Nuclear plant aging research program

International Nuclear Information System (INIS)

Eissenberg, D.M.

1987-01-01

The U.S. Nuclear Regulatory Commission, Office of Nuclear Regulatory Research, has established the Nuclear Plant Aging Research (NPAR) program in its Division of Engineering Technology. Principal contractors for this program include Oak Ridge National Laboratory, Brookhaven National Laboratory, Idaho National Engineering Laboratory, and Pacific Northwest Laboratory. The program goals are: to identify and characterize time-dependent degradation (aging) of nuclear plant safety-related electrical and mechanical components which could lead to loss of safety function; to identify and recommend methods for detecting and trending aging effects prior to loss of safety function so that timely maintenance can be implemented; and to recommend maintenance practices for mitigating the effects of aging. Research activities include prioritization of system and component aging in nuclear plants, characterization of aging degradation of specific components including identification of functional indicators useful for trending degradation, and testing of practical methods and devices for measuring the functional indicators. Aging assessments have been completed on electric motors, snubbers, motor-operated valves, and check valves. Testing of trending methods and devices for motor-operated valves and check valves is in progress

Increase in Red Blood Cell-Nitric Oxide Synthase Dependent Nitric Oxide Production during Red Blood Cell Aging in Health and Disease: A Study on Age Dependent Changes of Rheologic and Enzymatic Properties in Red Blood Cells

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Bizjak, Daniel Alexander; Brinkmann, Christian; Bloch, Wilhelm; Grau, Marijke

2015-01-01

Aim To investigate RBC-NOS dependent NO signaling during in vivo RBC aging in health and disease. Method RBC from fifteen healthy volunteers (HC) and four patients with type 2 diabetes mellitus (DM) were separated in seven subpopulations by Percoll density gradient centrifugation. Results The proportion of old RBC was significantly higher in DM compared to HC. In both groups, in vivo aging was marked by changes in RBC shape and decreased cell volume. RBC nitrite, as marker for NO, was higher in DM and increased in both HC and DM during aging. RBC deformability was lower in DM and significantly decreased in old compared to young RBC in both HC and DM. RBC-NOS Serine1177 phosphorylation, indicating enzyme activation, increased during aging in both HC and DM. Arginase I activity remained unchanged during aging in HC. In DM, arginase I activity was significantly higher in young RBC compared to HC but decreased during aging. In HC, concentration of L-arginine, the substrate of RBC-NOS and arginase I, significantly dropped from young to old RBC. In DM, L-arginine concentration was significantly higher in young RBC compared to HC and significantly decreased during aging. In blood from healthy subjects, RBC-NOS activation was additionally inhibited by N5-(1-iminoethyl)-L-Ornithine dihydrochloride which decreased RBC nitrite, and impaired RBC deformability of all but the oldest RBC subpopulation. Conclusion This study first-time showed highest RBC-NOS activation and NO production in old RBC, possibly to counteract the negative impact of cell shrinkage on RBC deformability. This was even more pronounced in DM. It is further suggested that highly produced NO only insufficiently affects cell function of old RBC maybe because of isolated RBC-NOS in old RBC thus decreasing NO bioavailability. Thus, increasing NO availability may improve RBC function and may extend cell life span in old RBC. PMID:25902315

Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition.

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Blagosklonny, Mikhail V

2006-09-01

While ruling out programmed aging, evolutionary theory predicts a quasi-program for aging, a continuation of the developmental program that is not turned off, is constantly on, becoming hyper-functional and damaging, causing diseases of aging. Could it be switched off pharmacologically? This would require identification of a molecular target involved in cell senescence, organism aging and diseases of aging. Notably, cell senescence is associated with activation of the TOR (target of rapamycin) nutrient- and mitogen-sensing pathway, which promotes cell growth, even though cell cycle is blocked. Is TOR involved in organism aging? In fact, in yeast (where the cell is the organism), caloric restriction, rapamycin and mutations that inhibit TOR all slow down aging. In animals from worms to mammals caloric restrictions, life-extending agents, and numerous mutations that increase longevity all converge on the TOR pathway. And, in humans, cell hypertrophy, hyper-function and hyperplasia, typically associated with activation of TOR, contribute to diseases of aging. Theoretical and clinical considerations suggest that rapamycin may be effective against atherosclerosis, hypertension and hyper-coagulation (thus, preventing myocardial infarction and stroke), osteoporosis, cancer, autoimmune diseases and arthritis, obesity, diabetes, macula-degeneration, Alzheimer's and Parkinson's diseases. Finally, I discuss that extended life span will reveal new causes for aging (e.g., ROS, 'wear and tear', Hayflick limit, stem cell exhaustion) that play a limited role now, when quasi-programmed senescence kills us first.

Bistable Epigenetic States Explain Age-Dependent Decline in Mesenchymal Stem Cell Heterogeneity.

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Hamidouche, Zahia; Rother, Karen; Przybilla, Jens; Krinner, Axel; Clay, Denis; Hopp, Lydia; Fabian, Claire; Stolzing, Alexandra; Binder, Hans; Charbord, Pierre; Galle, Joerg

2017-03-01

The molecular mechanisms by which heterogeneity, a major characteristic of stem cells, is achieved are yet unclear. We here study the expression of the membrane stem cell antigen-1 (Sca-1) in mouse bone marrow mesenchymal stem cell (MSC) clones. We show that subpopulations with varying Sca-1 expression profiles regenerate the Sca-1 profile of the mother population within a few days. However, after extensive replication in vitro, the expression profiles shift to lower values and the regeneration time increases. Study of the promoter of Ly6a unravels that the expression level of Sca-1 is related to the promoter occupancy by the activating histone mark H3K4me3. We demonstrate that these findings can be consistently explained by a computational model that considers positive feedback between promoter H3K4me3 modification and gene transcription. This feedback implicates bistable epigenetic states which the cells occupy with an age-dependent frequency due to persistent histone (de-)modification. Our results provide evidence that MSC heterogeneity, and presumably that of other stem cells, is associated with bistable epigenetic states and suggest that MSCs are subject to permanent state fluctuations. Stem Cells 2017;35:694-704. © The Authors Stem Cells published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Ursodeoxycholic acid suppresses mitochondria-dependent programmed cell death induced by sodium nitroprusside in SH-SY5Y cells

International Nuclear Information System (INIS)

Chun, Hong Sung; Low, Walter C.

2012-01-01

Although ursodeoxycholic acid (UDCA) and its highly water-soluble formula (Yoo's solution; YS) have been shown to prevent neuronal damage, the effects of UDCA or YS against Parkinson's disease (PD)-related dopaminergic cell death has not been studied. This study investigated the protective effects of UDCA and YS on sodium nitroprusside (SNP)-induced cytotoxicity in human dopaminergic SH-SY5Y cells. Both UDCA (50–200 μM) and YS (100–200 μM) dose-dependently prevented SNP (1 mM)-induced cell death. Results showed that both UDCA and YS effectively attenuated the production of total reactive oxygen species (ROS), peroxynitrite (ONOO − ) and nitric oxide (NO), and markedly inhibited the mitochondrial membrane potential (MMP) loss and intracellular reduced glutathione (GSH) depletion. SNP-induced programmed cell death events, such as nuclear fragmentation, caspase-3/7 and -9 activation, Bcl-2/Bax ratio decrease, and cytochrome c release, were significantly attenuated by both UDCA and YS. Furthermore, selective inhibitor of phosphatidylinositiol-3-kinase (PI3K), LY294002, and Akt/PKB inhibitor, triciribine, reversed the preventive effects of UDCA on the SNP-induced cytotoxicity and Bax translocation. These results suggest that UDCA can protect SH-SY5Y cells under programmed cell death process by regulating PI3K-Akt/PKB pathways.

Derivation of Pluripotent Cells from Mouse SSCs Seems to Be Age Dependent

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Hossein Azizi

2016-01-01

Full Text Available Here, we aimed to answer important and fundamental questions in germ cell biology with special focus on the age of the male donor cells and the possibility to generate embryonic stem cell- (ESC- like cells. While it is believed that spermatogonial stem cells (SSCs and truly pluripotent ESC-like cells can be isolated from adult mice, it remained unknown if the spontaneous conversion of SSCs to ESC-like cells fails at some age. Similarly, there have been differences in the literature about the duration of cultures during which ESC-like cells may appear. We demonstrate the possibility to derive ESC-like cells from SSC cultures until they reach adolescence or up to 7 weeks of age, but we point out the impossibility to derive these cells from older, mature adult mice. The inability of real adult SSCs to shift to a pluripotent state coincides with a decline in expression of the core pluripotency genes Oct4, Nanog, and Sox2 in SSCs with age. At the same time genes of the spermatogonial differentiation pathway increase. The generated ESC-like cells were similar to ESCs and express pluripotency markers. In vitro they differentiate into all three germ lineages; they form complex teratomas after transplantation in SCID mice and produce chimeric mice.

Antecedents of cell aging research.

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Hayflick, L

1989-01-01

Our observation that normal human and animal cells have a limited capacity to divide and function in vitro overturned a dogma held since the turn of the century. The dogma held that cultured normal cells are immortal and gerontologists interpreted this to mean that aging, therefore, could not be the result of intracellular events. We concluded that longevity and aging do result from intracellular events, and, in the subsequent 30 years, the validity of our finding has been widely confirmed. Other major findings have been made: (a) The number of population doublings and functional events that a cultured normal cell can undergo is inversely proportional to donor age and, probably, directly proportional to species longevity; (b) the limit on cell division and function also occurs in vivo when normal cells are transplanted seriatim; (c) as cell doublings or functional events reach their limit, changes occur in hundreds of variables from the molecular to the whole cell. Most importantly, many of these changes are identical to those seen in intact humans and animals as they age; (d) WI-38, the first widely distributed normal human cell strain has retained its memory of population doubling level during 27 years of cryogenic storage. This is the longest time that any normal human cell has ever been preserved. Evidence that longevity is determined by genetic events is overwhelming but evidence that age changes are the result of gene expression is not. Normal age changes must be distinguished from disease. Because few feral animals ever become old, natural selection could not have favored the development of a genetically programmed aging process. In the 2 or 3 million years of human existence, too few old humans existed to have provided a selective advantage favoring the development of a genetic program that would determine age changes. The selective advantage of maintaining physiological vigor for as long as possible in order to insure maximum reproductive success may be

Selective deletion of cochlear hair cells causes rapid age-dependent changes in spiral ganglion and cochlear nucleus neurons.

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Tong, Ling; Strong, Melissa K; Kaur, Tejbeer; Juiz, Jose M; Oesterle, Elizabeth C; Hume, Clifford; Warchol, Mark E; Palmiter, Richard D; Rubel, Edwin W

2015-05-20

During nervous system development, critical periods are usually defined as early periods during which manipulations dramatically change neuronal structure or function, whereas the same manipulations in mature animals have little or no effect on the same property. Neurons in the ventral cochlear nucleus (CN) are dependent on excitatory afferent input for survival during a critical period of development. Cochlear removal in young mammals and birds results in rapid death of target neurons in the CN. Cochlear removal in older animals results in little or no neuron death. However, the extent to which hair-cell-specific afferent activity prevents neuronal death in the neonatal brain is unknown. We further explore this phenomenon using a new mouse model that allows temporal control of cochlear hair cell deletion. Hair cells express the human diphtheria toxin (DT) receptor behind the Pou4f3 promoter. Injections of DT resulted in nearly complete loss of organ of Corti hair cells within 1 week of injection regardless of the age of injection. Injection of DT did not influence surrounding supporting cells directly in the sensory epithelium or spiral ganglion neurons (SGNs). Loss of hair cells in neonates resulted in rapid and profound neuronal loss in the ventral CN, but not when hair cells were eliminated at a more mature age. In addition, normal survival of SGNs was dependent on hair cell integrity early in development and less so in mature animals. This defines a previously undocumented critical period for SGN survival. Copyright © 2015 the authors 0270-6474/15/357878-14$15.00/0.

Adult Stem Cells and Diseases of Aging

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Lisa B. Boyette

2014-01-01

Full Text Available Preservation of adult stem cells pools is critical for maintaining tissue homeostasis into old age. Exhaustion of adult stem cell pools as a result of deranged metabolic signaling, premature senescence as a response to oncogenic insults to the somatic genome, and other causes contribute to tissue degeneration with age. Both progeria, an extreme example of early-onset aging, and heritable longevity have provided avenues to study regulation of the aging program and its impact on adult stem cell compartments. In this review, we discuss recent findings concerning the effects of aging on stem cells, contributions of stem cells to age-related pathologies, examples of signaling pathways at work in these processes, and lessons about cellular aging gleaned from the development and refinement of cellular reprogramming technologies. We highlight emerging therapeutic approaches to manipulation of key signaling pathways corrupting or exhausting adult stem cells, as well as other approaches targeted at maintaining robust stem cell pools to extend not only lifespan but healthspan.

Modulation of NADP(+)-dependent isocitrate dehydrogenase in aging.

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Kil, In Sup; Lee, Young Sup; Bae, Young Seuk; Huh, Tae Lin; Park, Jeen-Woo

2004-01-01

NADPH is an important cofactor in many biosynthesis pathways and the regeneration of reduced glutathione, critically important in cellular defense against oxidative damage. It is mainly produced by glucose-6-phosphate dehydrogenase, malic enzyme, and NADP(+)-specific isocitrate dehydrogenases (ICDHs). Here, we investigated age-related changes in ICDH activity and protein expression in IMR-90 human diploid fibroblast cells and tissues from Fischer 344 rats. We found that in IMR-90 cells the activity of cytosolic ICDH (IDPc) gradually increased with age up to the 46-48 population doubling level (PDL) and then gradually decreased at later PDL. 2',7'-Dichloro-fluorescein fluorescence which reflects intracellular ROS generation was increased with aging in IMR-90 cells. In ad libitum-fed rats, we noted age-related, tissue-specific modulations of IDPc and mitochondrial ICDH (IDPm) activities and protein expression in the liver, kidney and testes. In contrast, ICDH activities and protein expression were not significantly modulated in diet-restricted rats. These data suggest that modulation of ICDH is an age-dependent and a tissue-specific phenomenon.

Aging-induced dysregulation of dicer1-dependent microRNA expression impairs angiogenic capacity of rat cerebromicrovascular endothelial cells.

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Ungvari, Zoltan; Tucsek, Zsuzsanna; Sosnowska, Danuta; Toth, Peter; Gautam, Tripti; Podlutsky, Andrej; Csiszar, Agnes; Losonczy, Gyorgy; Valcarcel-Ares, M Noa; Sonntag, William E; Csiszar, Anna

2013-08-01

Age-related impairment of angiogenesis is likely to play a central role in cerebromicrovascular rarefaction and development of vascular cognitive impairment, but the underlying mechanisms remain elusive. To test the hypothesis that dysregulation of Dicer1 (ribonuclease III, a key enzyme of the microRNA [miRNA] machinery) impairs endothelial angiogenic capacity in aging, primary cerebromicrovascular endothelial cells (CMVECs) were isolated from young (3 months old) and aged (24 months old) Fischer 344 × Brown Norway rats. We found an age-related downregulation of Dicer1 expression both in CMVECs and in small cerebral vessels isolated from aged rats. In aged CMVECs, Dicer1 expression was increased by treatment with polyethylene glycol-catalase. Compared with young cells, aged CMVECs exhibited altered miRNA expression profile, which was associated with impaired proliferation, adhesion to vitronectin, collagen and fibronectin, cellular migration (measured by a wound-healing assay using electric cell-substrate impedance sensing technology), and impaired ability to form capillary-like structures. Overexpression of Dicer1 in aged CMVECs partially restored miRNA expression profile and significantly improved angiogenic processes. In young CMVECs, downregulation of Dicer1 (siRNA) resulted in altered miRNA expression profile associated with impaired proliferation, adhesion, migration, and tube formation, mimicking the aging phenotype. Collectively, we found that Dicer1 is essential for normal endothelial angiogenic processes, suggesting that age-related dysregulation of Dicer1-dependent miRNA expression may be a potential mechanism underlying impaired angiogenesis and cerebromicrovascular rarefaction in aging.

[What will happen to molecular cell biomarkers of aging in case we cancel its program (of course, if it does exist)?].

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Khokhlov, A N

2013-01-01

Currently, gerontologists, evaluating the effectiveness of various impacts on the aging process, as a rule, use a variety of molecular cell biomarkers of aging. This provides much more rapid results than in the case of the survival curve obtaining. However, in many cases the usefulness of these biomarkers of aging is grounded in works devoted to what is called cellular/cell senescence. Unfortunately, the evolution of the term in recent years has led to the loss, to a large extent, of its original meaning, that is the changes of the cells during their replicative senescence ("on Hayflick's grounds"), similar to the changes of cells in the aging organism. At present, most of the work in this area is related to the induction of the relevant changes in the cells (usually transformed) by various DNA damaging factors. Such an approach, although is very important to define a strategy to fight cancer, but, yet again, takes us away from the study of the real mechanisms of organismal aging. In addition, there are reasons to believe that the biomarkers of aging, proposed by these studies (and in particular, the most popular of them--the activity of senescence-associated beta-galactosidase), are related, as a rule, to the proliferative status of the cells, which in the whole body is generally determined by proper implementing the program of development and differentiation, leading to the emergence of tissues and organs composed of postmitotic or very slowly proliferating cells. Therefore, the possible disabling the aging program, apparently, will not lead to any changes in the age dynamics of those biomarkers of aging. This conclusion brings us back to the need for obtaining the survival curves of experimental animals or humans as the only true (although the most time- and money-consuming) approach to evaluating the effectiveness of the modification of the aging process.

Stem cell aging: mechanisms, regulators and therapeutic opportunities

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Oh, Juhyun; Lee, Yang David; Wagers, Amy J

2014-01-01

Aging tissues experience a progressive decline in homeostatic and regenerative capacities, which has been attributed to degenerative changes in tissue-specific stem cells, stem cell niches and systemic cues that regulate stem cell activity. Understanding the molecular pathways involved in this age-dependent deterioration of stem cell function will be critical for developing new therapies for diseases of aging that target the specific causes of age-related functional decline. Here we explore key molecular pathways that are commonly perturbed as tissues and stem cells age and degenerate. We further consider experimental evidence both supporting and refuting the notion that modulation of these pathways per se can reverse aging phenotypes. Finally, we ask whether stem cell aging establishes an epigenetic ‘memory’ that is indelibly written or one that can be reset. PMID:25100532

Age dependence of radiosensitivity of hemopoietic stem cells in rats

International Nuclear Information System (INIS)

Vacek, A.; Bartonickova, A.; Rotkovska, D.

1982-01-01

Within one week to 120 days of life the number of pluripotent hemopoietic stem cells in the femur increased 50-fold while in the spleen CFU dropped almost 6-fold. In adult mice hemopoiesis prevails in the bone marrow in early age, after birth it is significant in the spleen. The radioresistance of hemopoietic stem cells in adult mice is higher than in young. (M.D.)

Studies on the age-dependent proliferation kinetics of the epithelium of the rat small intestine

International Nuclear Information System (INIS)

Kranz, D.; Dietze, F.; Laue, R.; Fuhrmann, I.

1980-01-01

The small intestine of 244 Wistar rats, aged 6 days, 6 weeks, 6, 12, 23, and 28 months, respectively. were investigated autoradiographically as to their age-dependent cell proliferation kinetics of the mucosal epithelial cells. There were age-dependent differences concerning the hourly regeneration ratio of the crypt cells and the migration velocity of the enterocytes. Both parameters became greater while the existing non growth fraction became smaller with increasing age. The non growth fraction seems to be a reserve being involved into the proliferating pool if required

Cellular Mechanisms of Somatic Stem Cell Aging

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Jung, Yunjoon

2014-01-01

Tissue homeostasis and regenerative capacity rely on rare populations of somatic stem cells endowed with the potential to self-renew and differentiate. During aging, many tissues show a decline in regenerative potential coupled with a loss of stem cell function. Cells including somatic stem cells have evolved a series of checks and balances to sense and repair cellular damage to maximize tissue function. However, during aging the mechanisms that protect normal cell function begin to fail. In this review, we will discuss how common cellular mechanisms that maintain tissue fidelity and organismal lifespan impact somatic stem cell function. We will highlight context-dependent changes and commonalities that define aging, by focusing on three age-sensitive stem cell compartments: blood, neural, and muscle. Understanding the interaction between extrinsic regulators and intrinsic effectors that operate within different stem cell compartments is likely to have important implications for identifying strategies to improve health span and treat age-related degenerative diseases. PMID:24439814

GH mediates exercise-dependent activation of SVZ neural precursor cells in aged mice.

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Daniel G Blackmore

Full Text Available Here we demonstrate, both in vivo and in vitro, that growth hormone (GH mediates precursor cell activation in the subventricular zone (SVZ of the aged (12-month-old brain following exercise, and that GH signaling stimulates precursor activation to a similar extent to exercise. Our results reveal that both addition of GH in culture and direct intracerebroventricular infusion of GH stimulate neural precursor cells in the aged brain. In contrast, no increase in neurosphere numbers was observed in GH receptor null animals following exercise. Continuous infusion of a GH antagonist into the lateral ventricle of wild-type animals completely abolished the exercise-induced increase in neural precursor cell number. Given that the aged brain does not recover well after injury, we investigated the direct effect of exercise and GH on neural precursor cell activation following irradiation. This revealed that physical exercise as well as infusion of GH promoted repopulation of neural precursor cells in irradiated aged animals. Conversely, infusion of a GH antagonist during exercise prevented recovery of precursor cells in the SVZ following irradiation.

GH Mediates Exercise-Dependent Activation of SVZ Neural Precursor Cells in Aged Mice

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Blackmore, Daniel G.; Vukovic, Jana; Waters, Michael J.; Bartlett, Perry F.

2012-01-01

Here we demonstrate, both in vivo and in vitro, that growth hormone (GH) mediates precursor cell activation in the subventricular zone (SVZ) of the aged (12-month-old) brain following exercise, and that GH signaling stimulates precursor activation to a similar extent to exercise. Our results reveal that both addition of GH in culture and direct intracerebroventricular infusion of GH stimulate neural precursor cells in the aged brain. In contrast, no increase in neurosphere numbers was observed in GH receptor null animals following exercise. Continuous infusion of a GH antagonist into the lateral ventricle of wild-type animals completely abolished the exercise-induced increase in neural precursor cell number. Given that the aged brain does not recover well after injury, we investigated the direct effect of exercise and GH on neural precursor cell activation following irradiation. This revealed that physical exercise as well as infusion of GH promoted repopulation of neural precursor cells in irradiated aged animals. Conversely, infusion of a GH antagonist during exercise prevented recovery of precursor cells in the SVZ following irradiation. PMID:23209615

Mathematical modelling the age dependence of Epstein-Barr virus associated infectious mononucleosis.

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Huynh, Giao T; Adler, Frederick R

2012-09-01

Most people get Epstein-Barr virus (EBV) infection at young age and are asymptomatic. Primary EBV infection in adolescents and young adults, however, often leads to infectious mononucleosis (IM) with symptoms including fever, fatigue and sore throat that can persist for months. Expansion in the number of CD8(+) T cells, especially against EBV lytic proteins, are the main cause of these symptoms. We propose a mathematical model for the regulation of EBV infection within a host to address the dependence of IM on age. This model tracks the number of virus, infected B cell and epithelial cell and CD8(+) T-cell responses to the infection. We use this model to investigate three hypotheses for the high incidence of IM in teenagers and young adults: saliva and antibody effects that increase with age, high cross-reactive T-cell responses and a high initial viral load. The model supports the first two of these hypotheses and suggests that variation in host antibody responses and the complexity of the pre-existing cross-reactive T-cell repertoire, both of which depend on age, may play important roles in the etiology of IM.

Autoradiographic investigation of age-dependent proliferation kinetics in the mucosa of rat small intestine

International Nuclear Information System (INIS)

Kranz, D.; Laue, R.; Fuhrmann, I.

1980-01-01

Aging of cells depends on mitotic activity which is particularly evident in multicellular organisms. The cell kinetics of the mucosa of the small intestine in a total of 244 Wistar rats aged 6 days, 6 weeks, 6, 12, 23 and 28 months, resp., were studied histoautoradiographically. It could be demonstrated that the regeneration rate of cells per hour in the crypts of the small intestine and the migration velocity of the enterocytes differ in young and old individuals, and that the intermitotic cells have age-dependent properties as well. In addition, it could be proved that intermitotic cells have a non growth fraction, too, which, at an advanced age, decreases only slightly although significantly in terms of statistics. For the easily vulnerable crypt epithelium it is a reserve capacity and ban be included in the proliferating pool if necessary. (author)

Age-dependent reliability model considering effects of maintenance and working conditions

International Nuclear Information System (INIS)

Martorell, Sebastian; Sanchez, Ana; Serradell, Vicente

1999-01-01

Nowadays, there is some doubt about building new nuclear power plants (NPPs). Instead, there is a growing interest in analyzing the possibility to extend current NPP operation, where life management programs play an important role. The evolution of the NPP safety depends on the evolution of the reliability of its safety components, which, in turn, is a function of their age along the NPP operational life. In this paper, a new age-dependent reliability model is presented, which includes parameters related to surveillance and maintenance effectiveness and working conditions of the equipment, both environmental and operational. This model may be used to support NPP life management and life extension programs, by improving or optimizing surveillance and maintenance tasks using risk and cost models based on such an age-dependent reliability model. The results of the sensitivity study in the example application show that the selection of the most appropriate maintenance strategy would directly depend on the previous parameters. Then, very important differences are expected to appear under certain circumstances, particularly, in comparison with other models that do not consider maintenance effectiveness and working conditions simultaneously

Age- and Gene-Dosage–Dependent Cre-Induced Abnormalities in the Retinal Pigment Epithelium

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He, Lizhi; Marioutina, Mariya; Dunaief, Joshua L.; Marneros, Alexander G.

2015-01-01

To conditionally inactivate genes in the retinal pigment epithelium (RPE) transgenic mouse strains have been developed, in which Cre recombinase (Cre) expression is driven by an RPE-specific gene promoter. The RPE is a quiescent epithelium, and continuous expression of Cre could affect its function. Here, we tested the hypothesis that continuous postnatal Cre expression in the RPE may lead to cellular abnormalities, which may depend on both age and Cre gene dosage. We therefore examined the eyes of homozygous and heterozygous VMD2-Cre mice at various ages. In VMD2-Cre heterozygous mice variable progressive age-dependent RPE abnormalities were noticed, including attenuation of phalloidin and cytoplasmic active β-catenin staining, reduced cell size, and loss of the typical honeycomb pattern of RPE morphology in those RPE cells that stained for Cre. These morphological RPE abnormalities were not noticed in Cre-negative RPE cells in VMD2-Cre or age-matched control mice. In addition, an abnormal number and morphology of cell nuclei were noticed in a subset of Cre-expressing RPE cells in aged heterozygous VMD2-Cre mice, whereas more severe nuclear abnormalities were observed already in young homozygous VMD2-Cre mice. Thus, continuous postnatal expression of Cre causes abnormalities in the RPE in an age- and Cre gene dosage-dependent manner, which needs to be considered in the interpretation of gene targeting studies in the RPE. PMID:24854863

The influence of HIV infection on the age dependence of squamous ...

African Journals Online (AJOL)

diminishes with ageing, which may contribute to the age-related increase in cancer incidence. In the present analysis, the age dependence of squamous cell carcinoma of the skin (SCC) in the black African, coloured and white population groups of South. Africa (SA) was examined. The evidence that exposure to sunlight is ...

Involvement of WNT Signaling in the Regulation of Gestational Age-Dependent Umbilical Cord-Derived Mesenchymal Stem Cell Proliferation

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Sota Iwatani

2017-01-01

Full Text Available Mesenchymal stem cells (MSCs are a heterogeneous cell population that is isolated initially from the bone marrow (BM and subsequently almost all tissues including umbilical cord (UC. UC-derived MSCs (UC-MSCs have attracted an increasing attention as a source for cell therapy against various degenerative diseases due to their vigorous proliferation and differentiation. Although the cell proliferation and differentiation of BM-derived MSCs is known to decline with age, the functional difference between preterm and term UC-MSCs is poorly characterized. In the present study, we isolated UC-MSCs from 23 infants delivered at 22–40 weeks of gestation and analyzed their gene expression and cell proliferation. Microarray analysis revealed that global gene expression in preterm UC-MSCs was distinct from term UC-MSCs. WNT signaling impacts on a variety of tissue stem cell proliferation and differentiation, and its pathway genes were enriched in differentially expressed genes between preterm and term UC-MSCs. Cell proliferation of preterm UC-MSCs was significantly enhanced compared to term UC-MSCs and counteracted by WNT signaling inhibitor XAV939. Furthermore, WNT2B expression in UC-MSCs showed a significant negative correlation with gestational age (GA. These results suggest that WNT signaling is involved in the regulation of GA-dependent UC-MSC proliferation.

Involvement of WNT Signaling in the Regulation of Gestational Age-Dependent Umbilical Cord-Derived Mesenchymal Stem Cell Proliferation

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Shono, Akemi; Yoshida, Makiko; Yamana, Keiji; Thwin, Khin Kyae Mon; Kuroda, Jumpei; Kurokawa, Daisuke; Koda, Tsubasa; Nishida, Kosuke; Ikuta, Toshihiko; Mizobuchi, Masami; Taniguchi-Ikeda, Mariko

2017-01-01

Mesenchymal stem cells (MSCs) are a heterogeneous cell population that is isolated initially from the bone marrow (BM) and subsequently almost all tissues including umbilical cord (UC). UC-derived MSCs (UC-MSCs) have attracted an increasing attention as a source for cell therapy against various degenerative diseases due to their vigorous proliferation and differentiation. Although the cell proliferation and differentiation of BM-derived MSCs is known to decline with age, the functional difference between preterm and term UC-MSCs is poorly characterized. In the present study, we isolated UC-MSCs from 23 infants delivered at 22–40 weeks of gestation and analyzed their gene expression and cell proliferation. Microarray analysis revealed that global gene expression in preterm UC-MSCs was distinct from term UC-MSCs. WNT signaling impacts on a variety of tissue stem cell proliferation and differentiation, and its pathway genes were enriched in differentially expressed genes between preterm and term UC-MSCs. Cell proliferation of preterm UC-MSCs was significantly enhanced compared to term UC-MSCs and counteracted by WNT signaling inhibitor XAV939. Furthermore, WNT2B expression in UC-MSCs showed a significant negative correlation with gestational age (GA). These results suggest that WNT signaling is involved in the regulation of GA-dependent UC-MSC proliferation. PMID:29138639

Age-dependent risk-based methodology and its application to prioritization of nuclear power plant components and to maintenance for managing aging using PRAs

International Nuclear Information System (INIS)

Levy, I.S.; Vesely, W.E.

1990-01-01

This paper is based on a study to demonstrate several important ways that the age-dependent risk-based methodology developed by the Nuclear Plant Aging Research (NPAR) Program may be applied to resolving important issues related to the aging of nuclear power plant systems, structures, and components (SSCs). The study was sponsored by the NPAR Program of the Division of Engineering, Office of Nuclear Regulatory Research of the U.S. Nuclear Regulatory Commission (NRC). Initiated on the basis of a Users Need Request, the age-dependent risk-based methodology has been under development by the NPAR Program for several years. In this methodology, the time-dependent change in a component's risk contribution is the product of two factors: (1) the risk importance of the component (e.g., the change in its risk contribution when it is assumed to be totally unavailable to perform its intended safety function) and (2) the change in its unavailability with time. This change in the component's unavailability with time is a function of the component's aging rate and plant inspection and maintenance practices. The methodology permits evaluations of the age-dependent risk contributions from both single- and multiple-components. Principal results and conclusions generated by the methodology demonstrations are discussed

The role of age, gender, mood states and exercise frequency on exercise dependence.

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Costa, Sebastiano; Hausenblas, Heather A; Oliva, Patrizia; Cuzzocrea, Francesca; Larcan, Rosalba

2013-12-01

The purpose of our study was to explore the prevalence, and the role of mood, exercise frequency, age, and gender differences of exercise dependence. Regular exercisers (N = 409) completed a socio-demographic questionnaire, the Exercise Dependence Scale, and the Profile of Mood States. For data analyses, the participants were stratified for sex and age (age ranges = young adults: 18-24 years, adults: 25-44 years, and middle-aged adults: 45-64 years). We found that: (a) 4.4% of the participants were classified as at-risk for exercise dependence; (b) the men and the two younger groups (i.e., young adults and adults) had higher exercise dependence scores; and (c) age, gender, exercise frequency, and mood state were related to exercise dependence. Our results support previous research on the prevalence of exercise dependence and reveal that adulthood may be the critical age for developing exercise dependence. These findings have practical implication for identifying individuals at-risk for exercise dependence symptoms, and may aid in targeting and guiding the implementation of prevention program for adults.

Changes in the Proliferative Program Limit Astrocyte Homeostasis in the Aged Post-Traumatic Murine Cerebral Cortex.

Science.gov (United States)

Heimann, Gábor; Canhos, Luisa L; Frik, Jesica; Jäger, Gabriele; Lepko, Tjasa; Ninkovic, Jovica; Götz, Magdalena; Sirko, Swetlana

2017-08-01

Aging leads to adverse outcomes after traumatic brain injury. The mechanisms underlying these defects, however, are not yet clear. In this study, we found that astrocytes in the aged post-traumatic cerebral cortex develop a significantly reduced proliferative response, resulting in reduced astrocyte numbers in the penumbra. Moreover, experiments of reactive astrocytes in vitro reveal that their diminished proliferation is due to an age-related switch in the division mode with reduced cell-cycle re-entry rather than changes in cell-cycle length. Notably, reactive astrocytes in vivo and in vitro become refractory to stimuli increasing their proliferation during aging, such as Sonic hedgehog signaling. These data demonstrate for the first time that age-dependent, most likely intrinsic changes in the proliferative program of reactive astrocytes result in their severely hampered proliferative response to traumatic injury thereby affecting astrocyte homeostasis. © The Author 2017. Published by Oxford University Press.

AGE-DEPENDENT FEATURES OF EVOLVING HUMORAL IMMUNITY IN CHILDREN

Directory of Open Access Journals (Sweden)

A. P. Toptygina

2012-01-01

Full Text Available Abstract. Age dynamics of humoral immunity was studied in healthy children, i.e., 11 newborns, 33 infants of 4 to 8 months, 32 children of 1 to 2 years old,, 17 children of 4 to 5 years old, 25 children of 6 to 8 years old, 15 children of 9 to 11 years old, and 28 adolescents of 14 to 16 years old. Evaluation of membrane receptors on B cells was performed by means of three-colour fluorescent label and allowed of characterizing B1 subpopulations (CD19+CD5+CD27-, naпve B2 cells (CD19+CD5-CD27-, and B2 memory cells (CD19+CD5-CD27+. B1 cells have been shown to dominate in blood of newborns and younger children (up to 5 years old. By the contrary, B2 memory cells were nearly undetectable in newborns, and exceeded 20% in adolescents (by 15 years old. Meanwhile, it has been revealed that the amounts of IgG1 and IgG3 subclasses did progressively increase with age, whereas IgG2 remained decreased to 50% of adult values for a long time, and reached them by 11 years and later. We suggest that the age dynamics of IgG subclasses is connected with age-dependent changes in B cell subpopulations.

Age-dependent decline of beta-cell function in type 1 diabetes after diagnosis: a multi-centre longitudinal study

DEFF Research Database (Denmark)

Barker, A.; Lauria, A.; Schloot, N.

2014-01-01

C-peptide secretion is currently the only available clinical biomarker to measure residual β-cell function in type 1 diabetes. However, the natural history of C-peptide decline after diagnosis can vary considerably dependent upon several variables. We investigated the shape of C-peptide decline...... over time from type 1 diabetes onset in relation to age at diagnosis, HbA1c levels and insulin dose....

Hematopoietic stem cell aging and self-renewal

NARCIS (Netherlands)

Dykstra, Brad; de Haan, Gerald

A functional decline of the immune system occurs during organismal aging that is attributable, in large part, to changes in the hematopoietic stem cell (HSC) compartment. In the mouse, several hallmark age-dependent changes in the HSC compartment have been identified, including an increase in HSC

Impact of genomic damage and ageing on stem cell function

Science.gov (United States)

Behrens, Axel; van Deursen, Jan M.; Rudolph, K. Lenhard; Schumacher, Björn

2014-01-01

Impairment of stem cell function contributes to the progressive deterioration of tissue maintenance and repair with ageing. Evidence is mounting that age-dependent accumulation of DNA damage in both stem cells and cells that comprise the stem cell microenvironment are partly responsible for stem cell dysfunction with ageing. Here, we review the impact of the various types of DNA damage that accumulate with ageing on stem cell functionality, as well as the development of cancer. We discuss DNA-damage-induced cell intrinsic and extrinsic alterations that influence these processes, and review recent advances in understanding systemic adjustments to DNA damage and how they affect stem cells. PMID:24576896

β-Cell Ca(2+) dynamics and function are compromised in aging.

Science.gov (United States)

Barker, Christopher J; Li, Luosheng; Köhler, Martin; Berggren, Per-Olof

2015-01-01

Defects in pancreatic β-cell function and survival are key components in type 2 diabetes (T2D). An age-dependent deterioration in β-cell function has also been observed, but little is known about the molecular mechanisms behind this phenomenon. Our previous studies indicate that the regulation of cytoplasmic free Ca(2+) concentration ([Ca(2+)]i) may be critical and that this is dependent on the proper function of the mitochondria. The [Ca(2+)]i dynamics of the pancreatic β-cell are driven by an interplay between glucose-induced influx of extracellular Ca(2+) via voltage-dependent Ca(2+) channels and the inositol 1,4,5-trisphosphate (Ins(1,4,5)P3)-mediated liberation of Ca(2+) from intracellular stores. Our previous work has indicated a direct relationship between disruption of Ins(1,4,5)P3-mediated Ca(2+) regulation and loss of β-cell function, including disturbed [Ca(2+)]i dynamics and compromised insulin secretion. To investigate these processes in aging we used three mouse models, a premature aging mitochondrial mutator mouse, a mature aging phenotype (C57BL/6) and an aging-resistant phenotype (129). Our data suggest that age-dependent impairment in mitochondrial function leads to modest changes in [Ca(2+)]i dynamics in mouse β-cells, particularly in the pattern of [Ca(2+)]i oscillations. These changes are driven by modifications in both PLC/Ins(1,4,5)P3-mediated Ca(2+) mobilization from intracellular stores and decreased β-cell Ca(2+) influx over the plasma membrane. Our findings underscore an important concept, namely that even relatively small, time-dependent changes in β-cell signal-transduction result in compromised insulin release and in a diabetic phenotype. Copyright © 2014 Elsevier Ltd. All rights reserved.

[The mechanism of phenoptosis: I. Age-dependent decrease of the overall rate of protein synthesis is caused by the programmed attenuation of bio-energetics].

Science.gov (United States)

Trubitsyn, A G

2009-01-01

The age-dependent degradation of all vital processes of an organism can be result of influences of destructive factors (the stochastic mechanism of aging), or effect of realizations of the genetic program (phenoptosis). The stochastic free-radical theory of aging dominating now contradicts the set of empirical data, and the semicentenial attempts to create the means to slow down aging did not give any practical results. It makes obvious that the stochastic mechanism of aging is incorrect. At the same time, the alternative mechanism of the programmed aging is not developed yet but preconditions for it development have already been created. It is shown that the genes controlling process of aging exist (contrary to the customary opinion) and the increase in the level of damaged macromolecules (basic postulate of the free-radical theory) can be explained by programmed attenuation of bio-energetics. As the bio-energetics is a driving force of all vital processes, decrease of its level is capable to cause degradation of all functions of an organism. However to transform this postulate into a basis of the theory of phenoptosis it is necessary to show, that attenuation of bio-energetics predetermines such fundamental processes accompanying aging as decrease of the overall rate of protein biosynthesis, restriction of cellular proliferations (Hayflick limit), loss of telomeres etc. This article is the first step in this direction: the natural mechanism of interaction of overall rate of protein synthesis with a level of cellular bio-energetics is shown. This is built-in into the translation machine and based on dependence of recirculation rate of eukaryotic initiation factor 2 (elF2) from ATP/ADP value that is created by mitochondrial bio-energetic machine.

Transcriptional and Cell Cycle Alterations Mark Aging of Primary Human Adipose-Derived Stem Cells.

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Shan, Xiaoyin; Roberts, Cleresa; Kim, Eun Ji; Brenner, Ariana; Grant, Gregory; Percec, Ivona

2017-05-01

Adult stem cells play a critical role in the maintenance of tissue homeostasis and prevention of aging. While the regenerative potential of stem cells with low cellular turnover, such as adipose-derived stem cells (ASCs), is increasingly recognized, the study of chronological aging in ASCs is technically difficult and remains poorly understood. Here, we use our model of chronological aging in primary human ASCs to examine genome-wide transcriptional networks. We demonstrate first that the transcriptome of aging ASCs is distinctly more stable than that of age-matched fibroblasts, and further, that age-dependent modifications in cell cycle progression and translation initiation specifically characterize aging ASCs in conjunction with increased nascent protein synthesis and a distinctly shortened G1 phase. Our results reveal novel chronological aging mechanisms in ASCs that are inherently different from differentiated cells and that may reflect an organismal attempt to meet the increased demands of tissue and organ homeostasis during aging. Stem Cells 2017;35:1392-1401. © 2017 AlphaMed Press.

Cell-cycle-dependent repair of heavy-ion damage

International Nuclear Information System (INIS)

Blakely, E.A.; Chang, P.Y.; Lommel, L.; Tobias, C.A.

1985-01-01

Synchronized human T-1 cells have been used to investigate the G1-phase age dependence of repair of potentially lethal damage (PLDR). The cells were irradiated with single doses of either 225 kVp X rays or Bragg-peak 425 MeV/μ neon ions at ages between 1.5 and 6.0 hrs after mitotic selection, and then either trypsinized and plated immediately, or held at 37 0 C for 6 hrs in PBS, or PBS containing 60μM of the DNA-polymerase-inhibitor 1-β-D-arabinofurano-syladenine (β-araA) before trypsinization and plating. Delayed plating showed significant PLDR at all ages irradiated with X rays, with the increase of survival varying between 2- to 8-fold. At equivalent survival levels, there was a reduced capacity for PLDT at each cell age irradiated with neon ions. In early G1 after neon-ion exposures, delayed plating actually enhanced cell killing; whereas, in late G1 the survival increased about 2-fold. β-araA almost completely eliminated the PLDR after X rays, reducing the survival to that measured with immediate plating. β-araA slightly enhanced neon-ion cell killing at all cell ages

Aging-dependent DNA hypermethylation and gene expression of GSTM1 involved in T cell differentiation.

Science.gov (United States)

Yeh, Shu-Hui; Liu, Cheng-Ling; Chang, Ren-Chieh; Wu, Chih-Chiang; Lin, Chia-Hsueh; Yang, Kuender D

2017-07-25

This study investigated whether aging was associated with epigenetic changes of DNA hypermethylation on immune gene expression and lymphocyte differentiation. We screened CG sites of methylation in blood leukocytes from different age populations, picked up genes with age-related increase of CG methylation content more than 15%, and validated immune related genes with CG hypermethylation involved in lymphocyte differentiation in the aged population. We found that 12 genes (EXHX1、 IL-10、 TSP50、 GSTM1、SLC5A5、SPI1、F2R、LMO2、PTPN6、FGFR2、MMP9、MET) were associated with promoter or exon one DNA hypermethylation in the aged group. Two immune related genes, GSTM1 and LMO2, were chosen to validate its aging-related CG hypermethylation in different leukocytes. We are the first to validate that GSTM1_P266 and LMO2_E128 CG methylation contents in T lymphocytes but not polymorphonuclear cells (PMNs) or mononuclear cells (MNCs) were significantly increased in the aged population. The GSTM1 mRNA expression in T lymphocytes but not PMNs or MNCs was inversely associated with the GSTM1 CG hypermethylation levels in the aged population studied. Further studies showed that lower GSTM1 CG methylation content led to the higher GSTM1 mRNA expression in T cells and knockdown of GSTM1 mRNA expression decreased type 1 T helper cell (Th1) differentiation in Jurkat T cells and normal adult CD4 T cells. The GSTM1_P266 hypermethylation in the aged population associated with lower GSTM1 mRNA expression was involved in Th1 differentiation, highlighting that modulation of aging-associated GSTM1 methylation may be able to enhance T helper cell immunity in the elders.

Age-Dependence and Aging-Dependence: Neuronal Loss and Lifespan in a C. elegans Model of Parkinson's Disease.

Science.gov (United States)

Apfeld, Javier; Fontana, Walter

2017-12-23

It is often assumed, but not established, that the major neurodegenerative diseases, such as Parkinson's disease, are not just age-dependent (their incidence changes with time) but actually aging-dependent (their incidence is coupled to the process that determines lifespan). To determine a dependence on the aging process requires the joint probability distribution of disease onset and lifespan. For human Parkinson's disease, such a joint distribution is not available, because the disease cuts lifespan short. To acquire a joint distribution, we resorted to an established C. elegans model of Parkinson's disease in which the loss of dopaminergic neurons is not fatal. We find that lifespan is not correlated with the loss of individual neurons. Therefore, neuronal loss is age-dependent and aging-independent. We also find that a lifespan-extending intervention into insulin/IGF1 signaling accelerates the loss of specific dopaminergic neurons, while leaving death and neuronal loss times uncorrelated. This suggests that distinct and compartmentalized instances of the same genetically encoded insulin/IGF1 signaling machinery act independently to control neurodegeneration and lifespan in C. elegans . Although the human context might well be different, our study calls attention to the need to maintain a rigorous distinction between age-dependence and aging-dependence.

Functional dysregulation of stem cells during aging: a focus on skeletal muscle stem cells.

Science.gov (United States)

García-Prat, Laura; Sousa-Victor, Pedro; Muñoz-Cánoves, Pura

2013-09-01

Aging of an organism is associated with the functional decline of tissues and organs, as well as a sharp decline in the regenerative capacity of stem cells. A prevailing view holds that the aging rate of an individual depends on the ratio of tissue attrition to tissue regeneration. Therefore, manipulations that favor the balance towards regeneration may prevent or delay aging. Skeletal muscle is a specialized tissue composed of postmitotic myofibers that contract to generate force. Satellite cells are the adult stem cells responsible for skeletal muscle regeneration. Recent studies on the biology of skeletal muscle and satellite cells in aging have uncovered the critical impact of systemic and niche factors on stem cell functionality and demonstrated the capacity of aged satellite cells to rejuvenate and increase their regenerative potential when exposed to a youthful environment. Here we review the current literature on the coordinated relationship between cell extrinsic and intrinsic factors that regulate the function of satellite cells, and ultimately determine tissue homeostasis and repair during aging, and which encourage the search for new anti-aging strategies. © 2013 The Authors Journal compilation © 2013 FEBS.

The role of apoptotic cell death in Drosophila melanogaster radioinduced aging

International Nuclear Information System (INIS)

Moskalev, A.A.; Zajnullin, V.G.

