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Sample records for cell aging

  1. NIA Aging Cell Repository

    Data.gov (United States)

    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...

  2. 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.

  3. Mitochondrial role in cell aging

    Science.gov (United States)

    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.

  4. The cell biology of aging.

    Science.gov (United States)

    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

  5. Antecedents of cell aging research.

    Science.gov (United States)

    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

  6. Klotho, stem cells, and aging.

    Science.gov (United States)

    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.

  7. 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 ...

  8. Cellular Mechanisms of Somatic Stem Cell Aging

    Science.gov (United States)

    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

  9. Molecular mechanisms of adult stem cell aging

    National Research Council Canada - National Science Library

    Rudolph, K. Lenhard

    2010-01-01

    "There is growing evidence that adult stem cells age. This process can result in alterations in the number and function of stem cells, leading to distinct phenotypic outcomes in different organ systems...

  10. The Stem Cell Hypothesis of Aging

    Directory of Open Access Journals (Sweden)

    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.

  11. Young endothelial cells revive aging blood.

    Science.gov (United States)

    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.

  12. Mitochondria in aging cell differentiation

    Czech Academy of Sciences Publication Activity Database

    Palková, Zdena; Váchová, Libuše

    2016-01-01

    Roč. 8, č. 7 (2016), s. 1287-1288 ISSN 1945-4589 R&D Projects: GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61388971 Keywords : mitochondria * cell differentiation * retrograde signaling Subject RIV: EE - Microbiology, Virology Impact factor: 4.867, year: 2016

  13. Adult Stem Cells and Diseases of Aging

    Directory of Open Access Journals (Sweden)

    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.

  14. Changes of Langerhans cells during skin ageing

    Directory of Open Access Journals (Sweden)

    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.

  15. Merkel cells carcinoma of the aged patient

    International Nuclear Information System (INIS)

    Levy, A.; Assouline, A.; Mazeron, J.J.; Chargari, C.; Krzisch, C.

    2009-01-01

    The carcinoma at Merkel cells is a rare and aggressive skin cancer, principally of the aged adult. The surgery is the fundamental treatment. The interest of the adjuvant radiotherapy is discussed for the aged patient. In the limits of this retrospective analysis, the postoperative radiotherapy appeared to bring a similar benefit as for younger patients. (N.C.)

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

    Science.gov (United States)

    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.

  17. 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

  18. 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.

  19. Cell proliferation and ageing in mouse colon

    International Nuclear Information System (INIS)

    Hamilton, E.

    1978-01-01

    The descending colon of 4 month and 2 year old mice was exposed to 1250 rad X-rays. This killed most of the epithelial cells. The surviving cells formed new crypts and surface epithelium in animals of both ages. Not all of the crypts were replaced. The irradiated area contained not more than 80% of the control number of crypts per section for at least 6 weeks after irradiation. In the young mice new crypts were much larger and the labelling index (LI) was much higher than in unirradiated animals during the first week after irradiation. In the old mice the overshoot in LI and crypt size began later and continued longer than in young animals. This may be because the control of cell proliferation was much less precise in old than in young mice. The irradiation was repeated, in attempt to age prematurely the epithelial cells by increasing the number of divisions they underwent. The overshoot in LI and cells per crypt was smaller after a second dose than after the first in both young and old mice. There was almost no overshoot after a third dose was given to young mice. Increasing the number of divisions undergone by the surviving epithelial cells did not change the timing of repopulation in young mice compared to that found in old mice. Little evidence was found for the presence of a limited proliferative lifespan in colon epithelial cells. (author)

  20. Cell proliferation and ageing in mouse colon

    International Nuclear Information System (INIS)

    Hamilton, E.; Franks, L.M.

    1980-01-01

    Cell kinetic parameters in the descending colon of unirradiated mice, 3-30-months-old were compared with those in mice irradiated repeatedly from the age of 6 or 24 months. The latter animals were given 1250 rad local X-irradiation to the colon every 6 weeks. Dose-survival curves showed the colon crypts of 6 and 24-months-old mice were similarly radiosensitive. In unirradiated mice the number of crypts per colon section decreased significantly at 30 months, but no significant age-related changes were seen in crypt size or labelling index (LI). Cell proliferation returned to control levels within 6 weeks of each X-ray dose and remained at this level for 20 weeks after the final dose. Later, cell proliferation in the irradiated colon fell significantly below control. A total of 6 or 7 doses each of 1250 rad produced only 1 colon carcinoma amongst 50 mice kept until they died. (author)

  1. 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.

  2. 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.

  3. 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.

  4. 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

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

    Science.gov (United States)

    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.

  6. 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.

