseases including Alzheimer's disease. This impairment probably is due to the vulnerability of the brain cells to increased oxidative stress during aging process. Many studies have shown that certain phenolic antioxidants attenuate neuronal cell death induced by oxidative stress. The present work was undertaken to assess the effect of ethanolic extract of Punica granatum seeds on cognit...

  13. Spatial cognition in adult and aged mice exposed to high-fat diet

    OpenAIRE

    Kesby, JP; Kim, JJ; M. Scadeng; Woods, G.; Kado, DM; Olefsky, JM; Jeste, DV; Achim, CL; Semenova, S

    2015-01-01

    © 2015 Kesby et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Aging is associated with a decline in multiple aspects of cognitive function, with spatial cognition being particularly sensitive to age-related decline. Environmental stressors, such as high-fat diet (HFD) exposure, that produce a diabetic ...

  14. Fossil mice and rats show isotopic evidence of niche partitioning and change in dental ecomorphology related to dietary shift in Late Miocene of Pakistan.

    Science.gov (United States)

    Kimura, Yuri; Jacobs, Louis L; Cerling, Thure E; Uno, Kevin T; Ferguson, Kurt M; Flynn, Lawrence J; Patnaik, Rajeev

    2013-01-01

    Stable carbon isotope analysis in tooth enamel is a well-established approach to infer C3 and C4 dietary composition in fossil mammals. The bulk of past work has been conducted on large herbivorous mammals. One important finding is that their dietary habits of fossil large mammals track the late Miocene ecological shift from C3 forest and woodland to C4 savannah. However, few studies on carbon isotopes of fossil small mammals exist due to limitations imposed by the size of rodent teeth, and the isotopic ecological and dietary behaviors of small mammals to climate change remain unknown. Here we evaluate the impact of ecological change on small mammals by fine-scale comparisons of carbon isotope ratios (δ(13)C) with dental morphology of murine rodents, spanning 13.8 to ∼2.0 Ma, across the C3 to C4 vegetation shift in the Miocene Siwalik sequence of Pakistan. We applied in-situ laser ablation GC-IRMS to lower first molars and measured two grazing indices on upper first molars. Murine rodents yield a distinct, but related, record of past ecological conditions from large herbivorous mammals, reflecting available foods in their much smaller home ranges. In general, larger murine species show more positive δ(13)C values and have higher grazing indices than smaller species inhabiting the same area at any given age. Two clades of murine rodents experienced different rates of morphological change. In the faster-evolving clade, the timing and trend of morphological innovations are closely tied to consumption of C4 diet during the vegetation shift. This study provides quantitative evidence of linkages among diet, niche partitioning, and dental morphology at a more detailed level than previously possible. PMID:23936324

  15. Fossil mice and rats show isotopic evidence of niche partitioning and change in dental ecomorphology related to dietary shift in Late Miocene of Pakistan.

    Directory of Open Access Journals (Sweden)

    Yuri Kimura

    Full Text Available Stable carbon isotope analysis in tooth enamel is a well-established approach to infer C3 and C4 dietary composition in fossil mammals. The bulk of past work has been conducted on large herbivorous mammals. One important finding is that their dietary habits of fossil large mammals track the late Miocene ecological shift from C3 forest and woodland to C4 savannah. However, few studies on carbon isotopes of fossil small mammals exist due to limitations imposed by the size of rodent teeth, and the isotopic ecological and dietary behaviors of small mammals to climate change remain unknown. Here we evaluate the impact of ecological change on small mammals by fine-scale comparisons of carbon isotope ratios (δ(13C with dental morphology of murine rodents, spanning 13.8 to ∼2.0 Ma, across the C3 to C4 vegetation shift in the Miocene Siwalik sequence of Pakistan. We applied in-situ laser ablation GC-IRMS to lower first molars and measured two grazing indices on upper first molars. Murine rodents yield a distinct, but related, record of past ecological conditions from large herbivorous mammals, reflecting available foods in their much smaller home ranges. In general, larger murine species show more positive δ(13C values and have higher grazing indices than smaller species inhabiting the same area at any given age. Two clades of murine rodents experienced different rates of morphological change. In the faster-evolving clade, the timing and trend of morphological innovations are closely tied to consumption of C4 diet during the vegetation shift. This study provides quantitative evidence of linkages among diet, niche partitioning, and dental morphology at a more detailed level than previously possible.

  16. CCR2(+) monocytes infiltrate atrophic lesions in age-related macular disease and mediate photoreceptor degeneration in experimental subretinal inflammation in Cx3cr1 deficient mice.

    Science.gov (United States)

    Sennlaub, Florian; Auvynet, Constance; Calippe, Bertrand; Lavalette, Sophie; Poupel, Lucie; Hu, Shulong J; Dominguez, Elisa; Camelo, Serge; Levy, Olivier; Guyon, Elodie; Saederup, Noah; Charo, Israel F; Rooijen, Nico Van; Nandrot, Emeline; Bourges, Jean-Louis; Behar-Cohen, Francine; Sahel, José-Alain; Guillonneau, Xavier; Raoul, William; Combadiere, Christophe

    2013-11-01

    Atrophic age-related macular degeneration (AMD) is associated with the subretinal accumulation of mononuclear phagocytes (MPs). Their role in promoting or inhibiting retinal degeneration is unknown. We here show that atrophic AMD is associated with increased intraocular CCL2 levels and subretinal CCR2(+) inflammatory monocyte infiltration in patients. Using age- and light-induced subretinal inflammation and photoreceptor degeneration in Cx3cr1 knockout mice, we show that subretinal Cx3cr1 deficient MPs overexpress CCL2 and that both the genetic deletion of CCL2 or CCR2 and the pharmacological inhibition of CCR2 prevent inflammatory monocyte recruitment, MP accumulation and photoreceptor degeneration in vivo. Our study shows that contrary to CCR2 and CCL2, CX3CR1 is constitutively expressed in the retina where it represses the expression of CCL2 and the recruitment of neurotoxic inflammatory CCR2(+) monocytes. CCL2/CCR2 inhibition might represent a powerful tool for controlling inflammation and neurodegeneration in AMD. PMID:24142887

  17. CCR2+ monocytes infiltrate atrophic lesions in age-related macular disease and mediate photoreceptor degeneration in experimental subretinal inflammation in Cx3cr1 deficient mice

    Science.gov (United States)

    Sennlaub, Florian; Auvynet, Constance; Calippe, Bertrand; Lavalette, Sophie; Poupel, Lucie; Hu, Shulong J; Dominguez, Elisa; Camelo, Serge; Levy, Olivier; Guyon, Elodie; Saederup, Noah; Charo, Israel F; Van Rooijen, Nico; Nandrot, Emeline; Bourges, Jean-Louis; Behar-Cohen, Francine; Sahel, José-Alain; Guillonneau, Xavier; Raoul, William; Combadiere, Christophe

    2013-01-01

    Atrophic age-related macular degeneration (AMD) is associated with the subretinal accumulation of mononuclear phagocytes (MPs). Their role in promoting or inhibiting retinal degeneration is unknown. We here show that atrophic AMD is associated with increased intraocular CCL2 levels and subretinal CCR2+ inflammatory monocyte infiltration in patients. Using age- and light-induced subretinal inflammation and photoreceptor degeneration in Cx3cr1 knockout mice, we show that subretinal Cx3cr1 deficient MPs overexpress CCL2 and that both the genetic deletion of CCL2 or CCR2 and the pharmacological inhibition of CCR2 prevent inflammatory monocyte recruitment, MP accumulation and photoreceptor degeneration in vivo. Our study shows that contrary to CCR2 and CCL2, CX3CR1 is constitutively expressed in the retina where it represses the expression of CCL2 and the recruitment of neurotoxic inflammatory CCR2+ monocytes. CCL2/CCR2 inhibition might represent a powerful tool for controlling inflammation and neurodegeneration in AMD. PMID:24142887