2001-01-01

The attempt is made to estimate a role of programmed cell death (apoptosis) in radioinduced life span alteration and aging. It was shown with the use of mutant Drosophila melanogaster laboratory strains that the dysfunction of a reaper-dependent apoptosis pathway together with the action of ionizing radiation and/or apoptosis inductor etoposide could to lead to change of life span and a pace of aging. In Drosophila strain with defect of proapoptosis gene reaper the increase of life span after irradiation and etoposide treatment was observed. At the same time the strain with overexpression of a protease dcp-1 gene and the strain with the defect of antiapoptosis diap-1/th gene decreased the life span after irradiation and etoposide treatment. The obtained facts are discussed from a position of participation of apoptosis deregulation in radioinduced and natural aging of whole organisms [ru

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.

In Search for Anti-Aging Strategy: Can We Rejuvenate Our Aging Stem Cells?

Directory of Open Access Journals (Sweden)

Anna Meiliana

2015-08-01

Full Text Available BACKGROUND: Recent evidence suggested that we grow old partly because of our stem cells grow old as a result of mechanisms that suppress the development of cancer over a lifetime. We believe that a further, more precise mechanistic understanding of this process will be required before this knowledge can be translated into human anti-aging therapies. CONTENT: A diminished capacity to maintain tissue homeostasis is a central physiological characteristic of aging. As stem cells regulate tissue homeostasis, depletion of stem cell reserves and/or diminished stem cell function have been postulated to contribute to aging. It has further been suggested that accumulated DNA damage could be a principal mechanism underlying age-dependent stem cell decline. It is interesting that many of the rejuvenating interventions act on the stem cell compartments, perhaps reflecting shared genetic and biochemical pathways controlling stem cell function and longevity. Strategy to slow down the aging processes is based on caloric restriction refers to a dietary regimen low in calories but without undernutrition. Sirtuin (SIRT1 and 3, increases longevity by mimicking the beneficial effects of caloric restriction. SIRT3 regulates stress-responsive mitochondrial homeostasis, and more importantly, SIRT3 upregulation rejuvenates aged stem cells in tissues. Resveratrol (3,5,4’-trihydroxystilbene, a natural polyphenol found in grapes and wine, was the most powerful natural activator of SIRT1. In fact, resveratrol treatment has been demonstrated to rescue adult stem cell decline, slow down bodyweight loss, improve trabecular bone structure and mineral density, and significantly extend lifespan. SUMMARY: Tissue-specific stem cells persist throughout the entire lifespan to repair and maintain tissues, but their self-renewal and differentiation potential become dysregulated with aging. Given that adult stem cells are thought to be central to tissue maintenance and organismal

[Loss of total 5-methylcytosine from the genome during cell culture aging coincides with the Hayflick limit].

Science.gov (United States)

Mazin, A L

1993-01-01

Analyzing the data about the age-related 5-methylcytosine (5mC) loss from DNA of cell cultures, the following conclusions have been made: 1. The rate of 5mC loss from DNA does not depend on the cell donor age; it remains constant during the logarithmic phase of cell growth, and may vary significantly in different cell lines. 2. The rate is inversely proportional to their Hayflick limit and to the species lifespan of cell donors. 3. In immortal cell lines the 5mC content in DNA is stable or increases with aging. 4. Hayflick limit estimations coincide with or are lower than the number of cell population doublings that corresponds to all 5mC loss from cell genome. A simple and fast method has been proposed for Hayflick limit prognostication by analysis of the rate of DNA hypomethylation. It may be used for early diagnosis of precrisis and immortal cell lines. Evidence has been obtained that age-dependent 5mC loss from DNA is the result of accumulating 5mC-->T+C substitutions that occur during DNA methylation in every cell division. The loss of all genomic 5mC residues during the lifespan may correspond to accumulation of about 3 x 10(6) 5mC-->T transitions or, on average, one mutation per gene. This may be one of the main reasons of the "catastrophe of errors" and cessation of cell proliferation. It is calculated that the rate of 5mC-->T transitions in normal cells may be 2.3 x 10(-5) per site in each cell doubling in human, 6 x 10(-5) in hamster, and 4.6 x 10(-4) in mouse. DNA methylation as a generator of mutations may be a "counter" of cell divisions and thus be one of the molecular mechanisms of the Hayflick phenomenon. The conclusion is made that the DNA methylation system may be considered as a genetically programmed mechanism for accumulating mutations during cell aging.

Impact of radiobiological considerations on epidemiological inferences of age-dependent radiosensitivity

International Nuclear Information System (INIS)

Crawford-Brown, D.J.

1983-01-01

Current epidemiological studies of the age-dependent risk of radiogenic carcinomas are based on populations still in the early stages of cancer expression. The result is a set of logical uncertainties concerning the manner in which inferences may be drawn from the existing data. These uncertainties may be formalized and examined through the application of various radiobiological principles developed from more fundamental experimental data. Chief amongst these considerations are the time course of tumor expression, the role of relative and absolute risk models, the distribution of effects between initiation and promotion, the age-dependent fraction of time a critical cell remains in radiosensitive stages and the combinatorics of the critical cellular subpopulations. Each of these and the combinatorics of the critical cellular subpopulations. Each of these principles are examined in light of their impact on the structuring of epidemiologic data and the drawing of inferences concerning age-dependent radiogenic risk. The data on atomic bomb survivors are employed as a relevant example

Practical applications of age-dependent reliability models and analysis of operational data

Energy Technology Data Exchange (ETDEWEB)

Lannoy, A.; Nitoi, M.; Backstrom, O.; Burgazzi, L.; Couallier, V.; Nikulin, M.; Derode, A.; Rodionov, A.; Atwood, C.; Fradet, F.; Antonov, A.; Berezhnoy, A.; Choi, S.Y.; Starr, F.; Dawson, J.; Palmen, H.; Clerjaud, L

2005-07-01

The purpose of the workshop was to present the experience of practical application of time-dependent reliability models. The program of the workshop comprises the following sessions: -) aging management and aging PSA (Probabilistic Safety Assessment), -) modeling, -) operation experience, and -) accelerating aging tests. In order to introduce time aging effect of particular component to the PSA model, it has been proposed to use the constant unavailability values on the short period of time (one year for example) calculated on the basis of age-dependent reliability models. As for modeling, it appears that the problem of too detailed statistical models for application is the lack of data for required parameters. As for operating experience, several methods of operating experience analysis have been presented (algorithms for reliability data elaboration and statistical identification of aging trend). As for accelerated aging tests, it is demonstrated that a combination of operating experience analysis with the results of accelerated aging tests of naturally aged equipment could provide a good basis for continuous operation of instrumentation and control systems.

Practical applications of age-dependent reliability models and analysis of operational data

International Nuclear Information System (INIS)

Lannoy, A.; Nitoi, M.; Backstrom, O.; Burgazzi, L.; Couallier, V.; Nikulin, M.; Derode, A.; Rodionov, A.; Atwood, C.; Fradet, F.; Antonov, A.; Berezhnoy, A.; Choi, S.Y.; Starr, F.; Dawson, J.; Palmen, H.; Clerjaud, L.

2005-01-01

The purpose of the workshop was to present the experience of practical application of time-dependent reliability models. The program of the workshop comprises the following sessions: -) aging management and aging PSA (Probabilistic Safety Assessment), -) modeling, -) operation experience, and -) accelerating aging tests. In order to introduce time aging effect of particular component to the PSA model, it has been proposed to use the constant unavailability values on the short period of time (one year for example) calculated on the basis of age-dependent reliability models. As for modeling, it appears that the problem of too detailed statistical models for application is the lack of data for required parameters. As for operating experience, several methods of operating experience analysis have been presented (algorithms for reliability data elaboration and statistical identification of aging trend). As for accelerated aging tests, it is demonstrated that a combination of operating experience analysis with the results of accelerated aging tests of naturally aged equipment could provide a good basis for continuous operation of instrumentation and control systems

32 CFR 48.302 - Substantiating evidence regarding dependency and age of dependents.

Science.gov (United States)

2010-07-01

... 32 National Defense 1 2010-07-01 2010-07-01 false Substantiating evidence regarding dependency and age of dependents. 48.302 Section 48.302 National Defense Department of Defense OFFICE OF THE... Designation of Beneficiaries § 48.302 Substantiating evidence regarding dependency and age of dependents. At...

Morphometric study on age-dependent pulmonary lesions in rats exposed to nitrogen dioxide

Energy Technology Data Exchange (ETDEWEB)

Kyono, H.; Kawai, K.

1982-01-01

Electronmicroscopic morphometry was performed on lung of 1, 3, 12 and 21 months-old rats exposed to 0.1, 0.5, 3 and 10 ppm nitrogen dioxide (NO/sub 2/) continuously for one month. The rats used in this experiment were all supplied at one time from one colony and kept under a barrier system until exposure. Effects of aging on the responses of lungs to NO/sub 2/ were studied by comparing the dose-effect reaction patterns among the age groups. A trend of dose-dependent increase of arithmetic mean thickness of air-blood barrier was found in all age groups examined. The response of lung to NO/sub 2/ exposure showed age-related differences. Based on the morphometric index, the response declines from 1 to 12 months, but increases again in 21-months-old rats. The compartmental components of alveolar wall tissue such as type I epithelial cells, type II epithelial cells, interstitial cells, interstitial matrix and capillary endothelium appeared to have various degrees of response due to both age at onset of exposure and NO/sub 2/ concentration, resulting in the appearance of varying stages in impairment or repair. Accordingly, the response of each compartmental component of lung to the concentrations of NO/sub 2/ did not always exhibit a simple dose-dependent increase or decrease but sometimes indicated a multiphasic reaction pattern.

Aging research program at the LaCrosse nuclear power plant

International Nuclear Information System (INIS)

DiBenedetto, P.A.; Goller, K.R.; Sideris, T.

1988-01-01

A research program on the time-dependent, environmentally and operationally induced degradation of components, systems and structures---that is aging---is being conducted at the LaCrosse Boiling Water Reactor (LACBWR) nuclear power plant. In the spring of 1987, Dairyland Power Cooperative, the owner/licensee of the LACBWR plant announced that it was permanently shutting down this plant and intended to decommission it. Shortly thereafter, Dairyland entered into an agreement with DiBenedetto Associates (DBA) to be the exclusive agent and manager of the Aging Research Program (ARP). Wyle Laboratories is the primary supporting contractor to DBA in this effort

Structural aging program status report

International Nuclear Information System (INIS)

Naus, D.J.; Oland, C.B.; Ellingwood, B.; Graves, H.L. III

1994-01-01

Research is being conducted at the Oak Ridge National Laboratory under Nuclear Regulatory Commission (USNRC) sponsorship to address aging management of safety-related concrete structures. Documentation is being prepared to provide the USNRC with potential structural safety issues and acceptance criteria for use in continued service evaluations of nuclear power plants. Program accomplishments have included development of the Structural Materials Information Center containing data and information on the time variation of 144 material properties under the influence of pertinent environmental stressors or aging factors, performance assessments of reinforced concrete structures in several United Kingdom nuclear power facilities, evaluation of European and North American repair practices for concrete, an evaluation of factors affecting the corrosion of metals embedded in concrete, and application of the time-dependent reliability methodology to reinforced concrete flexure and shear structural elements to investigate the role of in-service inspection and repair on their probability of failure

Mutant alpha-synuclein causes age-dependent neuropathology in monkey brain.

Science.gov (United States)

Yang, Weili; Wang, Guohao; Wang, Chuan-En; Guo, Xiangyu; Yin, Peng; Gao, Jinquan; Tu, Zhuchi; Wang, Zhengbo; Wu, Jing; Hu, Xintian; Li, Shihua; Li, Xiao-Jiang

2015-05-27

Parkinson's disease (PD) is an age-dependent neurodegenerative disease that often occurs in those over age 60. Although rodents and small animals have been used widely to model PD and investigate its pathology, their short life span makes it difficult to assess the aging-related pathology that is likely to occur in PD patient brains. Here, we used brain tissues from rhesus monkeys at 2-3, 7-8, and >15 years of age to examine the expression of Parkin, PINK1, and α-synuclein, which are known to cause PD via loss- or gain-of-function mechanisms. We found that α-synuclein is increased in the older monkey brains, whereas Parkin and PINK1 are decreased or remain unchanged. Because of the gain of toxicity of α-synuclein, we performed stereotaxic injection of lentiviral vectors expressing mutant α-synuclein (A53T) into the substantia nigra of monkeys and found that aging also increases the accumulation of A53T in neurites and its associated neuropathology. A53T also causes more extensive reactive astrocytes and axonal degeneration in monkey brain than in mouse brain. Using monkey brain tissues, we found that A53T interacts with neurofascin, an adhesion molecule involved in axon subcellular targeting and neurite outgrowth. Aged monkey brain tissues show an increased interaction of neurofascin with A53T. Overexpression of A53T causes neuritic toxicity in cultured neuronal cells, which can be attenuated by transfected neurofascin. These findings from nonhuman primate brains reveal age-dependent pathological and molecular changes that could contribute to the age-dependent neuropathology in PD. Copyright © 2015 the authors 0270-6474/15/358345-14$15.00/0.

C/EBPα is dispensable for the ontogeny of PD-1+ CD4+ memory T cells but restricts their expansion in an age-dependent manner.

Science.gov (United States)

Norrie, Ida Christine; Ohlsson, Ewa; Nielsen, Olaf; Hasemann, Marie Sigurd; Porse, Bo T

2014-01-01

Ageing and cancer is often associated with altered T cell distributions and this phenomenon has been suggested to be the main driver in the development of immunosenescence. Memory phenotype PD-1+ CD4+ T cells accumulate with age and during leukemic development, and they might account for the attenuated T cell response in elderly or diseased individuals. The transcription factor C/EBPα has been suggested to be responsible for the accumulation as well as for the senescent features of these cells including impaired TCR signaling and decreased proliferation. Thus modulating the activity of C/EBPα could potentially target PD-1+ CD4+ T cells and consequently, impede the development of immunosenescence. To exploit this possibility we tested the importance of C/EBPα for the development of age-dependent PD-1+ CD4+ T cells as well as its role in the accumulation of PD-1+ CD4+ T cells during leukemic progression. In contrast to earlier suggestions, we find that loss of C/EBPα expression in the lymphoid compartment led to an increase of PD-1+ CD4+ T cells specifically in old mice, suggesting that C/EBPα repress the accumulation of these cells in elderly by inhibiting their proliferation. Furthermore, C/EBPα-deficiency in the lymphoid compartment had no effect on leukemic development and did not affect the accumulation of PD-1+ CD4+ T cells. Thus, in addition to contradict earlier suggestions of a role for C/EBPα in immunosenescence, these findings efficiently discard the potential of using C/EBPα as a target for the alleviation of ageing/cancer-associated immunosenescence.

Age-dependent dosimetry and metabolism

International Nuclear Information System (INIS)

Taylor, D.M.

1992-01-01

The release of radionuclides into the environment following the Chernobyl disaster in 1986 created an urgent need for internationally acceptable dose coefficients for calculating the doses delivered to all members of the public, from conception to old age. Organ masses and the kinetics of distribution and retention of elements in humans generally vary with age and often not in simple linear relationship to body weight. Unless variations are considered calculated radiation doses to children may be seriously underestimated. The International Commission on Radiological Protection created in 1987 a Task Group on Age-dependent Doses to Members of the Public from Intake of Radionuclides (AGDOS). The work of AGDOS and the general problems encountered in deriving age-dependent dose coefficients will be discussed in this paper. The first two AGDOS reports, ICRP Publication 56 Parts 1 and 2, provide dose coefficients for the ages 3 months, 1, 5, 10, 15 years and for adults for the 21 elements considered to be of most immediate importance for radiation protection. To develop these dose coefficients, the ICRP Publication 30 dosimetric and biokinetic models were reevaluated and extended. The basic dosimetric model is retained but equivalent dose is now integrated from age at intake to 70 years and the new ICRP Publication 60 tissue weighting factors are incorporated. The development of age-dependent biokinetic models is complicated by the lack of age-related human, or even animal data for the majority of the elements. Thus in formulating the models it has been necessary to use all the available information, biokinetic, physiological chemical and biochemical, and to adopt a number of new approaches including the development of generic biokinetic models for chemically related families of elements such as the actinides and the alkaline earth elements. (author)

Can aging be programmed?

DEFF Research Database (Denmark)

Kowald, Axel; Kirkwood, Thomas B. L.

2016-01-01

The evolution of the aging process has long been a biological riddle, because it is difficult to explain the evolution of a trait that has apparently no benefit to the individual. Over 60 years ago, Medawar realized that the force of natural selection declines with chronological age because...... of unavoidable environmental risks. This forms the basis of the mainstream view that aging arises as a consequence of a declining selection pressure to maintain the physiological functioning of living beings forever. Over recent years, however, a number of articles have appeared that nevertheless propose...... the existence of specific aging genes; that is, that the aging process is genetically programmed. If this view were correct, it would have serious implications for experiments to understand and postpone aging. Therefore, we studied in detail various specific proposals why aging should be programmed. We find...

Cells derived from young bone marrow alleviate renal aging.

Science.gov (United States)

Yang, Hai-Chun; Rossini, Michele; Ma, Li-Jun; Zuo, Yiqin; Ma, Ji; Fogo, Agnes B

2011-11-01

Bone marrow-derived stem cells may modulate renal injury, but the effects may depend on the age of the stem cells. Here we investigated whether bone marrow from young mice attenuates renal aging in old mice. We radiated female 12-mo-old 129SvJ mice and reconstituted them with bone marrow cells (BMC) from either 8-wk-old (young-to-old) or 12-mo-old (old-to-old) male mice. Transfer of young BMC resulted in markedly decreased deposition of collagen IV in the mesangium and less β-galactosidase staining, an indicator of cell senescence. These changes paralleled reduced expression of plasminogen activator inhibitor-1 (PAI-1), PDGF-B (PDGF-B), the transdifferentiation marker fibroblast-specific protein-1 (FSP-1), and senescence-associated p16 and p21. Tubulointerstitial and glomerular cells derived from the transplanted BMC did not show β-galactosidase activity, but after 6 mo, there were more FSP-1-expressing bone marrow-derived cells in old-to-old mice compared with young-to-old mice. Young-to-old mice also exhibited higher expression of the anti-aging gene Klotho and less phosphorylation of IGF-1 receptor β. Taken together, these data suggest that young bone marrow-derived cells can alleviate renal aging in old mice. Direct parenchymal reconstitution by stem cells, paracrine effects from adjacent cells, and circulating anti-aging molecules may mediate the aging of the kidney.

NPP Krsko Aging Management Program

International Nuclear Information System (INIS)

Glaser, B.; Spiler, J.

2002-01-01

As a part of Periodic Safety Review Program (PSR) NEK will review and perform some activities related to Equipment Qualification (EQ) and Aging Management Program (AMP). (EQ) and AMP are safety factors, which need to be assessed during PSR. The goal of PSR and AMP is to determine aging effects and give the conclusion whether the plant has been managed to control aging related degradations and that safety margins are maintained. The parallel goal is also to establish AMP for future plant operation and provide basis for possible Life Extension Program. NEK will develop NEK Aging and Life Cycle Management Program, similar by format and content to one determined by License Renewal program. The bases are in 10CFR54, and NEI 95-10 Industry Guidelines for 10 CFR 54 implementation. The process of establishment the AMP is to be done in two steps. The first step is dealing with SSC's (Systems Structures and Components) scoping and screening and identification of TLAA's (Time Limited Aging Analyses). That means, that a database of all SSC's and TLAA's will be created and then evaluated within AMP program. Based on the scope in first phase an evaluation will be performed in step two. NEK will maintain AMP program as a living program that may be also used for Life Extension and Life Cycle Management. This paper will present and describe AMP, scoping and screening process and the results achieved through the first phase of the project.(author)

Rescue of Outer Hair Cells with Antisense Oligonucleotides in Usher Mice Is Dependent on Age of Treatment.

Science.gov (United States)

Ponnath, Abhilash; Depreux, Frederic F; Jodelka, Francine M; Rigo, Frank; Farris, Hamilton E; Hastings, Michelle L; Lentz, Jennifer J

2018-02-01

The absence of functional outer hair cells is a component of several forms of hereditary hearing impairment, including Usher syndrome, the most common cause of concurrent hearing and vision loss. Antisense oligonucleotide (ASO) treatment of mice with the human Usher mutation, Ush1c c.216G>A, corrects gene expression and significantly improves hearing, as measured by auditory-evoked brainstem responses (ABRs), as well as inner and outer hair cell (IHC and OHC) bundle morphology. However, it is not clear whether the improvement in hearing achieved by ASO treatment involves the functional rescue of outer hair cells. Here, we show that Ush1c c.216AA mice lack OHC function as evidenced by the absence of distortion product otoacoustic emissions (DPOAEs) in response to low-, mid-, and high-frequency tone pairs. This OHC deficit is rescued by treatment with an ASO that corrects expression of Ush1c c.216G>A. Interestingly, although rescue of inner hairs cells, as measured by ABR, is achieved by ASO treatment as late as 7 days after birth, rescue of outer hair cells, measured by DPOAE, requires treatment before post-natal day 5. These results suggest that ASO-mediated rescue of both IHC and OHC function is age dependent and that the treatment window is different for the different cell types. The timing of treatment for congenital hearing disorders is of critical importance for the development of drugs such ASO-29 for hearing rescue.

c-Myb Regulates the T-Bet-Dependent Differentiation Program in B Cells to Coordinate Antibody Responses

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Dana Piovesan

2017-04-01

Full Text Available Summary: Humoral immune responses are tailored to the invading pathogen through regulation of key transcription factors and their networks. This is critical to establishing effective antibody-mediated responses, yet it is unknown how B cells integrate pathogen-induced signals to drive or suppress transcriptional programs specialized for each class of pathogen. Here, we detail the key role of the transcription factor c-Myb in regulating the T-bet-mediated anti-viral program. Deletion of c-Myb in mature B cells significantly increased serum IgG2c and CXCR3 expression by upregulating T-bet, normally suppressed during Th2-cell-mediated responses. Enhanced expression of T-bet resulted in aberrant plasma cell differentiation within the germinal center, mediated by CXCR3 expression. These findings identify a dual role for c-Myb in limiting inappropriate effector responses while coordinating plasma cell differentiation with germinal center egress. Identifying such intrinsic regulators of specialized antibody responses can assist in vaccine design and therapeutic intervention in B-cell-mediated immune disorders. : Piovesan et al. examine how B cells establish transcriptional programs that result in tailored responses to invading pathogens. The authors find that the transcription factor c-Myb represses the T-bet-mediated anti-viral program in B cells. c-Myb limits inappropriate effector responses while coordinating plasma cell differentiation with germinal center egress. Keywords: B cells, c-Myb, T-bet, immunoglobulin, CXCR3, plasma cell, germinal center

Stress Marker Signatures in Lesion Mimic Single and Double Mutants Identify a Crucial Leaf Age-Dependent Salicylic Acid Related Defense Signal.

Science.gov (United States)

Kaurilind, Eve; Brosché, Mikael

2017-01-01

Plants are exposed to abiotic and biotic stress conditions throughout their lifespans that activates various defense programs. Programmed cell death (PCD) is an extreme defense strategy the plant uses to manage unfavorable environments as well as during developmentally induced senescence. Here we investigated the role of leaf age on the regulation of defense gene expression in Arabidopsis thaliana. Two lesion mimic mutants with misregulated cell death, catalase2 (cat2) and defense no death1 (dnd1) were used together with several double mutants to dissect signaling pathways regulating defense gene expression associated with cell death and leaf age. PCD marker genes showed leaf age dependent expression, with the highest expression in old leaves. The salicylic acid (SA) biosynthesis mutant salicylic acid induction deficient2 (sid2) had reduced expression of PCD marker genes in the cat2 sid2 double mutant demonstrating the importance of SA biosynthesis in regulation of defense gene expression. While the auxin- and jasmonic acid (JA)- insensitive auxin resistant1 (axr1) double mutant cat2 axr1 also led to decreased expression of PCD markers; the expression of several marker genes for SA signaling (ISOCHORISMATE SYNTHASE 1, PR1 and PR2) were additionally decreased in cat2 axr1 compared to cat2. The reduced expression of these SA markers genes in cat2 axr1 implicates AXR1 as a regulator of SA signaling in addition to its known role in auxin and JA signaling. Overall, the current study reinforces the important role of SA signaling in regulation of leaf age-related transcript signatures.

Ovarian Stem Cell Nests in Reproduction and Ovarian Aging.

Science.gov (United States)

Ye, Haifeng; Zheng, Tuochen; Li, Wei; Li, Xiaoyan; Fu, Xinxin; Huang, Yaoqi; Hu, Chuan; Li, Jia; Huang, Jian; Liu, Zhengyv; Zheng, Liping; Zheng, Yuehui

2017-01-01

The fixed primordial follicles pool theory, which monopolized reproductive medicine for more than one hundred years, has been broken by the discovery, successful isolation and establishment of ovarian stem cells. It has brought more hope than ever of increasing the size of primordial follicle pool, improving ovarian function and delaying ovarian consenescence. Traditional view holds that stem cell aging contributes to the senility of body and organs. However, in the process of ovarian aging, the main factor leading to the decline of the reproductive function is the aging and degradation of ovarian stem cell nests, rather than the senescence of ovarian germ cells themselves. Recent studies have found that the immune system and circulatory system are involved in the formation of ovarian germline stem cell niches, as well as regulating the proliferation and differentiation of ovarian germline stem cells through cellular and hormonal signals. Therefore, we can improve ovarian function and delay ovarian aging by improving the immune system and circulatory system, which will provide an updated program for the treatment of premature ovarian failure (POF) and infertility. © 2017 The Author(s). Published by S. Karger AG, Basel.

C/EBPα is dispensable for the ontogeny of PD-1+ CD4+ memory T cells but restricts their expansion in an age-dependent manner.

Directory of Open Access Journals (Sweden)

Ida Christine Norrie

Full Text Available Ageing and cancer is often associated with altered T cell distributions and this phenomenon has been suggested to be the main driver in the development of immunosenescence. Memory phenotype PD-1+ CD4+ T cells accumulate with age and during leukemic development, and they might account for the attenuated T cell response in elderly or diseased individuals. The transcription factor C/EBPα has been suggested to be responsible for the accumulation as well as for the senescent features of these cells including impaired TCR signaling and decreased proliferation. Thus modulating the activity of C/EBPα could potentially target PD-1+ CD4+ T cells and consequently, impede the development of immunosenescence. To exploit this possibility we tested the importance of C/EBPα for the development of age-dependent PD-1+ CD4+ T cells as well as its role in the accumulation of PD-1+ CD4+ T cells during leukemic progression. In contrast to earlier suggestions, we find that loss of C/EBPα expression in the lymphoid compartment led to an increase of PD-1+ CD4+ T cells specifically in old mice, suggesting that C/EBPα repress the accumulation of these cells in elderly by inhibiting their proliferation. Furthermore, C/EBPα-deficiency in the lymphoid compartment had no effect on leukemic development and did not affect the accumulation of PD-1+ CD4+ T cells. Thus, in addition to contradict earlier suggestions of a role for C/EBPα in immunosenescence, these findings efficiently discard the potential of using C/EBPα as a target for the alleviation of ageing/cancer-associated immunosenescence.

Mouse embryonic stem cells undergo charontosis, a novel programmed cell death pathway dependent upon cathepsins, p53, and EndoG, in response to etoposide treatment.

Science.gov (United States)

Tichy, Elisia D; Stephan, Zachary A; Osterburg, Andrew; Noel, Greg; Stambrook, Peter J

2013-05-01

Embryonic stem cells (ESCs) are hypersensitive to many DNA damaging agents and can rapidly undergo cell death or cell differentiation following exposure. Treatment of mouse ESCs (mESCs) with etoposide (ETO), a topoisomerase II poison, followed by a recovery period resulted in massive cell death with characteristics of a programmed cell death pathway (PCD). While cell death was both caspase- and necroptosis-independent, it was partially dependent on the activity of lysosomal proteases. A role for autophagy in the cell death process was eliminated, suggesting that ETO induces a novel PCD pathway in mESCs. Inhibition of p53 either as a transcription factor by pifithrin α or in its mitochondrial role by pifithrin μ significantly reduced ESC death levels. Finally, EndoG was newly identified as a protease participating in the DNA fragmentation observed during ETO-induced PCD. We coined the term charontosis after Charon, the ferryman of the dead in Greek mythology, to refer to the PCD signaling events induced by ETO in mESCs. Copyright © 2013 Elsevier B.V. All rights reserved.

The Old-Age Healthy Dependency Ratio in Europe.

Science.gov (United States)

Muszyńska, Magdalena M; Rau, Roland

2012-09-01

The aim of this study is to answer the question of whether improvements in the health of the elderly in European countries could compensate for population ageing on the supply side of the labour market. We propose a state-of-health-specific (additive) decomposition of the old-age dependency ratio into an old-age healthy dependency ratio and an old-age unhealthy dependency ratio in order to participate in a discussion of the significance of changes in population health to compensate for the ageing of the labour force. Applying the proposed indicators to the Eurostat's population projection for the years 2010-2050, and assuming there will be equal improvements in life expectancy and healthy life expectancy at birth, we discuss various scenarios concerning future of the European labour force. While improvements in population health are anticipated during the years 2010-2050, the growth in the number of elderly people in Europe may be expected to lead to a rise in both healthy and unhealthy dependency ratios. The healthy dependency ratio is, however, projected to make up the greater part of the old-age dependency ratio. In the European countries in 2006, the value of the old-age dependency ratio was 25. But in the year 2050, with a positive migration balance over the years 2010-2050, there would be 18 elderly people in poor health plus 34 in good health per 100 people in the current working age range of 15-64. In the scenarios developed in this study, we demonstrate that improvements in health and progress in preventing disability will not, by themselves, compensate for the ageing of the workforce. However, coupled with a positive migration balance, at the level and with the age structure assumed in the Eurostat's population projections, these developments could ease the effect of population ageing on the supply side of the European labour market.

Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer.

Science.gov (United States)

Teschendorff, Andrew E; Menon, Usha; Gentry-Maharaj, Aleksandra; Ramus, Susan J; Weisenberger, Daniel J; Shen, Hui; Campan, Mihaela; Noushmehr, Houtan; Bell, Christopher G; Maxwell, A Peter; Savage, David A; Mueller-Holzner, Elisabeth; Marth, Christian; Kocjan, Gabrijela; Gayther, Simon A; Jones, Allison; Beck, Stephan; Wagner, Wolfgang; Laird, Peter W; Jacobs, Ian J; Widschwendter, Martin

2010-04-01

Polycomb group proteins (PCGs) are involved in repression of genes that are required for stem cell differentiation. Recently, it was shown that promoters of PCG target genes (PCGTs) are 12-fold more likely to be methylated in cancer than non-PCGTs. Age is the most important demographic risk factor for cancer, and we hypothesized that its carcinogenic potential may be referred by irreversibly stabilizing stem cell features. To test this, we analyzed the methylation status of over 27,000 CpGs mapping to promoters of approximately 14,000 genes in whole blood samples from 261 postmenopausal women. We demonstrate that stem cell PCGTs are far more likely to become methylated with age than non-targets (odds ratio = 5.3 [3.8-7.4], P cancer solid tissues and a population of bone marrow mesenchymal stem/stromal cells (P < 10(-5)). We find that the age-PCGT methylation signature is present in preneoplastic conditions and may drive gene expression changes associated with carcinogenesis. These findings shed substantial novel insights into the epigenetic effects of aging and support the view that age may predispose to malignant transformation by irreversibly stabilizing stem cell features.

Age dependence of tritium metabolism

International Nuclear Information System (INIS)

Inaba, Jiro

1983-01-01

3 H metabolism in vivo was studied by HTO administration to rats of varying ages for examination of the age dependence of 3 H metabolism in humans. When 1 μCi/g body weight of HTO was administered, the time-course changes of urine 3 H showed definite age dependence; the younger the rat, more rapidly did the 3 H concentration decrease. The biological half-life of whole body residues was about 2 days in nursing offsprings and about 4 days in mature rats. Tissue-bound 3 H showed high and rapid distribution to the liver, whereas it was slow in the brain and muscle, and this tendency was more prominent in younger rats. Compared with 3 H in tissue water, the concentration of bound 3 H was relatively high, being prominent in younger rats. The time-course changes of 3 H concentration from both origins also showed age dependence. The in vivo exposure dose after administration of 1 μCi/g body weight of HTO- 3 H was generally smaller in younger rats, the exposure at ages 10 and 25 days being about a half of that of mature rats. Supposing that human metabolism is similar, the estimated dose in one-year-olds after ingestion of 1 μCi/kg body weight of 3 H in the form of HTO is about 3 times that in adults, and that after 1 μCi/kg body weight of 3 H in infants, about a half of that in adults. (Chiba, N.)

Quality Saving Mechanisms of Mitochondria during Aging in a Fully Time-Dependent Computational Biophysical Model.

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Daniel Mellem

Full Text Available Mitochondria are essential for the energy production of eukaryotic cells. During aging mitochondria run through various processes which change their quality in terms of activity, health and metabolic supply. In recent years, many of these processes such as fission and fusion of mitochondria, mitophagy, mitochondrial biogenesis and energy consumption have been subject of research. Based on numerous experimental insights, it was possible to qualify mitochondrial behaviour in computational simulations. Here, we present a new biophysical model based on the approach of Figge et al. in 2012. We introduce exponential decay and growth laws for each mitochondrial process to derive its time-dependent probability during the aging of cells. All mitochondrial processes of the original model are mathematically and biophysically redefined and additional processes are implemented: Mitochondrial fission and fusion is separated into a metabolic outer-membrane part and a protein-related inner-membrane part, a quality-dependent threshold for mitophagy and mitochondrial biogenesis is introduced and processes for activity-dependent internal oxidative stress as well as mitochondrial repair mechanisms are newly included. Our findings reveal a decrease of mitochondrial quality and a fragmentation of the mitochondrial network during aging. Additionally, the model discloses a quality increasing mechanism due to the interplay of the mitophagy and biogenesis cycle and the fission and fusion cycle of mitochondria. It is revealed that decreased mitochondrial repair can be a quality saving process in aged cells. Furthermore, the model finds strategies to sustain the quality of the mitochondrial network in cells with high production rates of reactive oxygen species due to large energy demands. Hence, the model adds new insights to biophysical mechanisms of mitochondrial aging and provides novel understandings of the interdependency of mitochondrial processes.

Critical Age-Dependent Branching Markov Processes and their ...

Indian Academy of Sciences (India)

This paper studies: (i) the long-time behaviour of the empirical distribution of age and normalized position of an age-dependent critical branching Markov process conditioned on non-extinction; and (ii) the super-process limit of a sequence of age-dependent critical branching Brownian motions.

Active Aging Promotion: Results from the Vital Aging Program

Directory of Open Access Journals (Sweden)

Mariagiovanna Caprara

2013-01-01

Full Text Available Active aging is one of the terms in the semantic network of aging well, together with others such as successful, productive, competent aging. All allude to the new paradigm in gerontology, whereby aging is considered from a positive perspective. Most authors in the field agree active aging is a multidimensional concept, embracing health, physical and cognitive fitness, positive affect and control, social relationships and engagement. This paper describes Vital Aging, an individual active aging promotion program implemented through three modalities: Life, Multimedia, and e-Learning. The program was developed on the basis of extensive evidence about individual determinants of active aging. The different versions of Vital Aging are described, and four evaluation studies (both formative and summative are reported. Formative evaluation reflected participants’ satisfaction and expected changes; summative evaluations yielded some quite encouraging results using quasi-experimental designs: those who took part in the programs increased their physical exercise, significantly improved their diet, reported better memory, had better emotional balance, and enjoyed more cultural, intellectual, affective, and social activities than they did before the course, thus increasing their social relationships. These results are discussed in the context of the common literature within the field and, also, taking into account the limitations of the evaluations accomplished.

Active aging promotion: results from the vital aging program.

Science.gov (United States)

Caprara, Mariagiovanna; Molina, María Ángeles; Schettini, Rocío; Santacreu, Marta; Orosa, Teresa; Mendoza-Núñez, Víctor Manuel; Rojas, Macarena; Fernández-Ballesteros, Rocío

2013-01-01

Active aging is one of the terms in the semantic network of aging well, together with others such as successful, productive, competent aging. All allude to the new paradigm in gerontology, whereby aging is considered from a positive perspective. Most authors in the field agree active aging is a multidimensional concept, embracing health, physical and cognitive fitness, positive affect and control, social relationships and engagement. This paper describes Vital Aging, an individual active aging promotion program implemented through three modalities: Life, Multimedia, and e-Learning. The program was developed on the basis of extensive evidence about individual determinants of active aging. The different versions of Vital Aging are described, and four evaluation studies (both formative and summative) are reported. Formative evaluation reflected participants' satisfaction and expected changes; summative evaluations yielded some quite encouraging results using quasi-experimental designs: those who took part in the programs increased their physical exercise, significantly improved their diet, reported better memory, had better emotional balance, and enjoyed more cultural, intellectual, affective, and social activities than they did before the course, thus increasing their social relationships. These results are discussed in the context of the common literature within the field and, also, taking into account the limitations of the evaluations accomplished.

Long-term treatment of anterior pituitary cells with nitric oxide induces programmed cell death.

Science.gov (United States)

Velardez, Miguel Omar; Poliandri, Ariel Hernán; Cabilla, Jimena Paula; Bodo, Cristian Carlos Armando; Machiavelli, Leticia Inés; Duvilanski, Beatriz Haydeé

2004-04-01

Nitric oxide (NO) plays a complex role in modulating programmed cell death. It can either protect the cell from apoptotic death or mediate apoptosis, depending on its concentration and the cell type and/or status. In this study, we demonstrate that long-term exposition to NO induces cell death of anterior pituitary cells from Wistar female rats. DETA NONOate (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate, 1 mm], a NO donor that releases NO for an extended period of time, decreased cellular viability and prolactin release from primary cultures of anterior pituitary cells. Morphological studies showed an increase in the number of cells with chromatin condensation and nuclear fragmentation at 24 and 48 h after DETA/NO exposure. DNA internucleosomal fragmentation was also observed at the same time. Reversibility of the NO effect on cellular viability and prolactin release was observed only when the cells were incubated with DETA/NO for less than 6 h. Most apoptotic cells were immunopositive for prolactin, suggesting a high susceptibility of lactotrophs to the effect of NO. The cytotoxic effect of NO is dependent of caspase-9 and caspase-3, but seems to be independent of oxidative stress or nitrosative stress. Our results show that the exposition of anterior pituitary cells to NO for long periods induces programmed cell death of anterior pituitary cells.

When aging reaches CD4+ T-cells: phenotypic and functional changes

Directory of Open Access Journals (Sweden)

Marco Antonio Moro-García

2013-05-01

Full Text Available Beyond midlife, the immune system shows aging features and its defensive capability becomes impaired, by a process known as immunosenescence that involves many changes in the innate and adaptive responses. Innate immunity seems to be better preserved globally, while the adaptive immune response exhibits profound age-dependent modifications. Elderly people display a decline in numbers of naïve T-cells in peripheral blood and lymphoid tissues, while, in contrast, their proportion of highly differentiated effector and memory T-cells, such as the CD28null T-cells, increases markedly. Naïve and memory CD4+ T-cells constitute a highly dynamic system with constant homeostatic and antigen-driven proliferation, influx, and loss of T-cells. Thymic activity dwindles with age and essentially ceases in the later decades of life, severely constraining the generation of new T-cells. Homeostatic control mechanisms are very effective at maintaining a large and diverse subset of naïve CD4+ T-cells throughout life, but although later than in CD8+T-cell compartment, these mechanisms ultimately fail with age.

Analysis of mice radiosensitivity depending on age

International Nuclear Information System (INIS)

Bogatyrev, A.V.; Timoshenko, S.I.; Nikanorova, N.G.; Sverdlov, A.G.

1979-01-01

In order to elucidate mechanisms of age variations in radiosensitivity of mice a study was made of the sensitivity of in vitro irradiated bone marrow stem cells, taken from animals of different age, and postradiation recovery of leukocyte content of peripheral blood and cellularity of bone marrow and spleen. Using the method of spleen colonies similar affections were revealed in bone marrow cells of animals of different age. The degree of recovery of the hemopoietic cell pool was significantly lower in newborn mice than in adults after exposure to a dose (LDsub(50/30)) equally effective with respect to mortality

Sirtuins, Cell Senescence, and Vascular Aging.

Science.gov (United States)

Kida, Yujiro; Goligorsky, Michael S

2016-05-01

The sirtuins (SIRTs) constitute a class of proteins with nicotinamide adenine dinucleotide-dependent deacetylase or adenosine diphosphate-ribosyltransferase activity. Seven SIRT family members have been identified in mammals, from SIRT1, the best studied for its role in vascular aging, to SIRT7. SIRT1 and SIRT2 are localized in the nucleus and cytoplasm. SIRT3, SIRT4, and SIRT5 are mitochondrial, and SIRT6 and SIRT7 are nuclear. Extensive studies have clearly revealed that SIRT proteins regulate diverse cell functions and responses to stressors. Vascular aging involves the aging process (senescence) of endothelial and vascular smooth muscle cells. Two types of cell senescence have been identified: (1) replicative senescence with telomere attrition; and (2) stress-induced premature senescence without telomere involvement. Both types of senescence induce vascular cell growth arrest and loss of vascular homeostasis, and contribute to the initiation and progression of cardiovascular diseases. Previous mechanistic studies have revealed in detail that SIRT1, SIRT3, and SIRT6 show protective functions against vascular aging, and definite vascular function of other SIRTs is under investigation. Thus, direct SIRT modulation and nicotinamide adenine dinucleotide stimulation of SIRT are promising candidates for cardiovascular disease therapy. A small number of pilot studies have been conducted to assess SIRT modulation in humans. These clinical studies have not yet provided convincing evidence that SIRT proteins alleviate morbidity and mortality in patients with cardiovascular diseases. The outcomes of multiple ongoing clinical trials are awaited to define the efficacy of SIRT modulators and SIRT activators in cardiovascular diseases, along with the potential adverse effects of chronic SIRT modulation. Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Age-dependent changes of the antioxidant system in rat livers are accompanied by altered MAPK activation and a decline in motor signaling

Science.gov (United States)

Yang, Wei; Burkhardt, Britta; Fischer, Luise; Beirow, Maja; Bork, Nadja; Wönne, Eva C.; Wagner, Cornelia; Husen, Bettina; Zeilinger, Katrin; Liu, Liegang; Nussler, Andreas K.

2015-01-01

Aging is characterized by a progressive decrease of cellular functions, because cells gradually lose their capacity to respond to injury. Increased oxidative stress is considered to be one of the major contributors to age-related changes in all organs including the liver. Our study has focused on elucidating whether important antioxidative enzymes, the mTOR pathway, and MAPKs exhibit age-dependent changes in the liver of rats during aging. We found an age-dependent increase of GSH in the cytosol and mitochondria. The aged liver showed an increased SOD enzyme activity, while the CAT enzyme activity decreased. HO-1 and NOS-2 gene expression was lower in adult rats, but up-regulated in aged rats. Western blot analysis revealed that SOD1, SOD2, GPx, GR, γ-GCL, and GSS were age-dependent up-regulated, while CAT remained constant. We also demonstrated that the phosphorylation of Akt, JNK, p38, and TSC2Ser1254 decreased while ERK1/2 and TSC2Thr1462 increased age-dependently. Furthermore, our data show that the mTOR pathway seems to be activated in livers of aged rats, and hence stimulating cell proliferation/regeneration, as confirmed by an age-dependent increase of PCNA and p-eIF4ESer209 protein expression. Our data may help to explain the fact that liver cells only proliferate in cases of necessity, like injury and damage. In summary, we have demonstrated that, age-dependent changes of the antioxidant system and stress-related signaling pathways occur in the livers of rats, which may help to better understand organ aging. PMID:27004051

Age-dependence of the x-ray-induced deficiency in DNA synthesis in HeLa S3 cells during generation 1

International Nuclear Information System (INIS)

Griffiths, T.D.; Tolmach, L.J.

1975-01-01

The radiation-induced deficiency in DNA synthesis in Generation 1 was studied as a function of the age of HeLa S3 cells at the time of exposure to 220 kV x rays in the previous generation (Generation 0). The amount of DNA synthesized is dependent on the stage in the generation cycle at which cells are irradiated. The smallest deficiency (20 to 35 percent after a dose of 500 rad) is observed in cells irradiated in early G1 or early G2, while the greatest deficiency (55 to 70 percent after 500 rad) is found in cells irradiated at mitosis or at the G1/S transition. The high sensitivity of cells at G1/S is also manifested by a steeper dose-response curve. Cells irradiated in late G2, past the point where their progression is temporarily blocked by x rays, synthesize a normal amount of DNA in Generation 1, while cells that are held up in the G2 block exhibit deficient synthesis in the next generation. The extent of the deficiency in early G1 cells can be enhanced by treatment with 1 mM hydroxyurea for several hours immediately following irradiation. The possibility that deficient DNA synthesis is related to cell killing, and the relation between the G2 block and deficient synthesis, are discussed

Aging as an evolvability-increasing program which can be switched off by organism to mobilize additional resources for survival.

Science.gov (United States)

Skulachev, Maxim V; Severin, Fedor F; Skulachev, Vladimir P

2015-01-01

During the last decade, several pieces of convincing evidence were published indicating that aging of living organisms is programmed, being a particular case of programmed death of organism (phenoptosis). Among them, the following observations can be mentioned. (1) Species were described that show negligible aging. In mammals, the naked mole rat is the most impressive example. This is a rodent of mouse size living at least 10-fold longer than a mouse and having fecundity higher than a mouse and no agerelated diseases. (2) In some species with high aging rate, genes responsible for active organization of aging by poisoning of the organism with endogenous metabolites have been identified. (3) In women, standard deviations divided by the mean are the same for age of menarche (an event controlled by the ontogenetic program) and for age of menopause (an aging-related event). (4) Inhibitors of programmed cell death (apoptosis and necrosis) retard and in certain cases even reverse the development of age-dependent pathologies. (5) In aging species, the rate of aging is regulated by the individual which responds by changes in this rate to changes in the environmental conditions. In this review, we consider point (5) in detail. Data are summarized suggesting that inhibition of aging rate by moderate food restriction can be explained assuming that such restriction is perceived by the organism as a signal of future starvation. In response to this dramatic signal, the organism switches off such an optional program as aging, mobilizing in such a way additional reserves for survival. A similar explanation is postulated for geroprotective effects of heavy muscle work, a lowering or a rise in the external temperature, small amounts of metabolic poisons (hormesis), low doses of radiation, and other deleterious events. On the contrary, sometimes certain positive signals can prolong life by inhibiting the aging program in individuals who are useful for the community (e

Uncertainty and sensitivity analyses for age-dependent unavailability model integrating test and maintenance

International Nuclear Information System (INIS)

Kančev, Duško; Čepin, Marko

2012-01-01

Highlights: ► Application of analytical unavailability model integrating T and M, ageing, and test strategy. ► Ageing data uncertainty propagation on system level assessed via Monte Carlo simulation. ► Uncertainty impact is growing with the extension of the surveillance test interval. ► Calculated system unavailability dependence on two different sensitivity study ageing databases. ► System unavailability sensitivity insights regarding specific groups of BEs as test intervals extend. - Abstract: The interest in operational lifetime extension of the existing nuclear power plants is growing. Consequently, plants life management programs, considering safety components ageing, are being developed and employed. Ageing represents a gradual degradation of the physical properties and functional performance of different components consequently implying their reduced availability. Analyses, which are being made in the direction of nuclear power plants lifetime extension are based upon components ageing management programs. On the other side, the large uncertainties of the ageing parameters as well as the uncertainties associated with most of the reliability data collections are widely acknowledged. This paper addresses the uncertainty and sensitivity analyses conducted utilizing a previously developed age-dependent unavailability model, integrating effects of test and maintenance activities, for a selected stand-by safety system in a nuclear power plant. The most important problem is the lack of data concerning the effects of ageing as well as the relatively high uncertainty associated to these data, which would correspond to more detailed modelling of ageing. A standard Monte Carlo simulation was coded for the purpose of this paper and utilized in the process of assessment of the component ageing parameters uncertainty propagation on system level. The obtained results from the uncertainty analysis indicate the extent to which the uncertainty of the selected

Age-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus.