  18. A comparative study of age-related hearing loss in wild type and insulin-like growth factor I deficient mice

    Directory of Open Access Journals (Sweden)

    Raquel Riquelme

    2010-06-01

    Full Text Available Insulin-like growth factor-I (IGF-I belongs to the family of insulin-related peptides that fulfils a key role during the late development of the nervous system. Human IGF1 mutations cause profound deafness, poor growth and mental retardation. Accordingly, Igf1−/− null mice are dwarfs that have low survival rates, cochlear alterations and severe sensorineural deafness. Presbycusis (age-related hearing loss is a common disorder associated with aging that causes social and cognitive problems. Aging is also associated with a decrease in circulating IGF-I levels and this reduction has been related to cognitive and brain alterations, although there is no information as yet regarding the relationship between presbycusis and IGF-I biodisponibility. Here we present a longitudinal study of wild type Igf1+/+ and null Igf1−/− mice from 2 to 12 months of age comparing the temporal progression of several parameters: hearing, brain morphology, cochlear cytoarchitecture, insulin-related factors and IGF gene expression and IGF-I serum levels. Complementary invasive and non-invasive techniques were used, including auditory brainstem-evoked response (ABR recordings and in vivo MRI brain imaging. Igf1−/− null mice presented profound deafness at all the ages studied, without any obvious worsening of hearing parameters with aging. Igf1+/+ wild type mice suffered significant age-related hearing loss, their auditory thresholds and peak I latencies augmenting as they aged, in parallel with a decrease in the circulating levels of IGF-I. Accordingly, there was an age-related spiral ganglion degeneration in wild type mice that was not evident in the Igf1 null mice. However, the Igf1−/− null mice in turn developed a prematurely aged stria vascularis reminiscent of the diabetic strial phenotype. Our data indicate that IGF-I is required for the correct development and maintenance of hearing, supporting the idea that IGF-I-based therapies could contribute to

  19. NADPH oxidase 2-derived reactive oxygen species in the hippocampus might contribute to microglial activation in postoperative cognitive dysfunction in aged mice.

    Science.gov (United States)

    Qiu, Li-Li; Ji, Mu-Huo; Zhang, Hui; Yang, Jiao-Jiao; Sun, Xiao-Ru; Tang, Hui; Wang, Jing; Liu, Wen-Xue; Yang, Jian-Jun

    2016-01-01

    Microglial activation plays a key role in the development of postoperative cognitive dysfunction (POCD). Nox2, one of the main isoforms of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the central nervous system, is a predominant source of reactive oxygen species (ROS) overproduction in phagocytes including microglia. We therefore hypothesized that Nox2-induced microglial activation is involved in the development of POCD. Sixteen-month-old C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to mimic the clinical human abdominal surgery. Behavioral tests were performed at 6 and 7 d post-surgery with open field and fear conditioning tests, respectively. The levels of Nox2, 8-hydroxy-2'-deoxyguanosine (8-OH-dG, a marker of DNA oxidation), CD11b (a marker of microglial activation), interleukin-1β (IL-1β), and brain-derived neurotrophic factor (BDNF) were determined in the hippocampus and prefrontal cortex at 1 d and 7 d post-surgery, respectively. For the interventional study, mice were treated with a NADPH oxidase inhibitor apocynin (APO). Our results showed that exploratory laparotomy with isoflurane anesthesia impaired the contextual fear memory, increased expression of Nox2, 8-OH-dG, CD11b, and IL-1β, and down-regulated BDNF expression in the hippocampus at 7 d post-surgery. The surgery-induced microglial activation and neuroinflammation persisted to 7 d after surgery in the hippocampus, but only at 1 d in the prefrontal cortex. Notably, administration with APO could rescue these surgery-induced cognitive impairments and associated brain pathology. Together, our data suggested that Nox2-derived ROS in hippocampal microglia, at least in part, contributes to subsequent neuroinflammation and cognitive impairments induced by surgery in aged mice. PMID:26254234

  20. Effect of lifelong resveratrol supplementation and exercise training on skeletal muscle oxidative capacity in aging mice

    DEFF Research Database (Denmark)

    Ringholm, Stine; Olesen, Jesper; Pedersen, Jesper Thorhauge;

    2013-01-01

    The present study tested the hypothesis that lifelong resveratrol (RSV) supplementation counteracts an age-associated decrease in skeletal muscle oxidative capacity through peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and that RSV combined with lifelong exercise training (ET...

  1. CD11b+Ly6C++Ly6G- cells show distinct function in mice with chronic inflammation or tumor burden

    Directory of Open Access Journals (Sweden)

    Källberg Eva

    2012-12-01

    Full Text Available Abstract Background S100A9 has been shown to be important for the function of so called Myeloid Derived Suppressor Cells (MDSC. Cells with a similar phenotype are also involved in pro-inflammatory processes, and we therefore wanted to investigate the gene expression and function of these cells in animals that were either subjected to chronic inflammation, or inoculated with tumors. Methods CD11b+Ly6C++ and Ly6G+ cells were isolated from spleen, tumor tissue or inflammatory granulomas. S100A9, Arginase 1 and iNOS gene expression in the various CD11b+ cell populations was analyzed using Q-PCR. The suppressive activity of the CD11b+ cell populations from different donors was studied in co-culture experiments. Results S100A9 was shown to be expressed mainly in splenic CD11b+Ly6C+G+ cells both at the RNA and protein level. Arginase I and iNOS expression could be detected in both CD11b+Ly6C+Ly6G+ and CD11b+Ly6C+G-/C++G- derived from tumors or a site of chronic inflammation, but was very low in the same cell populations isolated from the spleen. CD11b+ cells isolated from mice with peritoneal chronic inflammation were able to stimulate T lymphocytes, while CD11b+ cells from mice with peritoneal tumors suppressed T cell growth. Conclusion An identical CD11b+Ly6C++G- cell population appears to have the ability to adopt immune stimulatory or immune suppressive functions dependent on the presence of a local inflammatory or tumor microenvironment. Thus, there is a functional plasticity in the CD11b+Ly6C++G- cell population that cannot be distinguished with the current molecular markers.

  2. Pi-class glutathione-S-transferase-positive hepatocytes in aging B6C3F1 mice undergo apoptosis induced by dietary restriction.

    OpenAIRE

    Muskhelishvili, L; Turturro, A.; Hart, R W; James, S J

    1996-01-01

    Liver sections from aging ad libitum-fed and diet-restricted B6C3F1 male mice were evaluated immunohistochemically for pi-class glutathione S-transferase (GST-II). GST-II immunostaining of hepatocytes was diffuse and occurred in periportal regions of hepatic acinus, whereas perivenous areas were weakly stained or were stain-free. Expression of GST-II was significantly diminished in diet-restricted mice in all age groups and was associated with a marked decrease in liver tumor development. As ...

  3. Mouse ECG findings in aging, with conduction system affecting drugs and in cardiac pathologies: Development and validation of ECG analysis algorithm in mice

    OpenAIRE

    Merentie, Mari; Jukka A Lipponen; Hedman, Marja; Hedman, Antti; Hartikainen, Juha; Huusko, Jenni; Lottonen‐Raikaslehto, Line; Parviainen, Viktor; Laidinen, Svetlana; KARJALAINEN, Pasi A.; Ylä‐Herttuala, Seppo

    2015-01-01

    Abstract Mouse models are extremely important in studying cardiac pathologies and related electrophysiology, but very few mouse ECG analysis programs are readily available. Therefore, a mouse ECG analysis algorithm was developed and validated. Surface ECG (lead II) was acquired during transthoracic echocardiography from C57Bl/6J mice under isoflurane anesthesia. The effect of aging was studied in young (2–3 months), middle‐aged (14 months) and old (20–24 months) mice. The ECG changes associat...

  4. Rejection of large HPV-16 expressing tumors in aged mice by a single immunization of VacciMax® encapsulated CTL/T helper peptides

    OpenAIRE

    MacDonald Lisa; Korets-Smith Ella; Fuentes-Ortega Antar; Pohajdak Bill; Mansour Marc; Daftarian Pirouz M; Weir Genevieve; Brown Robert G; Kast W Martin

    2007-01-01

    Abstract The incidence of cancer increases significantly in later life, yet few pre-clinical studies of cancer immunotherapy use mice of advanced age. A novel vaccine delivery platform (VacciMax®,VM) is described that encapsulates antigens and adjuvants in multilamellar liposomes in a water-in-oil emulsion. The therapeutic potential of VM-based vaccines administered as a single dose was tested in HLA-A2 transgenic mice of advanced age (48–58 weeks old) bearing large palpable TC1/A2 tumors. Th...

  5. Chronic consumption of a western diet induces robust glial activation in aging mice and in a mouse model of Alzheimer’s disease

    OpenAIRE

    Graham, Leah C.; Harder, Jeffrey M.; Ileana Soto; de Vries, Wilhelmine N.; Simon W M John; Gareth R Howell

    2016-01-01

    Studies have assessed individual components of a western diet, but no study has assessed the long-term, cumulative effects of a western diet on aging and Alzheimer’s disease (AD). Therefore, we have formulated the first western-style diet that mimics the fat, carbohydrate, protein, vitamin and mineral levels of western diets. This diet was fed to aging C57BL/6J (B6) mice to identify phenotypes that may increase susceptibility to AD, and to APP/PS1 mice, a mouse model of AD, to determine the e...

  6. 绞股蓝皂苷在小鼠皮肤衰老中的抗氧化损伤作用研究%Study on the effect of gypenosides on antioxidative injury in aged mice skin

    Institute of Scientific and Technical Information of China (English)

    苏秋香; 丛敬; 宫倩

    2015-01-01

    目的:探讨绞股蓝皂苷对衰老小鼠皮肤的抗氧化保护作用。方法:60只小鼠随机分成3组,青年组(A)、老年对照组(B)和老年给药组(C);A、B组灌胃生理盐水20ml/kg,C组灌胃绞股蓝皂苷提取液8g/kg,每天1次。30天后取皮肤组织,检测丙二醛(MDA)含量,超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、谷胱甘肽过氧化物酶(GSH-Px)活性。结果:与A组比较,B组、C组皮肤组织中MDA含量增加,SOD、CAT、GSH-Px活性降低(<0.05);与B组比较,C组皮肤组织中MDA含量减少,SOD、CAT、GSH-Px活性增加(<0.05)。结论:灌胃绞股蓝皂苷可减轻衰老小鼠皮肤的氧化损伤,具有延缓小鼠皮肤衰老的作用。%Objective To study the antioxidative protection of Gypenosides in aged mices skin. Methods 60 mices were selected and randomly divided into 3 groups:young control group (group A),aged control group (group B) and aged dose group (group C). In group A and group B,normal saline (20ml/kg) was given intragastricly. Gypenosides extracts at doses of 8g/kg was administered intragastricly in group C,once a day. Skin tissue from treated mices were prepared for analysis 30 days after treatments. Relative level changes of MDA,SOD,CAT and GSH- Px were measured. Results Increases in MDA and decreases in SOD,CAT and GSH- Px were observed in both group B and group C as compared with group A ( <0.05). Compared with mices in group B, mices in group C showed significant decreases in MDA and increases in SOD,CAT and GSH- Px ( <0.05). Conclusion Intragastric administration of Gypenosides extracts to mices could alleviate the oxidative injury to aged skin,and therefore could delay the skin aging in mices.

  7. n-3 polyunsaturated fatty acids supplementation enhances hippocampal functionality in aged mice

    OpenAIRE

    Debora Cutuli; Maurizio Ronci; Cristina Neri; Stefano Farioli Vecchioli

    2014-01-01

    As major components of neuronal membranes, omega-3 polyunsaturated acids (n-3 PUFA) exhibit a wide range of regulatory functions, modulating from synaptic plasticity to neuroinflammation, from oxidative stress to neuroprotection. Recent human and animal studies indicated the n-3 PUFA neuroprotective properties in aging, with a clear negative correlation between n-3 PUFA levels and hippocampal deficits. The present multidimensional study was aimed at associating cognition, hippocampal neurogen...

  8. Androgen Administration to Aged Male Mice Increases Anti-Anxiety Behavior and Enhances Cognitive Performance

    OpenAIRE

    Frye, Cheryl A.; Edinger, Kassandra; Sumida, Kanako

    2007-01-01

    Although androgen secretion is reduced with aging, and may underlie decrements in cognitive and affective performance, the effects and mechanisms of androgens to mediate these behaviors are not well understood. Testosterone (T), the primary male androgen, is aromatized to estrogen (E2), and reduced to dihydrotestosterone (DHT), which is converted to 5α-androstane, 3α, 17β-diol (3α-diol). To ascertain whether actions of the neuroactive metabolite of T, 3α-diol, mediates cognitive and affective...

  9. Palladium and Platinum Nanoparticles Attenuate Aging-Like Skin Atrophy via Antioxidant Activity in Mice

    OpenAIRE

    Shibuya, Shuichi; Ozawa, Yusuke; Watanabe, Kenji; Izuo, Naotaka; Toda, Toshihiko; Yokote, Koutaro; Shimizu, Takahiko

    2014-01-01

    Cu-Zn superoxide dismutase (Sod1) loss causes a redox imbalance as it leads to excess superoxide generation, which results in the appearance of various aging-related phenotypes, including skin atrophy. Noble metal nanoparticles, such as palladium (Pd) and platinum (Pt) nanoparticles, are considered to function as antioxidants due to their strong catalytic activity. In Japan, a mixture of Pd and Pt nanoparticles called PAPLAL has been used to treat chronic diseases over the past 60 years. In t...

  10. Mice lacking Ras-GRF1 show contextual fear conditioning but not spatial memory impairments: convergent evidence from two independently generated mouse mutant lines

    Directory of Open Access Journals (Sweden)

    Raffaele ed'Isa

    2011-12-01

    Full Text Available Ras-GRF1 is a neuronal specific guanine exchange factor that, once activated by both ionotropic and metabotropic neurotransmitter receptors, can stimulate Ras proteins, leading to long-term phosphorylation of downstream signaling. The two available reports on the behavior of two independently generated Ras-GRF1 deficient mouse lines provide contrasting evidence on the role of Ras-GRF1 in spatial memory and contextual fear conditioning. These discrepancies may be due to the distinct alterations introduced in the mouse genome by gene targeting in the two lines that could differentially affect expression of nearby genes located in the imprinted region containing the Ras-grf1 locus. In order to determine the real contribution of Ras-GRF1 to spatial memory we compared in Morris Water Maze learning the Brambilla’s mice with a third mouse line (GENA53 in which a nonsense mutation was introduced in the Ras-GRF1 coding region without additional changes in the genome and we found that memory in this task is normal. Also, we measured both contextual and cued fear conditioning, which were previously reported to be affected in the Brambilla’s mice, and we confirmed that contextual learning but not cued conditioning is impaired in both mouse lines. In addition, we also tested both lines for the first time in conditioned place aversion in the Intellicage, an ecological and remotely controlled behavioral test, and we observed normal learning. Finally, based on previous reports of other mutant lines suggesting that Ras-GRF1 may control body weight, we also measured this non-cognitive phenotype and we confirmed that both Ras-GRF1 deficient mutants are smaller than their control littermates. In conclusion, we demonstrate that Ras-GRF1 has no unique role in spatial memory while its function in contextual fear conditioning is likely to be due not only to its involvement in amygdalar functions but possibly to some distinct hippocampal connections specific to