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Krenzien, F; Quante, M; Heinbokel, T; Seyda, M; Minami, K; Uehara, H; Biefer, H R C; Schuitenmaker, J M; Gabardi, S; Splith, K; Schmelzle, M; Petrides, A K; Azuma, H; Pratschke, J; Li, X C; ElKhal, A; Tullius, S G

2017-05-01

Immunosuppression in elderly recipients has been underappreciated in clinical trials. Here, we assessed age-specific effects of the calcineurin inhibitor tacrolimus (TAC) in a murine transplant model and assessed its clinical relevance on human T cells. Old recipient mice exhibited prolonged skin graft survival compared with young animals after TAC administration. More important, half of the TAC dose was sufficient in old mice to achieve comparable systemic trough levels. TAC administration was able to reduce proinflammatory interferon-γ cytokine production and promote interleukin-10 production in old CD4 + T cells. In addition, TAC administration decreased interleukin-2 secretion in old CD4 + T cells more effectively while inhibiting the proliferation of CD4 + T cells in old mice. Both TAC-treated murine and human CD4 + T cells demonstrated an age-specific suppression of intracellular calcineurin levels and Ca 2+ influx, two critical pathways in T cell activation. Of note, depletion of CD8 + T cells did not alter allograft survival outcome in old TAC-treated mice, suggesting that TAC age-specific effects were mainly CD4 + T cell mediated. Collectively, our study demonstrates age-specific immunosuppressive capacities of TAC that are CD4 + T cell mediated. The suppression of calcineurin levels and Ca 2+ influx in both old murine and human T cells emphasizes the clinical relevance of age-specific effects when using TAC. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

NIA Aging Cell Repository

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Federal Laboratory Consortium — To facilitate aging research on cells in culture, the NIA provides support for the NIA Aging Cell Repository, located at the Coriell Institute for Medical Research...

Aging-dependent decline of IL-10 producing B cells coincides with production of antinuclear antibodies but not rheumatoid factors.

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van der Geest, Kornelis S M; Lorencetti, Pedro G; Abdulahad, Wayel H; Horst, Gerda; Huitema, Minke; Roozendaal, Caroline; Kroesen, Bart-Jan; Brouwer, Elisabeth; Boots, Annemieke M H

2016-03-01

Aging is associated with development of autoimmunity. Loss of B cell tolerance in the elderly is suggested by an increased prevalence of anti-nuclear antibodies (ANAs) and rheumatoid factors (RFs). Accumulating evidence indicates that B cells also impact autoimmunity via secretion of cytokines. So far, few studies have directly assessed the effect of aging on the latter B cell function. Here, we determined if and how human aging influences the production of cytokines by B cells. In a cross-sectional study, we found that absolute numbers of circulating B cells were similar in 31 young (ages 19-39) and 73 old (age ≥ 60) individuals. Numbers of transitional B cells (CD19(+)CD27(-)CD38(High)CD24(High)) were decreased in old individuals, whereas numbers of naive and memory B cell subsets were comparable in young and old individuals. Short-term in vitro stimulation of whole blood samples revealed that numbers of B cells capable of producing TNF-α were similar in young and old individuals. In contrast, B cells capable of IL-10 production were decreased in old subjects. This decline of IL-10(+) B cells was observed in old individuals that were ANA positive, and in those that were negative for both ANAs and RFs. However, IL-10(+) B cells were remarkably well retained in the circulation of old subjects that were RF positive. Thus, pro-inflammatory TNF-α(+) B cells are retained in the elderly, whereas IL-10(+) B cells generally decline. In addition, our findings indicate that IL-10(+) B cells may differentially impact the development of ANAs and RFs in the elderly. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of advanced glycosylation end products (AGEs) on proliferation of human bone marrow mesenchymal stem cells (MSCs) in vitro.

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Lu, Yi-Qun; Lu, Yan; Li, Hui-Juan; Cheng, Xing-Bo

2012-10-01

This study aims to explore the effect of advanced glycosylation end products (AGEs) on proliferation of human bone marrow mesenchymal stem cells in vitro and the underlying mechanism. Bone marrow cell proliferation was determined by WST-8 assay using Cell Counting Kit-8 under the intervention of AGEs. In addition, the content of maldondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were also measured. The proliferation activity of mesenchymal stem cells (MSCs) was significantly inhibited when AGEs were added to culture medium, and this effect was dose-dependent and time-dependent. As the concentration of AGEs-bovine serum albumin increased, the content of intracellular MDA was significantly increased, but the activity of SOD in cell homogenates was significantly suppressed, which also showed a dose-dependent manner. AGEs could significantly inhibit the proliferation of MSCs in vitro by improving the oxidative stress in MSCs and breaking the homeostasis of intracellular environment.

Cell age dependent variations in oxidative protective enzymes

International Nuclear Information System (INIS)

Blakely, E.A.; Chang, P.Y.; Lommel, L.; Tobias, C.A.

1986-01-01

Activity levels of antioxidant enzymes were correlated before and after heavy-ion exposures with cellular radiosensitivity. In preliminary feasibility experiments with human T-1 cells relatively high antioxidant enzyme levels were shown in the unirradiated G 1 phase prior to the normal DNA synthetic phase. Endogenous cellular levels of three antioxidant enzymes were measured at various times in the unirradiated human T-1 cell division cycle. The enzymes measured were: catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSHPX). Unlike the case in Chinese hamster V79 cells the early data with the synchronized human cell show that in very early G 1 phase (e.g., approximately 1.5 hours after mitotic selection) there are significant peaks in the levels (U/mg cell protein) of both CAT and SOD. Both enzymes show increases as the unirradiated cells progressed from mitosis into G 1 phase while the levels of GSHPX measured in duplicate samples were somewhat more variable than was the case for the other two enzymes. Studies were made in collaboration with the Armed Forces Radiobiology Research Institute

Age-dependent lung dosimetry of radon progeny

International Nuclear Information System (INIS)

Hofmann, W.; Martonen, T.B.; Menache, M.G.

1988-02-01

Two morphometric models differing in the tracheobronchial region, were compared in the present paper: Model 1 is based on the adult morphology of Weibel, assuming that all bronchial airways grow in equal proportion; while Model 2 adopts the adult structure proposed by Yeh and Schum, using measured airway dimensions in the right upper lobe as a function of age. Tidal volume and respiratory frequency also vary with age: while the breathing frequency decreases with rising age, tidal volume increases. Radiation doses in each bronchial airway generation were computed for the deep lying basal cells as well as for the more uniformly distributed serous (SMGS) cells, which are currently assumed to be the progenitor cells for bronchial carcinomas. Radiation doses to both target cells were significantly higher in the newborn than in the adult, for all simulated breathing patterns, showing the highest relative increase in upper bronchial airways. Comparing both tracheobronchial growth models, Model 1 predicts higher doses at early ages, but produced lower doses in the adult lung

Aging and insulin signaling differentially control normal and tumorous germline stem cells.

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Kao, Shih-Han; Tseng, Chen-Yuan; Wan, Chih-Ling; Su, Yu-Han; Hsieh, Chang-Che; Pi, Haiwei; Hsu, Hwei-Jan

2015-02-01

Aging influences stem cells, but the processes involved remain unclear. Insulin signaling, which controls cellular nutrient sensing and organismal aging, regulates the G2 phase of Drosophila female germ line stem cell (GSC) division cycle in response to diet; furthermore, this signaling pathway is attenuated with age. The role of insulin signaling in GSCs as organisms age, however, is also unclear. Here, we report that aging results in the accumulation of tumorous GSCs, accompanied by a decline in GSC number and proliferation rate. Intriguingly, GSC loss with age is hastened by either accelerating (through eliminating expression of Myt1, a cell cycle inhibitory regulator) or delaying (through mutation of insulin receptor (dinR) GSC division, implying that disrupted cell cycle progression and insulin signaling contribute to age-dependent GSC loss. As flies age, DNA damage accumulates in GSCs, and the S phase of the GSC cell cycle is prolonged. In addition, GSC tumors (which escape the normal stem cell regulatory microenvironment, known as the niche) still respond to aging in a similar manner to normal GSCs, suggesting that niche signals are not required for GSCs to sense or respond to aging. Finally, we show that GSCs from mated and unmated females behave similarly, indicating that female GSC-male communication does not affect GSCs with age. Our results indicate the differential effects of aging and diet mediated by insulin signaling on the stem cell division cycle, highlight the complexity of the regulation of stem cell aging, and describe a link between ovarian cancer and aging. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Mitochondrial fission proteins regulate programmed cell death in yeast.

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Fannjiang, Yihru; Cheng, Wen-Chih; Lee, Sarah J; Qi, Bing; Pevsner, Jonathan; McCaffery, J Michael; Hill, R Blake; Basañez, Gorka; Hardwick, J Marie

2004-11-15

The possibility that single-cell organisms undergo programmed cell death has been questioned in part because they lack several key components of the mammalian cell death machinery. However, yeast encode a homolog of human Drp1, a mitochondrial fission protein that was shown previously to promote mammalian cell death and the excessive mitochondrial fragmentation characteristic of apoptotic mammalian cells. In support of a primordial origin of programmed cell death involving mitochondria, we found that the Saccharomyces cerevisiae homolog of human Drp1, Dnm1, promotes mitochondrial fragmentation/degradation and cell death following treatment with several death stimuli. Two Dnm1-interacting factors also regulate yeast cell death. The WD40 repeat protein Mdv1/Net2 promotes cell death, consistent with its role in mitochondrial fission. In contrast to its fission function in healthy cells, Fis1 unexpectedly inhibits Dnm1-mediated mitochondrial fission and cysteine protease-dependent cell death in yeast. Furthermore, the ability of yeast Fis1 to inhibit mitochondrial fission and cell death can be functionally replaced by human Bcl-2 and Bcl-xL. Together, these findings indicate that yeast and mammalian cells have a conserved programmed death pathway regulated by a common molecular component, Drp1/Dnm1, that is inhibited by a Bcl-2-like function.

Demographic Trends of Adults in New York City Opioid Treatment Programs--An Aging Population.

Science.gov (United States)

Han, Benjamin; Polydorou, Soteri; Ferris, Rosie; Blaum, Caroline S; Ross, Stephen; McNeely, Jennifer

2015-01-01

The population of adults accessing opioid treatment is growing older, but exact estimates vary widely, and little is known about the characteristics of the aging treatment population. Further, there has been little research regarding the epidemiology, healt h status, and functional impairments in this population. To determine the utilization of opioid treatment services by older adults in New York City. This study used administrative data from New York State licensed drug treatment programs to examine overall age trends and characteristics of older adults in opioid treatment programs in New York City from 1996 to 2012. We found significant increases in utilization of opioid treatment programs by older adults in New York City. By 2012, those aged 50-59 made up the largest age group in opioid treatment programs. Among older adults there were notable shifts in demographic background including gender and ethnicity, and an increase in self-reported impairments. More research is needed to fully understand the specific characteristics and needs of older adults with opioid dependence.

Age-dependent complex noise fluctuations in the brain

International Nuclear Information System (INIS)

Mareš, Jan; Vyšata, Oldřich; Procházka, Aleš; Vališ, Martin

2013-01-01

We investigated the parameters of colored noise in EEG data of 17 722 professional drivers aged 18–70. The whole study is based upon experiments showing that biological neural networks may operate in the vicinity of the critical point and that the balance between excitation and inhibition in the human brain is important for the transfer of information. This paper is devoted to the study of EEG power spectrum which can be described best by a power function with 1/f λ distribution and colored noise corresponding to the critical point in the EEG signal has the value of λ = 1 (purple noise). The slow accumulation of energy and its quick release is a universal property of the 1/f distribution. The physiological mechanism causing energy dissipation in the brain seems to depend on the number and strength of the connections between clusters of neurons. With ageing, the number of connections between the neurons decreases. Learning ability and intellectual performance also decrease. Therefore, age-related changes in the λ coefficient can be anticipated. We found that absolute values of λ coefficients decrease significantly with increasing age. Deviations from this rule are related to age-dependent slowing of the dominant frequency in the alpha band. Age-dependent change in the parameter and colored noise may be indicative of age-related changes in the self-organization of brain activity. Results obtained include (i) the age-dependent decrease of the absolute values of the average λ coefficient with the regression coefficient 0.005 1/year, (ii) distribution of λ value changes related to EEG frequency bands and to localization of electrodes on the scalp, and (iii) relation of age-dependent changes of colored noise and EEG energy in separate frequency bands. (paper)

Aged garlic extract and S-allylcysteine prevent apoptotic cell death in a chemical hypoxia model

Directory of Open Access Journals (Sweden)

Marisol Orozco-Ibarra

Full Text Available BACKGROUND: Aged garlic extract (AGE and its main constituent S-allylcysteine (SAC are natural antioxidants with protective effects against cerebral ischemia or cancer, events that involve hypoxia stress. Cobalt chloride (CoCl2 has been used to mimic hypoxic conditions through the stabilization of the α subunit of hypoxia inducible factor (HIF-Ια and up-regulation of HIF-1a-dependent genes as well as activation of hypoxic conditions such as reactive oxygen species (ROS generation, loss of mitochondrial membrane potential and apoptosis. The present study was designed to assess the effect of AGE and SAC on the CoCl2-chemical hypoxia model in PC12 cells RESULTS: We found that CoCl2 induced the stabilization of HIF-1a and its nuclear localization. CoCl2 produced ROS and apoptotic cell death that depended on hypoxia extent. The treatment with AGE and SAC decreased ROS and protected against CoCl2-induced apoptotic cell death which depended on the CoCl2 concentration and incubation time. SAC or AGE decreased the number of cells in the early and late stages of apoptosis. Interestingly, this protective effect was associated with attenuation in HIF-1a stabilization, activity not previously reported for AGE and SAC CONCLUSIONS: Obtained results show that AGE and SAC decreased apoptotic CoCl2-induced cell death. This protection occurs by affecting the activity of HIF-1a and supports the use of these natural compounds as a therapeutic alternative for hypoxic conditions

Retinal pigment epithelial cell multinucleation in the aging eye - a mechanism to repair damage and maintain homoeostasis.

Science.gov (United States)

Chen, Mei; Rajapakse, Dinusha; Fraczek, Monika; Luo, Chang; Forrester, John V; Xu, Heping

2016-06-01

Retinal pigment epithelial (RPE) cells are central to retinal health and homoeostasis. Dysfunction or death of RPE cells underlies many age-related retinal degenerative disorders particularly age-related macular degeneration. During aging RPE cells decline in number, suggesting an age-dependent cell loss. RPE cells are considered to be postmitotic, and how they repair damage during aging remains poorly defined. We show that RPE cells increase in size and become multinucleate during aging in C57BL/6J mice. Multinucleation appeared not to be due to cell fusion, but to incomplete cell division, that is failure of cytokinesis. Interestingly, the phagocytic activity of multinucleate RPE cells was not different from that of mononuclear RPE cells. Furthermore, exposure of RPE cells in vitro to photoreceptor outer segment (POS), particularly oxidized POS, dose-dependently promoted multinucleation and suppressed cell proliferation. Both failure of cytokinesis and suppression of proliferation required contact with POS. Exposure to POS also induced reactive oxygen species and DNA oxidation in RPE cells. We propose that RPE cells have the potential to proliferate in vivo and to repair defects in the monolayer. We further propose that the conventionally accepted 'postmitotic' status of RPE cells is due to a modified form of contact inhibition mediated by POS and that RPE cells are released from this state when contact with POS is lost. This is seen in long-standing rhegmatogenous retinal detachment as overtly proliferating RPE cells (proliferative vitreoretinopathy) and more subtly as multinucleation during normal aging. Age-related oxidative stress may promote failure of cytokinesis and multinucleation in RPE cells. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Panels of tumor-derived RNA markers in peripheral blood of patients with non-small cell lung cancer: their dependence on age, gender and clinical stages.

Science.gov (United States)

Chian, Chih-Feng; Hwang, Yi-Ting; Terng, Harn-Jing; Lee, Shih-Chun; Chao, Tsui-Yi; Chang, Hung; Ho, Ching-Liang; Wu, Yi-Ying; Perng, Wann-Cherng

2016-08-02

Peripheral blood mononuclear cell (PBMC)-derived gene signatures were investigated for their potential use in the early detection of non-small cell lung cancer (NSCLC). In our study, 187 patients with NSCLC and 310 age- and gender-matched controls, and an independent set containing 29 patients for validation were included. Eight significant NSCLC-associated genes were identified, including DUSP6, EIF2S3, GRB2, MDM2, NF1, POLDIP2, RNF4, and WEE1. The logistic model containing these significant markers was able to distinguish subjects with NSCLC from controls with an excellent performance, 80.7% sensitivity, 90.6% specificity, and an area under the receiver operating characteristic curve (AUC) of 0.924. Repeated random sub-sampling for 100 times was used to validate the performance of classification training models with an average AUC of 0.92. Additional cross-validation using the independent set resulted in the sensitivity 75.86%. Furthermore, six age/gender-dependent genes: CPEB4, EIF2S3, GRB2, MCM4, RNF4, and STAT2 were identified using age and gender stratification approach. STAT2 and WEE1 were explored as stage-dependent using stage-stratified subpopulation. We conclude that these logistic models using different signatures for total and stratified samples are potential complementary tools for assessing the risk of NSCLC.

High fat programming of beta cell compensation, exhaustion, death and dysfunction.

Science.gov (United States)

Cerf, Marlon E

2015-03-01

Programming refers to events during critical developmental windows that shape progeny health outcomes. Fetal programming refers to the effects of intrauterine (in utero) events. Lactational programming refers to the effects of events during suckling (weaning). Developmental programming refers to the effects of events during both fetal and lactational life. Postnatal programming refers to the effects of events either from birth (lactational life) to adolescence or from weaning (end of lactation) to adolescence. Islets are most plastic during the early life course; hence programming during fetal and lactational life is most potent. High fat (HF) programming is the maintenance on a HF diet (HFD) during critical developmental life stages that alters progeny metabolism and physiology. HF programming induces variable diabetogenic phenotypes dependent on the timing and duration of the dietary insult. Maternal obesity reinforces HF programming effects in progeny. HF programming, through acute hyperglycemia, initiates beta cell compensation. However, HF programming eventually leads to chronic hyperglycemia that triggers beta cell exhaustion, death and dysfunction. In HF programming, beta cell dysfunction often co-presents with insulin resistance. Balanced, healthy nutrition during developmental windows is critical for preserving beta cell structure and function. Thus early positive nutritional interventions that coincide with the development of beta cells may reduce the overwhelming burden of diabetes and metabolic disease. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Short-term high dose of quercetin and resveratrol alters aging markers in human kidney cells

Directory of Open Access Journals (Sweden)

Fatemeh Abharzanjani

2017-01-01

Full Text Available Background: Hyperglycemia-mediated oxidative stress implicates in etiology of kidney cell aging and diabetic nephropathy. We evaluated the effects of different doses of resveratrol and quercetin and their combination therapy on aging marker in human kidney cell culture under hyperglycemia condition. Methods: Human embryonic kidney cell (HEK-293 was cultured in Dulbecco's Modified Eagle Medium (DMEM containing 100 mM (18 mg/L for 24 h. The cells were treated with resveratrol (2.5, 5, 10 μm, quercetin (3, 6, 12 μm, and combination of these (R 2.5 μm, Q 3 μm and (R 5 μm, Q 6 μm and (R 10 μm, Q 12 μm for 48 h, and then, cells were lysed to access RNA and lysate. Results: The analysis of data showed that beta-galactosidase enzyme gene expression as an aging marker in all treatment groups has reduced in a dose-dependent manner. Gene expression of Sirtuin1 and thioredoxin (Trx in all treated groups in comparison to control group increased in a dose-dependent fashion. Trx interacting protein (TXNIP gene expression decreased in a dose-dependent manner in all treated groups, especially in resveratrol and combination therapy. Conclusions: According to the results of this research, quercetin, resveratrol, and especially combination treatments with increased expression levels of antioxidants, can reduce aging markers in HEK cell line in hyperglycemia conditions. These results lead us to use flavonoids such as resveratrol for anti-aging potential.

Cellular aging of mitochondrial DNA-depleted cells

International Nuclear Information System (INIS)

Park, Sun Young; Choi, Bongkun; Cheon, Hwanju; Pak, Youngmi Kim; Kulawiec, Mariola; Singh, Keshav K.; Lee, Myung-Shik

2004-01-01

We have reported that mitochondrial DNA-depleted ρ 0 cells are resistant to cell death. Because aged cells have frequent mitochondrial DNA mutations, the resistance of ρ 0 cells against cell death might be related to the apoptosis resistance of aged cells and frequent development of cancers in aged individuals. We studied if ρ 0 cells have features simulating aged cells. SK-Hep1 hepatoma ρ 0 cells showed typical morphology associated with aging such as increased size and elongated appearance. They had increased senescence-associated β-Gal activity, lipofuscin pigment, and plasminogen activator inhibitor-1 expression. Consistent with their decreased proliferation, the expression of mitotic cyclins was decreased and that of cdk inhibitors was increased. Rb hypophosphorylation and decreased telomerase activity were also noted. Features simulating aged cells were also observed in MDA-MB-435 ρ 0 cells. These results support the mitochondrial theory of aging, and suggest that ρ 0 cells could serve as an in vitro model for aged cells

H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells.

Science.gov (United States)

Fernández, Agustín F; Bayón, Gustavo F; Urdinguio, Rocío G; Toraño, Estela G; García, María G; Carella, Antonella; Petrus-Reurer, Sandra; Ferrero, Cecilia; Martinez-Camblor, Pablo; Cubillo, Isabel; García-Castro, Javier; Delgado-Calle, Jesús; Pérez-Campo, Flor M; Riancho, José A; Bueno, Clara; Menéndez, Pablo; Mentink, Anouk; Mareschi, Katia; Claire, Fabian; Fagnani, Corrado; Medda, Emanuela; Toccaceli, Virgilia; Brescianini, Sonia; Moran, Sebastián; Esteller, Manel; Stolzing, Alexandra; de Boer, Jan; Nisticò, Lorenza; Stazi, Maria A; Fraga, Mario F

2015-01-01

In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone post-translational modifications. However, the chromatin marks associated with changes in DNA methylation in adult stem cells during lifetime are still largely unknown. Here, DNA methylation profiling of mesenchymal stem cells (MSCs) obtained from individuals aged 2 to 92 yr identified 18,735 hypermethylated and 45,407 hypomethylated CpG sites associated with aging. As in differentiated cells, hypermethylated sequences were enriched in chromatin repressive marks. Most importantly, hypomethylated CpG sites were strongly enriched in the active chromatin mark H3K4me1 in stem and differentiated cells, suggesting this is a cell type-independent chromatin signature of DNA hypomethylation during aging. Analysis of scedasticity showed that interindividual variability of DNA methylation increased during aging in MSCs and differentiated cells, providing a new avenue for the identification of DNA methylation changes over time. DNA methylation profiling of genetically identical individuals showed that both the tendency of DNA methylation changes and scedasticity depended on nongenetic as well as genetic factors. Our results indicate that the dynamics of DNA methylation during aging depend on a complex mixture of factors that include the DNA sequence, cell type, and chromatin context involved and that, depending on the locus, the changes can be modulated by genetic and/or external factors. © 2015 Fernández et al.; Published by Cold Spring Harbor Laboratory Press.

Age-dependent mixing of deep-sea sediments

International Nuclear Information System (INIS)

Smith, C.R.; Maggaard, L.; Pope, R.H.; DeMaster, D.J.

1993-01-01

Rates of bioturbation measured in deep-sea sediments commonly are tracer dependent; in particular, shorter lived radiotracers (such as 234 Th) often yield markedly higher diffusive mixing coefficients than their longer-lived counterparts (e.g., 210 Pb). At a single station in the 1,240-m deep Santa Catalina Basin, the authors document a strong negative correlation between bioturbation rate and tracer half-life. Sediment profiles of 234 Th (half-life = 24 days) yield an average mixing coefficient (60 cm 2 y -1 ) two orders of magnitude greater than that for 210 Pb (half-life = 22 y, mean mixing coefficient = 0.4 cm 2 y -1 ). A similar negative relationship between mixing rate and tracer time scale is observed at thirteen other deep-sea sites in which multiple radiotracers have been used to assess diffusive mixing rates. This relationship holds across a variety of radiotracer types and time scales. The authors hypothesize that this negative relationship results from age-dependent mixing, a process in which recently sedimented, food-rich particles are ingested and mixed at higher rates by deposit feeders than are older, food-poor particles. Results from an age-dependent mixing model demonstrate that this process indeed can yield the bioturbation-rate vs. tracer-time-scale correlations observed in deep-sea sediments. Field data on mixing rates of recently sedimented particles, as well as the radiotracer activity of deep-sea deposit feeders, provide strong support for the age-dependent mixing model. The presence of age-dependent mixing in deep-sea sediments may have major implications for diagenetic modeling, requiring a match between the characteristic time scales of mixing tracers and modeled reactants. 102 refs., 6 figs., 5 tabs

Age-related alteration in the composition of immunocompetent blood cells in atomic bomb survivors

International Nuclear Information System (INIS)

Kusunoki, Yoichiro; Akiyama, Mitoshi; Kyoizumi, Seishi; Bloom, E.T.; Makinodan, Takashi; California Univ., Los Angeles

1988-01-01

1328 survivors of Hiroshima were studied for alterations in the number of blood lymphocytes belonging to T-cell subpopulations, CD19 antigen-positive B cells and Leu 7 and CD16 antigen-positive lymphocytes. With increasing age, significant decreasing trends in the numbers of some lymphocytes in T-cell subpopulations and of B-cells were seen. The number of blood lymphocytes positive for CD5 antigen was significantly lower in those exposed to radiation (> 1Gy) in the older age group (more than 30 years at the time of bombing) and a similar tendency for decreases in the numbers of CD4, CD8, and CD19 antigen-positive cells was observed, but differences were not significant. The results suggest aging of the T-cell related immune system is accelerated in the irradiated people of advanced age, explained by the age-related decrease in thymic function in those subjects. The number of Leu 7 or CD19 antigen-positive cells was found to be increased significantly in the older age group compared to the younger, although there was little dose dependence. (U.K.)

Stem Cells and Aging.

Science.gov (United States)

Koliakos, George

2017-02-01

The article is a presentation at the 4th Conference of ESAAM, which took place on October 30-31, 2015, in Athens, Greece. Its purpose was not to cover all aspects of cellular aging but to share with the audience of the Conference, in a 15-minute presentation, current knowledge about the rejuvenating and repairing somatic stem cells that are distinct from other stem cell types (such as embryonic or induced pluripotent stem cells), emphasize that our body in old age cannot take advantage of these rejuvenating cells, and provide some examples of novel experimental stem cell applications in the field of rejuvenation and antiaging biomedical research.

A sphingolipid-dependent diffusion barrier confines ER stress to the yeast mother cell

Science.gov (United States)

Clay, Lori; Caudron, Fabrice; Denoth-Lippuner, Annina; Boettcher, Barbara; Buvelot Frei, Stéphanie; Snapp, Erik Lee; Barral, Yves

2014-01-01

In many cell types, lateral diffusion barriers compartmentalize the plasma membrane and, at least in budding yeast, the endoplasmic reticulum (ER). However, the molecular nature of these barriers, their mode of action and their cellular functions are unclear. Here, we show that misfolded proteins of the ER remain confined into the mother compartment of budding yeast cells. Confinement required the formation of a lateral diffusion barrier in the form of a distinct domain of the ER-membrane at the bud neck, in a septin-, Bud1 GTPase- and sphingolipid-dependent manner. The sphingolipids, but not Bud1, also contributed to barrier formation in the outer membrane of the dividing nucleus. Barrier-dependent confinement of ER stress into the mother cell promoted aging. Together, our data clarify the physical nature of lateral diffusion barriers in the ER and establish the role of such barriers in the asymmetric segregation of proteotoxic misfolded proteins during cell division and aging. DOI: http://dx.doi.org/10.7554/eLife.01883.001 PMID:24843009

The cell biology of T-dependent B cell activation

DEFF Research Database (Denmark)

Owens, T; Zeine, R

1989-01-01

The requirement that CD4+ helper T cells recognize antigen in association with class II Major Histocompatibility Complex (MHC) encoded molecules constrains T cells to activation through intercellular interaction. The cell biology of the interactions between CD4+ T cells and antigen-presenting cells...... includes multipoint intermolecular interactions that probably involve aggregation of both polymorphic and monomorphic T cell surface molecules. Such aggregations have been shown in vitro to markedly enhance and, in some cases, induce T cell activation. The production of T-derived lymphokines that have been...... implicated in B cell activation is dependent on the T cell receptor for antigen and its associated CD3 signalling complex. T-dependent help for B cell activation is therefore similarly MHC-restricted and involves T-B intercellular interaction. Recent reports that describe antigen-independent B cell...

THE PROGRAMED CELL DEATH REGULATORS OF ISOLATED MODEL SYSTEMS

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D. V. Vatlitsov

2016-06-01

Full Text Available The technology evolution creates the prerequisites for the emergence of new informational concept and approaches to the formation of a fundamentally new principles of biological objects understanding. The aim was to study the activators of the programmed cell death in an isolated system model. Cell culture aging parameters were performed on flow cytometer. It had formed the theory that the changes in the concentrations of metal ions and increase their extracellular concentration had formed a negative gradient into the cells.regulation of cell death. It was shown that the metals ions concentrations.

Cerebellar cortex development in the weaver condition presents regional and age-dependent abnormalities without differences in Purkinje cells neurogenesis.

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Martí, Joaquín; Santa-Cruz, María C; Hervás, José P; Bayer, Shirley A; Villegas, Sandra

2016-01-01

Ataxias are neurological disorders associated with the degeneration of Purkinje cells (PCs). Homozygous weaver mice (wv/wv) have been proposed as a model for hereditary cerebellar ataxia because they present motor abnormalities and PC loss. To ascertain the physiopathology of the weaver condition, the development of the cerebellar cortex lobes was examined at postnatal day (P): P8, P20 and P90. Three approaches were used: 1) quantitative determination of several cerebellar features; 2) qualitative evaluation of the developmental changes occurring in the cortical lobes; and 3) autoradiographic analyses of PC generation and placement. Our results revealed a reduction in the size of the wv/wv cerebellum as a whole, confirming previous results. However, as distinguished from these reports, we observed that quantified parameters contribute differently to the abnormal growth of the wv/wv cerebellar lobes. Qualitative analysis showed anomalies in wv/wv cerebellar cytoarchitecture, depending on the age and lobe analyzed. Such abnormalities included the presence of the external granular layer after P20 and, at P90, ectopic cells located in the molecular layer following several placement patterns. Finally, we obtained autoradiographic evidence that wild-type and wv/wv PCs presented similar neurogenetic timetables, as reported. However, the innovative character of this current work lies in the fact that the neurogenetic gradients of wv/wv PCs were not modified from P8 to P90. A tendency for the accumulation of late-formed PCs in the anterior and posterior lobes was found, whereas early-generated PCs were concentrated in the central and inferior lobes. These data suggested that wv/wv PCs may migrate properly to their final destinations. The extrapolation of our results to patients affected with cerebellar ataxias suggests that all cerebellar cortex lobes are affected with several age-dependent alterations in cytoarchitectonics. We also propose that PC loss may be regionally

Aging, metabolism and stem cells: Spotlight on muscle stem cells.

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García-Prat, Laura; Muñoz-Cánoves, Pura

2017-04-15

All tissues and organs undergo a progressive regenerative decline as they age. This decline has been mainly attributed to loss of stem cell number and/or function, and both stem cell-intrinsic changes and alterations in local niches and/or systemic environment over time are known to contribute to the stem cell aging phenotype. Advancing in the molecular understanding of the deterioration of stem cell cells with aging is key for targeting the specific causes of tissue regenerative dysfunction at advanced stages of life. Here, we revise exciting recent findings on why stem cells age and the consequences on tissue regeneration, with a special focus on regeneration of skeletal muscle. We also highlight newly identified common molecular pathways affecting diverse types of aging stem cells, such as altered proteostasis, metabolism, or senescence entry, and discuss the questions raised by these findings. Finally, we comment on emerging stem cell rejuvenation strategies, principally emanating from studies on muscle stem cells, which will surely burst tissue regeneration research for future benefit of the increasing human aging population. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Age dependencies in the modelling of radiation carcinogenesis

International Nuclear Information System (INIS)

Kellerer, A.M.; GSF, Neuherberg; Barclay, D.

1992-01-01

Models for the dose and age dependence of radiation induced cancer have been based primarily on the follow-up of the atomic bomb survivors. Two different concepts have been deduced for leukaemias and for other cancers. The excess leukaemias appear in a distinct temporal wave with a maximum 5 to 10 years after radiation exposure; the distribution is more narrow for younger ages, but there is little dependence of the total attributable risk on age at exposure. For other cancers the latent periods are longer and, according to the current interpretation, the excess rates are then proportional to the age specific spontaneous rates, so that most excess cases would arise at old age. The factors of proportionality, and thus the attributable risks, are assumed to be markedly higher for young ages at exposure. It is argued here, that there is no firm support for this interpretation. (author)

Effects of advanced glycation end products on ezrin-dependent functions in LLC-PK1 proximal tubule cells.

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Bach, Leon A; Gallicchio, Marisa A; McRobert, E Anne; Tikoo, Anjali; Cooper, Mark E

2005-06-01

We have recently shown that advanced glycation products (AGEs) bind to the ERM (ezrin, radixin, moesin) family of proteins. ERM proteins act as cross-linkers between cell membrane proteins and the actin cytoskeleton. They are also involved in signal transduction pathways. They therefore have a critical role in normal cell processes, including modulation of cell shape, adhesion, and motility. We postulate that AGEs may contribute to diabetic complications by disrupting ERM function. In support of this hypothesis, AGEs inhibit ezrin-dependent tubulogenesis of proximal tubule cells. Phosphorylation is an important activating mechanism for ERM proteins, and AGEs inhibit ezrin phosphorylation mediated by the epidermal growth factor receptor.

The Stem Cell Hypothesis of Aging

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Anna Meiliana

2010-04-01

Full Text Available BACKGROUND: There is probably no single way to age. Indeed, so far there is no single accepted explanation or mechanisms of aging (although more than 300 theories have been proposed. There is an overall decline in tissue regenerative potential with age, and the question arises as to whether this is due to the intrinsic aging of stem cells or rather to the impairment of stem cell function in the aged tissue environment. CONTENT: Recent data suggest that we age, in part, because our self-renewing stem cells grow old as a result of heritable intrinsic events, such as DNA damage, as well as extrinsic forces, such as changes in their supporting niches. Mechanisms that suppress the development of cancer, such as senescence and apoptosis, which rely on telomere shortening and the activities of p53 and p16INK4a may also induce an unwanted consequence: a decline in the replicative function of certain stem cells types with advancing age. This decrease regenerative capacity appears to pointing to the stem cell hypothesis of aging. SUMMARY: Recent evidence suggested that we grow old partly because of our stem cells grow old as a result of mechanisms that suppress the development of cancer over a lifetime. We believe that a further, more precise mechanistic understanding of this process will be required before this knowledge can be translated into human anti-aging therapies. KEYWORDS: stem cells, senescence, telomere, DNA damage, epigenetic, aging.

Age-dependent changes in innate immune phenotype and function in rhesus macaques (Macaca mulatta

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Mark Asquith

2012-06-01

Full Text Available Aged individuals are more susceptible to infections due to a general decline in immune function broadly referred to as immune senescence. While age-related changes in the adaptive immune system are well documented, aging of the innate immune system remains less well understood, particularly in nonhuman primates. A more robust understanding of age-related changes in innate immune function would provide mechanistic insight into the increased susceptibility of the elderly to infection. Rhesus macaques have proved a critical translational model for aging research, and present a unique opportunity to dissect age-dependent modulation of the innate immune system. We examined age-related changes in: (i innate immune cell frequencies; (ii expression of pattern recognition receptors (PRRs and innate signaling molecules; (iii cytokine responses of monocytes and dendritic cells (DC following stimulation with PRR agonists; and (iv plasma cytokine levels in this model. We found marked changes in both the phenotype and function of innate immune cells. This included an age-associated increased frequency of myeloid DC (mDC. Moreover, we found toll-like receptor (TLR agonists lipopolysaccharide (TLR4, fibroblast stimulating ligand-1 (TLR2/6, and ODN2006 (TLR7/9 induced reduced cytokine responses in aged mDC. Interestingly, with the exception of the monocyte-derived TNFα response to LPS, which increased with age, TNFα, IL-6, and IFNα responses declined with age. We also found that TLR4, TLR5, and innate negative regulator, sterile alpha and TIR motif containing protein (SARM, were all expressed at lower levels in young animals. By contrast, absent in melanoma 2 and retinoic acid-inducible gene I expression was lowest in aged animals. Together, these observations indicate that several parameters of innate immunity are significantly modulated by age and contribute to differential immune function in aged macaques.

BMAL1-dependent regulation of the mTOR signaling pathway delays aging.

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Khapre, Rohini V; Kondratova, Anna A; Patel, Sonal; Dubrovsky, Yuliya; Wrobel, Michelle; Antoch, Marina P; Kondratov, Roman V

2014-01-01

The circadian clock, an internal time-keeping system, has been linked with control of aging, but molecular mechanisms of regulation are not known. BMAL1 is a transcriptional factor and core component of the circadian clock; BMAL1 deficiency is associated with premature aging and reduced lifespan. Here we report that activity of mammalian Target of Rapamycin Complex 1 (mTORC1) is increased upon BMAL1 deficiency both in vivo and in cell culture. Increased mTOR signaling is associated with accelerated aging; in accordance with that, treatment with the mTORC1 inhibitor rapamycin increased lifespan of Bmal1-/- mice by 50%. Our data suggest that BMAL1 is a negative regulator of mTORC1 signaling. We propose that the circadian clock controls the activity of the mTOR pathway through BMAL1-dependent mechanisms and this regulation is important for control of aging and metabolism.

The cell biology of aging.

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Hayflick, L

1985-02-01

It is only within the past ten years that biogerontology has become attractive to a sufficient number of biologists so that the field can be regarded as a seriously studied discipline. Cytogerontology, or the study of aging at the cellular level, had its genesis about 20 years ago when the dogma that maintained that cultured normal cells could replicate forever was overturned. Normal human and animal cells have a finite capacity to replicate and function whether they are cultured in vitro or transplanted as grafts in vivo. This phenomenon has been interpreted to be aging at the cellular level. Only abnormal somatic cells are capable of immortality. In recent years it has been found that the number of population doublings of which cultured normal cells are capable is inversely proportional to donor age. There is also good evidence that the number of population doublings of cultured normal fibroblasts is directly proportional to the maximum lifespan of ten species that have been studied. Cultures prepared from patients with accelerated aging syndromes (progeria and Werner's syndrome) undergo far fewer doublings than do those of age-matched controls. The normal human fibroblast cell strain WI-38 was established in 1962 from fetal lung, and several hundred ampules of these cells were frozen in liquid nitrogen at that time. These ampules have been reconstituted periodically and shown to be capable of replication. This represents the longest period of time that a normal human cell has ever been frozen. Normal human fetal cell strains such as WI-38 have the capacity to double only about 50 times. If cultures are frozen at various population doublings, the number of doublings remaining after reconstitution is equal to 50 minus the number of doublings that occurred prior to freezing. The memory of the cells has been found to be accurate after 23 years of preservation in liquid nitrogen. Normal human cells incur many physiologic decrements that herald the approach of their

Klotho, stem cells, and aging.

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Bian, Ao; Neyra, Javier A; Zhan, Ming; Hu, Ming Chang

2015-01-01

Aging is an inevitable and progressive biological process involving dysfunction and eventually destruction of every tissue and organ. This process is driven by a tightly regulated and complex interplay between genetic and acquired factors. Klotho is an antiaging gene encoding a single-pass transmembrane protein, klotho, which serves as an aging suppressor through a wide variety of mechanisms, such as antioxidation, antisenescence, antiautophagy, and modulation of many signaling pathways, including insulin-like growth factor and Wnt. Klotho deficiency activates Wnt expression and activity contributing to senescence and depletion of stem cells, which consequently triggers tissue atrophy and fibrosis. In contrast, the klotho protein was shown to suppress Wnt-signaling transduction, and inhibit cell senescence and preserve stem cells. A better understanding of the potential effects of klotho on stem cells could offer novel insights into the cellular and molecular mechanisms of klotho deficiency-related aging and disease. The klotho protein may be a promising therapeutic agent for aging and aging-related disorders.

Programmed cell death

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NONE

1995-12-31

The purpose of this conference to provide a multidisciplinary forum for exchange of state-of-the-art information on the role programmed cell death plays in normal development and homeostasis of many organisms. This volume contains abstracts of papers in the following areas: invertebrate development; immunology/neurology; bcl-2 family; biochemistry; programmed cell death in viruses; oncogenesis; vertebrate development; and diseases.

Influence of aging on the activity of mice Sca-1+CD31- cardiac stem cells.

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Wu, Qiong; Zhan, Jinxi; Pu, Shiming; Qin, Liu; Li, Yun; Zhou, Zuping

2017-01-03

Therapeutic application of cardiac resident stem/progenitor cells (CSC/CPCs) is limited due to decline of their regenerative potential with donor age. A variety of studies have shown that the cardiac aging was the problem of the stem cells, but little is known about the impact of age on the subgroups CSC/CPCs, the relationship between subgroups CSC/CPCs ageing and age-related dysfunction. Here, we studied Sca-1+CD31- subgroups of CSCs from younger(2~3months) and older(22~24months) age mice, biological differentiation was realized using specific mediums for 14 days to induce cardiomyocyte, smooth muscle cells or endothelial cells and immunostain analysis of differentiated cell resulting were done. Proliferation and cell cycle were measured by flow cytometry assay, then used microarray to dissect variability from younger and older mice. Although the number of CSCs was higher in older mice, the advanced age significantly reduced the differentiation ability into cardiac cell lineages and the proliferation ability. Transcriptional changes in Sca-1+CD31- subgroups of CSCs during aging are related to Vitamin B6 metabolism, circadian rhythm, Tyrosine metabolism, Complement and coagulation cascades. Taking together these results indicate that Cardiac resident stem/progenitor cells have significant differences in their proliferative, pluripotency and gene profiles and those differences are age depending.

Age-Dependent Pre-Vaccination Immunity Affects the Immunogenicity of Varicella Zoster Vaccination in Middle-aged Adults

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Marieke van der Heiden

2018-01-01

Full Text Available BackgroundPrevention of infectious diseases is of high priority in the rapidly aging population. Unfortunately, vaccine responses in the elderly are frequently diminished. Timely vaccination of middle-aged adults might improve the immune responses to vaccines, although knowledge on pathogen-specific immune responses and factors affecting these responses, in middle-aged adults is currently limited. We thus investigated the immune responses after vaccination with Zostavax consisting of live-attenuated varicella zoster virus (VZV.MethodsBlood samples were taken pre-, 14 days, 28 days, and 1 year after a primary VZV vaccination (Zostavax at middle age (N = 53, 50–65 years of age. VZV-specific IFNγ-producing cells were measured by ELISpot, activated T-cells by flow cytometry, antibody levels and cytokine responses by fluorescent bead-based multiplex immunoassays, and whole blood cellular kinetics by TruCOUNT analysis.ResultsRobust short-term enhancement of the VZV-specific IFNγ-producing cell numbers was observed post-vaccination in the middle-aged adults. Remarkably, long-term enhancement of VZV-specific IFNγ-producing cell numbers was induced only in participants with low numbers of VZV-specific pre-vaccination IFNγ-producing cells, who were significantly older. These participants also showed enhancement of VZV-specific activated CD4 T-cells, contrary to “exhausted” VZV-specific CD8 T-cells in participants with high numbers of VZV-specific pre-vaccination IFNγ-producing cells. Finally, a high CD4/CD8 T-cell ratio was associated with low numbers of pre-vaccination VZV-specific IFNγ-producing cells.ConclusionThese results suggest that adults in their early sixties, who showed a high CD4/CD8 T-cell ratio and low numbers of VZV-specific IFNγ-producing cells, benefit from VZV vaccination. This provides important knowledge on factors affecting VZV-specific immune responses in middle-aged adults as well as for strategies to

Ecdysone-dependent and ecdysone-independent programmed cell death in the developing optic lobe of Drosophila.

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Hara, Yusuke; Hirai, Keiichiro; Togane, Yu; Akagawa, Hiromi; Iwabuchi, Kikuo; Tsujimura, Hidenobu

2013-02-01

The adult optic lobe of Drosophila develops from the primordium during metamorphosis from mid-3rd larval stage to adult. Many cells die during development of the optic lobe with a peak of the number of dying cells at 24 h after puparium formation (h APF). Dying cells were observed in spatio-temporal specific clusters. Here, we analyzed the function of a component of the insect steroid hormone receptor, EcR, in this cell death. We examined expression patterns of two EcR isoforms, EcR-A and EcR-B1, in the optic lobe. Expression of each isoform altered during development in isoform-specific manner. EcR-B1 was not expressed in optic lobe neurons from 0 to 6h APF, but was expressed between 9 and 48 h APF and then disappeared by 60 h APF. In each cortex, its expression was stronger in older glia-ensheathed neurons than in younger ones. EcR-B1 was also expressed in some types of glia. EcR-A was expressed in optic lobe neurons and many types of glia from 0 to 60 h APF in a different pattern from EcR-B1. Then, we genetically analyzed EcR function in the optic lobe cell death. At 0 h APF, the optic lobe cell death was independent of any EcR isoforms. In contrast, EcR-B1 was required for most optic lobe cell death after 24 h APF. It was suggested that cell death cell-autonomously required EcR-B1 expressed after puparium formation. βFTZ-F1 was also involved in cell death in many dying-cell clusters, but not in some of them at 24 h APF. Altogether, the optic lobe cell death occurred in ecdysone-independent manner at prepupal stage and ecdysone-dependent manner after 24 h APF. The acquisition of ecdysone-dependence was not directly correlated with the initiation or increase of EcR-B1 expression. Copyright © 2012 Elsevier Inc. All rights reserved.

Stability analysis for a general age-dependent vaccination model

International Nuclear Information System (INIS)

El Doma, M.