  11. Time- and age-dependent effects of serotonin on gasping and autoresuscitation in neonatal mice.

    Science.gov (United States)

    Chen, Jianping; Magnusson, Jennifer; Karsenty, Gerard; Cummings, Kevin J

    2013-06-15

    The role of brain stem serotonin (5-hydroxytryptamine, 5-HT) in autoresuscitation in neonatal life is unclear. We hypothesized that a specific loss of 5-HT would compromise gasping and autoresuscitation mainly in the second postnatal week and that acute restoration of 5-HT would reverse the defects. We exposed postnatal day (P)4-5, P8-9, and P11-12 tryptophan-hydroxylase-2 knockout (TPH2(-/-)) and wild-type littermates (WT) to 10 episodes of anoxia (97% N2, 3% CO2), measuring survival, gasp latency, gasp frequency (fB), and the time required to restore eupnea and heart rate. We also tested P8-9 TPH2(-/-) mice after restoring 5-HT with a single injection of 5-hydroxytryptophan (5-HTP) 1-2 h before testing or with multiple injections beginning 24 h before testing. At P4-5 and P8-9, but not at P11-12, gasp latency and the recovery of eupnea were delayed ~2- to 3-fold in TPH2(-/-) pups compared with WT (P pups displayed reduced gasp fB (~20-30%; P rate recovery (~60%; P = 0.002) compared with WT littermates. TPH2(-/-) survival was reduced compared with WT (P pups, improved cardiorespiratory recovery and survival required 24 h of treatment. Our data suggest that 5-HT operates over a long time span (24 h) to improve survival during episodic severe hypoxia. Early in development (P4-9), 5-HT is critical for both respiratory and cardiovascular components of autoresuscitation; later (P11-12), it is critical mainly for cardiovascular components. Nevertheless, the effect of 5-HT deficiency on survival is most striking from P8 to P12. PMID:23558391

  12. Polysaccharides from the Medicinal Mushroom Cordyceps taii Show Antioxidant and Immunoenhancing Activities in a D-Galactose-Induced Aging Mouse Model

    Directory of Open Access Journals (Sweden)

    Jian-Hui Xiao

    2012-01-01

    Full Text Available Cordyceps taii, an edible medicinal mushroom native to south China, is recognized as an unparalleled resource of healthy foods and drug discovery. In the present study, the antioxidant pharmacological properties of C. taii were systematically investigated. In vitro assays revealed the scavenging activities of the aqueous extract and polysaccharides of C. taii against various free radicals, that is, 1,1-diphenyl-2-picrylhydrazyl radical, hydroxyl radical, and superoxide anion radical. The EC50 values for superoxide anion-free radical ranged from 2.04 mg/mL to 2.49 mg/mL, which was at least 2.6-fold stronger than that of antioxidant thiourea. The polysaccharides also significantly enhanced the antioxidant enzyme activities (superoxide dismutase, catalase, and glutathione peroxidase and markedly decreased the malondialdehyde production of lipid peroxidation in a D-galactose-induced aging mouse model. Interestingly, the immune function of the administration group was significantly boosted compared with the D-galactose-induced aging model group. Therefore, the C. taii polysaccharides possessed potent antioxidant activity closely associated with immune function enhancement and free radical scavenging. These findings suggest that the polysaccharides are a promising source of natural antioxidants and antiaging drugs. Consequently, a preliminary chemical investigation was performed using gas chromatography-mass spectroscopy and revealed that the polysaccharides studied were mainly composed of glucose, mannose, and galactose. Fourier-transform infrared spectra also showed characteristic polysaccharide absorption bands.

  13. Maternal Obesity, Cage Density, and Age Contribute to Prostate Hyperplasia in Mice.

    Science.gov (United States)

    Benesh, Emily C; Gill, Jeff; Lamb, Laura E; Moley, Kelle H

    2016-02-01

    Identification of modifiable risk factors is gravely needed to prevent adverse prostate health outcomes. We previously developed a murine precancer model in which exposure to maternal obesity stimulated prostate hyperplasia in offspring. Here, we used generalized linear modeling to evaluate the influence of additional environmental covariates on prostate hyperplasia. As expected from our previous work, the model revealed that aging and maternal diet-induced obesity (DIO) each correlated with prostate hyperplasia. However, prostate hyperplasia was not correlated with the length of maternal DIO. Cage density positively associated with both prostate hyperplasia and offspring body weight. Expression of the glucocorticoid receptor in prostates also positively correlated with cage density and negatively correlated with age of the animal. Together, these findings suggest that prostate tissue was adversely patterned during early life by maternal overnutrition and was susceptible to alteration by environmental factors such as cage density. Additionally, prostate hyperplasia may be acutely influenced by exposure to DIO, rather than occurring as a response to worsening obesity and comorbidities experienced by the mother. Finally, cage density correlated with both corticosteroid receptor abundance and prostate hyperplasia, suggesting that overcrowding influenced offspring prostate hyperplasia. These results emphasize the need for multivariate regression models to evaluate the influence of coordinated variables in complicated animal systems. PMID:26243546

  14. Age-related morphometric changes in the pineal gland. A comparative study between C57BLI6J and CBA mice

    OpenAIRE

    Cernuda-Cernuda, R.; Huerta, J.J.; Muñoz Llamosas, M.; Alvarez-Uría, M.; García-Fernández, J.M. (José Manuel)

    2000-01-01

    Relatively little is known about the effects of melatonin on the aging of the pineal, the organ which is the main place for synthesis of this hormone. Using simple morphometric methods, some parameters of the pineal gland, such as total volume, number of pinealocytes and pinealocyte volume were estimated in two mice strains: normal CBA and melatonin-deficient C57BLl6J. Two age groups, 6 weeks and 10 months, were studied in order to evaluate possible differentia...

  15. 17β-Estradiol regulates histone alterations associated with memory consolidation and increases Bdnf promoter acetylation in middle-aged female mice

    OpenAIRE

    Fortress, Ashley M.; Kim, Jaekyoon; Rachel L Poole; Gould, Thomas J.; Frick, Karyn M.

    2014-01-01

    Histone acetylation is essential for hippocampal memory formation in young adult rodents. Although dysfunctional histone acetylation has been associated with age-related memory decline in male rodents, little is known about whether histone acetylation is altered by aging in female rodents. In young female mice, the ability of 17β-estradiol (E2) to enhance object recognition memory consolidation requires histone H3 acetylation in the dorsal hippocampus. However, the extent to which histone ace...

  16. Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice.

    NARCIS (Netherlands)

    Edgar, D.; Shabalina, I.; Camara, Y.; Wredenberg, A.; Calvaruso, M.A.; Nijtmans, L.G.J.; Nedergaard, J.; Cannon, B.; Larsson, N.G.; Trifunovic, A.

    2009-01-01

    The mtDNA mutator mice have high levels of point mutations and linear deletions of mtDNA causing a progressive respiratory chain dysfunction and a premature aging phenotype. We have now performed molecular analyses to determine the mechanism whereby these mtDNA mutations impair respiratory chain fun

  17. Amitriptyline-mediated cognitive enhancement in aged 3×Tg Alzheimer's disease mice is associated with neurogenesis and neurotrophic activity.

    Directory of Open Access Journals (Sweden)

    Wayne Chadwick

    Full Text Available Approximately 35 million people worldwide suffer from Alzheimer's disease (AD. Existing therapeutics, while moderately effective, are currently unable to stem the widespread rise in AD prevalence. AD is associated with an increase in amyloid beta (Aβ oligomers and hyperphosphorylated tau, along with cognitive impairment and neurodegeneration. Several antidepressants have shown promise in improving cognition and alleviating oxidative stress in AD but have failed as long-term therapeutics. In this study, amitriptyline, an FDA-approved tricyclic antidepressant, was administered orally to aged and cognitively impaired transgenic AD mice (3×TgAD. After amitriptyline treatment, cognitive behavior testing demonstrated that there was a significant improvement in both long- and short-term memory retention. Amitriptyline treatment also caused a significant potentiation of non-toxic Aβ monomer with a concomitant decrease in cytotoxic dimer Aβ load, compared to vehicle-treated 3×TgAD controls. In addition, amitriptyline administration caused a significant increase in dentate gyrus neurogenesis as well as increases in expression of neurosynaptic marker proteins. Amitriptyline treatment resulted in increases in hippocampal brain-derived neurotrophic factor protein as well as increased tyrosine phosphorylation of its cognate receptor (TrkB. These results indicate that amitriptyline has significant beneficial actions in aged and damaged AD brains and that it shows promise as a tolerable novel therapeutic for the treatment of AD.

  18. Age-dependent effects of esculetin on mood-related behavior and cognition from stressed mice are associated with restoring brain antioxidant status.

    Science.gov (United States)

    Martín-Aragón, Sagrario; Villar, Ángel; Benedí, Juana

    2016-02-01

    Dietary antioxidants might exert an important role in the aging process by relieving oxidative damage, a likely cause of age-associated brain dysfunctions. This study aims to investigate the influence of esculetin (6,7-dihydroxycoumarin), a naturally occurring antioxidant in the diet, on mood-related behaviors and cognitive function and its relation with age and brain oxidative damage. Behavioral tests were employed in 11-, 17- and 22-month-old male C57BL/6J mice upon an oral 35day-esculetin treatment (25mg/kg). Activity of antioxidant enzymes, GSH and GSSG levels, GSH/GSSG ratio, and mitochondrial function were analyzed in brain cortex at the end of treatment in order to assess the oxidative status related to mouse behavior. Esculetin treatment attenuated the increased immobility time and enhanced the diminished climbing time in the forced swim task elicited by acute restraint stress (ARS) in the 11- and 17-month-old mice versus their counterpart controls. Furthermore, ARS caused an impairment of contextual memory in the step-through passive avoidance both in mature adult and aged mice which was partially reversed by esculetin only in the 11-month-old mice. Esculetin was effective to prevent the ARS-induced oxidative stress mostly in mature adult mice by restoring antioxidant enzyme activities, augmenting the GSH/GSSG ratio and increasing cytochrome c oxidase (COX) activity in cortex. Modulation of the mood-related behavior and cognitive function upon esculetin treatment in a mouse model of ARS depends on age and is partly due to the enhancement of redox status and levels of COX activity in cortex. PMID:26290950

  19. Rosa26-GFP direct repeat (RaDR-GFP mice reveal tissue- and age-dependence of homologous recombination in mammals in vivo.

    Directory of Open Access Journals (Sweden)

    Michelle R Sukup-Jackson

    2014-06-01

    Full Text Available Homologous recombination (HR is critical for the repair of double strand breaks and broken replication forks. Although HR is mostly error free, inherent or environmental conditions that either suppress or induce HR cause genomic instability. Despite its importance in carcinogenesis, due to limitations in our ability to detect HR in vivo, little is known about HR in mammalian tissues. Here, we describe a mouse model in which a direct repeat HR substrate is targeted to the ubiquitously expressed Rosa26 locus. In the Rosa26 Direct Repeat-GFP (RaDR-GFP mice, HR between two truncated EGFP expression cassettes can yield a fluorescent signal. In-house image analysis software provides a rapid method for quantifying recombination events within intact tissues, and the frequency of recombinant cells can be evaluated by flow cytometry. A comparison among 11 tissues shows that the frequency of recombinant cells varies by more than two orders of magnitude among tissues, wherein HR in the brain is the lowest. Additionally, de novo recombination events accumulate with age in the colon, showing that this mouse model can be used to study the impact of chronic exposures on genomic stability. Exposure to N-methyl-N-nitrosourea, an alkylating agent similar to the cancer chemotherapeutic temozolomide, shows that the colon, liver and pancreas are susceptible to DNA damage-induced HR. Finally, histological analysis of the underlying cell types reveals that pancreatic acinar cells and liver hepatocytes undergo HR and also that HR can be specifically detected in colonic somatic stem cells. Taken together, the RaDR-GFP mouse model provides new understanding of how tissue and age impact susceptibility to HR, and enables future studies of genetic, environmental and physiological factors that modulate HR in mammals.

  20. New Hippocampal Neurons Are Not Obligatory for Memory Formation; Cyclin D2 Knockout Mice with No Adult Brain Neurogenesis Show Learning

    Science.gov (United States)

    Jaholkowski, Piotr; Kiryk, Anna; Jedynak, Paulina; Abdallah, Nada M. Ben; Knapska, Ewelina; Kowalczyk, Anna; Piechal, Agnieszka; Blecharz-Klin, Kamilla; Figiel, Izabela; Lioudyno, Victoria; Widy-Tyszkiewicz, Ewa; Wilczynski, Grzegorz M.; Lipp, Hans-Peter; Kaczmarek, Leszek; Filipkowski, Robert K.

    2009-01-01

    The role of adult brain neurogenesis (generating new neurons) in learning and memory appears to be quite firmly established in spite of some criticism and lack of understanding of what the new neurons serve the brain for. Also, the few experiments showing that blocking adult neurogenesis causes learning deficits used irradiation and various drugs…

  1. Age-related declines in general cognitive abilities of Balb/C mice are associated with disparities in working memory, body weight, and general activity

    OpenAIRE

    Matzel, Louis D.; Grossman, Henya; Light, Kenneth; Townsend, David; Kolata, Stefan

    2008-01-01

    A defining characteristic of age-related cognitive decline is a deficit in general cognitive performance. Here we use a testing and analysis regimen that allows us to characterize the general learning abilities of young (3–5 mo old) and aged (19–21 mo old) male and female Balb/C mice. Animals’ performance was assessed on a battery of seven diverse learning tasks. Aged animals exhibited deficits in five of the seven tasks and ranked significantly lower than their young counterparts in general ...

  2. Snobbish Show

    Institute of Scientific and Technical Information of China (English)

    YIN PUMIN

    2010-01-01

    @@ The State Administration of Radio,Film and Television (SARFT),China's media watchdog,issued a new set of mles on June 9 that strictly regulate TV match-making shows,which have been sweeping the country's primetime programming. "Improper social and love values such as money worship should not be presented in these shows.Humiliation,verbal attacks and sex-implied vulgar content are not allowed" the new roles said.

  3. Vitamin C reduces spatial learning deficits in middle-aged and very old APP/PSEN1 transgenic and wild-type mice

    OpenAIRE

    Harrison, F.E.; Hosseini, A. H.; McDonald, M. P.; May, J. M.

    2009-01-01

    Alzheimer's disease is a progressive and fatal neurodegenerative disease characterized by a build up of amyloid β (Aβ) deposits, elevated oxidative stress, and deterioration of the cholinergic system. The present study investigated short-term cognitive-enhancing effects of acute intraperitoneal (i.p.) Vitamin C (ascorbate) treatment in APP/PSEN1 mice, a mouse model of Alzheimer's disease. Middle-aged (12 months) and Very old (24 months) APP/PSEN1 bigenic and wild-type mice were treated with a...

  4. Di-(2-ethylhexyl phthalate metabolites in urine show age-related changes and associations with adiposity and parameters of insulin sensitivity in childhood.