1995-05-01

An SIR epidemic model of a general age-dependent vaccination model is investigated when the fertility, mortality and removal rates depends on age. We give threshold criteria of the existence of equilibriums and perform stability analysis. Furthermore a critical vaccination coverage that is sufficient to eradicate the disease is determined. (author). 12 refs

Role of Mitochondrial Complex IV in Age-Dependent Obesity

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Ines Soro-Arnaiz

2016-09-01

Full Text Available Aging is associated with progressive white adipose tissue (WAT enlargement initiated early in life, but the molecular mechanisms involved remain unknown. Here we show that mitochondrial complex IV (CIV activity and assembly are already repressed in white adipocytes of middle-aged mice and involve a HIF1A-dependent decline of essential CIV components such as COX5B. At the molecular level, HIF1A binds to the Cox5b proximal promoter and represses its expression. Silencing of Cox5b decreased fatty acid oxidation and promoted intracellular lipid accumulation. Moreover, local in vivo Cox5b silencing in WAT of young mice increased the size of adipocytes, whereas restoration of COX5B expression in aging mice counteracted adipocyte enlargement. An age-dependent reduction in COX5B gene expression was also found in human visceral adipose tissue. Collectively, our findings establish a pivotal role for CIV dysfunction in progressive white adipocyte enlargement during aging, which can be restored to alleviate age-dependent WAT expansion.

An update on the Structural Aging Program

International Nuclear Information System (INIS)

Naus, D.J.; Oland, C.B.; Ellingwood, B.; Mori, Y.; Arndt, E.G.

1992-01-01

The Structural Aging (SAG) Program is being conducted at the Oak Ridge National Laboratory (ORNL) for the Nuclear Regulatory Commission (NRC). The SAG Program is addressing the aging management of safety-related concrete structures in nuclear power plants for the purpose of providing improved technical bases for their continued service. The program is organized into four tasks: Program Management, Materials Property Data Base, Structural Component Assessment/Repair Technologies, and Quantitative Methodology for Continued Service Determinations. Objectives and a summary of accomplishments under each of these tasks are presented

Moderate Exercise Mitigates the Detrimental Effects of Aging on Tendon Stem Cells.

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Zhang, Jianying; Wang, James H-C

2015-01-01

Aging is known to cause tendon degeneration whereas moderate exercise imparts beneficial effects on tendons. Since stem cells play a vital role in maintaining tissue integrity, in this study we aimed to define the effects of aging and moderate exercise on tendon stem/progenitor cells (TSCs) using in vitro and in vivo models. TSCs derived from aging mice (9 and 24 months) proliferated significantly slower than TSCs obtained from young mice (2.5 and 5 months). In addition, expression of the stem cell markers Oct-4, nucleostemin (NS), Sca-1 and SSEA-1 in TSCs decreased in an age-dependent manner. Interestingly, moderate mechanical stretching (4%) of aging TSCs in vitro significantly increased the expression of the stem cell marker, NS, but 8% stretching decreased NS expression. Similarly, 4% mechanical stretching increased the expression of Nanog, another stem cell marker, and the tenocyte-related genes, collagen I and tenomodulin. However, 8% stretching increased expression of the non-tenocyte-related genes, LPL, Sox-9 and Runx-2, while 4% stretching had minimal effects on the expression of these genes. In the in vivo study, moderate treadmill running (MTR) of aging mice (9 months) resulted in the increased proliferation rate of aging TSCs in culture, decreased lipid deposition, proteoglycan accumulation and calcification, and increased the expression of NS in the patellar tendons. These findings indicate that while aging impairs the proliferative ability of TSCs and reduces their stemness, moderate exercise can mitigate the deleterious effects of aging on TSCs and therefore may be responsible for decreased aging-induced tendon degeneration.

Reduced Ang2 expression in aging endothelial cells

International Nuclear Information System (INIS)

Hohensinner, P.J.; Ebenbauer, B.; Kaun, C.; Maurer, G.; Huber, K.; Wojta, J.

2016-01-01

Aging endothelial cells are characterized by increased cell size, reduced telomere length and increased expression of proinflammatory cytokines. In addition, we describe here that aging reduces the migratory distance of endothelial cells. Furthermore, we observe an increase of the quiescence protein Ang1 and a decrease of the endothelial activation protein Ang2 upon aging. Supplementing Ang2 to aged endothelial cells restored their migratory capacity. We conclude that aging shifts the balance of the Ang1/Ang2 network favouring a quiescent state. Activation of endothelial cells in aging might be necessary to enhance wound healing capacities. -- Highlights: •Endothelial cells display signs of aging before reaching proliferative senescence. •Aging endothelial cells express more angiopoietin 1 and less angiopoietin 2 than young endothelial cells. •Migratory capacity is reduced in aging endothelial cells.

Reduced Ang2 expression in aging endothelial cells

Energy Technology Data Exchange (ETDEWEB)

Hohensinner, P.J., E-mail: philipp.hohensinner@meduniwien.ac.at [Department of Internal Medicine II, Medical University of Vienna, Vienna (Austria); Ebenbauer, B. [Department of Internal Medicine II, Medical University of Vienna, Vienna (Austria); Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna (Austria); Kaun, C.; Maurer, G. [Department of Internal Medicine II, Medical University of Vienna, Vienna (Austria); Huber, K. [Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna (Austria); 3rd Medical Department, Wilhelminenhospital, Vienna (Austria); Sigmund Freud University, Medical Faculty, Vienna (Austria); Wojta, J. [Department of Internal Medicine II, Medical University of Vienna, Vienna (Austria); Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna (Austria); Core Facilities, Medical University of Vienna, Vienna (Austria)

2016-06-03

Aging endothelial cells are characterized by increased cell size, reduced telomere length and increased expression of proinflammatory cytokines. In addition, we describe here that aging reduces the migratory distance of endothelial cells. Furthermore, we observe an increase of the quiescence protein Ang1 and a decrease of the endothelial activation protein Ang2 upon aging. Supplementing Ang2 to aged endothelial cells restored their migratory capacity. We conclude that aging shifts the balance of the Ang1/Ang2 network favouring a quiescent state. Activation of endothelial cells in aging might be necessary to enhance wound healing capacities. -- Highlights: •Endothelial cells display signs of aging before reaching proliferative senescence. •Aging endothelial cells express more angiopoietin 1 and less angiopoietin 2 than young endothelial cells. •Migratory capacity is reduced in aging endothelial cells.

Age-dependent decay in the landscape

International Nuclear Information System (INIS)

Winitzki, Sergei

2008-01-01

The picture of the 'multiverse' arising in diverse cosmological scenarios involves transitions between metastable vacuum states. It was pointed out by Krauss and Dent that the transition rates decrease at very late times, leading to a dependence of the transition probability between vacua on the age of each vacuum region. I investigate the implications of this non-Markovian, age-dependent decay on the global structure of the spacetime in landscape scenarios. I show that the fractal dimension of the eternally inflating domain is precisely equal to 3, instead of being slightly below 3, which is the case in scenarios with purely Markovian, age-independent decay. I develop a complete description of a non-Markovian landscape in terms of a nonlocal master equation. Using this description I demonstrate by an explicit calculation that, under some technical assumptions about the landscape, the probabilistic predictions of our position in the landscape are essentially unchanged, regardless of the measure used to extract these predictions. I briefly discuss the physical plausibility of realizing non-Markovian vacuum decay in cosmology in view of the possible decoherence of the metastable quantum state.

Short-lived, transitory cell-cell interactions foster migration-dependent aggregation.

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Melissa D Pope

Full Text Available During embryonic development, motile cells aggregate into cohesive groups, which give rise to tissues and organs. The role of cell migration in regulating aggregation is unclear. The current paradigm for aggregation is based on an equilibrium model of differential cell adhesivity to neighboring cells versus the underlying substratum. In many biological contexts, however, dynamics is critical. Here, we provide evidence that multicellular aggregation dynamics involves both local adhesive interactions and transport by cell migration. Using time-lapse video microscopy, we quantified the duration of cell-cell contacts among migrating cells that collided and adhered to another cell. This lifetime of cell-cell interactions exhibited a monotonic decreasing dependence on substratum adhesivity. Parallel quantitative measurements of cell migration speed revealed that across the tested range of adhesive substrata, the mean time needed for cells to migrate and encounter another cell was greater than the mean adhesion lifetime, suggesting that aggregation dynamics may depend on cell motility instead of the local differential adhesivity of cells. Consistent with this hypothesis, aggregate size exhibited a biphasic dependence on substratum adhesivity, matching the trend we observed for cell migration speed. Our findings suggest a new role for cell motility, alongside differential adhesion, in regulating developmental aggregation events and motivate new design principles for tuning aggregation dynamics in tissue engineering applications.

Fuel Cell and Hydrogen Technologies Program | Hydrogen and Fuel Cells |

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NREL Fuel Cell and Hydrogen Technologies Program Fuel Cell and Hydrogen Technologies Program Through its Fuel Cell and Hydrogen Technologies Program, NREL researches, develops, analyzes, and validates fuel cell and hydrogen production, delivery, and storage technologies for transportation

RIP3 Inhibits Inflammatory Hepatocarcinogenesis but Promotes Cholestasis by Controlling Caspase-8- and JNK-Dependent Compensatory Cell Proliferation

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Mihael Vucur

2013-08-01

Full Text Available For years, the term “apoptosis” was used synonymously with programmed cell death. However, it was recently discovered that receptor interacting protein 3 (RIP3-dependent “necroptosis” represents an alternative programmed cell death pathway activated in many inflamed tissues. Here, we show in a genetic model of chronic hepatic inflammation that activation of RIP3 limits immune responses and compensatory proliferation of liver parenchymal cells (LPC by inhibiting Caspase-8-dependent activation of Jun-(N-terminal kinase in LPC and nonparenchymal liver cells. In this way, RIP3 inhibits intrahepatic tumor growth and impedes the Caspase-8-dependent establishment of specific chromosomal aberrations that mediate resistance to tumor-necrosis-factor-induced apoptosis and underlie hepatocarcinogenesis. Moreover, RIP3 promotes the development of jaundice and cholestasis, because its activation suppresses compensatory proliferation of cholangiocytes and hepatic stem cells. These findings demonstrate a function of RIP3 in regulating carcinogenesis and cholestasis. Controlling RIP3 or Caspase-8 might represent a chemopreventive or therapeutic strategy against hepatocellular carcinoma and biliary disease.

Impaired respiration elicits SrrAB-dependent programmed cell lysis and biofilm formation in Staphylococcus aureus

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Mashruwala, Ameya A; van de Guchte, Adriana; Boyd, Jeffrey M

2017-01-01

Biofilms are communities of microorganisms attached to a surface or each other. Biofilm-associated cells are the etiologic agents of recurrent Staphylococcus aureus infections. Infected human tissues are hypoxic or anoxic. S. aureus increases biofilm formation in response to hypoxia, but how this occurs is unknown. In the current study we report that oxygen influences biofilm formation in its capacity as a terminal electron acceptor for cellular respiration. Genetic, physiological, or chemical inhibition of respiratory processes elicited increased biofilm formation. Impaired respiration led to increased cell lysis via divergent regulation of two processes: increased expression of the AtlA murein hydrolase and decreased expression of wall-teichoic acids. The AltA-dependent release of cytosolic DNA contributed to increased biofilm formation. Further, cell lysis and biofilm formation were governed by the SrrAB two-component regulatory system. Data presented support a model wherein SrrAB-dependent biofilm formation occurs in response to the accumulation of reduced menaquinone. DOI: http://dx.doi.org/10.7554/eLife.23845.001 PMID:28221135

Pluripotent stem cells: A therapeutic source for age-related macular degeneration

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Sowmya Parameswaran

2017-01-01

Full Text Available Age-related macular degeneration (AMD leads to progressive loss of central vision in the elderly. At a cellular level, there is aging of the retinal pigment epithelial (RPE cells, and accumulation of lipofuscin that interferes with the proper functioning of RPE which eventually leads to apoptosis. Treatment depends on the stage of the disease. Wet AMD which has neovascularization is managed by local therapies such as laser photocoagulation and photodynamic therapy and is managed with injections of antivascular endothelial growth factor-based therapy. Unlike the wet AMD, an effective therapy does not exist for dry AMD and geographic atrophy. Cell replacement therapy has shown promise. This review discusses the opportunities in the various types of cell-based therapy, their limitations, and what is possible for India.

Establishment of LIF-dependent human iPS cells closely related to basic FGF-dependent authentic iPS cells.

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Hiroyuki Hirai

Full Text Available Human induced pluripotent stem cells (iPSCs can be divided into a leukemia inhibitory factor (LIF-dependent naïve type and a basic fibroblast growth factor (bFGF-dependent primed type. Although the former are more undifferentiated than the latter, they require signal transduction inhibitors and sustained expression of the transgenes used for iPSC production. We used a transcriptionally enhanced version of OCT4 to establish LIF-dependent human iPSCs without the use of inhibitors and sustained transgene expression. These cells belong to the primed type of pluripotent stem cell, similar to bFGF-dependent iPSCs. Thus, the particular cytokine required for iPSC production does not necessarily define stem cell phenotypes as previously thought. It is likely that the bFGF and LIF signaling pathways converge on unidentified OCT4 target genes. These findings suggest that our LIF-dependent human iPSCs could provide a novel model to investigate the role of cytokine signaling in cellular reprogramming.

Young endothelial cells revive aging blood.

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Chang, Vivian Y; Termini, Christina M; Chute, John P

2017-11-01

The hematopoietic system declines with age, resulting in decreased hematopoietic stem cell (HSC) self-renewal capacity, myeloid skewing, and immune cell depletion. Aging of the hematopoietic system is associated with an increased incidence of myeloid malignancies and a decline in adaptive immunity. Therefore, strategies to rejuvenate the hematopoietic system have important clinical implications. In this issue of the JCI, Poulos and colleagues demonstrate that infusions of bone marrow (BM) endothelial cells (ECs) from young mice promoted HSC self-renewal and restored immune cell content in aged mice. Additionally, delivery of young BM ECs along with HSCs following total body irradiation improved HSC engraftment and enhanced survival. These results suggest an important role for BM endothelial cells (ECs) in regulating hematopoietic aging and support further research to identify the rejuvenating factors elaborated by BM ECs that restore HSC function and the immune repertoire in aged mice.

Expansion of myeloid-derived suppressor cells with aging in the bone marrow of mice through a NF-κB-dependent mechanism.

Science.gov (United States)

Flores, Rafael R; Clauson, Cheryl L; Cho, Joonseok; Lee, Byeong-Chel; McGowan, Sara J; Baker, Darren J; Niedernhofer, Laura J; Robbins, Paul D

2017-06-01

With aging, there is progressive loss of tissue homeostasis and functional reserve, leading to an impaired response to stress and an increased risk of morbidity and mortality. A key mediator of the cellular response to damage and stress is the transcription factor NF-κB. We demonstrated previously that NF-κB transcriptional activity is upregulated in tissues from both natural aged mice and in a mouse model of a human progeroid syndrome caused by defective repair of DNA damage (ERCC1-deficient mice). We also demonstrated that genetic reduction in the level of the NF-κB subunit p65(RelA) in the Ercc1 -/∆ progeroid mouse model of accelerated aging delayed the onset of age-related pathology including muscle wasting, osteoporosis, and intervertebral disk degeneration. Here, we report that the largest fraction of NF-κB -expressing cells in the bone marrow (BM) of aged (>2 year old) mice (C57BL/6-NF-κB EGFP reporter mice) are Gr-1 + CD11b + myeloid-derived suppressor cells (MDSCs). There was a significant increase in the overall percentage of MDSC present in the BM of aged animals compared with young, a trend also observed in the spleen. However, the function of these cells appears not to be compromised in aged mice. A similar increase of MDSC was observed in BM of progeroid Ercc1 -/∆ and BubR1 H/H mice. The increase in MDSC in Ercc1 -/∆ mice was abrogated by heterozygosity in the p65/RelA subunit of NF-κB. These results suggest that NF-κB activation with aging, at least in part, drives an increase in the percentage of MDSCs, a cell type able to suppress immune cell responses. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Age at onset typology in opioid dependent men: an exploratory study.

Science.gov (United States)

De, Biswajit; Mattoo, Surendra K; Basu, Debasish

2002-04-01

This study attempted to apply age at onset typology in ICD-10 diagnosed opioid dependence. The sample comprised 80 men seeking treatment at an addiction clinic. The measures included socio-demographic and clinical profile, Severity of Opioid Dependence Questionnaire, Modified Sensation Seeking Scale, Multiphasic Personality Questionnaire (MPQ) and Family History Assessment Module. A cut-off age of 20/21 years for an early-onset late-onset typology of opioid dependence was obtained using two methods - the modal age at onset method and one-third sample by age at onset method. The early onset group showed significant differences in terms of it being more often younger, urban, unmarried, wage earning or students, using oral opioids (not heroin or injectables), showing higher lifetime use and dependence of sedatives, earlier onset of use and dependence of sedatives and tobacco, and higher global psychopathology in terms of MPQ. The early onset group also showed statistically insignificant trends for lesser use and dependence of alcohol, higher severity of opioid dependence, more legal and less social complications, higher sensation seeking (except boredom susceptibility), and more frequent substance dependence in first degree relatives. The age at onset typology in opioid dependence appears to be feasible and having some similarities to similar typology in alcoholism.

Age-related Deterioration of Hematopoietic Stem Cells.

Science.gov (United States)

Kim, Mi Jung; Kim, Min Hwan; Kim, Seung Ah; Chang, Jae Suk

2008-11-01

Aging is the process of system deterioration over time in the whole body. Stem cells are self-renewing and therefore have been considered exempt from the aging process. Earlier studies by Hayflick showed that there is an intrinsic limit to the number of divisions that mammalian somatic cells can undergo, and cycling kinetics and ontogeny-related studies strongly suggest that even the most primitive stem cell functions exhibit a certain degree of aging. Despite these findings, studies on the effects of aging on stem cell functions are inconclusive. Here we review the age-related properties of hematopoietic stem cells in terms of intrinsic and extrinsic alterations, proliferative potential, signaling molecules, telomere and telomerase, senescence and cancer issues, regenerative potential and other indications of stem cell aging are discussed in detail.

Age Is Relative—Impact of Donor Age on Induced Pluripotent Stem Cell-Derived Cell Functionality

Directory of Open Access Journals (Sweden)

Elisabeth Tamara Strässler

2018-01-01

Full Text Available Induced pluripotent stem cells (iPSCs avoid many of the restrictions that hamper the application of human embryonic stem cells: limited availability of source material due to legal restrictions in some countries, immunogenic rejection and ethical concerns. Also, the donor’s clinical phenotype is often known when working with iPSCs. Therefore, iPSCs seem ideal to tackle the two biggest tasks of regenerative medicine: degenerative diseases with genetic cause (e.g., Duchenne’s muscular dystrophy and organ replacement in age-related diseases (e.g., end-stage heart or renal failure, especially in combination with recently developed gene-editing tools. In the setting of autologous transplantation in elderly patients, donor age becomes a potentially relevant factor that needs to be assessed. Here, we review and critically discuss available data pertinent to the questions: How does donor age influence the reprogramming process and iPSC functionality? Would it even be possible to reprogram senescent somatic cells? How does donor age affect iPSC differentiation into specialised cells and their functionality? We also identify research needs, which might help resolve current unknowns. Until recently, most hallmarks of ageing were attributed to an accumulation of DNA damage over time, and it was thus expected that DNA damage from a somatic cell would accumulate in iPSCs and the cells derived from them. In line with this, a decreased lifespan of cloned organisms compared with the donor was also observed in early cloning experiments. Therefore, it was questioned for a time whether iPSC derived from an old individual’s somatic cells would suffer from early senescence and, thus, may not be a viable option either for disease modelling nor future clinical applications. Instead, typical signs of cellular ageing are reverted in the process of iPSC reprogramming, and iPSCs from older donors do not show diminished differentiation potential nor do i

Nuclear Plant Aging Research (NPAR) program plan

International Nuclear Information System (INIS)

1991-06-01

A comprehensive Nuclear Plant Aging Research (NPAR) Program was implemented by the US NRC office of Nuclear Regulatory Research in 1985 to identify and resolve technical safety issues related to the aging of systems, structures, and components in operating nuclear power plants. This is Revision 2 to the Nuclear Plant Aging Research Program Plant. This planes defines the goals of the program the current status of research, and summarizes utilization of the research results in the regulatory process. The plan also describes major milestones and schedules for coordinating research within the agency and with organizations and institutions outside the agency, both domestic and foreign. Currently the NPAR Program comprises seven major areas: (1) hardware-oriented engineering research involving components and structures; (2) system-oriented aging interaction studies; (3) development of technical bases for license renewal rulemaking; (4) determining risk significance of aging phenomena; (5) development of technical bases for resolving generic safety issues; (6) recommendations for field inspection and maintenance addressing aging concerns; (7) and residual lifetime evaluations of major LWR components and structures. The NPAR technical database comprises approximately 100 NUREG/CR reports by June 1991, plus numerous published papers and proceedings that offer regulators and industry important insights to aging characteristics and aging management of safety-related equipment. Regulatory applications include revisions to and development of regulatory guides and technical specifications; support to resolve generic safety issues; development of codes and standards; evaluation of diagnostic techniques; (e.g., for cables and valves); and technical support for development of the license renewal rule. 80 refs., 25 figs., 10 tabs

Risk evaluations of aging: Procedures guide for an age-dependent PSA with emphasis on prioritization and sensitivity studies

International Nuclear Information System (INIS)

Vesely, W.E.

1991-01-01

Based on the previous work which has been performed in the project, a procedures guide is being developed for carrying out an age-dependent probabilistic safety assessment (PSA) for evaluating the core damage frequency with aging effects explicitly treated. A PSA is basically a Level 1 Probabilistic Risk Assessment (PRA). The emphasis of the guide is on prioritization and sensitivity studies. Focus is also on active components although consideration of aging effects in passive components is also treated. The guide is intended to become a NUREG/CR and is the first of three volumes which are being developed. The following topics with demonstrations and applications are described in the presentation: (1) the age-dependent PSA versus the standard PSA; (2) component reliability models used in an age-dependent PSA; (3) approaches for transforming a PSA into an age-dependent PSA; (4) application of an age-dependent PSA; (5) using a PSA to evaluate the risk effects from aging passive components; (6) evaluation of the risk importance of passive components; (7) prioritizations of aging contributors; (8) evaluations of test and maintenance effectiveness; and (9) sensitivity studies and uncertainty analyses of aging effects

CD4(+) type II NKT cells mediate ICOS and programmed death-1-dependent regulation of type 1 diabetes.

Science.gov (United States)

Kadri, Nadir; Korpos, Eva; Gupta, Shashank; Briet, Claire; Löfbom, Linda; Yagita, Hideo; Lehuen, Agnes; Boitard, Christian; Holmberg, Dan; Sorokin, Lydia; Cardell, Susanna L

2012-04-01

Type 1 diabetes (T1D) is a chronic autoimmune disease that results from T cell-mediated destruction of pancreatic β cells. CD1d-restricted NKT lymphocytes have the ability to regulate immunity, including autoimmunity. We previously demonstrated that CD1d-restricted type II NKT cells, which carry diverse TCRs, prevented T1D in the NOD mouse model for the human disease. In this study, we show that CD4(+) 24αβ type II NKT cells, but not CD4/CD8 double-negative NKT cells, were sufficient to downregulate diabetogenic CD4(+) BDC2.5 NOD T cells in adoptive transfer experiments. CD4(+) 24αβ NKT cells exhibited a memory phenotype including high ICOS expression, increased cytokine production, and limited display of NK cell markers, compared with double-negative 24αβ NKT cells. Blocking of ICOS or the programmed death-1/programmed death ligand 1 pathway was shown to abolish the regulation that occurred in the pancreas draining lymph nodes. To our knowledge, these results provide for the first time cellular and molecular information on how type II CD1d-restricted NKT cells regulate T1D.

Age-dependent metabolic model of radionuclides in Human body

International Nuclear Information System (INIS)

Ye Changqing

1986-01-01

Age-dependent metabolic model of radionuclides in human body was introduced briefly. These data are necessary in setting up the secondary dose limit of internal exposure of the general public. For the gastro-intestinal tract model, it was shown that the dose of various sections of GI tract caused by unsoluble radioactive materials were influenced by the mass of section and mean residence time, both of which are age-dependent, but the absorption fraction f 1 through gastro-intestinal tract should be corrected only for the infant less than 1 year of age. For the lung model, it was indicated that the fraction of deposition or clearance of particles in the different compartments of lung were related to age. The doses of tracheobronchial and pulmonary compartment of adult for 222 Rn or 220 Rn with their decay products were one third of that of 6-years old child who received the maximum dose in comparison with other ages. The age-dependent metabolic models in organ and/or body of Tritium, Iodine-131, Caesium-137, radioactive Strontium, Radium and Plutonium were reported. A generalized approach for estimating the effect of age on deposition fractions and retention half-time were presented. Calculated results indicated that younger ages were characterized by increased deposition fraction and decreased half-time for retention. Representative examples were provided for 21 elements of current interest in health physics

Cardiogenic programming of human pluripotent stem cells by dose-controlled activation of EOMES.

Science.gov (United States)

Pfeiffer, Martin J; Quaranta, Roberto; Piccini, Ilaria; Fell, Jakob; Rao, Jyoti; Röpke, Albrecht; Seebohm, Guiscard; Greber, Boris

2018-01-30

Master cell fate determinants are thought to induce specific cell lineages in gastrulation by orchestrating entire gene programs. The T-box transcription factor EOMES (eomesodermin) is crucially required for the development of the heart-yet it is equally important for endoderm specification suggesting that it may act in a context-dependent manner. Here, we define an unrecognized interplay between EOMES and the WNT signaling pathway in controlling cardiac induction by using loss and gain-of-function approaches in human embryonic stem cells. Dose-dependent EOMES induction alone can fully replace a cocktail of signaling molecules otherwise essential for the specification of cardiogenic mesoderm. Highly efficient cardiomyocyte programming by EOMES mechanistically involves autocrine activation of canonical WNT signaling via the WNT3 ligand, which necessitates a shutdown of this axis at a subsequent stage. Our findings provide insights into human germ layer induction and bear biotechnological potential for the robust production of cardiomyocytes from engineered stem cells.

Evolution of the clonogenic potential of human epidermal stem/progenitor cells with age

Directory of Open Access Journals (Sweden)

Zobiri O

2012-02-01

Full Text Available Olivia Zobiri, Nathalie Deshayes, Michelle Rathman-JosserandDepartment of Biological Research, L'Oréal Advanced Research, Clichy Cedex, FranceAbstract: A number of clinical observations have indicated that the regenerative potential and overall function of the epidermis is modified with age. The epidermis becomes thinner, repairs itself less efficiently after wounding, and presents modified barrier function recovery. In addition, the dermal papillae flatten out with increasing age, suggesting a modification in the interaction between epidermal and dermal compartments. As the epidermal regenerative capacity is dependent upon stem and progenitor cell function, it is naturally of interest to identify and understand age-related changes in these particular keratinocyte populations. Previous studies have indicated that the number of stem cells does not decrease with age in mouse models but little solid evidence is currently available concerning human skin. The objective of this study was to evaluate the clonogenic potential of keratinocyte populations isolated from the epidermis of over 50 human donors ranging from 18 to 71 years old. The data indicate that the number of epidermal cells presenting high regenerative potential does not dramatically decline with age in human skin. The authors believe that changes in the microenvironment controlling epidermal basal cell activity are more likely to explain the differences in epidermal function observed with increasing age.Keywords: skin, epidermal stem cells, aging, colony-forming efficiency test

Aging enhances the vulnerability of mesenchymal stromal cells to uniaxial tensile strain-induced apoptosis.

Science.gov (United States)

McKayed, Katey; Prendergast, Patrick J; Campbell, Veronica A

2016-02-08

Mechanical priming can be employed in tissue engineering strategies to control the fate and differentiation pattern of mesenchymal stromal cells. This is relevant to regenerative medicine whereby mechanical cues can promote the regeneration of a specific tissue type from mesenchymal precursors. The ability of cells to respond to mechanical forces is dependent upon mechanotransduction pathways that involve membrane-associated proteins, such as integrins. During the aging process changes in the mechanotransduction machinery may influence how cells from aged individuals respond to mechanical priming. In this study mesenchymal stromal cells were prepared from young adult and aged rats and exposed to uniaxial tensile strain at 5% and 10% for 3 days, or 2.5% for 7 days. Application of 5% tensile strain had no impact on cell viability. In contrast, application of 10% tensile strain evoked apoptosis and the strain-induced apoptosis was significantly higher in the mesenchymal stromal cells prepared from the aged rats. In parallel to the age-related difference in cellular responsiveness to strain, an age-related decrease in expression of α2 integrin and actin, and enhanced lipid peroxidation was observed. This study demonstrates that mesenchymal stem cells from aged animals have an altered membrane environment, are more vulnerable to the pro-apoptotic effects of 10% tensile strain and less responsive to the pro-osteogenic effects of 2.5% tensile strain. Thus, it is essential to consider how aged cells respond to mechanical stimuli in order to identify optimal mechanical priming strategies that minimise cell loss, particularly if this approach is to be applied to an aged population. Copyright © 2015 Elsevier Ltd. All rights reserved.

The acoustical significance of age-dependent ear elongation

DEFF Research Database (Denmark)

Christensen, Flemming

2015-01-01

, corresponding to what is reported in the literature. For female ears, virtually no acoustical effect was found. For male ears directional dependent effects in the range up to 5 dB on average was found for certain directions and frequencies. Implications on age dependent hearing loss (presbycusis...

TRAIL-induced programmed necrosis as a novel approach to eliminate tumor cells

International Nuclear Information System (INIS)

Voigt, Susann; Kalthoff, Holger; Adam, Dieter; Philipp, Stephan; Davarnia, Parvin; Winoto-Morbach, Supandi; Röder, Christian; Arenz, Christoph; Trauzold, Anna; Kabelitz, Dieter; Schütze, Stefan

2014-01-01

The cytokine TRAIL represents one of the most promising candidates for the apoptotic elimination of tumor cells, either alone or in combination therapies. However, its efficacy is often limited by intrinsic or acquired resistance of tumor cells to apoptosis. Programmed necrosis is an alternative, molecularly distinct mode of programmed cell death that is elicited by TRAIL under conditions when the classical apoptosis machinery fails or is actively inhibited. The potential of TRAIL-induced programmed necrosis in tumor therapy is, however, almost completely uncharacterized. We therefore investigated its impact on a panel of tumor cell lines of wide-ranging origin. Cell death/viability was measured by flow cytometry/determination of intracellular ATP levels/crystal violet staining. Cell surface expression of TRAIL receptors was detected by flow cytometry, expression of proteins by Western blot. Ceramide levels were quantified by high-performance thin layer chromatography and densitometric analysis, clonogenic survival of cells was determined by crystal violet staining or by soft agarose cloning. TRAIL-induced programmed necrosis killed eight out of 14 tumor cell lines. Clonogenic survival was reduced in all sensitive and even one resistant cell lines tested. TRAIL synergized with chemotherapeutics in killing tumor cell lines by programmed necrosis, enhancing their effect in eight out of 10 tested tumor cell lines and in 41 out of 80 chemotherapeutic/TRAIL combinations. Susceptibility/resistance of the investigated tumor cell lines to programmed necrosis seems to primarily depend on expression of the pro-necrotic kinase RIPK3 rather than the related kinase RIPK1 or cell surface expression of TRAIL receptors. Furthermore, interference with production of the lipid ceramide protected all tested tumor cell lines. Our study provides evidence that TRAIL-induced programmed necrosis represents a feasible approach for the elimination of tumor cells, and that this treatment may

The chromatin accessibility signature of human immune aging stems from CD8+ T cells.

Science.gov (United States)

Ucar, Duygu; Márquez, Eladio J; Chung, Cheng-Han; Marches, Radu; Rossi, Robert J; Uyar, Asli; Wu, Te-Chia; George, Joshy; Stitzel, Michael L; Palucka, A Karolina; Kuchel, George A; Banchereau, Jacques

2017-10-02

Aging is linked to deficiencies in immune responses and increased systemic inflammation. To unravel the regulatory programs behind these changes, we applied systems immunology approaches and profiled chromatin accessibility and the transcriptome in PBMCs and purified monocytes, B cells, and T cells. Analysis of samples from 77 young and elderly donors revealed a novel and robust aging signature in PBMCs, with simultaneous systematic chromatin closing at promoters and enhancers associated with T cell signaling and a potentially stochastic chromatin opening mostly found at quiescent and repressed sites. Combined analyses of chromatin accessibility and the transcriptome uncovered immune molecules activated/inactivated with aging and identified the silencing of the IL7R gene and the IL-7 signaling pathway genes as potential biomarkers. This signature is borne by memory CD8 + T cells, which exhibited an aging-related loss in binding of NF-κB and STAT factors. Thus, our study provides a unique and comprehensive approach to identifying candidate biomarkers and provides mechanistic insights into aging-associated immunodeficiency. © 2017 Ucar et al.

rhEPO Enhances Cellular Anti-oxidant Capacity to Protect Long-Term Cultured Aging Primary Nerve Cells.

Science.gov (United States)

Wang, Huqing; Fan, Jiaxin; Chen, Mengyi; Yao, Qingling; Gao, Zhen; Zhang, Guilian; Wu, Haiqin; Yu, Xiaorui

2017-08-01

Erythropoietin (EPO) may protect the nervous system of animals against aging damage, making it a potential anti-aging drug for the nervous system. However, experimental evidence from natural aging nerve cell models is lacking, and the efficacy of EPO and underlying mechanism of this effect warrant further study. Thus, the present study used long-term cultured primary nerve cells to successfully mimic the natural aging process of nerve cells. Starting on the 11th day of culture, cells were treated with different concentrations of recombinant human erythropoietin (rhEPO). Using double immunofluorescence labeling, we found that rhEPO significantly improved the morphology of long-term cultured primary nerve cells and increased the total number of long-term cultured primary cells. However, rhEPO did not improve the ratio of nerve cells. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to measure nerve cell activity and showed that rhEPO significantly improved the activity of long-term cultured primary nerve cells. Moreover, Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) double immunofluorescence labeling flow cytometry revealed that rhEPO reduced the apoptotic rate of long-term cultured primary nerve cells. Senescence-associated β-galactosidase (SA-β-gal) immunohistochemistry staining showed that rhEPO significantly reduced the aging rate of long-term cultured primary nerve cells. Immunochemistry revealed that rhEPO enhanced intracellular superoxide dismutase (SOD) activity and glutathione (GSH) abundance and reduced the intracellular malondialdehyde (MDA) level. In addition, this effect depended on the dose, was maximized at a dose of 100 U/ml and was more pronounced than that of vitamin E. In summary, this study finds that rhEPO protects long-term cultured primary nerve cells from aging in a dose-dependent manner. The mechanism of this effect may be associated with the enhancement of the intracellular anti

Oxidative Stress and Programmed Cell Death in Yeast

International Nuclear Information System (INIS)

Farrugia, Gianluca; Balzan, Rena

2012-01-01

Yeasts, such as Saccharomyces cerevisiae, have long served as useful models for the study of oxidative stress, an event associated with cell death and severe human pathologies. This review will discuss oxidative stress in yeast, in terms of sources of reactive oxygen species (ROS), their molecular targets, and the metabolic responses elicited by cellular ROS accumulation. Responses of yeast to accumulated ROS include upregulation of antioxidants mediated by complex transcriptional changes, activation of pro-survival pathways such as mitophagy, and programmed cell death (PCD) which, apart from apoptosis, includes pathways such as autophagy and necrosis, a form of cell death long considered accidental and uncoordinated. The role of ROS in yeast aging will also be discussed.

Assessing age-dependent susceptibility to measles in Japan.

Science.gov (United States)

Kinoshita, Ryo; Nishiura, Hiroshi

2017-06-05

Routine vaccination against measles in Japan started in 1978. Whereas measles elimination was verified in 2015, multiple chains of measles transmission were observed in 2016. We aimed to reconstruct the age-dependent susceptibility to measles in Japan so that future vaccination strategies can be elucidated. An epidemiological model was used to quantify the age-dependent immune fraction using datasets of vaccination coverage and seroepidemiological survey. The second dose was interpreted in two different scenarios, i.e., booster and random shots. The effective reproduction number, the average number of secondary cases generated by a single infected individual, and the age at infection were explored using the age-dependent transmission model and the next generation matrix. While the herd immunity threshold of measles likely ranges from 90% to 95%, assuming that the basic reproductive number ranges from 10 to 20, the estimated immune fraction in Japan was below those thresholds in 2016, despite the fact that the estimates were above 80% for all ages. If the second dose completely acted as the booster shot, a proportion immune above 90% was achieved only among those aged 5years or below in 2016. Alternatively, if the second dose was randomly distributed regardless of primary vaccination status, a proportion immune over 90% was achieved among those aged below 25years. The effective reproduction number was estimated to range from 1.50 to 3.01 and from 1.50 to 3.00, respectively, for scenarios 1 and 2 in 2016; if the current vaccination schedule were continued, the reproduction number is projected to range from 1.50 to 3.01 and 1.39 to 2.78, respectively, in 2025. Japan continues to be prone to imported cases of measles. Supplementary vaccination among adults aged 20-49years would be effective if the chains of transmission continue to be observed in that age group. Copyright © 2017 Elsevier Ltd. All rights reserved.

Impact of infant and preschool pertussis vaccinations on memory B-cell responses in children at 4 years of age.

Science.gov (United States)

Hendrikx, Lotte H; de Rond, Lia G H; Oztürk, Kemal; Veenhoven, Reinier H; Sanders, Elisabeth A M; Berbers, Guy A M; Buisman, Anne-Marie

2011-08-05

Whooping cough, caused by Bordetella pertussis, is reemerging in the vaccinated population. Antibody levels to pertussis antigens wane rapidly after both whole-cell (wP) and acellular pertussis (aP) vaccination and protection may largely depend on long-term B- and T-cell immunity. We studied the effect of wP and aP infant priming at 2, 3, 4 and 11 months according to the Dutch immunization program on pertussis-specific memory B-cell responses before and after a booster vaccination with either a high- or low-pertussis dose vaccine at 4 years of age. Purified B-cells were characterized by FACS-analysis and after polyclonal stimulation, memory B-cells were detected by ELISPOT-assays specific for pertussis toxin, filamentous haemagglutinin and pertactin. Before and after the booster, higher memory B-cell responses were measured in aP primed children compared with wP primed children. In contrast with antibody levels, no dose-effect was observed on the numbers of memory B-cell responses. In aP primed children a fifth high-dose aP vaccination tended to induce even lower memory B-cell responses than a low-dose aP booster. In both wP and aP primed children, the number of memory B-cells increased after the booster and correlated with the pertussis-specific antibody concentrations and observed affinity maturation. This study indicates that aP vaccinations in the first year of life induce higher pertussis-specific memory B-cell responses in children 4 years of age compared with Dutch wP primary vaccinations. Since infant aP vaccinations have improved protection against whooping cough in children despite waning antibody levels, this suggests that an enhanced memory B-cell pool induction may have an important role in protection. However, the pertussis-dose of the preschool booster needs to be considered depending on the vaccine used for priming to optimize long-term protection against whooping cough. Copyright © 2011 Elsevier Ltd. All rights reserved.

From lymphopoiesis to plasma cells differentiation, the age-related modifications of B cell compartment are influenced by "inflamm-ageing".

Science.gov (United States)

Bulati, Matteo; Caruso, Calogero; Colonna-Romano, Giuseppina

2017-07-01

Ageing is a complex process characterized by a general decline in physiological functions with increasing morbidity and mortality. The most important aspect of ageing is the chronic inflammatory status, named "inflamm-ageing", strictly associated with the deterioration of the immune function, termed "immunosenescence". Both are causes of increased susceptibility of elderly to infectious diseases, cancer, dementia, cardiovascular diseases and autoimmunity, and of a decreased response to vaccination. It has been widely demonstrated that ageing has a strong impact on the remodelling of the B cell branch of immune system. The first evident effect is the significant decrease in circulating B cells, primarily due to the reduction of new B cell coming from bone marrow (BM) progenitors, as inflammation directly impacts on B lymphopoiesis. Besides, in aged individuals, there is a shift from naïve to memory immunoglobulins production, accompanied by the impaired ability to produce high affinity protective antibodies against newly encountered antigens. This is accompanied by the increase of expanded clones of B cells, which correlates with poor health status. Age-related modifications also occur in naïve/memory B cells subsets. Indeed, in the elderly, there is a reduction of naïve B cells, accompanied by the expansion of memory B cells that show a senescence-associated phenotype. Finally, elderly show the impaired ability of memory B cells to differentiate into plasma cells. It can be concluded that inflammation is the leading cause of the age-related impairment of B cell compartment, which play certainly a key role in the development of age-related diseases. This makes study of B cells in the aged an important tool for monitoring immunosenescence, chronic inflammatory disorders and the effectiveness of vaccines or pharmacological therapies. Copyright © 2017 Elsevier B.V. All rights reserved.

Effectiveness of the Vital Aging program to promote active aging in Mexican older adults

Directory of Open Access Journals (Sweden)

Mendoza-Ruvalcaba NM

2016-11-01

Full Text Available Neyda Ma Mendoza-Ruvalcaba,1 Rocío Fernández-Ballesteros2 1Health Sciences Department, University of Guadalajara, University Center of Tonalá, Tonalá, Jalisco, Mexico; 2Department of Biological and Health Psychology, Autonomous University of Madrid, Madrid, Spain Introduction: Aging is not only a population phenomenon but also an experience and an individual reality. Vital Aging® is a program that considers active aging as the lifelong adaptation process of maximizing health and independence, physical and cognitive functioning, positive affect regulation and control, and social engagement. Through its different versions and editions, it has demonstrated being an effective program to promote active aging. The aim of this study is to determine the effectiveness of the “face-to-face” and “combined” versions of the program to promote active aging in Mexican older adults trial. Methods: Seventy-six older adults aged 60 years and over participated in a quasi-experimental study and were recruited in a senior center to participate in the two experimental conditions: Vital Aging face-to-face (VA-FF (n=35 and Vital Aging combined (VA-C; multimedia/face-to-face (n=15, and the remaining 26 adults were assigned to a control group. Pretest and posttest assessments were performed after the theoretical–practical intervention. Mean differences and size effects were calculated for estimating the effect of the program. Results: At the end of the study, participants showed improvements in the active aging outcome measures. Positive effects were observed in the frequency of intellectual, cultural – artistic, and social activities, perceptions of aging, satisfaction with social relationships, and self-efficacy for aging. Additionally, those who participated in VA-FF showed better memory performance, meta-memory, and a trend to report less memory problems, while older persons in VA-C showed a trend to have better life satisfaction. No effects were

A dimensionless ordered pull-through model of the mammalian lens epithelium evidences scaling across species and explains the age-dependent changes in cell density in the human lens

Science.gov (United States)

Wu, Jun Jie; Wu, Weiju; Tholozan, Frederique M.; Saunter, Christopher D.; Girkin, John M.; Quinlan, Roy A.

2015-01-01

We present a mathematical (ordered pull-through; OPT) model of the cell-density profile for the mammalian lens epithelium together with new experimental data. The model is based upon dimensionless parameters, an important criterion for inter-species comparisons where lens sizes can vary greatly (e.g. bovine (approx. 18 mm); mouse (approx. 2 mm)) and confirms that mammalian lenses scale with size. The validated model includes two parameters: β/α, which is the ratio of the proliferation rate in the peripheral and in the central region of the lens; and γGZ, a dimensionless pull-through parameter that accounts for the cell transition and exit from the epithelium into the lens body. Best-fit values were determined for mouse, rat, rabbit, bovine and human lens epithelia. The OPT model accounts for the peak in cell density at the periphery of the lens epithelium, a region where cell proliferation is concentrated and reaches a maximum coincident with the germinative zone. The β/α ratio correlates with the measured FGF-2 gradient, a morphogen critical to lens cell survival, proliferation and differentiation. As proliferation declines with age, the OPT model predicted age-dependent changes in cell-density profiles, which we observed in mouse and human lenses. PMID:26236824

Anomalous scaling in an age-dependent branching model.

Science.gov (United States)

Keller-Schmidt, Stephanie; Tuğrul, Murat; Eguíluz, Víctor M; Hernández-García, Emilio; Klemm, Konstantin

2015-02-01

We introduce a one-parametric family of tree growth models, in which branching probabilities decrease with branch age τ as τ(-α). Depending on the exponent α, the scaling of tree depth with tree size n displays a transition between the logarithmic scaling of random trees and an algebraic growth. At the transition (α=1) tree depth grows as (logn)(2). This anomalous scaling is in good agreement with the trend observed in evolution of biological species, thus providing a theoretical support for age-dependent speciation and associating it to the occurrence of a critical point.

Premature aging/senescence in cancer cells facing therapy: good or bad?

Science.gov (United States)

Gonzalez, Llilians Calvo; Ghadaouia, Sabrina; Martinez, Aurélie; Rodier, Francis

2016-02-01

Normal and cancer cells facing their demise following exposure to radio-chemotherapy can actively participate in choosing their subsequent fate. These programmed cell fate decisions include true cell death (apoptosis-necroptosis) and therapy-induced cellular senescence (TIS), a permanent "proliferative arrest" commonly portrayed as premature cellular aging. Despite a permanent loss of proliferative potential, senescent cells remain viable and are highly bioactive at the microenvironment level, resulting in a prolonged impact on tissue architecture and functions. Cellular senescence is primarily documented as a tumor suppression mechanism that prevents cellular transformation. In the context of normal tissues, cellular senescence also plays important roles in tissue repair, but contributes to age-associated tissue dysfunction when senescent cells accumulate. Theoretically, in multi-step cancer progression models, cancer cells have already bypassed cellular senescence during their immortalization step (see hallmarks of cancer). It is then perhaps surprising to find that cancer cells often retain the ability to undergo TIS, or premature aging. This occurs because cellular senescence results from multiple signalling pathways, some retained in cancer cells, aiming to prevent cell cycle progression in damaged cells. Since senescent cancer cells persist after therapy and secrete an array of cytokines and growth factors that can modulate the tumor microenvironment, these cells may have beneficial and detrimental effects regarding immune modulation and survival of remaining proliferation-competent cancer cells. Similarly, while normal cells undergoing senescence are believed to remain indefinitely growth arrested, whether this is true for senescent cancer cells remains unclear, raising the possibility that these cells may represent a reservoir for cancer recurrence after treatment. This review discusses our current knowledge on cancer cell senescence and highlight questions

Seafloor age dependence of Rayleigh wave phase velocities in the Indian Ocean

Science.gov (United States)

Godfrey, Karen E.; Dalton, Colleen A.; Ritsema, Jeroen

2017-05-01

Variations in the phase velocity of fundamental-mode Rayleigh waves across the Indian Ocean are determined using two inversion approaches. First, variations in phase velocity as a function of seafloor age are estimated using a pure-path age-dependent inversion method. Second, a two-dimensional parameterization is used to solve for phase velocity within 1.25° × 1.25° grid cells. Rayleigh wave travel time delays have been measured between periods of 38 and 200 s. The number of measurements in the study area ranges between 4139 paths at a period of 200 s and 22,272 paths at a period of 40 s. At periods Rodriguez Triple Junction and the Australian-Antarctic Discordance and anomalously low velocities immediately to the west of the Central Indian Ridge.

[Occlusion treatment for amblyopia. Age dependence and dose-response relationship].

Science.gov (United States)

Fronius, M

2016-04-01

Based on clinical experience and studies on animal models the age of 6-7 years was regarded as the limit for treatment of amblyopia, although functional improvement was also occasionally reported in older patients. New technical developments as well as insights from clinical studies and the neurosciences have attracted considerable attention to this topic. Various aspects of the age dependence of amblyopia treatment are discussed in this article, e. g. prescription, electronic monitoring of occlusion dosage, calculation of indicators for age-dependent plasticity of the visual system, and novel, alternative treatment approaches. Besides a discussion of the recent literature, results of studies by our "Child Vision Research Unit" in Frankfurt are presented: results of a questionnaire about prescription habits concerning age limits of patching, electronic recording of occlusion in patients beyond the conventional treatment age, calculation of dose-response function and efficiency of patching and their age dependence. The results of the questionnaire illustrate the uncertainty about age limits of prescription with significant deviations from the guideline of the German Ophthalmological Society (DOG). Electronic recording of occlusion allowed the quantification of declining dose-response function and treatment efficiency between 5 and 16 years of age. Reports about successful treatment with conventional and novel methods in adults are at variance with the notion of a rigid adult visual system lacking plasticity. Electronic recording of patching allowed new insights into the age-dependent susceptibility of the visual system and contributes to a more evidence-based treatment of amblyopia. Alternative approaches for adults challenge established notions about age limits of amblyopia therapy. Further studies comparing different treatment options are urgently needed.

c-Myc-Dependent Cell Competition in Human Cancer Cells.

Science.gov (United States)

Patel, Manish S; Shah, Heta S; Shrivastava, Neeta

2017-07-01

Cell Competition is an interaction between cells for existence in heterogeneous cell populations of multicellular organisms. This phenomenon is involved in initiation and progression of cancer where heterogeneous cell populations compete directly or indirectly for the survival of the fittest based on differential gene expression. In Drosophila, cells having lower dMyc expression are eliminated by cell competition through apoptosis when present in the milieu of cells having higher dMyc expression. Thus, we designed a study to develop c-Myc (human homolog) dependent in vitro cell competition model of human cancer cells. Cells with higher c-Myc were transfected with c-myc shRNA to prepare cells with lower c-Myc and then co-cultured with the same type of cells having a higher c-Myc in equal ratio. Cells with lower c-Myc showed a significant decrease in numbers when compared with higher c-Myc cells, suggesting "loser" and "winner" status of cells, respectively. During microscopy, engulfment of loser cells by winner cells was observed with higher expression of JNK in loser cells. Furthermore, elimination of loser cells was prevented significantly, when co-cultured cells were treated with the JNK (apoptosis) inhibitor. Above results indicate elimination of loser cells in the presence of winner cells by c-Myc-dependent mechanisms of cell competition in human cancer cells. This could be an important mechanism in human tumors where normal cells are eliminated by c-Myc-overexpressed tumor cells. J. Cell. Biochem. 118: 1782-1791, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Mitochondrial role in cell aging

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Miquel, J.; Fleming, J.; Economos, A. C.; Johnson, J. E., Jr.

1980-01-01

The experimental studies on the mitochondria of insect and mammalian cells are examined with a view to an analysis of intrinsic mitochondrial senescence, and its relation to the age-related changes in other cell organelles. The fine structural and biochemical data support the concept that the mitochondria of fixed postmitotic cells may be the site of intrinsic aging because of the attack by free radicals and lipid peroxides originating in the organelles as a by-product of oxygen reduction during respiration. Although the cells have numerous mechanisms for counteracting lipid peroxidation injury, there is a slippage in the antioxidant protection. Intrinsic mitochondrial aging could thus be considered as a specific manifestation of oxygen toxicity. It is proposed that free radical injury renders an increasing number of the mitochondria unable to divide, probably because of damage to the lipids of the inner membrane and to mitochondrial DNA.

Effectiveness of the Vital Aging program to promote active aging in Mexican older adults.

Science.gov (United States)

Mendoza-Ruvalcaba, Neyda Ma; Fernández-Ballesteros, Rocío

2016-01-01

Aging is not only a population phenomenon but also an experience and an individual reality. Vital Aging ® is a program that considers active aging as the lifelong adaptation process of maximizing health and independence, physical and cognitive functioning, positive affect regulation and control, and social engagement. Through its different versions and editions, it has demonstrated being an effective program to promote active aging. The aim of this study is to determine the effectiveness of the "face-to-face" and "combined" versions of the program to promote active aging in Mexican older adults trial. Seventy-six older adults aged 60 years and over participated in a quasi-experimental study and were recruited in a senior center to participate in the two experimental conditions: Vital Aging face-to-face (VA-FF) (n=35) and Vital Aging combined (VA-C; multimedia/face-to-face) (n=15), and the remaining 26 adults were assigned to a control group. Pretest and posttest assessments were performed after the theoretical-practical intervention. Mean differences and size effects were calculated for estimating the effect of the program. At the end of the study, participants showed improvements in the active aging outcome measures. Positive effects were observed in the frequency of intellectual, cultural - artistic, and social activities, perceptions of aging, satisfaction with social relationships, and self-efficacy for aging. Additionally, those who participated in VA-FF showed better memory performance, meta-memory, and a trend to report less memory problems, while older persons in VA-C showed a trend to have better life satisfaction. No effects were observed in physical activity, frequency of social relationships, and subjective health. Findings show that the Vital Aging program in face-to-face and combined versions encourages active aging in Mexican older persons. These results are in general similar to those found in editions performed in Spain, revealing its consistency

Effectiveness of the Vital Aging program to promote active aging in Mexican older adults

Science.gov (United States)

Mendoza-Ruvalcaba, Neyda Ma; Fernández-Ballesteros, Rocío

2016-01-01

Introduction Aging is not only a population phenomenon but also an experience and an individual reality. Vital Aging® is a program that considers active aging as the lifelong adaptation process of maximizing health and independence, physical and cognitive functioning, positive affect regulation and control, and social engagement. Through its different versions and editions, it has demonstrated being an effective program to promote active aging. The aim of this study is to determine the effectiveness of the “face-to-face” and “combined” versions of the program to promote active aging in Mexican older adults trial. Methods Seventy-six older adults aged 60 years and over participated in a quasi-experimental study and were recruited in a senior center to participate in the two experimental conditions: Vital Aging face-to-face (VA-FF) (n=35) and Vital Aging combined (VA-C; multimedia/face-to-face) (n=15), and the remaining 26 adults were assigned to a control group. Pretest and posttest assessments were performed after the theoretical–practical intervention. Mean differences and size effects were calculated for estimating the effect of the program. Results At the end of the study, participants showed improvements in the active aging outcome measures. Positive effects were observed in the frequency of intellectual, cultural – artistic, and social activities, perceptions of aging, satisfaction with social relationships, and self-efficacy for aging. Additionally, those who participated in VA-FF showed better memory performance, meta-memory, and a trend to report less memory problems, while older persons in VA-C showed a trend to have better life satisfaction. No effects were observed in physical activity, frequency of social relationships, and subjective health. Conclusion Findings show that the Vital Aging program in face-to-face and combined versions encourages active aging in Mexican older persons. These results are in general similar to those found in

Age Spreads and the Temperature Dependence of Age Estimates in Upper Sco

Energy Technology Data Exchange (ETDEWEB)

Fang Qiliang; Herczeg, Gregory J. [Kavli Institute for Astronomy and Astrophysics, Peking University, Yiheyuan Lu 5, Haidian Qu, 100871 Beijing (China); Rizzuto, Aaron [Department of Astronomy, University of Texas, 2515 Speedway, Stop C1400, Austin, TX 78712 (United States)

2017-06-20

Past estimates for the age of the Upper Sco Association are typically 11–13 Myr for intermediate-mass stars and 4–5 Myr for low-mass stars. In this study, we simulate populations of young stars to investigate whether this apparent dependence of estimated age on spectral type may be explained by the star formation history of the association. Solar and intermediate mass stars begin their pre-main sequence evolution on the Hayashi track, with fully convective interiors and cool photospheres. Intermediate-mass stars quickly heat up and transition onto the radiative Henyey track. As a consequence, for clusters in which star formation occurs on a timescale similar to that of the transition from a convective to a radiative interior, discrepancies in ages will arise when ages are calculated as a function of temperature instead of mass. Simple simulations of a cluster with constant star formation over several Myr may explain about half of the difference in inferred ages versus photospheric temperature; speculative constructions that consist of a constant star formation followed by a large supernova-driven burst could fully explain the differences, including those between F and G stars where evolutionary tracks may be more accurate. The age spreads of low-mass stars predicted from these prescriptions for star formation are consistent with the observed luminosity spread of Upper Sco. The conclusion that a lengthy star formation history will yield a temperature dependence in ages is expected from the basic physics of pre-main sequence evolution, and is qualitatively robust to the large uncertainties in pre-main sequence evolutionary models.

Age-dependent changes in mean and variance of gene expression across tissues in a twin cohort.

Science.gov (United States)

Viñuela, Ana; Brown, Andrew A; Buil, Alfonso; Tsai, Pei-Chien; Davies, Matthew N; Bell, Jordana T; Dermitzakis, Emmanouil T; Spector, Timothy D; Small, Kerrin S

2018-02-15

Changes in the mean and variance of gene expression with age have consequences for healthy aging and disease development. Age-dependent changes in phenotypic variance have been associated with a decline in regulatory functions leading to increase in disease risk. Here, we investigate age-related mean and variance changes in gene expression measured by RNA-seq of fat, skin, whole blood and derived lymphoblastoid cell lines (LCLs) expression from 855 adult female twins. We see evidence of up to 60% of age effects on transcription levels shared across tissues, and 47% of those on splicing. Using gene expression variance and discordance between genetically identical MZ twin pairs, we identify 137 genes with age-related changes in variance and 42 genes with age-related discordance between co-twins; implying the latter are driven by environmental effects. We identify four eQTLs whose effect on expression is age-dependent (FDR 5%). Combined, these results show a complicated mix of environmental and genetically driven changes in expression with age. Using the twin structure in our data, we show that additive genetic effects explain considerably more of the variance in gene expression than aging, but less that other environmental factors, potentially explaining why reliable expression-derived biomarkers for healthy-aging have proved elusive compared with those derived from methylation. © The Author(s) 2017. Published by Oxford University Press.

Cell-substrate interaction with cell-membrane-stress dependent adhesion.

Science.gov (United States)

Jiang, H; Yang, B

2012-01-10

Cell-substrate interaction is examined in a two-dimensional mechanics model. The cell and substrate are treated as a shell and an elastic solid, respectively. Their interaction through adhesion is treated using nonlinear springs. Compared to previous cell mechanics models, the present model introduces a cohesive force law that is dependent not only on cell-substrate distance but also on internal cell-membrane stress. It is postulated that a living cell would establish focal adhesion sites with density dependent on the cell-membrane stress. The formulated mechanics problem is numerically solved using coupled finite elements and boundary elements for the cell and the substrate, respectively. The nodes in the adhesion zone from either side are linked by the cohesive springs. The specific cases of a cell adhering to a homogeneous substrate and a heterogeneous bimaterial substrate are examined. The analyses show that the substrate stiffness affects the adhesion behavior significantly and regulates the direction of cell adhesion, in good agreement with the experimental results in the literature. By introducing a reactive parameter (i.e., cell-membrane stress) linking biological responses of a living cell to a mechanical environment, the present model offers a unified mechanistic vehicle for characterization and prediction of living cell responses to various kinds of mechanical stimuli including local extracellular matrix and neighboring cells. Copyright © 2011 Elsevier Ltd. All rights reserved.

Protective role of female gender in programmed accelerated renal aging in the rat.

Science.gov (United States)

Pijacka, Wioletta; Clifford, Bethan; Tilburgs, Chantal; Joles, Jaap A; Langley-Evans, Simon; McMullen, Sarah

2015-04-01

The aging kidney exhibits a progressive decline in glomerular filtration rate, accompanied by inflammatory and oxidative damage. We hypothesized that accelerated, age-related progression of renal injury is ovarian hormones-dependant. To address this we used an established model of developmentally programmed accelerated renal aging in the rat, superimposed by ovariectomy to assess interactions between ovarian hormones and the aging process. Under our experimental conditions, we found that kidney function worsens with age, that is GFR reduces over 18 month analyzed time-course and this was worsened by fetal exposure to maternal low-protein diet and absence of estrogen. Reduction in GFR was followed by increases in albuminuria, proteinuria, inflammatory markers, and tissue carbonyls, all suggesting inflammatory response and oxidative stress. This was associated with changes in AGTR2 expression which was greater at 18 months of age compared to earlier time points, but in MLP offspring only. Our studies show an influence of ovarian hormones on programmed accelerated renal aging and the AGTR2 across the lifespan. The main findings are that ovariectomy is a risk factor for increased aging-related renal injury and that this and oxidative damage might be related to changes in AGTR2 expression. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

A computational model for telomere-dependent cell-replicative aging.

Science.gov (United States)

Portugal, R D; Land, M G P; Svaiter, B F

2008-01-01

Telomere shortening provides a molecular basis for the Hayflick limit. Recent data suggest that telomere shortening also influence mitotic rate. We propose a stochastic growth model of this phenomena, assuming that cell division in each time interval is a random process which probability decreases linearly with telomere shortening. Computer simulations of the proposed stochastic telomere-regulated model provides good approximation of the qualitative growth of cultured human mesenchymal stem cells.

Distal Regeneration Involves the Age Dependent Activity of Branchial Sac Stem Cells in the Ascidian Ciona intestinalis.

Science.gov (United States)

Jeffery, William R

2015-02-01

Tunicates have high capacities for regeneration but the underlying mechanisms and their relationship to life cycle progression are not well understood. Here we investigate the regeneration of distal structures in the ascidian tunicate Ciona intestinalis . Analysis of regenerative potential along the proximal-distal body axis indicated that distal organs, such as the siphons, their pigmented sensory organs, and the neural complex, could only be replaced from body fragments containing the branchial sac. Distal regeneration involves the formation of a blastema composed of cells that undergo cell proliferation prior to differentiation and cells that differentiate without cell proliferation. Both cell types originate in the branchial sac and appear in the blastema at different times after distal injury. Whereas the branchial sac stem cells are present in young animals, they are depleted in old animals that have lost their regeneration capacity. Thus Ciona adults contain a population of age-related stem cells located in the branchial sac that are a source of precursors for distal body regeneration.

An Overview of Quality Programs that Support Transition-Aged Youth

Directory of Open Access Journals (Sweden)

Christopher M. Kalinyak

2016-12-01

Full Text Available This article provides a concise overview of several programs that deliver services to transition-aged youth, ages 14–29. Included are family support, the Assisting Unaccompanied Children and Youth program, the Substance Abuse and Mental Health Services Administration services, the wraparound approach, intensive home-based treatment, multisystemic therapy, foster care, independent living, mentoring, the Steps to Success program, the Jump on Board for Success program, the Options program, the Positive Action program, the Transition to Success model, and the Transition to Independence Program. Primary focus is placed upon the usefulness of each of the programs in facilitating successful outcomes for transition-aged youth.

ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age-Related Diseases

Directory of Open Access Journals (Sweden)

Pierpaola Davalli

2016-01-01

Full Text Available The aging process worsens the human body functions at multiple levels, thus causing its gradual decrease to resist stress, damage, and disease. Besides changes in gene expression and metabolic control, the aging rate has been associated with the production of high levels of Reactive Oxygen Species (ROS and/or Reactive Nitrosative Species (RNS. Specific increases of ROS level have been demonstrated as potentially critical for induction and maintenance of cell senescence process. Causal connection between ROS, aging, age-related pathologies, and cell senescence is studied intensely. Senescent cells have been proposed as a target for interventions to delay the aging and its related diseases or to improve the diseases treatment. Therapeutic interventions towards senescent cells might allow restoring the health and curing the diseases that share basal processes, rather than curing each disease in separate and symptomatic way. Here, we review observations on ROS ability of inducing cell senescence through novel mechanisms that underpin aging processes. Particular emphasis is addressed to the novel mechanisms of ROS involvement in epigenetic regulation of cell senescence and aging, with the aim to individuate specific pathways, which might promote healthy lifespan and improve aging.

Reduced Ang2 expression in aging endothelial cells.

Science.gov (United States)

Hohensinner, P J; Ebenbauer, B; Kaun, C; Maurer, G; Huber, K; Wojta, J

2016-06-03

Aging endothelial cells are characterized by increased cell size, reduced telomere length and increased expression of proinflammatory cytokines. In addition, we describe here that aging reduces the migratory distance of endothelial cells. Furthermore, we observe an increase of the quiescence protein Ang1 and a decrease of the endothelial activation protein Ang2 upon aging. Supplementing Ang2 to aged endothelial cells restored their migratory capacity. We conclude that aging shifts the balance of the Ang1/Ang2 network favouring a quiescent state. Activation of endothelial cells in aging might be necessary to enhance wound healing capacities. Copyright © 2016 Elsevier Inc. All rights reserved.

Centrosome and microtubule instability in aging Drosophila cells

Science.gov (United States)

Schatten, H.; Chakrabarti, A.; Hedrick, J.

1999-01-01

Several cytoskeletal changes are associated with aging which includes alterations in muscle structure leading to muscular atrophy, and weakening of the microtubule network which affects cellular secretion and maintenance of cell shape. Weakening of the microtubule network during meiosis in aging oocytes can result in aneuploidy or trisomic zygotes with increasing maternal age. Imbalances of cytoskeletal organization can lead to disease such as Alzheimer's, muscular disorders, and cancer. Because many cytoskeletal diseases are related to age we investigated the effects of aging on microtubule organization in cell cultures of the Drosophila cell model system (Schneider S-1 and Kc23 cell lines). This cell model is increasingly being used as an alternative system to mammalian cell cultures. Drosophila cells are amenable to genetic manipulations and can be used to identify and manipulate genes which are involved in the aging processes. Immunofluorescence, scanning, and transmission electron microscopy were employed for the analysis of microtubule organizing centers (centrosomes) and microtubules at various times after subculturing cells in fresh medium. Our results reveal that centrosomes and the microtubule network becomes significantly affected in aging cells after 5 days of subculture. At 5-14 days of subculture, 1% abnormal out of 3% mitoses were noted which were clearly distinguishable from freshly subcultured control cells in which 3% of cells undergo normal mitosis with bipolar configurations. Microtubules are also affected in the midbody during cell division. The midbody in aging cells becomes up to 10 times longer when compared with midbodies in freshly subcultured cells. During interphase, microtubules are often disrupted and disorganized, which may indicate improper function related to transport of cell organelles along microtubules. These results are likely to help explain some cytoskeletal disorders and diseases related to aging.

Stem cell aging: Survival of the laziest?

OpenAIRE

Muller-Sieburg, Christa; Sieburg, Hans B.

2008-01-01

The question whether stem cells age remains an enigma. Traditionally, aging was thought to change the properties of hematopoietic stem cells (HSC). We discuss here a new model of stem cell aging that challenges this view. It is now well-established that the HSC compartment is heterogeneous, consisting of epigenetically fixed subpopulations of HSC that differ in self-renewal and differentiation capacity. New data show that the representation of these HSC subsets changes during aging. HSC that ...

SirT1—A Sensor for Monitoring Self-Renewal and Aging Process in Retinal Stem Cells

Directory of Open Access Journals (Sweden)

Chi-Hsien Peng

2010-06-01

Full Text Available Retinal stem cells bear potency of proliferation, self-renewal, and differentiation into many retinal cells. Utilizing appropriate sensors one can effectively detect the self-renewal and aging process abilities. Silencing information regulator (SirT1, a member of the sirtuin family, is a NAD-dependent histone deacetylase and an essential mediator for longevity in normal cells by calorie restriction. We firstly investigate the SirT1 mRNA expression in retinal stem cells from rats and 19 human eyes of different ages. Results revealed that SirT1 expression was significantly decreased in in vivo aged eyes, associated with poor self-renewal abilities. Additionally, SirT1 mRNA levels were dose-dependently increased in resveratrol- treated retinal stem cells. The expression of SirT1 on oxidative stress-induced damage was significantly decreased, negatively correlated with the level of intracellular reactive oxygen species production. Treatment with resveratrol could effectively further reduce oxidative stress induced by H2O2 treatment in retinal stem cells. Importantly, the anti-oxidant effects of resveratrol in H2O2-treated retinal stem cells were significantly abolished by knockdown of SirT1 expression (sh-SirT1. SirT1 expression provides a feasible sensor in assessing self-renewal and aging process in retinal stem cells. Resveratrol can prevent reactive oxygen species-induced damages via increased retinal SirT1 expression.

B16 melanoma tumor growth is delayed in mice in an age-dependent manner

Directory of Open Access Journals (Sweden)

Christina Pettan-Brewer

2012-08-01

Full Text Available A major risk factor for cancer is increasing age, which suggests that syngeneic tumor implants in old mice would grow more rapidly. However, various reports have suggested that old mice are not as permissive to implanted tumor cells as young mice. In order to determine and characterize the age-related response to B16 melanoma, we implanted 5×105 tumor cells into 8, 16, 24, and 32-month-old male C57BL/6 (B6 and C57BL/6×BALB/c F1 (CB6 F1 mice subcutaneously in the inguinal and axillary spaces, or intradermally in the lateral flank. Results showed decreased tumor volume with increasing age, which varied according to mouse genetic background and the implanted site. The B6 strain showed robust tumor growth at 8 months of age at the inguinal implantation site, with an average tumor volume of 1341.25 mm3. The 16, 24, and 32-month age groups showed a decrease in tumor growth with tumor volumes of 563.69, 481.02, and 264.55 mm3, respectively (p≤0.001. The axillary implantation site was less permissive in 8-month-old B6 mice with an average tumor volume of 761.52 mm3. The 24- and 32-month age groups showed a similar decrease in tumor growth with tumor volumes of 440 and 178.19 mm3, respectively (p≤0.01. The CB6F1 strain was not as tumor permissive at 8 months of age as B6 mice with average tumor volumes of 446.96 and 426.91 mm3 for the inguinal and axillary sites, respectively. There was a decrease in tumor growth at 24 months of age at both inguinal and axillary sites with an average tumor volume of 271.02 and 249.12 mm3, respectively (p≤0.05. The strain dependence was not apparent in 8-month-old mice injected intradermally with B16 melanoma cells, with average tumor volumes of 736.82 and 842.85 mm3 for B6 and CB6 F1, respectively. However, a strain difference was seen in 32-month-old B6 mice with an average decrease in tumor volume of 250.83 mm3 (p≤0.01. In contrast, tumor growth significantly decreased earlier in CB6 F1 mice with average

Aging-dependent decline of IL-10 producing B cells coincides with production of antinuclear antibodies but not rheumatoid factors

NARCIS (Netherlands)

van der Geest, Kornelis S. M.; Lorencetti, Pedro G.; Abdulahad, Wayel H.; Horst, Gerda; Huitema, Minke; Roozendaal, Caroline; Kroesen, Bart-Jan; Brouwer, Elisabeth; Boots, Annemieke M. H.

Aging is associated with development of autoimmunity. Loss of B cell tolerance in the elderly is suggested by an increased prevalence of anti-nuclear antibodies (ANAs) and rheumatoid factors (RFs). Accumulating evidence indicates that B cells also impact autoimmunity via secretion of cytokines. So

β-Cell dedifferentiation, reduced duct cell plasticity, and impaired β-cell mass regeneration in middle-aged rats.

Science.gov (United States)

Téllez, Noèlia; Vilaseca, Marina; Martí, Yasmina; Pla, Arturo; Montanya, Eduard

2016-09-01

Limitations in β-cell regeneration potential in middle-aged animals could contribute to the increased risk to develop diabetes associated with aging. We investigated β-cell regeneration of middle-aged Wistar rats in response to two different regenerative stimuli: partial pancreatectomy (Px + V) and gastrin administration (Px + G). Pancreatic remnants were analyzed 3 and 14 days after surgery. β-Cell mass increased in young animals after Px and was further increased after gastrin treatment. In contrast, β-cell mass did not change after Px or after gastrin treatment in middle-aged rats. β-Cell replication and individual β-cell size were similarly increased after Px in young and middle-aged animals, and β-cell apoptosis was not modified. Nuclear immunolocalization of neurog3 or nkx6.1 in regenerative duct cells, markers of duct cell plasticity, was increased in young but not in middle-aged Px rats. The pancreatic progenitor-associated transcription factors neurog3 and sox9 were upregulated in islet β-cells of middle-aged rats and further increased after Px. The percentage of chromogranin A+/hormone islet cells was significantly increased in the pancreases of middle-aged Px rats. In summary, the potential for compensatory β-cell hyperplasia and hypertrophy was retained in middle-aged rats, but β-cell dedifferentiation and impaired duct cell plasticity limited β-cell regeneration. Copyright © 2016 the American Physiological Society.

Involvement of IRF4 dependent dendritic cells in T cell dependent colitis

DEFF Research Database (Denmark)

Pool, Lieneke; Rivollier, Aymeric Marie Christian; Agace, William Winston

in genetically susceptible individuals and pathogenic CD4+ T cells, which accumulate in the inflamed mucosa, are believed to be key drivers of the disease. While dendritic cells (DCs) are important in the priming of intestinal adaptive immunity and tolerance their role in the initiation and perpetuation...... of chronic intestinal inflammation remains unclear. In the current study we used the CD45RBhi T cell transfer model of colitis to determine the role of IRF4 dependent DCs in intestinal inflammation. In this model naïve CD4+ T cells when transferred into RAG-/- mice, proliferate and expand in response...... to bacterial derived luminal antigen, localize to the intestinal mucosa and induce colitis. Adoptive transfer of naïve T cells into CD11cCre.IRF4fl/fl.RAG-1-/- mice resulted in reduced monocyte recruitment to the intestine and mesenteric lymph nodes (MLN) compared to Cre- controls. Inflammatory cytokines...

Preparing the Workforce for Healthy Aging Programs: The Skills for Healthy Aging Resources and Programs (SHARP) Model

Science.gov (United States)

Frank, Janet C.; Altpeter, Mary; Damron-Rodriguez, JoAnn; Driggers, Joann; Lachenmayr, Susan; Manning, Colleen; Martinez, Dana M.; Price, Rachel M.; Robinson, Patricia

2014-01-01

Current public health and aging service agency personnel have little training in gerontology, and virtually no training in evidence-based health promotion and disease management programs for older adults. These programs are rapidly becoming the future of our community-based long-term care support system. The purpose of this project was to develop…

A review of age dependent radioiodine dosimetry

International Nuclear Information System (INIS)

Johnson, J.R.

1987-01-01

Age dependent models of radioiodine metabolism in humans have been described. These models have been used to calculate age dependent committed doses to the thyroid from intakes of radioiodines. A model of fetal iodine metabolism is also described and used to calculate fetal thyroid doses from intakes of radioiodines by the mother. These doses are calculated using model parameter values thought to be representative of average for North American/European populations. Considerable variability from these results can be expected for individuals. In addition, population with significant differences in stable iodine intake, and in body parameters, will have model parameters somewhat different than the ones described in this paper. These different model parameters will result in different doses from intakes of radioiodines, but it is doubtful if the differences in population would be as large as the variation between individuals. 25 refs.; 11 figs.; 1 table

The NPP Isar comprehensive Aging Management Program

International Nuclear Information System (INIS)

Zander, Andre; Ertl, Stefan

2012-01-01

The majority of System, Structure and Components (SSC) in a nuclear power plants are designed to experience a service life, which is far above the intended design life. In most cases, only a small percentage of SSCs are subject to significant aging effects, which may affect the integrity or the function of the component. The process of aging management (AM) has the objective to monitor and control degradation effects which may compromise safety functions of the plant. And furthermore, to ensure, that testing and maintenance programs sufficiently provide preventive measures to control degradation effects. Safety-related aspects and the targeted high availability of the power plant as well as the requirements stipulated by German regulatory authorities prompted the operator of NPP ISAR to introduce an aging surveillance program. The NPP Isar as well as the German NPPs has to be following in the scope of aging management the KTA 1403 guideline. The NPP Isar surveillance program based on the KTA 1403 guideline covers the following aspects: - Scoping and screening of safety relevant Systems, Structures and Components (SSC); - Identification of possible degradation mechanisms for safety relevant SSC; - Ensure, that testing and maintenance programs sufficiently provide preventive measures to control degradation effects; - Transferability check of industry experience (internal and external events); - Annual preparation of an AM status report. (author)

Total deposition of inhaled particles related to age: comparison with age-dependent model calculations

International Nuclear Information System (INIS)

Becquemin, M.H.; Bouchikhi, A.; Yu, C.P.; Roy, M.

1991-01-01

To compare experimental data with age-dependent model calculations, total airway deposition of polystyrene aerosols (1, 2.05 and 2.8 μm aerodynamic diameter) was measured in ten adults, twenty children aged 12 to 15 years, ten children aged 8 to 12, and eleven under 8 years old. Ventilation was controlled, and breathing patterns were appropriate for each age, either at rest or at light exercise. Individually, deposition percentages increased with particle size and also from rest to exercise, except in children under 12 years, in whom they decreased from 20-21.5 to 14-14.5 for 1 μm particles and from 36.8-36.9 to 32.2-33.1 for 2.05 μm particles. Comparisons with the age-dependent model showed that, at rest, the observed data concerning children agreed with those predicted and were close to the adults' values, when the latter were higher than predicted. At exercise, child data were lower than predicted and lower than adult experimental data, when the latter agreed fairly well with the model. (author)

Systematic aging of commercial LiFePO4|Graphite cylindrical cells including a theory explaining rise of capacity during aging

Science.gov (United States)

Lewerenz, Meinert; Münnix, Jens; Schmalstieg, Johannes; Käbitz, Stefan; Knips, Marcus; Sauer, Dirk Uwe

2017-03-01

The contribution introduces a new theory explaining the capacity increase that is often observed in early stages of life of lithium-ion batteries. This reversible and SOC-depending capacity rise is explained by the passive electrode effect in this work. The theory assumes a slow, compensating flow of active lithium between the passive and the active part of the anode, where the passive part represents the geometric excess anode with respect to the cathode. The theory is validated using a systematic test of 50 cylindrical 8 Ah LiFePO4|Graphite battery cells analyzed during cyclic and calendaric aging. The cyclic aging has been performed symmetrically at 40 °C cell temperature, varying current rates and DODs. The calendar aging is executed at three temperatures and up to four SOCs. The aging is dominated by capacity fade while the increase of internal resistance is hardly influenced. Surprisingly shallow cycling between 45 and 55% SOC shows stronger aging than aging at higher DOD and tests at 4 C exhibit less aging than aging at lower C-rates. Aging mechanisms at 60 °C seem to deviate from those at 40 °C or lower. The data of this aging matrix is used for further destructive and non-destructive characterization in future contributions.

Age-specific functional epigenetic changes in p21 and p16 in injury-activated satellite cells

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Li, Ju; Han, Suhyoun; Cousin, Wendy; Conboy, Irina M.

2014-01-01

The regenerative capacity of muscle dramatically decreases with age because old muscle stem cells fail to proliferate in response to tissue damage. Here we uncover key age-specific differences underlying this proliferative decline: namely, the genetic loci of CDK inhibitors (CDKI) p21 and p16 are more epigenetically silenced in young muscle stem cells, as compared to old, both in quiescent cells and those responding to tissue injury. Interestingly, phosphorylated ERK (pERK) induced in these cells by ectopic FGF-2 is found in association with p21 and p16 promoters, and moreover, only in the old cells. Importantly, in the old satellite cells FGF-2/pERK silences p21 epigenetically and transcriptionally, which leads to reduced p21 protein levels and enhanced cell proliferation. In agreement with the epigenetic silencing of the loci, young muscle stem cells do not depend as much as old on ectopic FGF/pERK for their myogenic proliferation. In addition, other CDKIs, such asp15INK4B and p27KIP1, become elevated in satellite cells with age, confirming and explaining the profound regenerative defect of old muscle. This work enhances our understanding of tissue aging, promoting strategies for combating age-imposed tissue degeneration. PMID:25447026

Age-dependent change of HMGB1 and DNA double-strand break accumulation in mouse brain

International Nuclear Information System (INIS)

Enokido, Yasushi; Yoshitake, Ayaka; Ito, Hikaru; Okazawa, Hitoshi

2008-01-01

HMGB1 is an evolutionarily conserved non-histone chromatin-associated protein with key roles in maintenance of nuclear homeostasis; however, the function of HMGB1 in the brain remains largely unknown. Recently, we found that the reduction of nuclear HMGB1 protein level in the nucleus associates with DNA double-strand break (DDSB)-mediated neuronal damage in Huntington's disease [M.L. Qi, K. Tagawa, Y. Enokido, N. Yoshimura, Y. Wada, K. Watase, S. Ishiura, I. Kanazawa, J. Botas, M. Saitoe, E.E. Wanker, H. Okazawa, Proteome analysis of soluble nuclear proteins reveals that HMGB1/2 suppress genotoxic stress in polyglutamine diseases, Nat. Cell Biol. 9 (2007) 402-414]. In this study, we analyze the region- and cell type-specific changes of HMGB1 and DDSB accumulation during the aging of mouse brain. HMGB1 is localized in the nuclei of neurons and astrocytes, and the protein level changes in various brain regions age-dependently. HMGB1 reduces in neurons, whereas it increases in astrocytes during aging. In contrast, DDSB remarkably accumulates in neurons, but it does not change significantly in astrocytes during aging. These results indicate that HMGB1 expression during aging is differentially regulated between neurons and astrocytes, and suggest that the reduction of nuclear HMGB1 might be causative for DDSB in neurons of the aged brain

Effects of x rays on histogenesis of abnormal epidermis and age dependency of radiosensitivity during metamorphosis of the flesh fly, Sarcophaga peregrina

International Nuclear Information System (INIS)

Sasaki, S.; Sakka, M.

1978-01-01

Effects of x rays on metamorphosis of the abdominal epidermis in the flesh fly, Sarcophaga peregrina, and age dependence of radiosensitivity were studied. The imaginal epidermis of abdomen is formed from the histoblast nests, which are composed of undifferentiated tiny cells lying between large larval epidermal cells. There were two types of effects of x rays: (1) the arrest of metamorphosis including degeneration of larval epidermal cells and histogenesis of imaginal epidermis; (2) partial deficit of imaginal epidermis at the final stage of development. It was suggested that the second type of effect was brought about by a decrease in the number of abdominal histoblasts caused by x rays. Age dependency of radiosensitivity on the second type of effect was examined in detail, and it was shown that the most sensitive stage occurred just before transition to a highly radiation-resistant period

Adverse fibrosis in the aging heart depends on signaling between myeloid and mesenchymal cells; role of inflammatory fibroblasts.

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Cieslik, Katarzyna A; Trial, JoAnn; Crawford, Jeffrey R; Taffet, George E; Entman, Mark L

2014-05-01

Aging has been associated with adverse fibrosis. Here we formulate a new hypothesis and present new evidence that unresponsiveness of mesenchymal stem cells (MSC) and fibroblasts to transforming growth factor beta (TGF-β), due to reduced expression of TGF-β receptor I (TβRI), provides a foundation for cardiac fibrosis in the aging heart via two mechanisms. 1) TGF-β promotes expression of Nanog, a transcription factor that retains MSC in a primitive state. In MSC derived from the aging heart, Nanog expression is reduced and therefore MSC gradually differentiate and the number of mesenchymal fibroblasts expressing collagen increases. 2) As TGF-β signaling pathway components negatively regulate transcription of monocyte chemoattractant protein-1 (MCP-1), a reduced expression of TβRI prevents aging mesenchymal cells from shutting down their own MCP-1 expression. Elevated MCP-1 levels that originated from MSC attract transendothelial migration of mononuclear leukocytes from blood to the tissue. MCP-1 expressed by mesenchymal fibroblasts promotes further migration of monocytes and T lymphocytes away from the endothelial barrier and supports the monocyte transition into macrophages and finally into myeloid fibroblasts. Both myeloid and mesenchymal fibroblasts contribute to fibrosis in the aging heart via collagen synthesis. This article is part of a Special Issue entitled "Myocyte-Fibroblast Signalling in Myocardium ". © 2013. Published by Elsevier Ltd. All rights reserved.

Cellular and epigenetic drivers of stem cell ageing.

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Ermolaeva, Maria; Neri, Francesco; Ori, Alessandro; Rudolph, K Lenhard

2018-06-01

Adult tissue stem cells have a pivotal role in tissue maintenance and regeneration throughout the lifespan of multicellular organisms. Loss of tissue homeostasis during post-reproductive lifespan is caused, at least in part, by a decline in stem cell function and is associated with an increased incidence of diseases. Hallmarks of ageing include the accumulation of molecular damage, failure of quality control systems, metabolic changes and alterations in epigenome stability. In this Review, we discuss recent evidence in support of a novel concept whereby cell-intrinsic damage that accumulates during ageing and cell-extrinsic changes in ageing stem cell niches and the blood result in modifications of the stem cell epigenome. These cumulative epigenetic alterations in stem cells might be the cause of the deregulation of developmental pathways seen during ageing. In turn, they could confer a selective advantage to mutant and epigenetically drifted stem cells with altered self-renewal and functions, which contribute to the development of ageing-associated organ dysfunction and disease.

Molecular and cellular mechanisms of the age-dependency of opioid analgesia and tolerance

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Zhao Jing

2012-05-01

Full Text Available Abstract The age-dependency of opioid analgesia and tolerance has been noticed in both clinical observation and laboratory studies. Evidence shows that many molecular and cellular events that play essential roles in opioid analgesia and tolerance are actually age-dependent. For example, the expression and functions of endogenous opioid peptides, multiple types of opioid receptors, G protein subunits that couple to opioid receptors, and regulators of G protein signaling (RGS proteins change with development and age. Other signaling systems that are critical to opioid tolerance development, such as N-methyl-D-aspartic acid (NMDA receptors, also undergo age-related changes. It is plausible that the age-dependent expression and functions of molecules within and related to the opioid signaling pathways, as well as age-dependent cellular activity such as agonist-induced opioid receptor internalization and desensitization, eventually lead to significant age-dependent changes in opioid analgesia and tolerance development.

When stem cells grow old: phenotypes and mechanisms of stem cell aging

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Schultz, Michael B.; Sinclair, David A.

2016-01-01

All multicellular organisms undergo a decline in tissue and organ function as they age. An attractive theory is that a loss in stem cell number and/or activity over time causes this decline. In accordance with this theory, aging phenotypes have been described for stem cells of multiple tissues, including those of the hematopoietic system, intestine, muscle, brain, skin and germline. Here, we discuss recent advances in our understanding of why adult stem cells age and how this aging impacts diseases and lifespan. With this increased understanding, it is feasible to design and test interventions that delay stem cell aging and improve both health and lifespan. PMID:26732838

Aging and senescence of skin cells in culture

DEFF Research Database (Denmark)

Rattan, Suresh

2015-01-01

Studying age-related changes in the physiology, biochemistry, and molecular biology of isolated skin cell populations in culture has greatly expanded the understanding of the fundamental aspects of skin aging. The three main cell types that have been studied extensively with respect to cellular...... aging in vitro are dermal fibroblasts, epidermal keratinocytes, and melanocytes. Serial subcultivation of normal diploid skin cells can be performed only a limited number of times, and the emerging senescent phenotype can be categorized into structural, physiological, biochemical, and molecular...... phenotypes, which can be used as biomarkers of cellular aging in vitro. The rate and phenotype of aging are different in different cell types. There are both common features and specific features of aging of skin fibroblasts, keratinocytes, melanocytes, and other cell types. A progressive accumulation...

C/EBPα is dispensable for the ontogeny of PD-1+ CD4+ memory T cells but restricts their expansion in an age-dependent manner

DEFF Research Database (Denmark)

Norrie, Ida Christine; Ohlsson, Ewa; Nielsen, Olaf

2014-01-01

Ageing and cancer is often associated with altered T cell distributions and this phenomenon has been suggested to be the main driver in the development of immunosenescence. Memory phenotype PD-1+ CD4+ T cells accumulate with age and during leukemic development, and they might account for the atte......Ageing and cancer is often associated with altered T cell distributions and this phenomenon has been suggested to be the main driver in the development of immunosenescence. Memory phenotype PD-1+ CD4+ T cells accumulate with age and during leukemic development, and they might account...... for the attenuated T cell response in elderly or diseased individuals. The transcription factor C/EBPα has been suggested to be responsible for the accumulation as well as for the senescent features of these cells including impaired TCR signaling and decreased proliferation. Thus modulating the activity of C...

Stochastic modeling indicates that aging and somatic evolution in the hematopoetic system are driven by non-cell-autonomous processes.

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Rozhok, Andrii I; Salstrom, Jennifer L; DeGregori, James

2014-12-01

Age-dependent tissue decline and increased cancer incidence are widely accepted to be rate-limited by the accumulation of somatic mutations over time. Current models of carcinogenesis are dominated by the assumption that oncogenic mutations have defined advantageous fitness effects on recipient stem and progenitor cells, promoting and rate-limiting somatic evolution. However, this assumption is markedly discrepant with evolutionary theory, whereby fitness is a dynamic property of a phenotype imposed upon and widely modulated by environment. We computationally modeled dynamic microenvironment-dependent fitness alterations in hematopoietic stem cells (HSC) within the Sprengel-Liebig system known to govern evolution at the population level. Our model for the first time integrates real data on age-dependent dynamics of HSC division rates, pool size, and accumulation of genetic changes and demonstrates that somatic evolution is not rate-limited by the occurrence of mutations, but instead results from aged microenvironment-driven alterations in the selective/fitness value of previously accumulated genetic changes. Our results are also consistent with evolutionary models of aging and thus oppose both somatic mutation-centric paradigms of carcinogenesis and tissue functional decline. In total, we demonstrate that aging directly promotes HSC fitness decline and somatic evolution via non-cell-autonomous mechanisms.

Two separate defects affecting true naive or virtual memory T cell precursors combine to reduce naive T cell responses with aging.

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Renkema, Kristin R; Li, Gang; Wu, Angela; Smithey, Megan J; Nikolich-Žugich, Janko

2014-01-01

Naive T cell responses are eroded with aging. We and others have recently shown that unimmunized old mice lose ≥ 70% of Ag-specific CD8 T cell precursors and that many of the remaining precursors acquire a virtual (central) memory (VM; CD44(hi)CD62L(hi)) phenotype. In this study, we demonstrate that unimmunized TCR transgenic (TCRTg) mice also undergo massive VM conversion with age, exhibiting rapid effector function upon both TCR and cytokine triggering. Age-related VM conversion in TCRTg mice directly depended on replacement of the original TCRTg specificity by endogenous TCRα rearrangements, indicating that TCR signals must be critical in VM conversion. Importantly, we found that VM conversion had adverse functional effects in both old wild-type and old TCRTg mice; that is, old VM, but not old true naive, T cells exhibited blunted TCR-mediated, but not IL-15-mediated, proliferation. This selective proliferative senescence correlated with increased apoptosis in old VM cells in response to peptide, but decreased apoptosis in response to homeostatic cytokines IL-7 and IL-15. Our results identify TCR as the key factor in differential maintenance and function of Ag-specific precursors in unimmunized mice with aging, and they demonstrate that two separate age-related defects--drastic reduction in true naive T cell precursors and impaired proliferative capacity of their VM cousins--combine to reduce naive T cell responses with aging.

Detection of satellite cells during skeletal muscle wound healing in rats: time-dependent expressions of Pax7 and MyoD in relation to wound age.

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Tian, Zhi-Ling; Jiang, Shu-Kun; Zhang, Miao; Wang, Meng; Li, Jiao-Yong; Zhao, Rui; Wang, Lin-Lin; Li, Shan-Shan; Liu, Min; Zhang, Meng-Zhou; Guan, Da-Wei

2016-01-01

The study was focused on time-dependent expressions of paired-box transcription factor 7 (Pax7) and myoblast determination protein (MyoD) during skeletal muscle wound healing. An animal model of skeletal muscle contusion was established in 40 Sprague-Dawley male rats. Samples were taken at 1, 3, 5, 7, 9, 13, 17, and 21 days after injury, respectively (five rats in each posttraumatic interval). Five rats were employed as control. By morphometric analysis, the data based on the number of Pax7(+)/MyoD(-), Pax7(+)/MyoD(+), and Pax7(-)/MyoD(+) cells were highly correlated with the wound age. Pax7 and MyoD expressions were upregulated after injury by Western blot and quantitative real-time PCR assays. The relative quantity of Pax7 protein peaked at 5 days after injury, which was >1.13, and decreased thereafter. Similarly, the relative quantity of MyoD mRNA expression peaked at 3 days after injury, which was >2.59. The relative quantity of Pax7 protein >0.73 or mRNA expression >2.38 or the relative quantity of MyoD protein >1.33 suggested a wound age of 3 to 7 days. The relative quantity of MyoD mRNA expression >2.02 suggested a wound age of 1 to 7 days post-injury. In conclusion, the expressions of Pax7 and MyoD are upregulated in a time-dependent manner during skeletal muscle wound healing, suggesting that Pax7 and MyoD may be potential markers for wound age estimation in skeletal muscle.

Cell-Nonautonomous Mechanisms Underlying Cellular and Organismal Aging.

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Medkour, Younes; Svistkova, Veronika; Titorenko, Vladimir I

2016-01-01

Cell-autonomous mechanisms underlying cellular and organismal aging in evolutionarily distant eukaryotes have been established; these mechanisms regulate longevity-defining processes within a single eukaryotic cell. Recent findings have provided valuable insight into cell-nonautonomous mechanisms modulating cellular and organismal aging in eukaryotes across phyla; these mechanisms involve a transmission of various longevity factors between different cells, tissues, and organisms. Herein, we review such cell-nonautonomous mechanisms of aging in eukaryotes. We discuss the following: (1) how low molecular weight transmissible longevity factors modulate aging and define longevity of cells in yeast populations cultured in liquid media or on solid surfaces, (2) how communications between proteostasis stress networks operating in neurons and nonneuronal somatic tissues define longevity of the nematode Caenorhabditis elegans by modulating the rates of aging in different tissues, and (3) how different bacterial species colonizing the gut lumen of C. elegans define nematode longevity by modulating the rate of organismal aging. Copyright © 2016. Published by Elsevier Inc.

Cell-Cell Contact Area Affects Notch Signaling and Notch-Dependent Patterning.

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Shaya, Oren; Binshtok, Udi; Hersch, Micha; Rivkin, Dmitri; Weinreb, Sheila; Amir-Zilberstein, Liat; Khamaisi, Bassma; Oppenheim, Olya; Desai, Ravi A; Goodyear, Richard J; Richardson, Guy P; Chen, Christopher S; Sprinzak, David

2017-03-13

During development, cells undergo dramatic changes in their morphology. By affecting contact geometry, these morphological changes could influence cellular communication. However, it has remained unclear whether and how signaling depends on contact geometry. This question is particularly relevant for Notch signaling, which coordinates neighboring cell fates through direct cell-cell signaling. Using micropatterning with a receptor trans-endocytosis assay, we show that signaling between pairs of cells correlates with their contact area. This relationship extends across contact diameters ranging from micrometers to tens of micrometers. Mathematical modeling predicts that dependence of signaling on contact area can bias cellular differentiation in Notch-mediated lateral inhibition processes, such that smaller cells are more likely to differentiate into signal-producing cells. Consistent with this prediction, analysis of developing chick inner ear revealed that ligand-producing hair cell precursors have smaller apical footprints than non-hair cells. Together, these results highlight the influence of cell morphology on fate determination processes. Copyright © 2017 Elsevier Inc. All rights reserved.