    Directory of Open Access Journals (Sweden)

    Arianna Smerieri

    Full Text Available Phthalates might be implicated with obesity and insulin sensitivity. We evaluated the levels of primary and secondary metabolites of Di-(2-ethylhexyl phthalate (DEHP in urine in obese and normal-weight subjects both before and during puberty, and investigated their relationships with auxological parameters and indexes of insulin sensitivity.DEHP metabolites (MEHP, 6-OH-MEHP, 5-oxo-MEHP, 5-OH-MEHP, and 5-CX-MEHP, were measured in urine by RP-HPLC-ESI-MS. Traditional statistical analysis and a data mining analysis using the Auto-CM analysis were able to offer an insight into the complex biological connections between the studied variables.The data showed changes in DEHP metabolites in urine related with obesity, puberty, and presence of insulin resistance. Changes in urine metabolites were related with age, height and weight, waist circumference and waist to height ratio, thus to fat distribution. In addition, clear relationships in both obese and normal-weight subjects were detected among MEHP, its products of oxidation and measurements of insulin sensitivity.It remains to be elucidated whether exposure to phthalates per se is actually the risk factor or if the ability of the body to metabolize phthalates is actually the key point. Further studies that span from conception to elderly subjects besides further understanding of DEHP metabolism are warranted to clarify these aspects.

  5. Infants with complex congenital heart diseases show poor short-term memory in the mobile paradigm at 3 months of age.

    Science.gov (United States)

    Chen, Chao-Ying; Harrison, Tondi; Heathcock, Jill

    2015-08-01

    The purpose of this study was to examine learning, short-term memory and general development including cognitive, motor, and language domains in infants with Complex Congenital Heart Defects (CCDH). Ten infants with CCHD (4 males, 6 females) and 14 infants with typical development (TD) were examined at 3 months of age. The mobile paradigm, where an infant's leg is tethered to an overhead mobile, was used to evaluate learning and short-term memory. The Bayley Scales of Infant Development 3rd edition (Bayley-III) was used to evaluate general development in cognitive, motor, and language domains. Infants with CCHD and infants with TD both showed learning with significant increase in kicking rate (pshort-term memory (p=0.017) in the mobile paradigm. There were no differences on cognitive, motor, and language development between infants with CCHD and infants with TD on the Bayley-III. Early assessment is necessary to guide targeted treatment in infants with CCHD. One-time assessment may fail to detect potential cognitive impairments during early infancy in infants with CCHD. Supportive intervention programs for infants with CCHD that focuses on enhancing short-term memory are recommended. PMID:25919428

  6. Ghrelin Is Produced in Taste Cells and Ghrelin Receptor Null Mice Show Reduced Taste Responsivity to Salty (NaCl) and Sour (Citric Acid) Tastants

    OpenAIRE

    Yu-Kyong Shin; Bronwen Martin; Wook Kim; White, Caitlin M.; Sunggoan Ji; Yuxiang Sun; Smith, Roy G.; Jean Sévigny; Tschöp, Matthias H.; Stuart Maudsley; Egan, Josephine M.

    2010-01-01

    BACKGROUND: The gustatory system plays a critical role in determining food preferences, food intake and energy balance. The exact mechanisms that fine tune taste sensitivity are currently poorly defined, but it is clear that numerous factors such as efferent input and specific signal transduction cascades are involved. METHODOLOGY/PRINCIPAL FINDINGS: Using immunohistochemical analyses, we show that ghrelin, a hormone classically considered to be an appetite-regulating hormone, is present with...

  7. BALB/c mice genetically susceptible to proteoglycan-induced arthritis and spondylitis show colony-dependent differences in disease penetrance

    OpenAIRE

    Farkas, Balint; Boldizsar, Ferenc; Tarjanyi, Oktavia; Laszlo, Anna; Lin, Simon M.; Hutas, Gabor; Tryniszewska, Beata; Mangold, Aaron; Nagyeri, Gyorgy; Rosenzweig, Holly L.; Finnegan, Alison; Mikecz, Katalin; Glant, Tibor T.

    2009-01-01

    Introduction The major histocompatibility complex (H-2d) and non-major histocompatibility complex genetic backgrounds make the BALB/c strain highly susceptible to inflammatory arthritis and spondylitis. Although different BALB/c colonies develop proteoglycan-induced arthritis and proteoglycan-induced spondylitis in response to immunization with human cartilage proteoglycan, they show significant differences in disease penetrance despite being maintained by the same vendor at either the same o...

  8. Oral treatment with the herbal formula B401 protects against aging-dependent neurodegeneration by attenuating oxidative stress and apoptosis in the brain of R6/2 mice

    Directory of Open Access Journals (Sweden)

    Wang SE

    2015-11-01

    Full Text Available Sheue-Er Wang,1,2 Ching-Lung Lin,1 Chih-Hsiang Hsu,1 Shuenn-Jyi Sheu,3 Chung-Hsin Wu1 1Department of Life Science, National Taiwan Normal University, Taipei, 2Department of Pathological Inspection, Saint Paul’s Hospital, Taoyuan, 3Brion Research Institute of Taiwan, Taipei, Taiwan Background: Neurodegeneration is characterized by progressive neurological deficits due to selective neuronal loss in the nervous system. Huntington’s disease (HD is an incurable neurodegenerative disorder. Neurodegeneration in HD patients shows aging-dependent pattern. Our previous study has suggested that a herbal formula B401 may have neuroprotective effects in the brains of R6/2 mice. Objective: To clarify possible mechanisms for neurodegeneration, which improves the understanding the aging process. This study focuses on clarifying neurodegenerative mechanisms and searching potential therapeutic targets in HD patients. Methods: The oxidative stress and apoptosis were compared in the brain tissue between R6/2 HD mice with and without oral B401 treatment. Expressions of proteins for oxidative stress and apoptosis in the brain tissue of R6/2 HD mice were examined by using immunostaining and Western blotting techniques. Results: R6/2 HD mice with oral B401 treatment significantly reduced reactive oxygen species levels in the blood, but markedly increased expressions of superoxide dismutase 2 in the brain tissue. Furthermore, R6/2 HD mice with oral B401 treatment significantly increased expressions of B-cell lymphoma 2 (Bcl-2, but significantly reduced expressions of Bcl-2-associated X protein (Bax, calpain, and caspase-3 in the brain tissue. Conclusion: Our findings provide evidence that the herbal formula B401 can remedy for aging-dependent neurodegeneration of R6/2 mice via suppressing oxidative stress and apoptosis in the brain. We suggest that the herbal formula B401 can be developed as a potential health supplement for ameliorating aging

  9. Myristoylation negative msbB-mutants of probiotic E. coli Nissle 1917 retain tumor specific colonization properties but show less side effects in immunocompetent mice

    OpenAIRE

    Stritzker, Jochen; Hill, Philip J.; Gentschev, Ivaylo; Szalay, Aladar A.

    2009-01-01

    Specific colonization of solid tumors by bacteria opens the way to novel approaches in both tumor diagnosis and therapy. However, even non-pathogenic bacteria induce responses by the immune system, which could be devastating for a tumor bearing patient. As such effects are caused e.g., by the lipid A moiety of the lipopolysaccharide, a msbB-mutant of the probiotic E. coli Nissle 1917 strain was investigated. Bacteria of the mutant strain did not show any growth defects in culture media when c...