Nanosilica induced dose-dependent cytotoxicity and cell type-dependent multinucleation in HepG2 and L-02 cells

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Yu, Yongbo [Capital Medical University, Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Pediatric Research Institute, Beijing Children’s Hospital (China); Duan, Junchao; Li, Yang; Yu, Yang; Hu, Hejing; Wu, Jing; Zhang, Yannan; Li, Yanbo; CaixiaGuo; Zhou, Xianqing; Sun, Zhiwei, E-mail: zwsun@ccmu.edu.cn [Capital Medical University, School of Public Health (China)

2016-11-15

The prevalent exposure to nanosilica gained concerns about health effects of these particles on human beings. Although nanosilica-induced multinucleation has been confirmed previously, the underlying mechanism was still not clear; this study was to investigate the origination of multinucleated cells caused by nanosilica (62 nm) in both HepG2 and L-02 cells. Cell viability and cellular uptake was determined by MTT assay and transmission electron microscope (TEM), respectively. Giemsa staining was applied to detect multinucleation. To clarify the origination of multinucleated cells, fluorescent probes, PKH26 and PKH67, time-lapse observation were further conducted by confocal microscopy. Results indicated that nanosilica particles were internalized into cells and induced cytotoxicity in a dose-dependent manner. Quantification analysis showed that nanosilica significantly increased the rates of binucleated and multinucleated cells, which suggested mitotic catastrophe induction. Moreover, dynamic visualization verified that multinucleation resulted from cell fusion in HepG2 cells not in L-02 cells after nanosilica exposure, suggesting cell type-dependent multinucleation formation. Both multinucleation and cell fusion were involved in genetic instability, which emphasized the significance to explore the multinucleation induced by nanosilica via environmental, occupational and consumer product exposure.

Cellular Programming and Reprogramming: Sculpting Cell Fate for the Production of Dopamine Neurons for Cell Therapy

Directory of Open Access Journals (Sweden)

Julio C. Aguila

2012-01-01

success of clinical applications depends on our ability to steer pluripotent stem cells towards the right neuronal identity. In Parkinson disease, the loss of dopamine neurons is more pronounced in the ventrolateral population that projects to the sensorimotor striatum. Because synapses are highly specific, only neurons with this precise identity will contribute, upon transplantation, to the synaptic reconstruction of the dorsal striatum. Thus, understanding the developmental cell program of the mesostriatal dopamine neurons is critical for the identification of the extrinsic signals and cell-intrinsic factors that instruct and, ultimately, determine cell identity. Here, we review how extrinsic signals and transcription factors act together during development to shape midbrain cell fates. Further, we discuss how these same factors can be applied in vitro to induce, select, and reprogram cells to the mesostriatal dopamine fate.

When stem cells grow old: phenotypes and mechanisms of stem cell aging.

Science.gov (United States)

Schultz, Michael B; Sinclair, David A

2016-01-01

All multicellular organisms undergo a decline in tissue and organ function as they age. An attractive theory is that a loss in stem cell number and/or activity over time causes this decline. In accordance with this theory, aging phenotypes have been described for stem cells of multiple tissues, including those of the hematopoietic system, intestine, muscle, brain, skin and germline. Here, we discuss recent advances in our understanding of why adult stem cells age and how this aging impacts diseases and lifespan. With this increased understanding, it is feasible to design and test interventions that delay stem cell aging and improve both health and lifespan. © 2016. Published by The Company of Biologists Ltd.

Influence of the Self-Perception of Old Age on the Effect of a Healthy Aging Program.

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Mendoza-Núñez, Víctor Manuel; Sarmiento-Salmorán, Elia; Marín-Cortés, Regulo; Martínez-Maldonado, María de la Luz; Ruiz-Ramos, Mirna

2018-05-07

It has been shown that health programs are useful for the prevention and control of chronic diseases in community-dwelling older people; however, a negative self-perception of old age could have an effect on the results. Therefore, our aim was to evaluate the effect of a healthy aging program linked to self-perception of old age in Mexican community-dwelling older people. A pre-test/post-test single-group design study was conducted in a convenience sample of 64 older people who undertook the entire healthy aging program workshop (five months’ duration). We measured self-perception of old age, efficacy of self-care, blood glucose concentration, anthropometric measures, and blood pressure before and after the workshop. A statistically significant decrease in blood glucose concentration was observed (baseline 136 ± 50 vs. post-intervention, 124 ± 45 ± 29 mg/dL, p self-perception, we found that this difference was only maintained in the subgroup of older adults with a positive self-perception of old age. Our findings suggest that the self-perception of old age influences the effect of healthy aging programs on the health of community-dwelling older people.

An age dependent model for radium metabolism in man.

Science.gov (United States)

Johnson, J R

1983-01-01

The model developed by a Task Group of Committee 2 of ICRP to describe Alkaline Earth Metabolism in Adult Man (ICRP Publication 20) has been modified so that recycling is handled explicitly, and retention in mineral bone is represented by second compartments rather than by the product of a power function and an exponential. This model has been extended to include all ages from birth to adult man, and has been coupled with modified "ICRP" lung and G.I. tract models so that activity in organs can be calculated as functions of time during or after exposures. These activities, and age dependent "specific effective energy" factors, are then used to calculate age dependent dose rates, and dose commitments. This presentation describes this work, with emphasis on the model parameters and results obtained for radium.

Reduced satellite cell numbers and myogenic capacity in aging can be alleviated by endurance exercise.

Directory of Open Access Journals (Sweden)

Gabi Shefer

2010-10-01

Full Text Available Muscle regeneration depends on satellite cells, myogenic stem cells that reside on the myofiber surface. Reduced numbers and/or decreased myogenic aptitude of these cells may impede proper maintenance and contribute to the age-associated decline in muscle mass and repair capacity. Endurance exercise was shown to improve muscle performance; however, the direct impact on satellite cells in aging was not yet thoroughly determined. Here, we focused on characterizing the effect of moderate-intensity endurance exercise on satellite cell, as possible means to attenuate adverse effects of aging. Young and old rats of both genders underwent 13 weeks of treadmill-running or remained sedentary.Gastrocnemius muscles were assessed for the effect of age, gender and exercise on satellite-cell numbers and myogenic capacity. Satellite cells were identified in freshly isolated myofibers based on Pax7 immunostaining (i.e., ex-vivo. The capacity of individual myofiber-associated cells to produce myogenic progeny was determined in clonal assays (in-vitro. We show an age-associated decrease in satellite-cell numbers and in the percent of myogenic clones in old sedentary rats. Upon exercise, there was an increase in myofibers that contain higher numbers of satellite cells in both young and old rats, and an increase in the percent of myogenic clones derived from old rats. Changes at the satellite cell level in old rats were accompanied with positive effects on the lean-to-fat Gast muscle composition and on spontaneous locomotion levels. The significance of these data is that they suggest that the endurance exercise-mediated boost in both satellite numbers and myogenic properties may improve myofiber maintenance in aging.

Tendon Contraction After Cyclic Elongation Is an Age-Dependent Phenomenon: In Vitro and In Vivo Comparisons.

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Lavagnino, Michael; Bedi, Asheesh; Walsh, Christopher P; Sibilsky Enselman, Elizabeth R; Sheibani-Rad, Shahin; Arnoczky, Steven P

2014-06-01

Tendons are viscoelastic tissues that deform (elongate) in response to cyclic loading. However, the ability of a tendon to recover this elongation is unknown. Tendon length significantly increases after in vivo or in vitro cyclic loading, and the ability to return to its original length through a cell-mediated contraction mechanism is an age-dependent phenomenon. Controlled laboratory study. In vitro, rat tail tendon fascicles (RTTfs) from Sprague-Dawley rats of 3 age groups (1, 3, and 12 months) underwent 2% cyclic strain at 0.17 Hz for 2 hours, and the percentages of elongation were determined. After loading, the RTTfs were suspended for 3 days under tissue culture conditions and photographed daily to determine the amount of length contraction. In vivo, healthy male participants (n = 29; age, 19-49 years) had lateral, single-legged weightbearing radiographs taken of the knee at 60° of flexion immediately before, immediately after, and 24 hours after completing eccentric quadriceps loading exercises on the dominant leg to fatigue. Measurements of patellar tendon length were taken from the radiographs, and the percentages of tendon elongation and subsequent contraction were calculated. In vitro, cyclic loading increased the length of all RTTfs, with specimens from younger (1 and 3 months) rats demonstrating significantly greater elongation than those from older (12 months) rats (P = .009). The RTTfs contracted to their original length significantly faster (P fashion, with younger animals contracting faster. In vivo, repetitive eccentric loading exercises significantly increased patellar tendon length (P 30 years). Cyclic tendon loading results in a significant increase in tendon elongation under both in vitro and in vivo conditions. Tendons in both conditions demonstrated an incomplete return to their original length after 24 hours, and the extent of this return was age dependent. The age- and time-dependent contraction of tendons, elongated after repetitive

Single cell analysis of yeast replicative aging using a new generation of microfluidic device.

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Yi Zhang

Full Text Available A major limitation to yeast aging study has been the inability to track mother cells and observe molecular markers during the aging process. The traditional lifespan assay relies on manual micro-manipulation to remove daughter cells from the mother, which is laborious, time consuming, and does not allow long term tracking with high resolution microscopy. Recently, we have developed a microfluidic system capable of retaining mother cells in the microfluidic chambers while removing daughter cells automatically, making it possible to observe fluorescent reporters in single cells throughout their lifespan. Here we report the development of a new generation of microfluidic device that overcomes several limitations of the previous system, making it easier to fabricate and operate, and allowing functions not possible with the previous design. The basic unit of the device consists of microfluidic channels with pensile columns that can physically trap the mother cells while allowing the removal of daughter cells automatically by the flow of the fresh media. The whole microfluidic device contains multiple independent units operating in parallel, allowing simultaneous analysis of multiple strains. Using this system, we have reproduced the lifespan curves for the known long and short-lived mutants, demonstrating the power of the device for automated lifespan measurement. Following fluorescent reporters in single mother cells throughout their lifespan, we discovered a surprising change of expression of the translation elongation factor TEF2 during aging, suggesting altered translational control in aged mother cells. Utilizing the capability of the new device to trap mother-daughter pairs, we analyzed mother-daughter inheritance and found age dependent asymmetric partitioning of a general stress response reporter between mother and daughter cells.

Symbiotic Origin of Aging.

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Greenberg, Edward F; Vatolin, Sergei

2018-06-01

Normally aging cells are characterized by an unbalanced mitochondrial dynamic skewed toward punctate mitochondria. Genetic and pharmacological manipulation of mitochondrial fission/fusion cycles can contribute to both accelerated and decelerated cellular or organismal aging. In this work, we connect these experimental data with the symbiotic theory of mitochondrial origin to generate new insight into the evolutionary origin of aging. Mitochondria originated from autotrophic α-proteobacteria during an ancient endosymbiotic event early in eukaryote evolution. To expand beyond individual host cells, dividing α-proteobacteria initiated host cell lysis; apoptosis is a product of this original symbiont cell lytic exit program. Over the course of evolution, the host eukaryotic cell attenuated the harmful effect of symbiotic proto-mitochondria, and modern mitochondria are now functionally interdependent with eukaryotic cells; they retain their own circular genomes and independent replication timing. In nondividing differentiated or multipotent eukaryotic cells, intracellular mitochondria undergo repeated fission/fusion cycles, favoring fission as organisms age. The discordance between cellular quiescence and mitochondrial proliferation generates intracellular stress, eventually leading to a gradual decline in host cell performance and age-related pathology. Hence, aging evolved from a conflict between maintenance of a quiescent, nonproliferative state and the evolutionarily conserved propagation program driving the life cycle of former symbiotic organisms: mitochondria.

Cell cycle dependent RRM2 may serve as proliferation marker and pharmaceutical target in adrenocortical cancer.

Science.gov (United States)

Grolmusz, Vince Kornél; Karászi, Katalin; Micsik, Tamás; Tóth, Eszter Angéla; Mészáros, Katalin; Karvaly, Gellért; Barna, Gábor; Szabó, Péter Márton; Baghy, Kornélia; Matkó, János; Kovalszky, Ilona; Tóth, Miklós; Rácz, Károly; Igaz, Péter; Patócs, Attila

2016-01-01

Adrenocortical cancer (ACC) is a rare, but agressive malignancy with poor prognosis. Histopathological diagnosis is challenging and pharmacological options for treatment are limited. By the comparative reanalysis of the transcriptional malignancy signature with the cell cycle dependent transcriptional program of ACC, we aimed to identify novel biomarkers which may be used in the histopathological diagnosis and for the prediction of therapeutical response of ACC. Comparative reanalysis of publicly available microarray datasets included three earlier studies comparing transcriptional differences between ACC and benign adrenocortical adenoma (ACA) and one study presenting the cell cycle dependent gene expressional program of human ACC cell line NCI-H295R. Immunohistochemical analysis was performed on ACC samples. In vitro effects of antineoplastic drugs including gemcitabine, mitotane and 9-cis-retinoic acid alone and in combination were tested in the NCI-H295R adrenocortical cell line. Upon the comparative reanalysis, ribonucleotide reductase subunit 2 (RRM2), responsible for the ribonucleotide dezoxyribonucleotide conversion during the S phase of the cell cycle has been validated as cell cycle dependently expressed. Moreover, its expression was associated with the malignancy signature, as well. Immunohistochemical analysis of RRM2 revealed a strong correlation with Ki67 index in ACC. Among the antiproliferative effects of the investigated compounds, gemcitabine showed a strong inhibition of proliferation and an increase of apoptotic events. Additionally, RRM2 has been upregulated upon gemcitabine treatment. Upon our results, RRM2 might be used as a proliferation marker in ACC. RRM2 upregulation upon gemcitabine treatment might contribute to an emerging chemoresistance against gemcitabine, which is in line with its limited therapeutical efficacy in ACC, and which should be overcome for successful clinical applications.

Efficiency and fidelity of cell-free protein synthesis by transfer RNA from aged mice

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Foote, R.S.; Stulberg, M.P.

1980-01-01

Transfer RNAs (tRNAs) from heart, kidney, liver, and spleen of mature (10 to 12 months old) and aged (29 months old) C57BL/6 mice were tested for their ability to translate encephalomyocarditis viral RNA in a tRNA-dependent cell-free system derived from mouse ascites tumor cells. The rates of in vitro protein synthesis were compared as a function of tRNA concentration, and the fidelity of translation was examined by sodium dodecyl sulfate gel electrophoresis and isoelectric focusing of the viral polypeptides synthesized in vitro. No significant age-related differences in either the efficiency or fidelity of synthesis were discovered, indicating that alternations in tRNAs are probably not involved in the cellular aging of these tissues.

Changes of Langerhans cells during skin ageing

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Barbara Zegarska

2017-05-01

Full Text Available Introduction : During the process of skin ageing, changes occur in all skin layers and all cells, including the Langerhans cells. Aim: To assess whether any quantitative difference in the number of CD1a+ LC cells/mm 2 and HLA-DR+ LC cells/mm 2 as well as in their morphological features can be observed during the course of different types of skin ageing. Material and methods: The study was conducted in a group of 60 women, which was divided into three independent groups: group I with symptoms of menopausal skin ageing, group II with symptoms of photoageing, group III with symptoms of chronological ageing. Skin biopsy samples were taken from the pre-auricular region from all of the participants. The number of CD1a+ LC cells/mm 2 and HLA-DR+ LC cells/mm 2 as well as their morphological features were evaluated. Results : The frequency of CD1a+ LC and HLA-DR+ LC in all the studied groups was diverse. In groups I and III, the LC with large cell bodies and long, multi-branched processes were the majority. In group II, the LC had small cell bodies and their processes were mainly short and unbranched. Conclusions : The obtained results indicate the presence of quantitative and morphological changes of the CD1a+ LC and HLA-DR+ LC during the course of different types of skin ageing.

Ageing induced vascular smooth muscle cell senescence in atherosclerosis.

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Uryga, Anna K; Bennett, Martin R

2016-04-15

Atherosclerosis is a disease of ageing in that its incidence and prevalence increase with age. However, atherosclerosis is also associated with biological ageing, manifest by a number of typical hallmarks of ageing in the atherosclerotic plaque. Thus, accelerated biological ageing may be superimposed on the effects of chronological ageing in atherosclerosis. Tissue ageing is seen in all cells that comprise the plaque, but particularly in vascular smooth muscle cells (VSMCs). Hallmarks of ageing include evidence of cell senescence, DNA damage (including telomere attrition), mitochondrial dysfunction, a pro-inflammatory secretory phenotype, defects in proteostasis, epigenetic changes, deregulated nutrient sensing, and exhaustion of progenitor cells. In this model, initial damage to DNA (genomic, telomeric, mitochondrial and epigenetic changes) results in a number of cellular responses (cellular senescence, deregulated nutrient sensing and defects in proteostasis). Ultimately, ongoing damage and attempts at repair by continued proliferation overwhelm reparative capacity, causing loss of specialised cell functions, cell death and inflammation. This review summarises the evidence for accelerated biological ageing in atherosclerosis, the functional consequences of cell ageing on cells comprising the plaque, and the causal role that VSMC senescence plays in atherogenesis. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Notch signaling mediates the age-associated decrease in adhesion of germline stem cells to the niche.

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Chen-Yuan Tseng

2014-12-01

Full Text Available Stem cells have an innate ability to occupy their stem cell niche, which in turn, is optimized to house stem cells. Organ aging is associated with reduced stem cell occupancy in the niche, but the mechanisms involved are poorly understood. Here, we report that Notch signaling is increased with age in Drosophila female germline stem cells (GSCs, and this results in their removal from the niche. Clonal analysis revealed that GSCs with low levels of Notch signaling exhibit increased adhesiveness to the niche, thereby out-competing their neighbors with higher levels of Notch; adhesiveness is altered through regulation of E-cadherin expression. Experimental enhancement of Notch signaling in GSCs hastens their age-dependent loss from the niche, and such loss is at least partially mediated by Sex lethal. However, disruption of Notch signaling in GSCs does not delay GSC loss during aging, and nor does it affect BMP signaling, which promotes self-renewal of GSCs. Finally, we show that in contrast to GSCs, Notch activation in the niche (which maintains niche integrity, and thus mediates GSC retention is reduced with age, indicating that Notch signaling regulates GSC niche occupancy both intrinsically and extrinsically. Our findings expose a novel role of Notch signaling in controlling GSC-niche adhesion in response to aging, and are also of relevance to metastatic cancer cells, in which Notch signaling suppresses cell adhesion.

Deciphering early events involved in hyperosmotic stress-induced programmed cell death in tobacco BY-2 cells.

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Monetti, Emanuela; Kadono, Takashi; Tran, Daniel; Azzarello, Elisa; Arbelet-Bonnin, Delphine; Biligui, Bernadette; Briand, Joël; Kawano, Tomonori; Mancuso, Stefano; Bouteau, François

2014-03-01

Hyperosmotic stresses represent one of the major constraints that adversely affect plants growth, development, and productivity. In this study, the focus was on early responses to hyperosmotic stress- (NaCl and sorbitol) induced reactive oxygen species (ROS) generation, cytosolic Ca(2+) concentration ([Ca(2+)]cyt) increase, ion fluxes, and mitochondrial potential variations, and on their links in pathways leading to programmed cell death (PCD). By using BY-2 tobacco cells, it was shown that both NaCl- and sorbitol-induced PCD seemed to be dependent on superoxide anion (O2·(-)) generation by NADPH-oxidase. In the case of NaCl, an early influx of sodium through non-selective cation channels participates in the development of PCD through mitochondrial dysfunction and NADPH-oxidase-dependent O2·(-) generation. This supports the hypothesis of different pathways in NaCl- and sorbitol-induced cell death. Surprisingly, other shared early responses, such as [Ca(2+)]cyt increase and singlet oxygen production, do not seem to be involved in PCD.

Age-dependent increase in green autofluorescence of blood ...

Indian Academy of Sciences (India)

PRAKASH KUMAR

Protective enzymes against oxidative ... School of Life Sciences, Jawaharlal Nehru University, New Delhi 110 067, India ... provide evidence for an age dependent increase in the GAF of blood erythrocytes that is accentuated by depletion of.

The common oncogenomic program of NOTCH1 and NOTCH3 signaling in T-cell acute lymphoblastic leukemia.

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Sung Hee Choi

Full Text Available Notch is a major oncogenic driver in T cell acute lymphoblastic leukemia (T-ALL, in part because it binds to an enhancer that increases expression of MYC. Here, we exploit the capacity of activated NOTCH1 and NOTCH3 to induce T-ALL, despite substantial divergence in their intracellular regions, as a means to elucidate a broad, common Notch-dependent oncogenomic program through systematic comparison of the transcriptomes and Notch-bound genomic regulatory elements of NOTCH1- and NOTCH3-dependent T-ALL cells. ChIP-seq studies show a high concordance of functional NOTCH1 and NOTCH3 genomic binding sites that are enriched in binding motifs for RBPJ, the transcription factor that recruits activated Notch to DNA. The interchangeability of NOTCH1 and NOTCH3 was confirmed by rescue of NOTCH1-dependent T-ALL cells with activated NOTCH3 and vice versa. Despite remarkable overall similarity, there are nuanced differences in chromatin landscapes near critical common Notch target genes, most notably at a Notch-dependent enhancer that regulates MYC, which correlates with responsiveness to Notch pathway inhibitors. Overall, a common oncogenomic program driven by binding of either Notch is sufficient to maintain T-ALL cell growth, whereas cell-context specific differences appear to influence the response of T-ALL cells to Notch inhibition.

Age-dependent effect of every-other-day feeding and aerobic exercise in ubiquinone levels and related antioxidant activities in mice muscle.

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Rodríguez-Bies, Elizabeth; Navas, Plácido; López-Lluch, Guillermo

2015-01-01

Aging affects many biochemical, cellular, and physiological processes in the organisms. Accumulation of damage based on oxidized macromolecules is found in many age-associated diseases. Coenzyme Q (Q) is one of the main molecules involved in metabolic and antioxidant activities in cells. Q-dependent antioxidant activities are importantly involved on the protection of cell membranes against oxidation. Many studies indicate that Q decay in most of the organs during aging. In our study, no changes in Q levels were found in old animals in comparison with young animals. On the other hand, the interventions, caloric restriction based on every-other-day feeding procedure, and physical exercise were able to increase Q levels in muscle, but only in old and not in young animals. Probably, this effect prevented the increase in lipid peroxidation found in aged animals and also protein carbonylation. Further, Q-dependent antioxidant activities such as NADH-cytochrome b5 reductase and NAD(P)H-quinone oxidoreductase 1 are also modulated by both exercise and every other day feeding. Taken together, we demonstrate that exercise and dietary restriction as every-other-day procedure can regulate endogenous synthesized Q levels and Q-dependent antioxidant activities in muscle, preventing oxidative damage in aged muscle. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

IL-6 Production by TLR-Activated APC Broadly Enhances Aged Cognate CD4 Helper and B Cell Antibody Responses In Vivo.

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Brahmakshatriya, Vinayak; Kuang, Yi; Devarajan, Priyadharshini; Xia, Jingya; Zhang, Wenliang; Vong, Allen Minh; Swain, Susan L

2017-04-01

Naive CD4 T cell responses, especially their ability to help B cell responses, become compromised with aging. We find that using APC pretreated ex vivo with TLR agonists, polyinosinic-polycytidylic acid and CpG, to prime naive CD4 T cells in vivo, restores their ability to expand and become germinal center T follicular helpers and enhances B cell IgG Ab production. Enhanced helper responses are dependent on IL-6 production by the activated APC. Aged naive CD4 T cells respond suboptimally to IL-6 compared with young cells, such that higher doses are required to induce comparable signaling. Preactivating APC overcomes this deficiency. Responses of young CD4 T cells are also enhanced by preactivating APC with similar effects but with only partial IL-6 dependency. Strikingly, introducing just the activated APC into aged mice significantly enhances otherwise compromised Ab production to inactivated influenza vaccine. These findings reveal a central role for the production of IL-6 by APC during initial cognate interactions in the generation of effective CD4 T cell help, which becomes greater with age. Without APC activation, aging CD4 T cell responses shift toward IL-6-independent Th1 and CD4 cytotoxic Th cell responses. Thus, strategies that specifically activate and provide Ag to APC could potentially enhance Ab-mediated protection in vaccine responses. Copyright © 2017 by The American Association of Immunologists, Inc.

Recent advances in the cell biology of aging.

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Hayflick, L

1980-01-01

Cultured normal human and animal cells are predestined to undergo irreversible functional decrements that mimic age changes in the whole organism. When normal human embryonic fibroblasts are cultured in vitro, 50 +/- 10 population doublings occur. This maximum potential is diminished in cells derived from older donors and appears to be inversely proportional to their age. The 50 population doubling limit can account for all cells produced during a lifetime. The limitation on doubling potential of cultured normal cells is also expressed in vivo when serial transplants are made. There may be a direct correlation between the mean maximum life spans of several species and the population doubling potential of their cultured cells. A plethora of functional decrements occurs in cultured normal cells as they approach their maximum division capability. Many of these decrements are similar to those occurring in intact animals as they age. We have concluded that these functional decrements expressed in vitro, rather than cessation of cell division, are the essential contributors to age changes in intact animals. Thus, the study of events leading to functional losses in cultured normal cells may provide useful insights into the biology of aging.

Adipose Tissue Inflammation Induces B Cell Inflammation and Decreases B Cell Function in Aging

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Daniela Frasca

2017-08-01

Full Text Available Aging is the greatest risk factor for developing chronic diseases. Inflamm-aging, the age-related increase in low-grade chronic inflammation, may be a common link in age-related diseases. This review summarizes recent published data on potential cellular and molecular mechanisms of the age-related increase in inflammation, and how these contribute to decreased humoral immune responses in aged mice and humans. Briefly, we cover how aging and related inflammation decrease antibody responses in mice and humans, and how obesity contributes to the mechanisms for aging through increased inflammation. We also report data in the literature showing adipose tissue infiltration with immune cells and how these cells are recruited and contribute to local and systemic inflammation. We show that several types of immune cells infiltrate the adipose tissue and these include macrophages, neutrophils, NK cells, innate lymphoid cells, eosinophils, T cells, B1, and B2 cells. Our main focus is how the adipose tissue affects immune responses, in particular B cell responses and antibody production. The role of leptin in generating inflammation and decreased B cell responses is also discussed. We report data published by us and by other groups showing that the adipose tissue generates pro-inflammatory B cell subsets which induce pro-inflammatory T cells, promote insulin resistance, and secrete pathogenic autoimmune antibodies.

Aging up-regulates ARA55 in stromal cells, inducing androgen-mediated prostate cancer cell proliferation and migration.

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Zou, Qingsong; Cui, Di; Liang, Shengjie; Xia, Shujie; Jing, Yifeng; Han, Bangmin

2016-06-01

Stromal cells in the peripheral zone (PZ) of the prostate from older males (PZ-old) could significantly promote Prostate cancer (PCa) growth compared with stromal cells from young males (PZ-young). But the mechanism is still unknown. In the co-culture system with PZ-old cells, Pc3/Du145 cells showed advanced proliferation and migration after Dihydrotestosterone (DHT) incubation, but DHT didn't show the similar effect in PZ-young co-culture system. Also, higher androgen/AR signal pathway activity and AR-related cytokines secretion (FGF-2, KGF, IGF-1) were found in PZ-old cells. As AR exprssison was equivalent in PZ-old and PZ-young cells, we focused on Androgen receptor associated protein-55(ARA55), a stromal-specific androgen receptor (AR) coactivator. ARA55 expression was higher in PZ-old cells compared with PZ-young cells in vitro. After knocking down ARA55 expression in PZ-old cells, the PCa growth- promoting effect from the PZ-old cells was diminished, which may be explained by the decreased the progressive cytokines secretion (FGF-2, KGF, IGF-1) from PZ-old stromal cells. In vivo, the consistent results were also found: PZ-old cells promoted prostate cancer cells growth, but this effect receded when knocking down ARA55 expression in PZ-old cells. From our study, we found PZ stromal cells presented age-related effects in proliferation and migration of prostate cancer cells in the androgen/AR dependent manner. As aging increased, more ARA55 were expressed in PZ stromal cells, leading to more sensitive androgen/androgen receptor (AR) signal pathway, then constituting a more feasible environment to cancer cells.

Stem Cell Models: A Guide to Understand and Mitigate Aging?

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Brunauer, Regina; Alavez, Silvestre; Kennedy, Brian K

2017-01-01

Aging is studied either on a systemic level using life span and health span of animal models, or on the cellular level using replicative life span of yeast or mammalian cells. While useful in identifying general and conserved pathways of aging, both approaches provide only limited information about cell-type specific causes and mechanisms of aging. Stem cells are the regenerative units of multicellular life, and stem cell aging might be a major cause for organismal aging. Using the examples of hematopoietic stem cell aging and human pluripotent stem cell models, we propose that stem cell models of aging are valuable for studying tissue-specific causes and mechanisms of aging and can provide unique insights into the mammalian aging process that may be inaccessible in simple model organisms. © 2016 S. Karger AG, Basel.

Aging, Clonality and Rejuvenation of Hematopoietic Stem Cells

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Akunuru, Shailaja; Geiger, Hartmut

2016-01-01

Aging is associated with reduced organ function and increased disease incidence. Hematopoietic stem cell (HSC) aging driven by both cell intrinsic and extrinsic factors is linked to impaired HSC self-renewal and regeneration, aging-associated immune remodeling, and increased leukemia incidence. Compromised DNA damage responses and increased production of reactive oxygen species have been previously causatively attributed to HSC aging. However, recent paradigm-shifting concepts such as global epigenetic and cytoskeletal polarity shifts, cellular senescence, as well as clonal selection of HSCs upon aging provide new insights into HSC aging mechanisms. Rejuvenating agents that can reprogram the epigenetic status of aged HSCs or senolytic drugs that selectively deplete senescent cells provide promising translational avenues for attenuating hematopoietic aging and potentially, alleviating aging-associated immune remodeling and myeloid malignancies. PMID:27380967

The Influence of the Brain on Overpopulation, Ageing and Dependency.

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Cape, Ronald D. T.

1989-01-01

With time, an increasing number in the world population is becoming old, and changes in the aging brain mean that a significant proportion of the aged are likely to be dependent on others. The devotion of resources to research into the aging brain could bring benefits far outweighing the investment. (Author/CW)

Epigenetic regulation of hematopoietic stem cell aging

International Nuclear Information System (INIS)

Beerman, Isabel; Rossi, Derrick J.

2014-01-01

Aging is invariably associated with alterations of the hematopoietic stem cell (HSC) compartment, including loss of functional capacity, altered clonal composition, and changes in lineage contribution. Although accumulation of DNA damage occurs during HSC aging, it is unlikely such consistent aging phenotypes could be solely attributed to changes in DNA integrity. Another mechanism by which heritable traits could contribute to the changes in the functional potential of aged HSCs is through alterations in the epigenetic landscape of adult stem cells. Indeed, recent studies on hematopoietic stem cells have suggested that altered epigenetic profiles are associated with HSC aging and play a key role in modulating the functional potential of HSCs at different stages during ontogeny. Even small changes of the epigenetic landscape can lead to robustly altered expression patterns, either directly by loss of regulatory control or through indirect, additive effects, ultimately leading to transcriptional changes of the stem cells. Potential drivers of such changes in the epigenetic landscape of aged HSCs include proliferative history, DNA damage, and deregulation of key epigenetic enzymes and complexes. This review will focus largely on the two most characterized epigenetic marks – DNA methylation and histone modifications – but will also discuss the potential role of non-coding RNAs in regulating HSC function during aging

Epigenetic regulation of hematopoietic stem cell aging

Energy Technology Data Exchange (ETDEWEB)

Beerman, Isabel, E-mail: isabel.beerman@childrens.harvard.edu [Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138 (United States); Department of Pediatrics, Harvard Medical School, Boston, MA 02115 (United States); Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children' s Hospital, MA 02116 (United States); Rossi, Derrick J. [Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138 (United States); Department of Pediatrics, Harvard Medical School, Boston, MA 02115 (United States); Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children' s Hospital, MA 02116 (United States)

2014-12-10

Aging is invariably associated with alterations of the hematopoietic stem cell (HSC) compartment, including loss of functional capacity, altered clonal composition, and changes in lineage contribution. Although accumulation of DNA damage occurs during HSC aging, it is unlikely such consistent aging phenotypes could be solely attributed to changes in DNA integrity. Another mechanism by which heritable traits could contribute to the changes in the functional potential of aged HSCs is through alterations in the epigenetic landscape of adult stem cells. Indeed, recent studies on hematopoietic stem cells have suggested that altered epigenetic profiles are associated with HSC aging and play a key role in modulating the functional potential of HSCs at different stages during ontogeny. Even small changes of the epigenetic landscape can lead to robustly altered expression patterns, either directly by loss of regulatory control or through indirect, additive effects, ultimately leading to transcriptional changes of the stem cells. Potential drivers of such changes in the epigenetic landscape of aged HSCs include proliferative history, DNA damage, and deregulation of key epigenetic enzymes and complexes. This review will focus largely on the two most characterized epigenetic marks – DNA methylation and histone modifications – but will also discuss the potential role of non-coding RNAs in regulating HSC function during aging.

Cell ageing: a flourishing field for neurodegenerative diseases

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Dora Brites

2015-06-01

Full Text Available Cellular senescence is viewed as an irreversible cell-cycle arrest mechanism involving a complexity of biological progressive processes and the acquisition of diverse cellular phenotypes. Several cell-intrinsic and extrinsic causes (stresses may lead to diverse cellular signaling cascades that include oxidative stress, mitochondrial dysfunction, DNA damage, excessive accumulation of misfolded proteins, impaired microRNA processing and inflammation. Here we review recent advances in the causes and consequences of brain cell ageing, including the senescence of endothelial cells at the central nervous system barriers, as well as of neurons and glial cells. We address what makes ageing an important risk factor for neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and cerebrovascular disease. In particular, we highlight the importance of defects in mitochondrial dynamics, in the cathepsin activity imbalance, in cell-cell communication, in the accumulation of misfolded and unfolded proteins and in the microRNA profiling as having potential impact on cellular ageing processes. Another important aspect is that the absence of specific senescence biomarkers has hampered the characterization of senescent cells in ageing and age-associated diseases. In accordance, the senescence-associated secretory phenotype (SASP or secretome was shown to vary in distinct cell types and upon different stressors, and SASP heterogeneity is believed to create subsets of senenescent cells. In addition to secreted proteins, we then place extracellular vesicles (exosomes and ectosomes as important mediators of intercellular communication with pathophysiological roles in disease spreading, and as emerging targets for therapeutic intervention. We also discuss the application of engineered extracellular vesicles as vehicles for drug delivery. Finally, we summarize current knowledge on methods to rejuvenate senescent cells

Cellular programming and reprogramming: sculpting cell fate for the production of dopamine neurons for cell therapy.

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Aguila, Julio C; Hedlund, Eva; Sanchez-Pernaute, Rosario

2012-01-01

Pluripotent stem cells are regarded as a promising cell source to obtain human dopamine neurons in sufficient amounts and purity for cell replacement therapy. Importantly, the success of clinical applications depends on our ability to steer pluripotent stem cells towards the right neuronal identity. In Parkinson disease, the loss of dopamine neurons is more pronounced in the ventrolateral population that projects to the sensorimotor striatum. Because synapses are highly specific, only neurons with this precise identity will contribute, upon transplantation, to the synaptic reconstruction of the dorsal striatum. Thus, understanding the developmental cell program of the mesostriatal dopamine neurons is critical for the identification of the extrinsic signals and cell-intrinsic factors that instruct and, ultimately, determine cell identity. Here, we review how extrinsic signals and transcription factors act together during development to shape midbrain cell fates. Further, we discuss how these same factors can be applied in vitro to induce, select, and reprogram cells to the mesostriatal dopamine fate.

Vasotrophic Regulation of Age-Dependent Hypoxic Cerebrovascular Remodeling

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Silpanisong, Jinjutha; Pearce, William J.

2015-01-01

Hypoxia can induce functional and structural vascular remodeling by changing the expression of trophic factors to promote homeostasis. While most experimental approaches have been focused on functional remodeling, structural remodeling can reflect changes in the abundance and organization of vascular proteins that determine functional remodeling. Better understanding of age-dependent hypoxic macrovascular remodeling processes of the cerebral vasculature and its clinical implications require knowledge of the vasotrophic factors that influence arterial structure and function. Hypoxia can affect the expression of transcription factors, classical receptor tyrosine kinase factors, non-classical G-protein coupled factors, catecholamines, and purines. Hypoxia’s remodeling effects can be mediated by Hypoxia Inducible Factor (HIF) upregulation in most vascular beds, but alterations in the expression of growth factors can also be independent of HIF. PPARγ is another transcription factor involved in hypoxic remodeling. Expression of classical receptor tyrosine kinase ligands, including vascular endothelial growth factor, platelet derived growth factor, fibroblast growth factor and angiopoietins, can be altered by hypoxia which can act simultaneously to affect remodeling. Tyrosine kinase-independent factors, such as transforming growth factor, nitric oxide, endothelin, angiotensin II, catecholamines, and purines also participate in the remodeling process. This adaptation to hypoxic stress can fundamentally change with age, resulting in different responses between fetuses and adults. Overall, these mechanisms integrate to assure that blood flow and metabolic demand are closely matched in all vascular beds and emphasize the view that the vascular wall is a highly dynamic and heterogeneous tissue with multiple cell types undergoing regular phenotypic transformation. PMID:24063376

Aging and stem cell therapy: AMPK as an applicable pharmacological target for rejuvenation of aged stem cells and achieving higher efficacy in stem cell therapy.

Science.gov (United States)

Khorraminejad-Shirazi, Mohammadhossein; Farahmandnia, Mohammad; Kardeh, Bahareh; Estedlal, Alireza; Kardeh, Sina; Monabati, Ahmad

2017-10-19

In recent years, tissue regeneration has become a promising field for developing stem cell-based transplantation therapies for human patients. Adult stem cells are affected by the same aging mechanisms that involve somatic cells. One of the mechanisms involved in cellular aging is hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and disruption of 5' adenosine monophosphate-activated protein kinase (AMPK). Aging of stem cells results in their impaired regenerative capacity and depletion of stem cell pools in adult tissue, which results in lower efficacy of stem cell therapy. By utilizing an effective therapeutic intervention for aged stem cells, stem cell therapy can become more promising for future application. mTORC1 inhibition is a practical approach to preserve the stem cell pool. In this article, we review the dynamic interaction between sirtuin (silent mating type information regulation 2 homolog) 1, AMPK, and mTORC1. We propose that using AMPK activators such as 5-aminoimidazole-4-carboxamide ribonucleotide, A769662, metformin, and oxidized nicotinamide adenine dinucleotide (NAD + ) are practical ways to be employed for achieving better optimized results in stem cell-based transplantation therapies. Copyright © 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

Application of quality assurance program to safety related aging equipment or components

International Nuclear Information System (INIS)

Papaiya, N.C.

1990-01-01

This paper addresses how quality assurance programs and their criteria are applied to safety related and aging equipment or components used in commercial nuclear plant applications. The QA Programs referred to are 10CFR50 Appendix B and EPRI NP-5652. The QA programs as applicable are applied to equipment/component aging qualification, preventive maintenance, surveillance testing and procurement engineering. The intent of this paper is not the technical issues, methods and research of aging. The paper addresses QA program's application to age-related equipment or components in safety related applications. Quality Assurance Program 10CFR50 Appendix B applies to all safety related aging components or equipment related to the qualification program and associated preventive maintenance and surveillance testing programs. Quality Assurance involvement with procurement engineering for age-related commercial grade items supports EPRI NP-5652 and assures that the dedicated OGI is equal to the item purchased as a basic component to 10CFR50 Appendix B requirements

Interplay between mast cells, enterochromaffin cells, and sensory signaling in the aging human bowel.

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Yu, Y; Daly, D M; Adam, I J; Kitsanta, P; Hill, C J; Wild, J; Shorthouse, A; Grundy, D; Jiang, W

2016-10-01

Advanced age is associated with a reduction in clinical visceral pain perception. However, the underlying mechanisms remain largely unknown. Previous studies have suggested that an abnormal interplay between mast cells, enterochromaffin (EC) cells, and afferent nerves contribute to nociception in gastrointestinal disorders. The aim of this study was to investigate how aging affects afferent sensitivity and neuro-immune association in the human bowel. Mechanical and chemical sensitivity of human bowel afferents were examined by ex vivo afferent nerve recordings. Age-related changes in the density of mast cells, EC cells, sensory nerve terminals, and mast cell-nerve micro-anatomical association were investigated by histological and immune staining. Human afferents could be broadly classified into subpopulations displaying mechanical and chemical sensitivity, adaptation, chemo-sensitization, and recruitment. Interestingly human bowel afferent nerve sensitivity was attenuated with age. The density of substance P-immunoreactive (SP-IR) nerve varicosities was also reduced with age. In contrast, the density of ileal and colonic mucosal mast cells was increased with age, as was ileal EC cell number. An increased proportion of mast cells was found in close apposition to SP-IR nerves. Afferent sensitivity in human bowel was reduced with advancing age. Augmentation of mast cells and EC cell numbers and the mast cell-nerve association suggest a compensatory mechanism for sensory neurodegeneration. © 2016 The Authors. Neurogastroenterology & Motility Published by John Wiley & Sons Ltd.

Friend or foe: the dichotomous impact of T cells on neuro-de/re-generation during aging.

Science.gov (United States)

Coder, Brandon; Wang, Weikan; Wang, Liefeng; Wu, Zhongdao; Zhuge, Qichuan; Su, Dong-Ming

2017-01-24

The interaction between T cells and the central nervous system (CNS) in homeostasis and injury has been recognized being both pathogenic (CD4+ T-helper 1 - Th1, Th17 and γδT) and ameliorative (Th2 and regulatory T cells - Tregs). However, in-depth studies aimed to elucidate the precise in the aged microenvironment and the dichotomous role of Tregs have just begun and many aspects remain unclear. This is due, not only to a mutual dependency and reciprocal causation of alterations and diseases between the nervous and T cell immune systems, but also to an inconsistent aging of the two systems, which dynamically changes with CNS injury/recovery and/or aging process. Cellular immune system aging, particularly immunosenescence and T cell aging initiated by thymic involution - sources of chronic inflammation in the elderly (termed inflammaging), potentially induces an acceleration of brain aging and memory loss. In turn, aging of the brain via neuro-endocrine-immune network drives total body systemic aging, including that of the immune system. Therefore, immunotherapeutics including vaccination and "protective autoimmunity" provide promising means to rejuvenate neuro-inflammatory disorders and repair CNS acute injury and chronic neuro-degeneration. We review the current understanding and recent discoveries linking the aging immune system with CNS injury and neuro-degeneration. Additionally, we discuss potential recovery and rejuvenation strategies, focusing on targeting the aging T cell immune system in an effort to alleviate acute brain injury and chronic neuro-degeneration during aging, via the "thymus-inflammaging-neurodegeneration axis".

Econometric model for age- and population-dependent radiation exposures

International Nuclear Information System (INIS)

Sandquist, G.M.; Slaughter, D.M.; Rogers, V.C.

1991-01-01

The economic impact associated with ionizing radiation exposures in a given human population depends on numerous factors including the individual's mean economic status as a function age, the age distribution of the population, the future life expectancy at each age, and the latency period for the occurrence of radiation-induced health effects. A simple mathematical model has been developed that provides an analytical methodology for estimating the societal econometrics associated with radiation effects are to be assessed and compared for economic evaluation

Programmed cell death of tobacco BY-2 cells induced by still culture conditions is affected by the age of the culture under agitation.

Science.gov (United States)

Hiraga, Asahi; Kaneta, Tsuyoshi; Sato, Yasushi; Sato, Seiichi

2010-01-25

Evans Blue staining indicated that actively growing tobacco BY-2 cells in the exponential phase died more rapidly than quiescent cells in the stationary phase when the cells cultured under agitation were placed under still conditions. Fifty percent cell death was induced at about 18, 26, 80 and 140 h for early, mid, late exponential- and stationary-phase cells, respectively. Actively growing cells became TUNEL (transferase-mediated dUTP nick end labelling)-positive more rapidly than quiescent cells, suggesting that the cell death evaluated by Evans Blue is accompanied by DNA cleavages. Electrophoresis of genomic DNA showed a typical 'DNA laddering' pattern formed by multiples of about 200 bp internucleosomal units. Chromatin condensation was first detected at least within 24 h by light microscopy, and then cell shrinkage followed. These findings suggest that the death of BY-2 cells induced by still conditions is PCD (programmed cell death).

Psychological changes in alcohol-dependent patients during a residential rehabilitation program

Directory of Open Access Journals (Sweden)

Giorgi I

2015-12-01

Full Text Available Ines Giorgi,1 Marcella Ottonello,2,3 Giovanni Vittadini,4 Giorgio Bertolotti5 1Psychology Unit, Salvatore Maugeri Foundation, Clinica del Lavoro e della Riabilitazione, IRCCS, Pavia, 2Department of Physical & Rehabilitation Medicine, Salvatore Maugeri Foundation, Clinica del Lavoro e della Riabilitazione, IRCCS, Genoa, 3Department of Medicine, PhD Program in Advanced Sciences and Technologies in Rehabilitation Medicine and Sport, Università di Tor Vergata, Rome, 4Alcohol Rehabilitation Unit, Salvatore Maugeri Foundation, Clinica del Lavoro e della Riabilitazione, IRCCS, Pavia, 5Psychology Unit, Salvatore Maugeri Foundation, Clinica del Lavoro e della Riabilitazione, IRCCS, Tradate, Italy Background: Alcohol-dependent patients usually experience negative affects under the influence of alcohol, and these affective symptoms have been shown to decrease as a result of alcohol-withdrawal treatment. A recent cognitive–affective model suggests an interaction between drug motivation and affective symptoms. The aim of this multicenter study was to evaluate the psychological changes in subjects undergoing a residential rehabilitation program specifically designed for alcohol addiction, and to identify at discharge patients with greater affective symptoms and therefore more at risk of relapse.Materials and methods: The sample included 560 subjects (mean age 46.91±10.2 years who completed 28-day rehabilitation programs for alcohol addiction, following a tailored routine characterized by short duration and high intensity of medical and psychotherapeutic treatment. The psychological clinical profiles of anxiety, depression, psychological distress, psychological well-being, and self-perception of a positive change were assessed using the Cognitive Behavioral Assessment – Outcome Evaluation questionnaire at the beginning and at the end of the program. The changes in the psychological variables of the questionnaire were identified and considered as outcome

Triiodothyronine regulates angiogenic growth factor and cytokine secretion by isolated human decidual cells in a cell-type specific and gestational age-dependent manner.

Science.gov (United States)

Vasilopoulou, E; Loubière, L S; Lash, G E; Ohizua, O; McCabe, C J; Franklyn, J A; Kilby, M D; Chan, S Y

2014-06-01

cell isolates were unaffected by T3 so changes in cell numbers could not account for any observed effects. In the first trimester, T3 decreased VEGF-A secretion by total decidual cells (P < 0.05) and increased angiopoietin-2 secretion by stromal-depleted cells (P < 0.05) but in the second trimester total decidual cells showed only increased angiogenin secretion (P < 0.05). In the first trimester, T3 reduced IL-10 secretion by total decidual cells (P < 0.05), and reduced granulocyte macrophage colony stimulating factor (P < 0.01), IL-8 (P < 0.05), IL-10 (P < 0.01), IL-1β (P < 0.05) and monocyte chemotactic protein -1 (P < 0.001) secretion by macrophages, but increased tumour necrosis factor-α secretion by stromal-depleted cells (P < 0.05) and increased IL-6 by uNK cells (P < 0.05). In contrast, in the second trimester T3 increased IL-10 secretion by total decidual cells (P < 0.01) but did not affect cytokine secretion by uNK cells and macrophages. Conditioned media from first trimester T3-treated total decidual cells and macrophages did not alter EVT invasion compared with untreated controls. Thus, treatment of decidual cells with T3 resulted in changes in both angiogenic growth factor and cytokine secretion in a cell type-specific and gestational age-dependent manner, with first trimester decidual macrophages being the most responsive to T3 treatment, but these changes in decidual cell secretome did not affect EVT invasion in vitro. Our results are based on in vitro findings and we cannot be certain if a similar response occurs in human pregnancy in vivo. Optimal maternal thyroid hormone concentrations could play a critical role in maintaining a balanced inflammatory response in early pregnancy to prevent fetal immune rejection and promote normal placental development through the regulation of the secretion of critical cytokines and angiogenic growth factors by human decidual cells. Our data suggest that there is an ontogenically determined regulatory 'switch' in T3

Knockout of Arabidopsis accelerated-cell-death11 encoding a sphingosine transfer protein causes activation of programmed cell death and defense

DEFF Research Database (Denmark)

Brodersen, Peter; Petersen, Morten; Pike, Helen M

2002-01-01

by avirulent pathogens. Global transcriptional changes during programmed cell death (PCD) and defense activation in acd11 were monitored by cDNA microarray hybridization. The PCD and defense pathways activated in acd11 are salicylic acid (SA) dependent, but do not require intact jasmonic acid or ethylene...

State-age-dependent maintenance policies for deteriorating systems with Erlang sojourn time distributions

International Nuclear Information System (INIS)

Yeh, R.H.

1997-01-01

This paper investigates state-age-dependent maintenance policies for multistate deteriorating systems with Erlang sojourn time distributions. Since Erlang distributions are serial combinations of exponential phases, the deteriorating process can be modeled by a multi-phase Markovian model and hence easily analyzed. Based on the Markovian model, the optimal phase-dependent inspection and replacement policy can be obtained by using a policy improvement algorithm. However, since phases are fictitious and can not be identified by inspections, two procedures are developed to construct state-age-dependent policies based on the optimal phase-dependent policy. The properties of the constructed state-age-dependent policies are further investigated and the performance of the policy is evaluated through a numerical example

Age and dosage-level dependence of radium retention in beagles

International Nuclear Information System (INIS)

Parks, N.J.; Pool, R.R.; Williams, J.R.; Wolf, H.G.

1978-01-01

Radium retention was measured over the lifespan of 46 beagles exposed by eight semimonthly injections at 60 to 160, 120 to 220, or 435 to 535 days of age. Injection dosage levels ranged from 0.37 to 10 μCi of 226 Ra/kg. The fractional retention of each animal is described in terms of a modified power function, R = [(t + d)/d] - /sup b/. Young adult beagles (approximately equal to 10 kg) injected at a mean age (A) of 485 days with 226 Ra at dosage levels of 10, 3.3, 1.11, and 0.37 μCi/kg had mean values for d and b of [0.897; 0.187], [2.015; 0.206], [2.778; 0.257], and [3.894; 0.274], respectively. Juvenile beagles injected with 10 μCi/kg at A = 110 days (average weight approximately equal to 6 kg) and at A = 170 days (average weight approximately equal to 10 kg) had mean values for d and b of [137; 0.277] and [5.53; 0.086], respectively. The d values are geometric means and the units are days; b values are arithmetic means. The formula for deriving the age-dependent retention function for dogs is given. The beagle results were correlated with human data in terms of age-to-equivalent fraction of adult body calcium content and were used to construct a similar age-dependent retention function for chronically exposed people. The correlation of age-dependent retention functions for beagles and humans is used to estimate scaling factors between the two species for the fraction of injected dosage associated with bone for various ages of exposure

Dependent-Chance Programming Models for Capital Budgeting in Fuzzy Environments

Institute of Scientific and Technical Information of China (English)

LIANG Rui; GAO Jinwu

2008-01-01

Capital budgeting is concerned with maximizing the total net profit subject to budget constraints by selecting an appropriate combination of projects. This paper presents chance maximizing models for capital budgeting with fuzzy input data and multiple conflicting objectives. When the decision maker sets a prospec-tive profit level and wants to maximize the chances of the total profit achieving the prospective profit level, a fuzzy dependent-chance programming model, a fuzzy multi-objective dependent-chance programming model, and a fuzzy goal dependent-chance programming model are used to formulate the fuzzy capital budgeting problem. A fuzzy simulation based genetic algorithm is used to solve these models. Numerical examples are provided to illustrate the effectiveness of the simulation-based genetic algorithm and the po-tential applications of these models.

Potential importance of B cells in aging and aging-associated neurodegenerative diseases.

Science.gov (United States)

Biragyn, Arya; Aliseychik, Maria; Rogaev, Evgeny

2017-04-01

Our understanding of B cells as merely antibody producers is slowly changing. Alone or in concert with antibody, they control outcomes of seemingly different diseases such as cancer, rheumatoid arthritis, diabetes, and multiple sclerosis. While their role in activation of effector immune cells is beneficial in cancer but bad in autoimmune diseases, their immunosuppressive and regulatory subsets (Bregs) inhibit autoimmune and anticancer responses. These pathogenic and suppressive functions are not static and appear to be regulated by the nature and strength of inflammation. Although aging increases inflammation and changes the composition and function of B cells, surprisingly, little is known whether the change affects aging-associated neurodegenerative disease, such as Alzheimer's disease (AD). Here, by analyzing B cells in cancer and autoimmune and neuroinflammatory diseases, we elucidate their potential importance in AD and other aging-associated neuroinflammatory diseases.

Age-dependent terminal declines in reproductive output in a wild bird.

Directory of Open Access Journals (Sweden)

Martijn Hammers

Full Text Available In many iteroparous species individual fitness components, such as reproductive output, first increase with age and then decline during late-life. However, individuals differ greatly in reproductive lifespan, but reproductive declines may only occur in the period just before their death as a result of an age-independent decline in physiological condition. To fully understand reproductive senescence it is important to investigate to what extent declines in late-life reproduction can be explained by age, time until death, or both. However, the study of late-life fitness performance in natural populations is challenging as the exact birth and death dates of individuals are often not known, and most individuals succumb to extrinsic mortality before reaching old age. Here, we used an exceptional long-term longitudinal dataset of individuals from a natural, closed, and predator-free population of the Seychelles warbler (Acrocephalus sechellensis to investigate reproductive output, both in relation to age and to the time until the death of an individual (reverse-age approach. We observed an initial age-dependent increase in reproductive output that was followed by a decline in old age. However, we found no significant decline in reproductive output in the years directly preceding death. Although post-peak reproductive output declined with age, this pattern differed between terminal and non-terminal reproductive attempts, and the age-dependence of the terminal breeding attempt explained much of the variation in age-specific reproductive output. In fact, terminal declines in reproductive output were steeper in very old individuals. These results indicate that not only age-dependent, but also age-independent factors, such as physiological condition, need to be considered to understand reproductive senescence in wild-living animals.

Expression and mechanism of mammalian target of rapamycin in age-related renal cell senescence and organ aging.

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Zhuo, Li; Cai, Guangyan; Liu, Fuyou; Fu, Bo; Liu, Weiping; Hong, Quan; Ma, Qiang; Peng, Youming; Wang, Jianzhong; Chen, Xiangmei

2009-10-01

The mammalian target of rapamycin (mTOR) is relevant to cell senescence and organismal aging. This study firstly showed that the level of mTOR expression increased with aging in rat kidneys, rat mesangial cells and WI-38 cells (P aging-related phenotypes were all reduced in cells treated with rapamycin (an inhibitor of mTOR) than in control cells (P aging, and that mTOR may promote cellular senescence by regulating the cell cycle through p21(WAF1/CIP1/SDI1), which might provide a new target for preventing renal aging.

Dependence on age at intake of committed dose equivalents from radionuclides

International Nuclear Information System (INIS)

Adams, N.

1981-01-01

The dependence of committed dose equivalents on age at intake is needed to assess the significance of exposures of young persons among the general public resulting from inhaled or ingested radionuclides. The committed dose equivalents, evaluated using ICRP principles, depend on the body dimensions of the young person at the time of intake of a radionuclide and on subsequent body growth. Representation of growth by a series of exponential segments facilitates the derivation of general expressions for the age dependence of committed dose equivalents if metabolic models do not change with age. The additional assumption that intakes of radionuclides in air or food are proportional to a person's energy expenditure (implying age-independent dietary composition) enables the demonstration that the age of the most highly exposed 'critical groups' of the general public from these radionuclides is either about 1 year or 17 years. With the above assumptions the exposure of the critical group is less than three times the exposure of adult members of the general public. Approximate values of committed dose equivalents which avoid both underestimation and excessive overestimation are shown to be obtainable by simplified procedures. Modified procedures are suggested for use if metabolic models change with age. (author)

Mineralization by mesenchymal stromal cells is variously modulated depending on commercial platelet lysate preparations.

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Boraldi, Federica; Burns, Jorge S; Bartolomeo, Angelica; Dominici, Massimo; Quaglino, Daniela

2018-03-01

Numerous cellular models have been developed to investigate calcification for regenerative medicine applications and for the identification of therapeutic targets in various complications associated with age-related diseases. However, results have often been contradictory due to specific culture conditions, cell type ontogeny and aging status. Human platelet lysate (hPL) has been recently investigated as valuable alternative to fetal bovine serum (FBS) in cell culture and bone regeneration. A parallel comparison of how all these multiple factors may converge to influence mineralization has yet to be reported. To compare mineralization of human mesenchymal cell types known to differ in extracellular matrix calcification potency, bone marrow-derived mesenchymal stromal cells and dermal fibroblasts from neonatal and adult donors, at both low and high passages, were investigated in an ex vivo experimental model by supplementing the osteogenic induction medium with FBS or with hPL. Four commercial hPL preparations were profiled by liquid chromatography/electrospray ionization quadrupole time-of-flight spectrometry, and mineralization was visualized by von Kossa staining and quantified by morphometric evaluations after 9, 14 and 21 days of culture. Data demonstrate that (i) commercial hPL preparations differ according to mass spectra profiles, (ii) hPL variously influences mineral deposition depending on cell line and possibly on platelet product preparation methods, (iii) donor age modifies mineral deposition in the presence of the same hPL and (iv) reduced in vitro proliferative capacity affects osteogenic induction and response to hPL. Despite the standardized procedures applied to obtain commercial hPL, this study highlights the divergent effects of different preparations and emphasizes the importance of cellular ontology, donor age and cell proliferative capacity to optimize the osteogenic induction capabilities of mesenchymal stromal cells and design more effective

Aged dominant negative p38α MAPK mice are resistant to age-dependent decline in adult-neurogenesis and context discrimination fear conditioning.

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Cortez, IbDanelo; Bulavin, Dmitry V; Wu, Ping; McGrath, Erica L; Cunningham, Kathryn A; Wakamiya, Maki; Papaconstantinou, John; Dineley, Kelly T

2017-03-30

A major aspect of mammalian aging is the decline in functional competence of many self-renewing cell types, including adult-born neuronal precursors. Since age-related senescence of self-renewal occurs simultaneously with chronic up-regulation of the p38MAPKalpha (p38α) signaling pathway, we used the dominant negative mouse model for attenuated p38α activity (DN-p38α AF/+ ) in which Thr180 and Tyr182 are mutated (T→A/Y→F) to prevent phosphorylation activation (DN-p38α AF/+ ) and kinase activity. As a result, aged DN-p38α AF/+ mice are resistant to age-dependent decline in proliferation and regeneration of several peripheral tissue progenitors when compared to wild-type littermates. Aging is the major risk factor for non-inherited forms of Alzheimer's disease (AD); environmental and genetic risk factors that accelerate the senescence phenotype are thought to contribute to an individual's relative risk. In the present study, we evaluated aged DN-p38α AF/+ and wildtype littermates in a series of behavioral paradigms to test if p38α mutant mice exhibit altered baseline abnormalities in neurological reflexes, locomotion, anxiety-like behavior, and age-dependent cognitive decline. While aged DN-p38α AF/+ and wildtype littermates appear equal in all tested baseline neurological and behavioral parameters, DN-p38α AF/+ exhibit superior context discrimination fear conditioning. Context discrimination is a cognitive task that is supported by proliferation and differentiation of adult-born neurons in the dentate gyrus of the hippocampus. Consistent with enhanced context discrimination in aged DN-p38α AF/+ , we discovered enhanced production of adult-born neurons in the dentate gyrus of DN-p38α AF/+ mice compared to wildtype littermates. Our findings support the notion that p38α inhibition has therapeutic utility in aging diseases that affect cognition, such as AD. Copyright © 2016 Elsevier B.V. All rights reserved.

Osteopontin attenuates aging-associated phenotypes of hematopoietic stem cells.

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Guidi, Novella; Sacma, Mehmet; Ständker, Ludger; Soller, Karin; Marka, Gina; Eiwen, Karina; Weiss, Johannes M; Kirchhoff, Frank; Weil, Tanja; Cancelas, Jose A; Florian, Maria Carolina; Geiger, Hartmut

2017-04-03

Upon aging, hematopoietic stem cells (HSCs) undergo changes in function and structure, including skewing to myeloid lineages, lower reconstitution potential and loss of protein polarity. While stem cell intrinsic mechanisms are known to contribute to HSC aging, little is known on whether age-related changes in the bone marrow niche regulate HSC aging. Upon aging, the expression of osteopontin (OPN) in the murine bone marrow stroma is reduced. Exposure of young HSCs to an OPN knockout niche results in a decrease in engraftment, an increase in long-term HSC frequency and loss of stem cell polarity. Exposure of aged HSCs to thrombin-cleaved OPN attenuates aging of old HSCs, resulting in increased engraftment, decreased HSC frequency, increased stem cell polarity and a restored balance of lymphoid and myeloid cells in peripheral blood. Thus, our data suggest a critical role for reduced stroma-derived OPN for HSC aging and identify thrombin-cleaved OPN as a novel niche informed therapeutic approach for ameliorating HSC phenotypes associated with aging. © 2017 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

Paradoxical aging in HIV: immune senescence of B Cells is most prominent in young age.

Science.gov (United States)

Rinaldi, Stefano; Pallikkuth, Suresh; George, Varghese K; de Armas, Lesley R; Pahwa, Rajendra; Sanchez, Celeste M; Pallin, Maria Fernanda; Pan, Li; Cotugno, Nicola; Dickinson, Gordon; Rodriguez, Allan; Fischl, Margaret; Alcaide, Maria; Gonzalez, Louis; Palma, Paolo; Pahwa, Savita

2017-04-01

Combination antiretroviral therapies (cART)can lead to normal life expectancy in HIV-infected persons, and people aged >50 yrs represent the fastest growing HIV group. Although HIV and aging are independently associated with impaired humoral immunity, immune status in people aging with HIV is relatively unexplored. In this study influenza vaccination was used to probe age associated perturbations in the B cell compartment of HIV-negative "healthy controls" (HC) and virologically controlled HIV-infected participants on cART (HIV) (n=124), grouped by age as young (aged (40-59yrs) or old ( > 60 yrs). H1N1 antibody response at d21 post-vaccination correlated inversely with age in both HC and HIV. Immunophenotyping of cryopreserved PBMC demonstrated increased frequencies of double negative B cells and decreased plasmablasts in old compared to young HC. Remarkably, young HIV were different from young HC but similar to old HC in B cell phenotype, influenza specific spontaneous (d7) or memory (d21) antibody secreting cells. We conclude that B cell immune senescence is a prominent phenomenon in young HIV in comparison to young HC, but distinctions between old HIV and old HC are less evident though both groups manifest age-associated B cell dysfunction.

Paradoxical aging in HIV: immune senescence of B Cells is most prominent in young age

Science.gov (United States)

George, Varghese K.; de Armas, Lesley R.; Pahwa, Rajendra; Sanchez, Celeste M.; Pallin, Maria Fernanda; Pan, Li; Cotugno, Nicola; Dickinson, Gordon; Rodriguez, Allan; Fischl, Margaret; Alcaide, Maria; Gonzalez, Louis; Palma, Paolo; Pahwa, Savita

2017-01-01

Combination antiretroviral therapies (cART) can lead to normal life expectancy in HIV-infected persons, and people aged >50 yrs represent the fastest growing HIV group. Although HIV and aging are independently associated with impaired humoral immunity, immune status in people aging with HIV is relatively unexplored. In this study influenza vaccination was used to probe age associated perturbations in the B cell compartment of HIV-negative “healthy controls” (HC) and virologically controlled HIV-infected participants on cART (HIV) (n=124), grouped by age as young (<40 yrs), middle-aged (40-59yrs) or old (≥60 yrs). H1N1 antibody response at d21 post-vaccination correlated inversely with age in both HC and HIV. Immunophenotyping of cryopreserved PBMC demonstrated increased frequencies of double negative B cells and decreased plasmablasts in old compared to young HC. Remarkably, young HIV were different from young HC but similar to old HC in B cell phenotype, influenza specific spontaneous (d7) or memory (d21) antibody secreting cells. We conclude that B cell immune senescence is a prominent phenomenon in young HIV in comparison to young HC, but distinctions between old HIV and old HC are less evident though both groups manifest age-associated B cell dysfunction. PMID:28448963

Age Dependent Hypothalamic and Pituitary Responses to Novel Environment Stress or Lipopolysaccharide in Rats

Directory of Open Access Journals (Sweden)

Sandy Koenig

2018-03-01

Full Text Available Previously, we have shown that the transcription factor nuclear factor interleukin (NF-IL6 can be used as an activation marker for inflammatory lipopolysaccharide (LPS-induced and psychological novel environment stress (NES in the rat brain. Here, we aimed to investigate age dependent changes of hypothalamic and pituitary responses to NES (cage switch or LPS (100 μg/kg in 2 and 24 months old rats. Animals were sacrificed at specific time points, blood and brains withdrawn and analyzed using immunohistochemistry, RT-PCR and bioassays. In the old rats, telemetric recording revealed that NES-induced hyperthermia was enhanced and prolonged compared to the young group. Plasma IL-6 levels remained unchanged and hypothalamic IL-6 mRNA expression was increased in the old rats. Interestingly, this response was accompanied by a significant upregulation of corticotropin-releasing hormone mRNA expression only in young rats after NES and overall higher plasma corticosterone levels in all aged animals. Immunohistochemical analysis revealed a significant upregulation of NF-IL6-positive cells in the pituitary after NES or LPS-injection. In another important brain structure implicated in immune-to-brain communication, namely, in the median eminence (ME, NF-IL6-immunoreactivity was increased in aged animals, while the young group showed just minor activation after LPS-stimulation. Interestingly, we found a higher amount of NF-IL6-CD68-positive cells in the posterior pituitary of old rats compared to the young counterparts. Moreover, aging affected the regulation of cytokine interaction in the anterior pituitary lobe. LPS-treatment significantly enhanced the secretion of the cytokines IL-6 and TNFα into supernatants of primary cell cultures of the anterior pituitary. Furthermore, in the young rats, incubation with IL-6 and IL-10 antibodies before LPS-stimulation led to a robust decrease of IL-6 production and an increase of TNFα production by the pituitary

Special regulatory T-cell review: T-cell dependent suppression revisited.

Science.gov (United States)

Basten, Antony; Fazekas de St Groth, Barbara

2008-01-01

The concept of T-cell dependent regulation of immune responses has been a central tenet of immunological thinking since the delineation of the two cell system in the 1960s. Indeed T-cell dependent suppression was discovered before MHC restriction. When reviewing the data from the original wave of suppression, it is intriguing to reflect not just on the decline and fall of suppressor T cells in the 1980s, but on their equally dramatic return to respectability over the past decade. Hopefully their resurgence will be supported by solid mechanistic data that will underpin their central place in our current and future understanding of the immune system. Cannon to right of them, Cannon to left of them, Cannon in front of them Volley'd and thunder'd Storm'd at with shot and shell, Boldly they rode and well, Into the jaws of Death, Into the mouth of Hell, Rode the six hundred (suppressionists). (Adapted from The Charge of the Light Brigade, Alfred, Lord Tennyson)

Summary of JAPEIC age program

International Nuclear Information System (INIS)

Miyoshi, S.; Maeda, N.; Yamaguchi, A.

1992-01-01

Japan Power Engineering and Inspection Corporation (JAPEIC) is a statutory foundation charged with responsibility of enhancing thermal and nuclear power plant quality. JAPEIC performs construction and pre-service inspections as well as periodic inspections of many types of power plants including nuclear, gas turbine and internal combustion systems. In 1987 a research center was established to permit the systematic examination of advanced inspection technologies. One of the Structural Materials in Use for commercial Nuclear Power Plants provides the link to this workshop. The project is also referred to as the Aging General Evaluation (AGE) project. The AGE project is a six year, multi-task effort addressing material condition monitoring. One set of tasks emphasizes instrumentation simulation tasks to aid in application and utilization. All tasks are in their initial phases. The program is described in this paper

Catalase and NO CATALASE ACTIVITY1 Promote Autophagy-Dependent Cell Death in Arabidopsis

DEFF Research Database (Denmark)

Hackenberg, Thomas; Juul, Trine Maxel; Auzina, Aija

2013-01-01

Programmed cell death often depends on generation of reactive oxygen species, which can be detoxified by antioxidative enzymes, including catalases. We previously isolated catalase-deficient mutants (cat2) in a screen for resistance to hydroxyurea-induced cell death. Here, we identify...... an Arabidopsis thaliana hydroxyurea-resistant autophagy mutant, atg2, which also shows reduced sensitivity to cell death triggered by the bacterial effector avrRpm1. To test if catalase deficiency likewise affected both hydroxyurea and avrRpm1 sensitivity, we selected mutants with extremely low catalase...... activities and showed that they carried mutations in a gene that we named NO CATALASE ACTIVITY1 (NCA1). nca1 mutants showed severely reduced activities of all three catalase isoforms in Arabidopsis, and loss of NCA1 function led to strong suppression of RPM1-triggered cell death. Basal and starvation...

Restoration of Mitochondrial NAD+ Levels Delays Stem Cell Senescence and Facilitates Reprogramming of Aged Somatic Cells.

Science.gov (United States)

Son, Myung Jin; Kwon, Youjeong; Son, Taekwon; Cho, Yee Sook

2016-12-01

The fundamental tenet that aging is irreversible has been challenged by the development of reprogramming technology that can restore molecular and cellular age by reversing the progression of aging. The use of cells from aged individuals as sources for reprogramming or transplantation creates a major barrier in stem cell therapy with respect to cell quality and quantity. Here, we investigated the molecular features underlying senescence and rejuvenation during aged cell reprogramming and identified novel factors that can overcome age-associated barriers. Enzymes, such as nicotinamide nucleotide transhydrogenase (NNT) and nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3), that control mitochondrial NAD + levels appear to be susceptible to aging. In aged cells, mitochondrial NAD + levels decrease, accompanied by reduced SIRT3 activity; these changes severely impede cell fate transition. However, in cells collected from aged p16 knockout mice, which exhibit delayed cellular senescence, no changes in NNT or NMNAT3 expression were found. Importantly, restoring mitochondrial NAD + levels by overexpressing NNT and NMNAT3 enhanced reprogramming efficiency of aged somatic cells and extended the lifespan of human mesenchymal stem cells by delaying replicative senescence. These results demonstrate that maintenance of mitochondrial NAD + levels is critical for reversing the mechanisms of aging and ensuring that cells collected from aged individuals are of high quality. Stem Cells 2016;34:2840-2851. © 2016 AlphaMed Press.

Quantitative identification of senescent cells in aging and disease.

Science.gov (United States)

Biran, Anat; Zada, Lior; Abou Karam, Paula; Vadai, Ezra; Roitman, Lior; Ovadya, Yossi; Porat, Ziv; Krizhanovsky, Valery

2017-08-01

Senescent cells are present in premalignant lesions and sites of tissue damage and accumulate in tissues with age. In vivo identification, quantification and characterization of senescent cells are challenging tasks that limit our understanding of the role of senescent cells in diseases and aging. Here, we present a new way to precisely quantify and identify senescent cells in tissues on a single-cell basis. The method combines a senescence-associated beta-galactosidase assay with staining of molecular markers for cellular senescence and of cellular identity. By utilizing technology that combines flow cytometry with high-content image analysis, we were able to quantify senescent cells in tumors, fibrotic tissues, and tissues of aged mice. Our approach also yielded the finding that senescent cells in tissues of aged mice are larger than nonsenescent cells. Thus, this method provides a basis for quantitative assessment of senescent cells and it offers proof of principle for combination of different markers of senescence. It paves the way for screening of senescent cells for identification of new senescence biomarkers, genes that bypass senescence or senolytic compounds that eliminate senescent cells, thus enabling a deeper understanding of the senescent state in vivo. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Loss of E-Cadherin-Dependent Cell-Cell Adhesion and the Development and Progression of Cancer.

Science.gov (United States)

Bruner, Heather C; Derksen, Patrick W B

2018-03-01

Classical cadherins are the key molecules that control cell-cell adhesion. Notwithstanding this function, it is also clear that classical cadherins are more than just the "glue" that keeps the cells together. Cadherins are essential regulators of tissue homeostasis that govern multiple facets of cellular function and development, by transducing adhesive signals to a complex network of signaling effectors and transcriptional programs. In cancer, cadherins are often inactivated or functionally inhibited, resulting in disease development and/or progression. This review focuses on E-cadherin and its causal role in the development and progression of breast and gastric cancer. We provide a summary of the biochemical consequences and consider the conceptual impact of early (mutational) E-cadherin loss in cancer. We advocate that carcinomas driven by E-cadherin loss should be considered "actin-diseases," caused by the specific disruption of the E-cadherin-actin connection and a subsequent dependence on sustained actomyosin contraction for tumor progression. Based on the available data from mouse and human studies we discuss opportunities for targeted clinical intervention. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

Role of Blimp-1 in programing Th effector cells into IL-10 producers

Science.gov (United States)

Neumann, Christian; Heinrich, Frederik; Neumann, Katrin; Junghans, Victoria; Mashreghi, Mir-Farzin; Ahlers, Jonas; Janke, Marko; Rudolph, Christine; Mockel-Tenbrinck, Nadine; Kühl, Anja A.; Heimesaat, Markus M.; Esser, Charlotte; Im, Sin-Hyeog; Radbruch, Andreas

2014-01-01

Secretion of the immunosuppressive cytokine interleukin (IL) 10 by effector T cells is an essential mechanism of self-limitation during infection. However, the transcriptional regulation of IL-10 expression in proinflammatory T helper (Th) 1 cells is insufficiently understood. We report a crucial role for the transcriptional regulator Blimp-1, induced by IL-12 in a STAT4-dependent manner, in controlling IL-10 expression in Th1 cells. Blimp-1 deficiency led to excessive inflammation during Toxoplasma gondii infection with increased mortality. IL-10 production from Th1 cells was strictly dependent on Blimp-1 but was further enhanced by the synergistic function of c-Maf, a transcriptional regulator of IL-10 induced by multiple factors, such as the Notch pathway. We found Blimp-1 expression, which was also broadly induced by IL-27 in effector T cells, to be antagonized by transforming growth factor (TGF) β. While effectively blocking IL-10 production from Th1 cells, TGF-β shifted IL-10 regulation from a Blimp-1–dependent to a Blimp-1–independent pathway in IL-27–induced Tr1 (T regulatory 1) cells. Our findings further illustrate how IL-10 regulation in Th cells relies on several transcriptional programs that integrate various signals from the environment to fine-tune expression of this critical immunosuppressive cytokine. PMID:25073792

Roles of Mitochondrial DNA Mutations in Stem Cell Ageing

Directory of Open Access Journals (Sweden)

Tianhong Su

2018-03-01

Full Text Available Mitochondrial DNA (mtDNA mutations accumulate in somatic stem cells during ageing and cause mitochondrial dysfunction. In this review, we summarize the studies that link mtDNA mutations to stem cell ageing. We discuss the age-related behaviours of the somatic mtDNA mutations in stem cell populations and how they potentially contribute to stem cell ageing by altering mitochondrial properties in humans and in mtDNA-mutator mice. We also draw attention to the diverse fates of the mtDNA mutations with different origins during ageing, with potential selective pressures on the germline inherited but not the somatic mtDNA mutations.

Aging of hematopoietic stem cells: DNA damage and mutations?

Science.gov (United States)

Moehrle, Bettina M; Geiger, Hartmut

2016-10-01

Aging in the hematopoietic system and the stem cell niche contributes to aging-associated phenotypes of hematopoietic stem cells (HSCs), including leukemia and aging-associated immune remodeling. Among others, the DNA damage theory of aging of HSCs is well established, based on the detection of a significantly larger amount of γH2AX foci and a higher tail moment in the comet assay, both initially thought to be associated with DNA damage in aged HSCs compared with young cells, and bone marrow failure in animals devoid of DNA repair factors. Novel data on the increase in and nature of DNA mutations in the hematopoietic system with age, the quality of the DNA damage response in aged HSCs, and the nature of γH2AX foci question a direct link between DNA damage and the DNA damage response and aging of HSCs, and rather favor changes in epigenetics, splicing-factors or three-dimensional architecture of the cell as major cell intrinsic factors of HSCs aging. Aging of HSCs is also driven by a strong contribution of aging of the niche. This review discusses the DNA damage theory of HSC aging in the light of these novel mechanisms of aging of HSCs. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

Impact of aging on antigen presentation cell function of dendritic cells.

Science.gov (United States)

Wong, Christine; Goldstein, Daniel R

2013-08-01

Older people exhibit increased mortality to infections and cancer as compared to younger people, indicating that aging impairs immunity. Dendritic cells (DCs) are key for bridging the innate and adaptive arms of the immune system by priming antigen specific T cells. Discerning how aging impacts DC function to initiate adaptive immune responses is of great biomedical importance as this could lead to the development of novel therapeutics to enhance immunity with aging. This review details reports indicating that aging impairs the antigen presenting function of DCs but highlights other studies indicating preserved DC function with aging. How aging impacts antigen presentation by DCs is complex and without a clear unifying biological underpinning. Copyright © 2013 Elsevier Ltd. All rights reserved.

Age differences in empathy: Multidirectional and context-dependent.

Science.gov (United States)

Wieck, Cornelia; Kunzmann, Ute

2015-06-01

This study investigated age differences in empathy, focusing on empathic accuracy (the ability to perceive another's emotions accurately), emotional congruence (the capacity to share another's emotions), and sympathy. Participants, 101 younger (Mage = 24 years) and 101 older (Mage = 69 years) women, viewed 6 film clips, each portraying a younger or an older woman reliving and thinking aloud about an autobiographical memory. The emotional quality (anger, sadness, happiness) and the age relevance (young, old) of the memorized events were systematically varied. In comparison to their younger counterparts, older women were less accurate in perceiving the protagonists' emotions, but they reported similar levels of emotional congruence and greater sympathy. In addition, age deficits in empathic accuracy were moderated by the age relevance of the task, that is, younger and older women's empathic accuracy did not differ if the protagonists' memorized personal experience was of high relevance to older adults. These findings speak for multidirectional and context-dependent age differences in empathy. (c) 2015 APA, all rights reserved.

On the dynamics of the age structure, dependency, and consumption

Science.gov (United States)

Hock, Heinrich

2013-01-01

We examine the effects of population aging due to declining fertility and rising elderly life expectancy on consumption possibilities in the presence of intergenerational transfers. Our analysis is based on a highly tractable continuous-time overlapping generations model in which the population is divided into three groups (youth dependents, workers, and elderly dependents) and lifecourse transitions take place in a probabilistic fashion. We show that the consumption-maximizing response to greater longevity in highly developed countries is an increase in fertility. However, with larger transfer payments, the actual fertility response will likely be the opposite, leading to further population aging. PMID:24353374

Temperature-dependent imaging of living cells by AFM

International Nuclear Information System (INIS)

Espenel, Cedric; Giocondi, Marie-Cecile; Seantier, Bastien; Dosset, Patrice; Milhiet, Pierre-Emmanuel; Le Grimellec, Christian

2008-01-01

Characterization of lateral organization of plasma membranes is a prerequisite to the understanding of membrane structure-function relationships in living cells. Lipid-lipid and lipid-protein interactions are responsible for the existence of various membrane microdomains involved in cell signalization and in numerous pathologies. Developing approaches for characterizing microdomains associate identification tools like recognition imaging with high-resolution topographical imaging. Membrane properties are markedly dependent on temperature. However, mesoscopic scale topographical information of cell surface in a temperature range covering most of cell biology experimentation is still lacking. In this work we have examined the possibility of imaging the temperature-dependent behavior of eukaryotic cells by atomic force microscopy (AFM). Our results establish that the surface of living CV1 kidney cells can be imaged by AFM, between 5 and 37 deg. C, both in contact and tapping modes. These first temperature-dependent data show that large cell structures appeared essentially stable at a microscopic scale. On the other hand, as shown by contact mode AFM, the surface was highly dynamic at a mesoscopic scale, with marked changes in apparent topography, friction, and deflection signals. When keeping the scanning conditions constant, a progressive loss in the image contrast was however observed, using tapping mode, on decreasing the temperature

Rapid assay for cell age response to radiation by electronic volume flow cell sorting

International Nuclear Information System (INIS)

Freyer, J.P.; Wilder, M.E.; Raju, M.R.

1987-01-01

A new technique is described for measuring cell survival as a function of cell cycle position using flow cytometric cell sorting on the basis of electronic volume signals. Sorting of cells into different cell age compartments is demonstrated for three different cell lines commonly used in radiobiological research. Using flow cytometric DNA content analysis and [ 3 H]thymidine autoradiography of the sorted cell populations, it is demonstrated that resolution of the age compartment separation is as good as or better than that reported for other cell synchronizing techniques. Variation in cell survival as a function of position in the cell cycle after a single dose of radiation as measured by volume cell sorting is similar to that determined by other cell synchrony techniques. Advantages of this method include: (1) no treatment of the cells is required, thus, this method is noncytotoxic; (2) no cell cycle progression is needed to obtain different cell age compartments; (3) the cell population can be held in complete growth medium at any desired temperature during sorting; (4) a complete radiation age - response assay can be plated in 2 h. Applications of this method are discussed, along with some technical limitations. (author)

Area, age and gender dependence of the nucleoside system in the brain: a review of current literature.

Science.gov (United States)

Kovács, Zsolt; Juhász, Gábor; Palkovits, Miklós; Dobolyi, Arpád; Kékesi, Katalin A

2011-01-01

Nucleosides, such as uridine, inosine, guanosine and adenosine, may participate in the regulation of sleep, cognition, memory and nociception, the suppression of seizures, and have also been suggested to play a role in the pathophysiology of some neurodegenerative and neuropsychiatric diseases. Under pathological conditions, levels of nucleosides change extremely in the brain, indicating their participation in the pathophysiology of disorders like Alzheimer's disease, Parkinson's disease and schizophrenia. These findings have resulted in an increasing attention to the roles of nucleosides in the central nervous system. The specific effects of nucleosides depend on the expression of their receptors and transporters in neuronal and glial cells, as well as their extracellular concentrations in the brain. A complex interlinked metabolic network and transporters of nucleosides may balance nucleoside levels in the brain tissue under normal conditions and enable the fine modulation of neuronal and glial processes via nucleoside receptor signaling mechanisms. Brain levels of nucleosides were found to vary when measured in a variety of different brain regions. In addition, nucleoside levels also depend on age and gender. Furthermore, distributions of nucleoside transporters and receptors as well as nucleoside metabolic enzyme activities demonstrate the area, age and gender dependence of the nucleoside system, suggesting different roles of nucleosides in functionally different brain areas. The aim of this review article is to summarize our present knowledge of the area-, age- and gender-dependent distribution of nucleoside levels, nucleoside metabolic enzyme activity, nucleoside receptors and nucleoside transporters in the brain.

Aging as Evolution-Facilitating Program and a Biochemical Approach to Switch It Off

Science.gov (United States)

Skulachev, Vladimir P.

A concept is presented considering aging of living organisms as a final step of their ontogenetic program. It is assumed that such an aging program was invented by biological evolution to facilitate the evolutionary process. Indications are summarized suggesting that controlled production of toxic forms of oxygen (so called reactive oxygen species) by respiring intracellular organelles (mitochondria) is an obligatory component of the aging program. First results of a research project devoted to an attempt to interrupt aging program by antioxidants specifically addressed to mitochondria have been described. Within the framework of the project, antioxidants of a new type (SkQ) were synthesized. SkQs are composed of (i) plastoquinone (an antioxidant moiety), (ii) a penetrating cation, and (iii) a decane or pentane linker. Using planar bilayer phospholipid membranes, we selected SkQ derivatives of the highest penetrability, namely plastoquinonyl decyl triphenylphosphonium (SkQ1), plastoquinonyl decyl rhodamine 19 (SkQR1), and methylplastoquinonyl decyl triphenylphosphonium (SkQ3). Anti- and prooxidant properties of these substances and also of ubiquinonyl-decyl-triphenylphosphonium (MitoQ) were tested in isolated mitochondria. Micromolar concentrations of cationic quinones are found to be very strong prooxidants, but in the lower (sub-micromolar) concentrations they display antioxidant activity which decreases in the series SkQ1 = SkQR1 > SkQ3 > MitoQ. Thus, the window between the anti- and prooxidant effects is the smallest for MitoQ and the largest for SkQ1 and SkQR1. SkQ1 is rapidly reduced by complex III of the mitochondrial respiratory chain, i.e. it is a rechargeable antioxidant. Extremely low concentrations of SkQ1 and SkQR1 completely arrest the H2O2-induced apoptosis in human fibroblasts and HeLa cells (for SkQ1, C 1/2 = 8 · 10-9M). Higher concentrations of SkQ1 are required to block necrosis initiated by reactive oxygen species (ROS). In mice, SkQ1

Role of Dependence in Chance-constrained and Robust Programming

Czech Academy of Sciences Publication Activity Database

Houda, Michal

2007-01-01

Roč. 15, č. 4 (2007), s. 111-120 ISSN 0572-3043 R&D Projects: GA ČR GD402/03/H057; GA ČR GA402/07/1113 Institutional research plan: CEZ:AV0Z10750506 Keywords : stochastic programming * robust programming * weak dependence Subject RIV: AH - Economics

Age-Dependent and Lineage-Dependent Speciation and Extinction in the Imbalance of Phylogenetic Trees.

Science.gov (United States)

Holman, Eric W

2017-11-01

It is known that phylogenetic trees are more imbalanced than expected from a birth-death model with constant rates of speciation and extinction, and also that imbalance can be better fit by allowing the rate of speciation to decrease as the age of the parent species increases. If imbalance is measured in more detail, at nodes within trees as a function of the number of species descended from the nodes, age-dependent models predict levels of imbalance comparable to real trees for small numbers of descendent species, but predicted imbalance approaches an asymptote not found in real trees as the number of descendent species becomes large. Age-dependence must therefore be complemented by another process such as inheritance of different rates along different lineages, which is known to predict insufficient imbalance at nodes with few descendent species, but can predict increasing imbalance with increasing numbers of descendent species. [Crump-Mode-Jagers process; diversification; macroevolution; taxon sampling; tree of life.]. © The Author(s) 2017. Published by Oxford University Press, on behalf of the Society of Systematic Biologists. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

E2-2 Dependent Plasmacytoid Dendritic Cells Control Autoimmune Diabetes.

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Lisbeth Hansen

Full Text Available Autoimmune diabetes is a consequence of immune-cell infiltration and destruction of pancreatic β-cells in the islets of Langerhans. We analyzed the cellular composition of the insulitic lesions in the autoimmune-prone non-obese diabetic (NOD mouse and observed a peak in recruitment of plasmacytoid dendritic cells (pDCs to NOD islets around 8-9 weeks of age. This peak coincides with increased spontaneous expression of type-1-IFN response genes and CpG1585 induced production of IFN-α from NOD islets. The transcription factor E2-2 is specifically required for the maturation of pDCs, and we show that knocking out E2-2 conditionally in CD11c+ cells leads to a reduced recruitment of pDCs to pancreatic islets and reduced CpG1585 induced production of IFN-α during insulitis. As a consequence, insulitis has a less aggressive expression profile of the Th1 cytokine IFN-γ and a markedly reduced diabetes incidence. Collectively, these observations demonstrate a disease-promoting role of E2-2 dependent pDCs in the pancreas during autoimmune diabetes in the NOD mouse.

Skin Aging-Dependent Activation of the PI3K Signaling Pathway via Downregulation of PTEN Increases Intracellular ROS in Human Dermal Fibroblasts

Directory of Open Access Journals (Sweden)

Eun-Mi Noh

2016-01-01

Full Text Available Reactive oxygen species (ROS play a major role in both chronological aging and photoaging. ROS induce skin aging through their damaging effect on cellular constituents. However, the origins of ROS have not been fully elucidated. We investigated that ROS generation of replicative senescent fibroblasts is generated by the modulation of phosphatidylinositol 3,4,5-triphosphate (PIP3 metabolism. Reduction of the PTEN protein, which dephosphorylates PIP3, was responsible for maintaining a high level of PIP3 in replicative cells and consequently mediated the activation of the phosphatidylinositol-3-OH kinase (PI3K/Akt pathway. Increased ROS production was blocked by inhibition of PI3K or protein kinase C (PKC or by NADPH oxidase activating in replicative senescent cells. These data indicate that the signal pathway to ROS generation in replicative aged skin cells can be stimulated by reduced PTEN level. Our results provide new insights into skin aging-associated modification of the PI3K/NADPH oxidase signaling pathway and its relationship with a skin aging-dependent increase of ROS in human dermal fibroblasts.

Characterization of bone marrow-derived mesenchymal stem cells in aging.

Science.gov (United States)

Baker, Natasha; Boyette, Lisa B; Tuan, Rocky S

2015-01-01

Adult mesenchymal stem cells are a resource for autologous and allogeneic cell therapies for immune-modulation and regenerative medicine. However, patients most in need of such therapies are often of advanced age. Therefore, the effects of the aged milieu on these cells and their intrinsic aging in vivo are important considerations. Furthermore, these cells may require expansion in vitro before use as well as for future research. Their aging in vitro is thus also an important consideration. Here, we focus on bone marrow mesenchymal stem cells (BMSCs), which are unique compared to other stem cells due to their support of hematopoietic cells in addition to contributing to bone formation. BMSCs may be sensitive to age-related diseases and could perpetuate degenerative diseases in which bone remodeling is a contributory factor. Here, we review (1) the characterization of BMSCs, (2) the characterization of in vivo-aged BMSCs, (3) the characterization of in vitro-aged BMSCs, and (4) potential approaches to optimize the performance of aged BMSCs. This article is part of a Special Issue entitled "Stem Cells and Bone". Copyright © 2014 Elsevier Inc. All rights reserved.

Predictors of buprenorphine treatment success of opioid dependence in two Baltimore City grassroots recovery programs.

Science.gov (United States)

Damian, April Joy; Mendelson, Tamar; Agus, Deborah

2017-10-01

Despite evidence for the efficacy of buprenorphine treatment in primary care, few studies have identified factors associated with treatment success, nor have such factors been evaluated in community settings. Identifying correlates of treatment success can facilitate the development of treatment models tailored for distinct populations, including low-income communities of color. The current study examined client-level socio-demographic factors associated with treatment success in community-based buprenorphine programs serving vulnerable populations. Data were abstracted from client records for participants (N=445) who met DSM-IV criteria for opioid dependence and sought treatment at one of Behavioral Health Leadership Institute's two community-based recovery programs in Baltimore City from 2010 to 2015. Logistic regression estimated the odds ratios of treatment success (defined as retention in treatment for ≥90days) by sociodemographic predictors including age, race, gender, housing, legal issues and incarceration. The odds of being retained in treatment ≥90days increased with age (5% increase with each year of age; pfactors. Clients who reported unstable housing had a 41% decreased odds of remaining in treatment for 90 or more days compared to clients who lived independently at intake. Treatment success did not significantly differ by several other client-level characteristics including gender, race, employment, legal issues and incarceration. In vulnerable populations, the age factor appears sufficiently significant to justify creating models formulated for younger populations. The data also support attention to housing needs for people in treatment. Findings from this paper can inform future research and program development. Copyright © 2017 Elsevier Ltd. All rights reserved.

NEPO cable system aging management programs

International Nuclear Information System (INIS)

Toman, G.

2002-01-01

Full text: Cable polymer aging and condition monitoring is being studied in detail under the Nuclear Energy Plant Optimization Program (NEPO) that is co-sponsored by the U.S. Department of Energy and EPRI. Significant advances in modeling of polymer aging and condition monitoring have occurred and continue to be developed. The activities include: Analysis of the linearity of the Arrhenius model to room temperature; Development of a wear-out technique for determining remaining life of cable polymers; Determination of the aging fragility point for composite EPR/CSPE insulation with respect to LOCA function; Development of visual/tactile training aids for cable assessment; Development of a totally new nuclear magnetic resonance condition monitoring technique; Assessment of existing techniques with regard to repeatability, accuracy and ease of use. Through use of highly precise oxygen consumption experiments, the linearity of the Arrhenius model is being evaluated. In these experiments, polymer is placed in vials with a known amount of oxygen and aged at much lower temperatures than is possible with standard accelerated aging techniques. aging results are possible at room temperature. The technique is being applied to commonly used insulation and jacket polymers. The wear-out technique allows highly non-linear aging behavior to be made linear. The wearout point of a polymer is determined through high-rate aging and use of a condition monitoring technique to establish the end point. Then, micro-samples of cable that have been naturally aged are subjected to high rate aging to the same end point. The ratio of the remaining high rate aging period to the total high rate aging time provides a linear indication of the remaining service time. Initial screening of nuclear plant cable systems can use visual/tactile techniques to identify cable that has aged significantly. Training aids have been developed by developing sets of specimens with accelerated aging ranging from none

Human T cell immunosenescence and inflammation in aging.