  10. Impact of sex, MHC, and age of recipients on the therapeutic effect of transferred leukocytes from cancer-resistant SR/CR mice

    Directory of Open Access Journals (Sweden)

    Adams Jonathan M

    2009-09-01

    Full Text Available Abstract Background Spontaneous Regression/Complete Resistant (SR/CR mice are resistant to cancer through a mechanism that is mediated entirely by leukocytes of innate immunity. Transfer of leukocytes from SR/CR mice can confer cancer resistance in wild-type (WT recipients in both preventative and therapeutic settings. In the current studies, we investigated factors that may impact the efficacy and functionality of SR/CR donor leukocytes in recipients. Results In sex-mismatched transfers, functionality of female donor leukocytes was not affected in male recipients. In contrast, male donor leukocytes were greatly affected in the female recipients. In MHC-mismatches, recipients of different MHC backgrounds, or mice of different strains, showed a greater negative impact on donor leukocytes than sex-mismatches. The negative effects of sex-mismatch and MHC-mismatch on donor leukocytes were additive. Old donor leukocytes performed worse than young donor leukocytes in all settings including in young recipients. Young recipients were not able to revive the declining function of old donor leukocytes. However, the function of young donor leukocytes declined gradually in old recipients, suggesting that an aged environment may contain factors that are deleterious to cellular functions. The irradiation of donor leukocytes prior to transfers had a profound suppressive effect on donor leukocyte functions, possibly as a result of impaired transcription. The cryopreserving of donor leukocytes in liquid nitrogen had no apparent effect on donor leukocyte functions, except for a small loss of cell number after revival from freezing. Conclusion Despite the functional suppression of donor leukocytes in sex- and MHC-mismatched recipients, as well as old recipients, there was a therapeutic time period during the initial few weeks during which donor leukocytes were functional before their eventual rejection or functional decline. The eventual rejection of donor

  11. A novel recombinant 6Aβ15-THc-C chimeric vaccine (rCV02) mitigates Alzheimer’s disease-like pathology, cognitive decline and synaptic loss in aged 3 × Tg-AD mice

    Science.gov (United States)

    Yu, Yun-Zhou; Liu, Si; Wang, Hai-Chao; Shi, Dan-Yang; Xu, Qing; Zhou, Xiao-Wei; Sun, Zhi-Wei; Huang, Pei-Tang

    2016-01-01

    Alzheimer’s disease (AD) is a neurodegenerative disorder that impairs memory and cognition. Targeting amyloid-β (Aβ) may be currently the most promising immunotherapeutic strategy for AD. In this study, a recombinant chimeric 6Aβ15-THc-C immunogen was formulated with alum adjuvant as a novel Aβ B-cell epitope candidate vaccine (rCV02) for AD. We examined its efficacy in preventing the cognitive deficit and synaptic impairment in 3 × Tg-AD mice. Using a toxin-derived carrier protein, the rCV02 vaccine elicited robust Aβ-specific antibodies that markedly reduced AD-like pathology and improved behavioral performance in 3 × Tg-AD mice. Along with the behavioral improvement in aged 3 × Tg-AD mice, rCV02 significantly decreased calpain activation concurrent with reduced soluble Aβ or oligomeric forms of Aβ, probably by preventing dynamin 1 and PSD-95 degradation. Our data support the hypothesis that reducing Aβ levels in rCV02-immunized AD mice increases the levels of presynaptic dynamin 1 and postsynaptic PSD-95 allowing functional recovery of cognition. In conclusion, this novel and highly immunogenic rCV02 shows promise as a new candidate prophylactic vaccine for AD and may be useful for generating rapid and strong Aβ-specific antibodies in AD patients with pre-existing memory Th cells generated after immunization with conventional tetanus toxoid vaccine. PMID:27255752

  12. A novel recombinant 6Aβ15-THc-C chimeric vaccine (rCV02) mitigates Alzheimer's disease-like pathology, cognitive decline and synaptic loss in aged 3 × Tg-AD mice.

    Science.gov (United States)

    Yu, Yun-Zhou; Liu, Si; Wang, Hai-Chao; Shi, Dan-Yang; Xu, Qing; Zhou, Xiao-Wei; Sun, Zhi-Wei; Huang, Pei-Tang

    2016-01-01

    Alzheimer's disease (AD) is a neurodegenerative disorder that impairs memory and cognition. Targeting amyloid-β (Aβ) may be currently the most promising immunotherapeutic strategy for AD. In this study, a recombinant chimeric 6Aβ15-THc-C immunogen was formulated with alum adjuvant as a novel Aβ B-cell epitope candidate vaccine (rCV02) for AD. We examined its efficacy in preventing the cognitive deficit and synaptic impairment in 3 × Tg-AD mice. Using a toxin-derived carrier protein, the rCV02 vaccine elicited robust Aβ-specific antibodies that markedly reduced AD-like pathology and improved behavioral performance in 3 × Tg-AD mice. Along with the behavioral improvement in aged 3 × Tg-AD mice, rCV02 significantly decreased calpain activation concurrent with reduced soluble Aβ or oligomeric forms of Aβ, probably by preventing dynamin 1 and PSD-95 degradation. Our data support the hypothesis that reducing Aβ levels in rCV02-immunized AD mice increases the levels of presynaptic dynamin 1 and postsynaptic PSD-95 allowing functional recovery of cognition. In conclusion, this novel and highly immunogenic rCV02 shows promise as a new candidate prophylactic vaccine for AD and may be useful for generating rapid and strong Aβ-specific antibodies in AD patients with pre-existing memory Th cells generated after immunization with conventional tetanus toxoid vaccine. PMID:27255752

  13. Mouse ECG findings in aging, with conduction system affecting drugs and in cardiac pathologies: Development and validation of ECG analysis algorithm in mice.

    Science.gov (United States)

    Merentie, Mari; Lipponen, Jukka A; Hedman, Marja; Hedman, Antti; Hartikainen, Juha; Huusko, Jenni; Lottonen-Raikaslehto, Line; Parviainen, Viktor; Laidinen, Svetlana; Karjalainen, Pasi A; Ylä-Herttuala, Seppo

    2015-12-01

    Mouse models are extremely important in studying cardiac pathologies and related electrophysiology, but very few mouse ECG analysis programs are readily available. Therefore, a mouse ECG analysis algorithm was developed and validated. Surface ECG (lead II) was acquired during transthoracic echocardiography from C57Bl/6J mice under isoflurane anesthesia. The effect of aging was studied in young (2-3 months), middle-aged (14 months) and old (20-24 months) mice. The ECG changes associated with pharmacological interventions and common cardiac pathologies, that is, acute myocardial infarction (AMI) and progressive left ventricular hypertrophy (LVH), were studied. The ECG raw data were analyzed with an in-house ECG analysis program, modified specially for mouse ECG. Aging led to increases in P-wave duration, atrioventricular conduction time (PQ interval), and intraventricular conduction time (QRS complex width), while the R-wave amplitude decreased. In addition, the prevalence of arrhythmias increased during aging. Anticholinergic atropine shortened PQ time, and beta blocker metoprolol and calcium-channel blocker verapamil increased PQ interval and decreased heart rate. The ECG changes after AMI included early JT elevation, development of Q waves, decreased R-wave amplitude, and later changes in JT/T segment. In progressive LVH model, QRS complex width was increased at 2 and especially 4 weeks timepoint, and also repolarization abnormalities were seen. Aging, drugs, AMI, and LVH led to similar ECG changes in mice as seen in humans, which could be reliably detected with this new algorithm. The developed method will be very useful for studies on cardiovascular diseases in mice. PMID:26660552

  14. Cardiac structure and function during ageing in energetically compromised Guanidinoacetate N-methyltransferase (GAMT-knockout mice – a one year longitudinal MRI study

    Directory of Open Access Journals (Sweden)