Science.gov (United States)

Bektas, Arsun; Schurman, Shepherd H; Sen, Ranjan; Ferrucci, Luigi

2017-10-01

The aging process is driven by a finite number of inter-related mechanisms that ultimately lead to the emergence of characteristic phenotypes, including increased susceptibility to multiple chronic diseases, disability, and death. New assays and analytical tools have become available that start to unravel some of these mechanisms. A prevailing view is that aging leads to an imbalance between stressors and stress-buffering mechanisms that causes loss of compensatory reserve and accumulation of unrepaired damage. Central to this paradigm are changes in the immune system and the chronic low-grade proinflammatory state that affect many older individuals, even when they are apparently healthy and free of risk factors. Independent of chronological age, high circulating levels of proinflammatory markers are associated with a high risk of multiple adverse health outcomes in older persons. In this review, we discuss current theories about causes and consequences of the proinflammatory state of aging, with a focus on changes in T cell function. We examine the role of NF-κB activation and its dysregulation and how NF-κB activity differs among subgroups of T cells. We explore emerging hypotheses about immunosenescence and changes in T cell behavior with age, including consideration of the T cell antigen receptor and regulatory T cells (T regs ). We conclude by illustrating how research using advanced technology is uncovering clues at the core of inflammation and aging. Some of the preliminary work in this field is already improving our understanding of the complex mechanisms by which immunosenescence of T cells is intertwined during human aging. © Society for Leukocyte Biology.

Collective cell streams in epithelial monolayers depend on cell adhesion

International Nuclear Information System (INIS)

Czirók, András; Varga, Katalin; Méhes, Előd; Szabó, András

2013-01-01

We report spontaneously emerging, randomly oriented, collective streaming behavior within a monolayer culture of a human keratinocyte cell line, and explore the effect of modulating cell adhesions by perturbing the function of calcium-dependent cell adhesion molecules. We demonstrate that decreasing cell adhesion induces narrower and more anisotropic cell streams, reminiscent of decreasing the Taylor scale of turbulent liquids. To explain our empirical findings, we propose a cell-based model that represents the dual nature of cell–cell adhesions. Spring-like connections provide mechanical stability, while a cellular Potts model formalism represents surface-tension driven attachment. By changing the relevance and persistence of mechanical links between cells, we are able to explain the experimentally observed changes in emergent flow patterns. (paper)

Age-dependent male mating investment in Drosophila pseudoobscura.

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Sumit Dhole

Full Text Available Male mating investment can strongly influence fitness gained from a mating. Yet, male mating investment often changes with age. Life history theory predicts that mating investment should increase with age, and males should become less discriminatory about their mate as they age. Understanding age-dependent changes in male behavior and their effects on fitness is important for understanding how selection acts in age-structured populations. Although the independent effects of male or female age have been studied in many species, how these interact to influence male mating investment and fitness is less well understood. We mated Drosophila pseudoobscura males of five different age classes (4-, 8-, 11-, 15-, 19-day old to either young (4-day or old (11-day females, and measured copulation duration and early post-mating fecundity. Along with their independent effects, we found a strong interaction between the effects of male and female ages on male mating investment and fitness from individual matings. Male mating investment increased with male age, but this increase was more prominent in matings with young females. Male D. pseudoobscura made smaller investments when mating with old females. The level of such discrimination based on female age, however, also changed with male age. Intermediate aged males were most discriminatory, while the youngest and the oldest males did not discriminate between females of different ages. We also found that larger male mating investments resulted in higher fitness payoffs. Our results show that male and female ages interact to form a complex pattern of age-specific male mating investment and fitness.

An overview of the Structural Aging Program

International Nuclear Information System (INIS)

Naus, D.J.; Arndt, E.G.

1992-01-01

The structural Aging Program is conducted at the Oak Ridge National Laboratory (ORNL) for the Nuclear Regulatory Commission (NRC). The program has the overall objective of preparing an expandable handbook or report which will provide NRC with potential structural safety issues and acceptance criteria for use in nuclear power plant evaluations for continued service. Initial focus of the program is on concrete and concrete-related materials which comprise safety-related (Category I) structures in light-water reactor facilities. The program is organized into four tasks: Task S.1 -- Program Management, Task S.2 -- Materials Property Data Base, Task S.3 -- Structural Component Assessment/Repair Technology, and Task S.4 -- Quantitative Methodology for Continued Service Determinations. Objectives, background information, and accomplishments under each of these tasks are presented

Normal function of immunologic stem cells from aged mice

International Nuclear Information System (INIS)

Harrison, D.E.; Doubleday, J.W.

1975-01-01

Marrow or spleen grafts from aged donor mice produced antibody-forming cells as effectively as did grafts from younger controls in recipients tested 3 to 10 months after the transplantation. All recipients were lethally irradiated, and the T6 chromosome marker was used to demonstrate that they were populated by donor cell lines. Recipients of aged or younger control grafts gave similar responses when stimulated with varying doses of antigen and when tested at different times after the transplantation except in two cases. Recipients of aged spleen grafts gave significantly lower responses than younger controls for the first few weeks after the transplantation. If recipients had been thymectomized before lethal irradiation, aged cell lines (pooled marrow and spleen cells) gave only 37 percent of the responses of younger controls. Given sufficient time and intact young recipients, immunologic stem cell lines from old donors populated recipients with cells having normal immune responses. These results suggest that age-related immunologic defects are not intrinsically timed in the precursor cell lines that populate the immune system. (U.S.)

Figures of merit for measuring aging management program effectiveness

International Nuclear Information System (INIS)

Knudson, R.; Sciacca, F.; Walsh, R.; Zigler, G.

1991-01-01

One of the requirements for nuclear plant license renewal may be the establishment and demonstration of an effective aging management program. An analysis of both qualitative and quantitative information will be required to define the contents of this aging management program. The authors propose two quantitative figures of merit, Mean Event Detection Frequency and Mean Renewal Rate, that can be used to compare the effectiveness of various inspection, surveillance, test, and monitoring (ISTM) activities for aging mitigation. An example showing the relative effectiveness of an enhanced Loose Parts Monitoring System with current ISTM activities for steam generators and reactor internals is provided. (author)

Molecular aging and rejuvenation of human muscle stem cells

DEFF Research Database (Denmark)

Carlson, Morgan E; Suetta, Charlotte; Conboy, Michael J

2009-01-01

. Our findings establish key evolutionarily conserved mechanisms of human stem cell aging. We find that satellite cells are maintained in aged human skeletal muscle, but fail to activate in response to muscle attrition, due to diminished activation of Notch compounded by elevated transforming growth...... factor beta (TGF-beta)/phospho Smad3 (pSmad3). Furthermore, this work reveals that mitogen-activated protein kinase (MAPK)/phosphate extracellular signal-regulated kinase (pERK) signalling declines in human muscle with age, and is important for activating Notch in human muscle stem cells. This molecular......Very little remains known about the regulation of human organ stem cells (in general, and during the aging process), and most previous data were collected in short-lived rodents. We examined whether stem cell aging in rodents could be extrapolated to genetically and environmentally variable humans...

Exercise-Dependent Regulation of NK Cells in Cancer Protection

DEFF Research Database (Denmark)

Idorn, Manja; Hojman, Pernille

2016-01-01

Natural killer (NK) cells are the most responsive immune cells to exercise, displaying an acute mobilization to the circulation during physical exertion. Recently, exercise-dependent mobilization of NK cells was found to play a central role in exercise-mediated protection against cancer. Here, we...... a mechanistic explanation for the protective effect of exercise on cancer, and we propose that exercise represents a potential strategy as adjuvant therapy in cancer, by improving NK cell recruitment and infiltration in solid tumors....... review the link between exercise and NK cell function, focusing on circulating exercise factors and additional effects, including vascularization, hypoxia, and body temperature in mediating the effects on NK cell functionality. Exercise-dependent mobilization and activation of NK cells provides...

[Is it possible to "cancel" aging process of cell cultures under optimal conditions for cultivation?].

Science.gov (United States)

Bozhkov, A I; Kovaleva, M K; Menzianova, N G

2011-01-01

The characteristics of the cells epigenotypes Dunaliella viridis Teod. in the process of chronological and replicative aging were investigated. By 40th day of accumulative cultivation (which coincided with the stationary growth phase) DNA content in the cells of Dunaliella viridis increased 2 times, triacylglycerides 3 times, beta-carotene and carbonyl proteins 2 times, RNA content decreased in comparison with cells in exponential growth phase, i. e., the 40th day of growth of culture forms the age-related epigenotype. 4 received subcultures were being transplanted during 2 years in mid-logarithmic growth phase (subculture-10), early stationary phase of growth (subculture-20), in the mid-stationary growth phase (subculture-30), and late stationary growth phase (subculture-40). It is shown that epigenotype of subculture-10 remained unchanged over 2 years of cultivation, i. e., it does not manifest replicative aging. At the same time, the subculture-20, although long enough (at least 40 passages), maintained epigenotype characteristic of young cultures, and showed age-related changes. Pronounced age-dependent changes of epigenotype in the course of cultivation were identified for subculture-30, and subculture-40 was characterized by unstable epigenotype. Thus, cultivation conditions determine the intensity of replicative aging in Dunaliella viridis.

Aging Converts Innate B1a Cells into Potent CD8+ T Cell Inducers.

Science.gov (United States)

Lee-Chang, Catalina; Bodogai, Monica; Moritoh, Kanako; Chen, Xin; Wersto, Robert; Sen, Ranjan; Young, Howard A; Croft, Michael; Ferrucci, Luigi; Biragyn, Arya

2016-04-15

B cell dysregulation in aging is thought to mostly occur in conventional B2 cells without affecting innate B1 cells. Elderly humans and mice also accumulate 4-1BBL(+)MHC class-I(Hi)CD86(Hi)B cells of unknown origin. In this article, we report that these cells, termed 4BL cells, are activated murine and possibly human B1a cells. The activation is mediated by aging human monocytes and murine peritoneal macrophages. They induce expression and activation of 4-1BBL and IFN-γR1 on B1a cells to subsequently upregulate membrane TNF-α and CD86. As a result, activated B1a/4BL cells induce expression of granzyme B in CD8(+)T cells by targeting TNFR2 via membrane TNF-α and providing costimulation with CD86. Thus, for the first time, to our knowledge, these results indicate that aging affects the function of B1a cells. Upon aging, these cells lose their tumor-supporting activity and become inducers of potentially antitumor and autoimmune CD8(+)T cells. Copyright © 2016 by The American Association of Immunologists, Inc.

How aging affects sleep-dependent memory consolidation?

Directory of Open Access Journals (Sweden)

Caroline eHarand

2012-02-01

Full Text Available Sleep plays multiple functions among which energy conservation or recuperative processes. Besides, growing evidence indicate that sleep plays also a major role in memory consolidation, a process by which recently acquired and labile memory traces are progressively strengthened into more permanent and/or enhanced forms. Indeed, memories are not stored as they were initially encoded but rather undergo a gradual reorganization process, which is favoured by the neurochemical environment and the electrophysiological activity observed during sleep. Two putative, probably not exclusive, models (hippocampo-neocortical dialogue and synaptic homeostasis hypothesis have been proposed to explain the beneficial effect of sleep on memory processes. It is worth noting that all data gathered until now emerged from studies conducted in young subjects. The investigation of the relationships between sleep and memory in older adults has sparked off little interest until recently. Though, aging is characterized by memory impairment, changes in sleep architecture, as well as brain and neurochemical alterations. All these elements suggest that sleep-dependent memory consolidation may be impaired or occurs differently in older adults.Here, we give an overview of the mechanisms governing sleep-dependent memory consolidation, and the crucial points of this complex process that may dysfunction and result in impaired memory consolidation in aging.

Oxygen-dependent sensitization of irradiated cells

International Nuclear Information System (INIS)

Ewing, D.; Powers, E.L.

1979-01-01

Attention is focused primarily on O 2 effects in three biological systems, all tested in suspension: bacterial spores, vegetative bacterial cells, and mammalian cells. Information from these systems shows that O 2 has more than one process through which it can act. Studies with bacterial spore suspensions provide clear evidence that multiple components to oxygen-dependent radiation sensitization exist. Studies with mammalian cell suspensions also show that at least two oxygen-dependent sensitization processes can be distinguished. Similar studies with vegetative bacteria in suspension have not resolved oxic sensitization into components. The roles of water-derived radicals in radiation sensitivity and, specifically, in sensitization by O 2 were examined. OH radicals are clearly implicated in damage in all three biological test systems. However, the specific roles proposed for OH radicals are different in these organisms. In bacterial spores, OH radical removal in itself does not protect in anoxia or in high concentrations of O 2 . OH radical removal over a limited intermediate range of O 2 concentrations will, however, protect. OH radical scavenging probably results in the formation of the actual protector. In bacteria, the supposition is that OH radical removal will protect both in anoxia and in the presence of O 2 . OH radicals probably react with a cellular target molecule and leave a radicalsite; this is the site which can then react with O 2 to cause damage; DNA is the likely cellular target. In mammalian cells, a reaction scheme, similar to that proposed for bacteria, has been suggested for O 2 -dependent sensitization

Pilot study to determine interest of adult civilian dependents of active duty military personnel in participation in a weight control program.

Science.gov (United States)

Bukhari, Asma; Roberts, Susan B; Young, Andrew J; McGraw, Susan; Dallal, Gerard E; Das, Sai Krupa

2014-03-01

Adult civilian dependents of active duty military personnel (ADMP) may play a central role in influencing the home food environment and the risk of overweight and obesity in American Warfighters and military families. However, there is no information on whether this group would be receptive to weight control programs. We conducted a survey to determine the level of interest of adult civilian dependents of ADMP in participating in a group weight control program. Subjects were a convenience sample of 191 adult civilian dependents of ADMP (94% women, 6% men) based in Massachusetts and aged 33.8 ± 8.4 years, body mass index 25.5 ± 5.5 kg/m(2). Overall, there was a significant effect of body mass index on interest in program participation (p = 0.004). Eighty five percent of overweight participants and 100% of obese participants reported being Moderately Likely or Very Likely to participate in a provided weight control program. In overweight and obese survey respondents there was no significant effect of ADMP rank on interest in program participation (p = 0.34). These findings suggest that overweight and obese adult civilian dependents of ADMP may be very receptive targets for programs to control overweight and obesity in military families. Reprint & Copyright © 2014 Association of Military Surgeons of the U.S.

Bcl11a Deficiency Leads to Hematopoietic Stem Cell Defects with an Aging-like Phenotype

Directory of Open Access Journals (Sweden)

Sidinh Luc

2016-09-01

Full Text Available B cell CLL/lymphoma 11A (BCL11A is a transcription factor and regulator of hemoglobin switching that has emerged as a promising therapeutic target for sickle cell disease and thalassemia. In the hematopoietic system, BCL11A is required for B lymphopoiesis, yet its role in other hematopoietic cells, especially hematopoietic stem cells (HSCs remains elusive. The extensive expression of BCL11A in hematopoiesis implicates context-dependent roles, highlighting the importance of fully characterizing its function as part of ongoing efforts for stem cell therapy and regenerative medicine. Here, we demonstrate that BCL11A is indispensable for normal HSC function. Bcl11a deficiency results in HSC defects, typically observed in the aging hematopoietic system. We find that downregulation of cyclin-dependent kinase 6 (Cdk6, and the ensuing cell-cycle delay, correlate with HSC dysfunction. Our studies define a mechanism for BCL11A in regulation of HSC function and have important implications for the design of therapeutic approaches to targeting BCL11A.

DOE Hydrogen and Fuel Cells Program Plan (September 2011)

Energy Technology Data Exchange (ETDEWEB)

none,

2011-09-01

The Department of Energy Hydrogen and Fuel Cells Program Plan outlines the strategy, activities, and plans of the DOE Hydrogen and Fuel Cells Program, which includes hydrogen and fuel cell activities within the EERE Fuel Cell Technologies Program and the DOE offices of Nuclear Energy, Fossil Energy, and Science.

Pentazocine dependence among sickle cell disease patients ...

African Journals Online (AJOL)

Introduction: Sickle cell disease is a chronic disease. Severe bone pain is commonly the hallmark of clinical features. This commonly necessitates the use of analgesics especially Opioids which unfortunately have a high potential to produce dependence. The complications of dependence in patients on any psychoactive ...

A stochastic step model of replicative senescence explains ROS production rate in ageing cell populations.

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Conor Lawless

Full Text Available Increases in cellular Reactive Oxygen Species (ROS concentration with age have been observed repeatedly in mammalian tissues. Concomitant increases in the proportion of replicatively senescent cells in ageing mammalian tissues have also been observed. Populations of mitotic human fibroblasts cultured in vitro, undergoing transition from proliferation competence to replicative senescence are useful models of ageing human tissues. Similar exponential increases in ROS with age have been observed in this model system. Tracking individual cells in dividing populations is difficult, and so the vast majority of observations have been cross-sectional, at the population level, rather than longitudinal observations of individual cells.One possible explanation for these observations is an exponential increase in ROS in individual fibroblasts with time (e.g. resulting from a vicious cycle between cellular ROS and damage. However, we demonstrate an alternative, simple hypothesis, equally consistent with these observations which does not depend on any gradual increase in ROS concentration: the Stochastic Step Model of Replicative Senescence (SSMRS. We also demonstrate that, consistent with the SSMRS, neither proliferation-competent human fibroblasts of any age, nor populations of hTERT overexpressing human fibroblasts passaged beyond the Hayflick limit, display high ROS concentrations. We conclude that longitudinal studies of single cells and their lineages are now required for testing hypotheses about roles and mechanisms of ROS increase during replicative senescence.

A stochastic step model of replicative senescence explains ROS production rate in ageing cell populations.

Science.gov (United States)

Lawless, Conor; Jurk, Diana; Gillespie, Colin S; Shanley, Daryl; Saretzki, Gabriele; von Zglinicki, Thomas; Passos, João F

2012-01-01

Increases in cellular Reactive Oxygen Species (ROS) concentration with age have been observed repeatedly in mammalian tissues. Concomitant increases in the proportion of replicatively senescent cells in ageing mammalian tissues have also been observed. Populations of mitotic human fibroblasts cultured in vitro, undergoing transition from proliferation competence to replicative senescence are useful models of ageing human tissues. Similar exponential increases in ROS with age have been observed in this model system. Tracking individual cells in dividing populations is difficult, and so the vast majority of observations have been cross-sectional, at the population level, rather than longitudinal observations of individual cells.One possible explanation for these observations is an exponential increase in ROS in individual fibroblasts with time (e.g. resulting from a vicious cycle between cellular ROS and damage). However, we demonstrate an alternative, simple hypothesis, equally consistent with these observations which does not depend on any gradual increase in ROS concentration: the Stochastic Step Model of Replicative Senescence (SSMRS). We also demonstrate that, consistent with the SSMRS, neither proliferation-competent human fibroblasts of any age, nor populations of hTERT overexpressing human fibroblasts passaged beyond the Hayflick limit, display high ROS concentrations. We conclude that longitudinal studies of single cells and their lineages are now required for testing hypotheses about roles and mechanisms of ROS increase during replicative senescence.

A comprehensive approach to age-dependent dosimetric modeling

International Nuclear Information System (INIS)

Leggett, R.W.; Cristy, M.; Eckerman, K.F.

1986-01-01

In the absence of age-specific biokinetic models, current retention models of the International Commission on Radiological Protection (ICRP) frequently are used as a point of departure for evaluation of exposures to the general population. These models were designed and intended for estimation of long-term integrated doses to the adult worker. Their format and empirical basis preclude incorporation of much valuable physiological information and physiologically reasonable assumptions that could be used in characterizing the age-specific behavior of radioelements in humans. In this paper we discuss a comprehensive approach to age-dependent dosimetric modeling in which consideration is given not only to changes with age in masses and relative geometries of body organs and tissues but also to best available physiological and radiobiological information relating to the age-specific biobehavior of radionuclides. This approach is useful in obtaining more accurate estimates of long-term dose commitments as a function of age at intake, but it may be particularly valuable in establishing more accurate estimates of dose rate as a function of age. Age-specific dose rates are needed for a proper analysis of the potential effects on estimates or risk of elevated dose rates per unit intake in certain stages of life, elevated response per unit dose received during some stages of life, and age-specific non-radiogenic competing risks

A comprehensive approach to age-dependent dosimetric modeling

International Nuclear Information System (INIS)

Leggett, R.W.; Cristy, M.; Eckerman, K.F.

1987-01-01

In the absence of age-specific biokinetic models, current retention models of the International Commission of Radiological Protection (ICRP) frequently are used as a point of departure for evaluation of exposures to the general population. These models were designed and intended for estimation of long-term integrated doses to the adult worker. Their format and empirical basis preclude incorporation of much valuable physiological information and physiologically reasonable assumptions that could be used in characterizing the age-specific behavior of radioelements in humans. In this paper a comprehensive approach to age-dependent dosimetric modeling is discussed in which consideration is given not only to changes with age in masses and relative geometries of body organs and tissues but also to best available physiological and radiobiological information relating to the age-specific biobehavior of radionuclides. This approach is useful in obtaining more accurate estimates of long-term dose commitments as a function of age at intake, but it may be particularly valuable in establishing more accurate estimates of dose rate as a function of age. Age-specific dose rates are needed for a proper analysis of the potential effects on estimates of risk of elevated dose rates per unit intake in certain stages of life, elevated response per unit dose received during some stages of life, and age-specific non-radiogenic competing risks. 16 refs.; 3 figs.; 1 table

Interplay between autophagy and programmed cell death in mammalian neural stem cells

Directory of Open Access Journals (Sweden)

Kyung Min Chung

2013-08-01

Full Text Available Mammalian neural stem cells (NSCs are of particular interestbecause of their role in brain development and function. Recentfindings suggest the intimate involvement of programmed celldeath (PCD in the turnover of NSCs. However, the underlyingmechanisms of PCD are largely unknown. Although apoptosis isthe best-defined form of PCD, accumulating evidence hasrevealed a wide spectrum of PCD encompassing apoptosis,autophagic cell death (ACD and necrosis. This mini-reviewaims to illustrate a unique regulation of PCD in NSCs. Theresults of our recent studies on autophagic death of adulthippocampal neural stem (HCN cells are also discussed. HCNcell death following insulin withdrawal clearly provides areliable model that can be used to analyze the molecularmechanisms of ACD in the larger context of PCD. Moreresearch efforts are needed to increase our understanding of themolecular basis of NSC turnover under degenerating conditions,such as aging, stress and neurological diseases. Efforts aimed atprotecting and harnessing endogenous NSCs will offer novelopportunities for the development of new therapeutic strategiesfor neuropathologies. [BMB Reports 2013; 46(8: 383-390

Modelling Anopheles gambiae s.s. Population Dynamics with Temperature- and Age-Dependent Survival

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Céline Christiansen-Jucht

2015-05-01

Full Text Available Climate change and global warming are emerging as important threats to human health, particularly through the potential increase in vector- and water-borne diseases. Environmental variables are known to affect substantially the population dynamics and abundance of the poikilothermic vectors of disease, but the exact extent of this sensitivity is not well established. Focusing on malaria and its main vector in Africa, Anopheles gambiae sensu stricto, we present a set of novel mathematical models of climate-driven mosquito population dynamics motivated by experimental data suggesting that in An. gambiae, mortality is temperature and age dependent. We compared the performance of these models to that of a “standard” model ignoring age dependence. We used a longitudinal dataset of vector abundance over 36 months in sub-Saharan Africa for comparison between models that incorporate age dependence and one that does not, and observe that age-dependent models consistently fitted the data better than the reference model. This highlights that including age dependence in the vector component of mosquito-borne disease models may be important to predict more reliably disease transmission dynamics. Further data and studies are needed to enable improved fitting, leading to more accurate and informative model predictions for the An. gambiae malaria vector as well as for other disease vectors.

The aPKC-CBP Pathway Regulates Adult Hippocampal Neurogenesis in an Age-Dependent Manner

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Ayden Gouveia

2016-10-01

Full Text Available While epigenetic modifications have emerged as attractive substrates to integrate environmental changes into the determination of cell identity and function, specific signals that directly activate these epigenetic modifications remain unknown. Here, we examine the role of atypical protein kinase C (aPKC-mediated Ser436 phosphorylation of CBP, a histone acetyltransferase, in adult hippocampal neurogenesis and memory. Using a knockin mouse strain (CbpS436A in which the aPKC-CBP pathway is deficient, we observe impaired hippocampal neuronal differentiation, maturation, and memory and diminished binding of CBP to CREB in 6-month-old CbpS436A mice, but not at 3 months of age. Importantly, elevation of CREB activity rescues these deficits, and CREB activity is reduced whereas aPKC activity is increased in the murine hippocampus as they age from 3 to 6 months regardless of genotype. Thus, the aPKC-CBP pathway is a homeostatic compensatory mechanism that modulates hippocampal neurogenesis and memory in an age-dependent manner in response to reduced CREB activity.

High-Dimensional Phenotyping Identifies Age-Emergent Cells in Human Mammary Epithelia

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Fanny A. Pelissier Vatter

2018-04-01

Full Text Available Summary: Aging is associated with tissue-level changes in cellular composition that are correlated with increased susceptibility to disease. Aging human mammary tissue shows skewed progenitor cell potency, resulting in diminished tumor-suppressive cell types and the accumulation of defective epithelial progenitors. Quantitative characterization of these age-emergent human cell subpopulations is lacking, impeding our understanding of the relationship between age and cancer susceptibility. We conducted single-cell resolution proteomic phenotyping of healthy breast epithelia from 57 women, aged 16–91 years, using mass cytometry. Remarkable heterogeneity was quantified within the two mammary epithelial lineages. Population partitioning identified a subset of aberrant basal-like luminal cells that accumulate with age and originate from age-altered progenitors. Quantification of age-emergent phenotypes enabled robust classification of breast tissues by age in healthy women. This high-resolution mapping highlighted specific epithelial subpopulations that change with age in a manner consistent with increased susceptibility to breast cancer. : Vatter et al. find that single-cell mass cytometry of human mammary epithelial cells from 57 women, from 16 to 91 years old, depicts an in-depth phenotyping of aging mammary epithelia. Subpopulations of altered luminal and progenitor cells that accumulate with age may be at increased risk for oncogenic transformation. Keywords: human mammary epithelia, aging, mass cytometry, single-cell analysis, heterogeneity, breast cancer

Structural Aging Program approach to providing an improved basis for aging management of safety-related concrete structures

International Nuclear Information System (INIS)

Naus, D.J.; Oland, C.B.; Ellingwood, B.

1993-01-01

The Structural Aging (SAG) Program is being conducted at the Oak Ridge National Laboratory (ORNL) for the United States Nuclear Regulatory Commission (USNRC). The SAG Program is addressing the aging management of safety-related concrete structures in nuclear power plants for the purpose of providing improved technical bases for their continued service. The program is organized into four tasks: Program Management, Materials Property Data Base, Structural Component Assessment/Repair Technologies, and Quantitative Methodology for Continued Service Determinations. Objectives and a summary of recent accomplishments under each of these tasks are presented

Programmed death-1 (PD-1)-dependent functional impairment of CD4(+) T cells in recurrent genital papilloma.

Science.gov (United States)

Chang, Dong-Yeop; Song, Sang Hoon; You, Sooseong; Lee, Jino; Kim, Jihye; Racanelli, Vito; Son, Hwancheol; Shin, Eui-Cheol

2014-08-01

Genital papilloma is caused by human papilloma virus (HPV) infection and recurs frequently. Although T cells are known to play a critical role in the control of HPV infection and papilloma development, the function and phenotype of these cells in the lesion remain to be elucidated. In the present study, we examined the function and phenotype of CD4(+) T cells isolated from the lesions of primary (n = 9) and recurrent (n = 11) genital papillomas. In recurrent papillomas, the frequency of proliferating (Ki-67(+)) CD4(+) T cells was significantly reduced compared with primary papillomas. Cytokine production was evaluated by intracellular cytokine staining in anti-CD3/anti-CD28-stimulated CD4(+) T cells. CD4(+) T cells from recurrent lesions showed impaired production of IL-2, IFN-γ, and TNF-α. Of interest, the frequency of cytokine-producing CD4(+) T cells significantly correlated with the frequency of Ki-67(+)CD4(+) T cells. We also studied expression of programmed death-1 (PD-1), a T-cell exhaustion marker. The frequency of PD-1(+)CD4(+) T cells was significantly increased in recurrent lesions and inversely correlated with the frequency of cytokine-producing CD4(+) T cells. The functional significance of PD-1 expression was determined in blocking assays with anti-PD-L1, which restored cytokine production of CD4(+) T cells from recurrent lesions. Taken together, in recurrent genital papilloma lesions, proliferation, and cytokine production by CD4(+) T cells are impaired and the PD-1/PD-L1 interaction is responsible for the functional impairment of CD4(+) T cells.

Mixed models, linear dependency, and identification in age-period-cohort models.

Science.gov (United States)

O'Brien, Robert M

2017-07-20

This paper examines the identification problem in age-period-cohort models that use either linear or categorically coded ages, periods, and cohorts or combinations of these parameterizations. These models are not identified using the traditional fixed effect regression model approach because of a linear dependency between the ages, periods, and cohorts. However, these models can be identified if the researcher introduces a single just identifying constraint on the model coefficients. The problem with such constraints is that the results can differ substantially depending on the constraint chosen. Somewhat surprisingly, age-period-cohort models that specify one or more of ages and/or periods and/or cohorts as random effects are identified. This is the case without introducing an additional constraint. I label this identification as statistical model identification and show how statistical model identification comes about in mixed models and why which effects are treated as fixed and which are treated as random can substantially change the estimates of the age, period, and cohort effects. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Apolipoprotein E4 Causes Age- and Sex-Dependent Impairments of Hilar GABAergic Interneurons and Learning and Memory Deficits in Mice

Science.gov (United States)

Leung, Laura; Andrews-Zwilling, Yaisa; Yoon, Seo Yeon; Jain, Sachi; Ring, Karen; Dai, Jessica; Wang, Max Mu; Tong, Leslie; Walker, David; Huang, Yadong

2012-01-01

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. PMID:23300939

Rejuvenating Strategies for Stem Cell-based Therapies in Aging

Science.gov (United States)

Neves, Joana; Sousa-Victor, Pedro; Jasper, Heinrich

2017-01-01

SUMMARY Recent advances in our understanding of tissue regeneration and the development of efficient approaches to induce and differentiate pluripotent stem cells for cell replacement therapies promise exciting avenues for treating degenerative age-related diseases. However, clinical studies and insights from model organisms have identified major roadblocks that normal aging processes impose on tissue regeneration. These new insights suggest that specific targeting of environmental niche components, including growth factors, ECM and immune cells, and intrinsic stem cell properties that are affected by aging will be critical for development of new strategies to improve stem cell function and optimize tissue repair processes. PMID:28157498

Aging Educational Program to Reduce Ageism: Intergenerational Approach

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Shima Sum

2016-06-01

Full Text Available Introduction: Ageing brings different experiences for individuals. Any individual learn about ageing from childhood whatever formal or informal. No matter they learn, what and how they learn is important. This study aimed to assess impact of an educational program on ageism in those people lower 20 years of age. Methods: This interventional study was conducted among school and university students of Babol city, Mazandaran province, Iran. Study was carried out in two stages. First 373 participants (187 school students and 186 university undergraduate students under age of 20 who recruited form Babol department of education and Babol University of Medical Sciences went under study of assessing attitudes toward ageing. In the second stage, courses on lifespan human development were delivered in 10 workshops for 151 people. Sampling method was stratified randomly from different age groups.  Workshops consisted of lecturing, discussion, watching movie, reading pamphlets and having conversations with experienced older adults. Data was gathered by a questionnaire consisting of demographic characteristics and The Fraboni Scale of Ageism. Results: The mean of ageism score among school and university students were 49.93 ± 9.25 and 46.96 ± 7.64 respectively. There was statistically significant difference between two groups in ageism scores (p = 0.001 so that ageism was higher among school students However after implementation of education program, ageism score reduced for all 151 students from 46.92 ± 7.82 to 45.85 ± 7.79 which was statistically significant (p = 0.001. Conclusion: Educational program to reduce ageism is beneficial and could reduce the level of ageism. Suggestions for educators to combat ageism are provided.

A microfluidic system for studying ageing and dynamic single-cell responses in budding yeast.

Directory of Open Access Journals (Sweden)

Matthew M Crane

Full Text Available Recognition of the importance of cell-to-cell variability in cellular decision-making and a growing interest in stochastic modeling of cellular processes has led to an increased demand for high density, reproducible, single-cell measurements in time-varying surroundings. We present ALCATRAS (A Long-term Culturing And TRApping System, a microfluidic device that can quantitatively monitor up to 1000 cells of budding yeast in a well-defined and controlled environment. Daughter cells are removed by fluid flow to avoid crowding allowing experiments to run for over 60 hours, and the extracellular media may be changed repeatedly and in seconds. We illustrate use of the device by measuring ageing through replicative life span curves, following the dynamics of the cell cycle, and examining history-dependent behaviour in the general stress response.

The role of HSP70 in mediating age-dependent mortality in sepsis

Science.gov (United States)

McConnell, Kevin W.; Fox, Amy C.; Clark, Andrew T.; Chang, Nai-Yuan Nicholas; Dominguez, Jessica A.; Farris, Alton B.; Buchman, Timothy G.; Hunt, Clayton R.; Coopersmith, Craig M.

2011-01-01

Sepsis is primarily a disease of the aged, with increased incidence and mortality occurring in aged hosts. Heat shock protein (HSP) 70 plays an important role in both healthy aging and the stress response to injury. The purpose of this study was to determine the role of HSP70 in mediating mortality and the host inflammatory response in aged septic hosts. Sepsis was induced in both young (6–12week old) and aged (16–17 month old) HSP70−/− and wild type (WT) mice to determine if HSP70 modulated outcome in an age-dependent fashion. Young HSP70−/− and WT mice subjected to cecal ligation and puncture (CLP), Pseudomonas aeruginosa pneumonia or Streptococcus pneumoniae pneumonia had no differences in mortality, suggesting HSP70 does not mediate survival in young septic hosts. In contrast, mortality was higher in aged HSP70−/− mice than aged WT mice subjected to CLP (p=0.01), suggesting HSP70 mediates mortality in sepsis in an age-dependent fashion. Compared to WT mice, aged septic HSP70−/− mice had increased gut epithelial apoptosis and pulmonary inflammation. In addition, HSP70−/−mice had increased systemic levels of TNF-α, IL-6, IL-10 and IL-1β compared to WT mice. These data demonstrate that HSP70 is a key determinant of mortality in aged but not young hosts in sepsis. HSP70 may play a protective role in an age-dependent response to sepsis by preventing excessive gut apoptosis and both pulmonary and systemic inflammation. PMID:21296977

Effects of the activin A-myostatin-follistatin system on aging bone and muscle progenitor cells

Science.gov (United States)

Bowser, Matthew; Herberg, Samuel; Arounleut, Phonepasong; Shi, Xingming; Fulzele, Sadanand; Hill, William D.; Isales, Carlos M.; Hamrick, Mark W.

2013-01-01

The activin A-myostatin-follistatin system is thought to play an important role in the regulation of muscle and bone mass throughout growth, development, and aging; however, the effects of these ligands on progenitor cell proliferation and differentiation in muscle and bone are not well understood. In addition, age-associated changes in the relative expression of these factors in musculoskeletal tissues have not been described. We therefore examined changes in protein levels of activin A, follistatin, and myostatin (GDF-8) in both muscle and bone with age in C57BL6 mice using ELISA. We then investigated the effects of activin A, myostatin and follistatin on the proliferation and differentiation of primary myoblasts and mouse bone marrow stromal cells (BMSCs) in vitro. Myostatin levels and the myostatin:follistatin ratio increased with age in the primarily slow-twitch mouse soleus muscle, whereas the pattern was reversed with age in the fast-twitch extensor digitorum longus muscle. Myostatin levels and the myostatin: follistatin ratio increased significantly (+75%) in mouse bone marrow with age, as did activin A levels (+17%). Follistatin increased the proliferation of primary myoblasts from both young and aged mice, whereas myostatin increased proliferation of younger myoblasts but decreased proliferation of older myoblasts. Myostatin reduced proliferation of both young and aged BMSCs in a dose-dependent fashion, and activin A increased mineralization in both young and aged BMSCs. Together these data suggest that aging in mice is accompanied by changes in the expression of activin A and myostatin, as well as changes in the response of bone and muscle progenitor cells to these factors. Myostatin appears to play a particularly important role in the impaired proliferative capacity of muscle and bone progenitor cells from aged mice. PMID:23178301

Stem cells: Potential therapy for age-related diseases

DEFF Research Database (Denmark)

Kassem, Moustapha

2006-01-01

Aging is associated with a progressive failing of tissues and organs of the human body leading to a large number of age-related diseases. Regenerative medicine is an emerging clinical discipline that aims to employ cellular medicines (normal cells, ex vivo expanded cells, or tissue......-engineered organs) to restore the functions of damaged or defective tissues and organs and thus to "rejuvenate" the failing aging body. One of the most important sources for cellular medicine is embryonic and adult (somatic) stem cells (SSCs). One example of SCCs with enormous clinical potential is the mesenchymal...... and organs in tissue-engineering protocols. However, several challenges confront the use of these cells in the clinic, ranging from biological challenges (e.g., how to isolate a homogenous populations of the cells with specific criteria from the bone marrow and how to expand them ex vivo without affecting...

Effects of aging on action-intentional programming.

Science.gov (United States)

Shoraka, Ali R; Otzel, Dana M; M Zilli, Eduardo; Finney, Glen R; Doty, Leilani; Falchook, Adam D; Heilman, Kenneth M

2018-03-01

Action-intentional programs control "when" we initiate, inhibit, continue, and stop motor actions. The purpose of this study was to learn if there are changes in the action-intentional system with healthy aging, and if these changes are asymmetrical (right versus left upper limb) or related to impaired interhemispheric communication. We administered tests of action-intention to 41 middle-aged and older adults (61.9 ± 12.3 years). Regression analyses revealed that older age predicted a decrement in performance for tests of crossed motor response inhibition as well as slower motor initiation with the left hand. Changes in action-intention with aging appear to be related to alterations of interhemispheric communication and/or age-related right hemisphere dysfunction; however, further research is needed to identify the mechanisms for age-related changes in the brain networks that mediate action-intention.

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

International Nuclear Information System (INIS)

Otsu, Hiroshi; Kobayashi, Shigeru; Furuse, Takeshi; Noda, Yuko; Shiragai, Akihiro; Sato, Fumiaki.

1992-01-01

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)

Analysis of a general age-dependent vaccination model for a vertically transmitted disease

International Nuclear Information System (INIS)

El Doma, M.

1995-05-01

A SIR epidemic model of a general age-dependent vaccination for a vertically as well as horizontally transmitted disease is investigated when the total population is time dependent, and fertility, mortality and removal rates depend on age. We establish the existence and the uniqueness of the solution and obtain the asymptotic behaviour for the solution. For the steady state solution a critical vaccination coverage which will eventually eradicate the disease is determined. (author). 18 refs

Nox2-dependent ROS signaling protects against skeletal ageing

Science.gov (United States)

Bone remodeling is age-dependently regulated and changes dramatically during the course of development. Progressive accumulation of reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and hydroxyl radicals, has been suspected to be the leading cause of many inflammatory and degen...

The slippery slope of hematopoietic stem cell aging.

Science.gov (United States)

Wahlestedt, Martin; Bryder, David

2017-12-01

The late stages of life, in most species including humans, are associated with a decline in the overall maintenance and health of the organism. This applies also to the hematopoietic system, where aging is not only associated with an increased predisposition for hematological malignancies, but also identified as a strong comorbidity factor for other diseases. Research during the last two decades has proposed that alterations at the level of hematopoietic stem cells (HSCs) might be a root cause for the hematological changes observed with age. However, the recent realization that not all HSCs are alike with regard to fundamental stem cell properties such as self-renewal and lineage potential has several implications for HSC aging, including the synchrony and the stability of the aging HSC state. To approach HSC aging from a clonal perspective, we recently took advantage of technical developments in cellular barcoding and combined this with the derivation of induced pluripotent stem cells (iPSCs). This allowed us to selectively approach HSCs functionally affected by age. The finding that such iPSCs were capable of fully regenerating multilineage hematopoiesis upon morula/blastocyst complementation provides compelling evidence that many aspects of HSC aging can be reversed, which indicates that a central mechanism underlying HSC aging is a failure to uphold the epigenomes associated with younger age. Here we discuss these findings in the context of the underlying causes that might influence HSC aging and the requirements and prospects for restoration of the aging HSC epigenome. Copyright © 2017 ISEH – Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

Strong adhesion by regulatory T cells induces dendritic cell cytoskeletal polarization and contact-dependent lethargy.

Science.gov (United States)

Chen, Jiahuan; Ganguly, Anutosh; Mucsi, Ashley D; Meng, Junchen; Yan, Jiacong; Detampel, Pascal; Munro, Fay; Zhang, Zongde; Wu, Mei; Hari, Aswin; Stenner, Melanie D; Zheng, Wencheng; Kubes, Paul; Xia, Tie; Amrein, Matthias W; Qi, Hai; Shi, Yan

2017-02-01

Dendritic cells are targeted by regulatory T (T reg) cells, in a manner that operates as an indirect mode of T cell suppression. In this study, using a combination of single-cell force spectroscopy and structured illumination microscopy, we analyze individual T reg cell-DC interaction events and show that T reg cells exhibit strong intrinsic adhesiveness to DCs. This increased DC adhesion reduces the ability of contacted DCs to engage other antigen-specific cells. We show that this unusually strong LFA-1-dependent adhesiveness of T reg cells is caused in part by their low calpain activities, which normally release integrin-cytoskeleton linkage, and thereby reduce adhesion. Super resolution imaging reveals that such T reg cell adhesion causes sequestration of Fascin-1, an actin-bundling protein essential for immunological synapse formation, and skews Fascin-1-dependent actin polarization in DCs toward the T reg cell adhesion zone. Although it is reversible upon T reg cell disengagement, this sequestration of essential cytoskeletal components causes a lethargic state of DCs, leading to reduced T cell priming. Our results reveal a dynamic cytoskeletal component underlying T reg cell-mediated DC suppression in a contact-dependent manner. © 2017 Chen et al.

BMP signaling regulates satellite cell-dependent postnatal muscle growth.

Science.gov (United States)

Stantzou, Amalia; Schirwis, Elija; Swist, Sandra; Alonso-Martin, Sonia; Polydorou, Ioanna; Zarrouki, Faouzi; Mouisel, Etienne; Beley, Cyriaque; Julien, Anaïs; Le Grand, Fabien; Garcia, Luis; Colnot, Céline; Birchmeier, Carmen; Braun, Thomas; Schuelke, Markus; Relaix, Frédéric; Amthor, Helge

2017-08-01

Postnatal growth of skeletal muscle largely depends on the expansion and differentiation of resident stem cells, the so-called satellite cells. Here, we demonstrate that postnatal satellite cells express components of the bone morphogenetic protein (BMP) signaling machinery. Overexpression of noggin in postnatal mice (to antagonize BMP ligands), satellite cell-specific knockout of Alk3 (the gene encoding the BMP transmembrane receptor) or overexpression of inhibitory SMAD6 decreased satellite cell proliferation and accretion during myofiber growth, and ultimately retarded muscle growth. Moreover, reduced BMP signaling diminished the adult satellite cell pool. Abrogation of BMP signaling in satellite cell-derived primary myoblasts strongly diminished cell proliferation and upregulated the expression of cell cycle inhibitors p21 and p57 In conclusion, these results show that BMP signaling defines postnatal muscle development by regulating satellite cell-dependent myofiber growth and the generation of the adult muscle stem cell pool. © 2017. Published by The Company of Biologists Ltd.

Response (re-)programming in aging: a kinematic analysis.

Science.gov (United States)

Bellgrove, M A; Phillips, J G; Bradshaw, J L; Gallucci, R M

1998-05-01

Age-related motor slowing may reflect either motor programming deficits, poorer movement execution, or mere strategic preferences for online guidance of movement. We controlled such preferences, limiting the extent to which movements could be programmed. Twenty-four young and 24 older adults performed a line drawing task that allowed movements to be prepared in advance in one case (i.e., cue initially available indicating target location) and not in another (i.e., no cue initially available as to target location). Participants connected large or small targets illuminated by light-emitting diodes upon a graphics tablet that sampled pen tip position at 200 Hz. Older adults had a disproportionate difficulty initiating movement when prevented from programming in advance. Older adults produced slower, less efficient movements, particularly when prevented from programming under greater precision requirements. The slower movements of older adults do not simply reflect a preference for online control, as older adults have less efficient movements when forced to reprogram their movements. Age-related motor slowing kinematically resembles that seen in patients with cerebellar dysfunction.

Metformin Antagonizes Cancer Cell Proliferation by Suppressing Mitochondrial-Dependent Biosynthesis.

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Takla Griss

2015-12-01

Full Text Available Metformin is a biguanide widely prescribed to treat Type II diabetes that has gained interest as an antineoplastic agent. Recent work suggests that metformin directly antagonizes cancer cell growth through its actions on complex I of the mitochondrial electron transport chain (ETC. However, the mechanisms by which metformin arrests cancer cell proliferation remain poorly defined. Here we demonstrate that the metabolic checkpoint kinases AMP-activated protein kinase (AMPK and LKB1 are not required for the antiproliferative effects of metformin. Rather, metformin inhibits cancer cell proliferation by suppressing mitochondrial-dependent biosynthetic activity. We show that in vitro metformin decreases the flow of glucose- and glutamine-derived metabolic intermediates into the Tricarboxylic Acid (TCA cycle, leading to reduced citrate production and de novo lipid biosynthesis. Tumor cells lacking functional mitochondria maintain lipid biosynthesis in the presence of metformin via glutamine-dependent reductive carboxylation, and display reduced sensitivity to metformin-induced proliferative arrest. Our data indicate that metformin inhibits cancer cell proliferation by suppressing the production of mitochondrial-dependent metabolic intermediates required for cell growth, and that metabolic adaptations that bypass mitochondrial-dependent biosynthesis may provide a mechanism of tumor cell resistance to biguanide activity.

Age-related patterns in human myeloid dendritic cell populations in people exposed to Schistosoma haematobium infection.

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Norman Nausch

Full Text Available Urogenital schistosomiasis is caused by the helminth parasite Schistosoma haematobium. In high transmission areas, children acquire schistosome infection early in life with infection levels peaking in early childhood and subsequently declining in late childhood. This age-related infection profile is thought to result from the gradual development of protective acquired immunity. Age-related differences in schistosome-specific humoral and cellular responses have been reported from several field studies. However there has not yet been a systematic study of the age-related changes in human dendritic cells, the drivers of T cell polarisation.Peripheral blood mononuclear cells were obtained from a cohort of 61 Zimbabwean aged 5-45 years with a S. haematobium prevalence of 47.5%. Two subsets of dendritic cells, myeloid and plasmacytoid dendritic cells (mDCs and pDCs, were analyzed by flow cytometry.In this population, schistosome infection levels peaked in the youngest age group (5-9 years, and declined in late childhood and adulthood (10+ years. The proportions of both mDCs and pDCs varied with age. However, for mDCs the age profile depended on host infection status. In the youngest age group infected people had enhanced proportions of mDCs as well as lower levels of HLA-DR on mDCs than un-infected people. In the older age groups (10-13 and 14-45 years infected people had lower proportions of mDCs compared to un-infected individuals, but no infection status-related differences were observed in their levels of HLA-DR. Moreover mDC proportions correlated with levels of schistosome-specific IgG, which can be associated with protective immunity. In contrast proportions of pDCs varied with host age, but not with infection status.Our results show that dendritic cell proportions and activation in a human population living in schistosome-endemic areas vary with host age reflecting differences in cumulative history of exposure to schistosome infection.

Increased centrosome amplification in aged stem cells of the Drosophila midgut

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