    Clarke Kieran

    2008-02-01

    Full Text Available Abstract Background High-resolution magnetic resonance imaging (cine-MRI is well suited for determining global cardiac function longitudinally in genetically or surgically manipulated mice, but in practice it is seldom used to its full potential. In this study, male and female guanidinoacetate N-methyltransferase (GAMT knockout, and wild type littermate mice were subjected to a longitudinal cine-MRI study at four time points over the course of one year. GAMT is an essential enzyme in creatine biosynthesis, such that GAMT deficient mice are entirely creatine-free. Since creatine plays an important role in the buffering and transfer of high-energy phosphate bonds in the heart, it was hypothesized that lack of creatine would be detrimental for resting cardiac performance during ageing. Methods Measurements of cardiac structure (left ventricular mass and volumes and function (ejection fraction, stroke volume, cardiac output were obtained using high-resolution cine-MRI at 9.4 T under isoflurane anaesthesia. Results There were no physiologically significant differences in cardiac function between wild type and GAMT knockout mice at any time point for male or female groups, or for both combined (for example ejection fraction: 6 weeks (KO vs. WT: 70 ± 6% vs. 65 ± 7%; 4 months: 70 ± 6% vs. 62 ± 8%; 8 months: 62 ± 11% vs. 62 ± 6%; 12 months: 61 ± 7% vs. 59 ± 11%, respectively. Conclusion These findings suggest the presence of comprehensive adaptations in the knockout mice that can compensate for a lack of creatine. Furthermore, this study clearly demonstrates the power of cine-MRI for accurate non-invasive, serial cardiac measurements. Cardiac growth curves could easily be defined for each group, in the same set of animals for all time points, providing improved statistical power, and substantially reducing the number of mice required to conduct such a study. This technique should be eminently useful for following changes of cardiac structure and

  15. Rejection of large HPV-16 expressing tumors in aged mice by a single immunization of VacciMax® encapsulated CTL/T helper peptides

    Directory of Open Access Journals (Sweden)

    MacDonald Lisa

    2007-06-01

    Full Text Available Abstract The incidence of cancer increases significantly in later life, yet few pre-clinical studies of cancer immunotherapy use mice of advanced age. A novel vaccine delivery platform (VacciMax®,VM is described that encapsulates antigens and adjuvants in multilamellar liposomes in a water-in-oil emulsion. The therapeutic potential of VM-based vaccines administered as a single dose was tested in HLA-A2 transgenic mice of advanced age (48–58 weeks old bearing large palpable TC1/A2 tumors. The VM-based vaccines contained one or more peptides having human CTL epitopes derived from HPV 16 E6 and E7. VM formulations contained a single peptide, a mixture of four peptides or the same four peptides linked together in a single long peptide. All VM formulations contained PADRE and CpG as adjuvants and ISA51 as the hydrophobic component of the water-in-oil emulsion. VM-formulated vaccines containing the four peptides as a mixture or linked together in one long peptide eradicated 19-day old established tumors within 21 days of immunization. Peptide-specific cytotoxic cellular responses were confirmed by ELISPOT and intracellular staining for IFN-γ producing CD8+ T cells. Mice rendered tumor-free by vaccination were re-challenged in the opposite flank with 10 million HLF-16 tumor cells, another HLA-A2/E6/E7 expressing tumor cell line. None of these mice developed tumors following the re-challenge. In summary, this report describes a VM-formulated therapeutic vaccine with the following unprecedented outcome: a eradication of large tumors (> 700 mm3 b in mice of advanced age c in less than three weeks post-immunization d following a single vaccination.

  16. Aging.

    Science.gov (United States)

    Park, Dong Choon; Yeo, Seung Geun

    2013-09-01

    Aging is initiated based on genetic and environmental factors that operate from the time of birth of organisms. Aging induces physiological phenomena such as reduction of cell counts, deterioration of tissue proteins, tissue atrophy, a decrease of the metabolic rate, reduction of body fluids, and calcium metabolism abnormalities, with final progression onto pathological aging. Despite the efforts from many researchers, the progression and the mechanisms of aging are not clearly understood yet. Therefore, the authors would like to introduce several theories which have gained attentions among the published theories up to date; genetic program theory, wear-and-tear theory, telomere theory, endocrine theory, DNA damage hypothesis, error catastrophe theory, the rate of living theory, mitochondrial theory, and free radical theory. Although there have been many studies that have tried to prevent aging and prolong life, here we introduce a couple of theories which have been proven more or less; food, exercise, and diet restriction. PMID:24653904

  17. Genetic variants in three genes and smoking show strong associations with susceptibility to exudative age-related macular degeneration in a Chinese population

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Background The present study was undertaken to replicate the associations of representative polymorphisms in three genes (complement factor H (CFH), complement factor B (BF) and HtrA serine peptidase 1 (HTRA1)) with exudative age-related macular degeneration (AMD) in a Hart Chinese population, and to test if the modifiable environmental factors affect AMD susceptibility associated with different type of genotype in these genes. Methods An age, gender and ethnicity matched case-control study was conducted to genotype the representative single neucleotide polymorphisms (SNPs) loci including rs1061170 and rs1410996 in CFH, rs641153 and rs4151667 in BF and rs11200638 in HTRA1 gene in 144 exudative AMD patients and 126 normal controls using PCR-RFLP and directresequencing. The demographic characteristics and behavioral risk factors were also recorded. Allelic and genotypic associations for individual SNP and joint associations with two loci were performed. The gene-gene and gene-environment interactions were analyzed using multivariate non-conditional Logistic regression analysis. Results The C risk allele frequencies for CFH Y402H (rs1061170) in cases and controls were 12.5% and 5.4% respectively, which were much lower than those in Caucasians (P<0.001). Compared with TT homozygous genotype, the CT heterozygous genotype was positively associated with AMD with odds ratio (OR) of 3.23 (1.36-5.07). However, the population attributable risk (PAR) of C allele was only 3.3% (1.4%-4.3%). rs1410996 was also associated with AMD independent of Y402H. The ORs of exudative AMD for individuals carrying one copy risk allele and two copy risk alleles were 2.57 (1.21-5.45) and 4.76 (2.15-10.55) respectively, with correspondent PARs of 28.3% (2.0%-40.5%) and 38.2% (21.8%-45.4%). rs11200638 in HTRA1 was another susceptible locus for AMD and the risk homozygotes were significantly susceptible for exudutive AMD (OR=3.98, 1.88-8.43) with PAR of 38.9% (24.3%-45.8%). Education status and

  18. Effects of Shenlong Decoction on Learning and Memory Abilities as well as SOD and MDA in Brain-aging Model Mice Induced by D-Galactose

    Institute of Scientific and Technical Information of China (English)

    Liu Yi; Wang Fawei; Yang Minghui; Zheng Qingping; Wang Youjing

    2006-01-01

    @@ Brain aging (dementia) model mice were made by cervical subcutaneous injection of D-galactose solution.Learning and memory abilities were detected with water maze test and superoxide dismulase(SOD)activities and malondiadehyde (MDA) contents in the liver and brain were determined after intragastrical administration of Shenlong Decoction (参龙汤) for 6 weeks. The results indicated that the swimming time was shortened and the correct swimming times increased, SOD activity raised and MDA content decreased in the three Shenlong Decoction groups with different doses as compared with the model group. It is concluded that Shenlong Decoction has the effects of anti-free radical injuries and improving the learning and memory abilities of the brain-aging mice induced by D-galactose.

  19. Sideritis spp. Extracts Enhance Memory and Learning in Alzheimer’s β-Amyloidosis Mouse Models and Aged C57Bl/6 Mice

    Science.gov (United States)

    Hofrichter, Jacqueline; Krohn, Markus; Schumacher, Toni; Lange, Cathleen; Feistel, Bjöorn; Walbroel, Bernd; Pahnke, Jens

    2016-01-01

    Nowadays, Alzheimer’s disease is the most prevalent epiphenomenon of the aging population. Although soluble amyloid-β (Aβ) species (monomers, oligomers) are recognized triggers of the disease, no therapeutic approach is able to stop it. Herbal medicines are used to treat different diseases in many regions of the world. On the Balkan Peninsula, at the eastern Mediterranean Sea, and adjacent regions, Sideritis species are used as traditional medicine to prevent age</