  7. 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

  8. Defective TFH Cell Function and Increased TFR Cells Contribute to Defective Antibody Production in Aging.

    Science.gov (United States)

    Sage, Peter T; Tan, Catherine L; Freeman, Gordon J; Haigis, Marcia; Sharpe, Arlene H

    2015-07-14

    Defective antibody production in aging is broadly attributed to immunosenescence. However, the precise immunological mechanisms remain unclear. Here, we demonstrate an increase in the ratio of inhibitory T follicular regulatory (TFR) cells to stimulatory T follicular helper (TFH) cells in aged mice. Aged TFH and TFR cells are phenotypically distinct from those in young mice, exhibiting increased programmed cell death protein-1 expression but decreased ICOS expression. Aged TFH cells exhibit defective antigen-specific responses, and programmed cell death protein-ligand 1 blockade can partially rescue TFH cell function. In contrast, young and aged TFR cells have similar suppressive capacity on a per-cell basis in vitro and in vivo. Together, these studies reveal mechanisms contributing to defective humoral immunity in aging: an increase in suppressive TFR cells combined with impaired function of aged TFH cells results in reduced T-cell-dependent antibody responses in aged mice. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Stem cell aging: mechanisms, regulators and therapeutic opportunities

    Science.gov (United States)

    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

  10. 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.

  11. 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.

  12. 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.

  13. Ageing induced vascular smooth muscle cell senescence in atherosclerosis.

    Science.gov (United States)

    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.

  14. 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

  15. Aging, Clonality and Rejuvenation of Hematopoietic Stem Cells

    Science.gov (United States)

    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

  16. 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...

  17. 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.

  18. Aging of perennial cells and organ parts according to the programmed aging paradigm.

    Science.gov (United States)

    Libertini, Giacinto; Ferrara, Nicola

    2016-04-01

    If aging is a physiological phenomenon-as maintained by the programmed aging paradigm-it must be caused by specific genetically determined and regulated mechanisms, which must be confirmed by evidence. Within the programmed aging paradigm, a complete proposal starts from the observation that cells, tissues, and organs show continuous turnover: As telomere shortening determines both limits to cell replication and a progressive impairment of cellular functions, a progressive decline in age-related fitness decline (i.e., aging) is a clear consequence. Against this hypothesis, a critic might argue that there are cells (most types of neurons) and organ parts (crystalline core and tooth enamel) that have no turnover and are subject to wear or manifest alterations similar to those of cells with turnover. In this review, it is shown how cell types without turnover appear to be strictly dependent on cells subjected to turnover. The loss or weakening of the functions fulfilled by these cells with turnover, due to telomere shortening and turnover slowing, compromises the vitality of the served cells without turnover. This determines well-known clinical manifestations, which in their early forms are described as distinct diseases (e.g., Alzheimer's disease, Parkinson's disease, age-related macular degeneration, etc.). Moreover, for the two organ parts (crystalline core and tooth enamel) without viable cells or any cell turnover, it is discussed how this is entirely compatible with the programmed aging paradigm.

  19. 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.

  20. Dynamic changes in mouse hematopoietic stem cell numbers during aging

    NARCIS (Netherlands)

    de Haan, G; Van Zant, G

    1999-01-01

    To address the fundamental question of whether or not stem cell populations age, we performed quantitative measurements of the cycling status and frequency of hematopoietic stem cells in long-lived C57BL/6 (B6) and short-lived DBA/2 (DBA) mice at different developmental and aging stages. The

  1. 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

  2. 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...

  3. Skeletal muscle aging: stem cell function and tissue homeostasis

    OpenAIRE

    Victor, Pedro Sousa

    2012-01-01

    Muscle aging, in particular, is characterized by the reduction of tissue mass and function, which are particularly prominent in geriatric individuals undergoing sarcopenia. The age-associated muscle wasting is also associated with a decline in regenerative ability and a reduction in resident muscle stem cell (satellite cell) number and function. Although sarcopenia is one of the major contributors to the general loss of physiological function, the mechanisms involved in age-related loss of mu...

  4. Organization of haemopoietic stem cells: the generation-age hypothesis

    International Nuclear Information System (INIS)

    Rosendaal, M.; Hodgson, G.S.; Bradley, T.R.

    1978-01-01

    This paper proposes that the previous division history of each stem cell is one determinant of the functional organisation of the haemopoietic stem cell population. Older stem cell are used to form blood before younger ones. The stem cells generating capacity of a lineage is finite, and cells are eventually lost to the system by forming two committed precursors of the cell lines, and the next oldest stem cell takes over. Hence the proposed term 'generation-age hypothesis', supported by experimental evidence. Older stem cells from normal bone marrow and 13 day foetal liver were stripped away with phase-specific drugs revealing a younger population of stem cells with three-to four-fold greater stem cell generating capacity. Normal stem cells aged by continuous irradiation and serial retransplantation had eight-fold reduced generating capacity. That of stem cells in the bloodstream was half to a quarter that of normal bone marrow stem cells. There were some circulating stem cells, identified by reaction to brain-associated antigen, positive for 75% of normal femoral stem cells but not their progeny, whose capacity for stem cell generation was an eighth to one fortieth that of normal cells. (U.K.)

  5. Hematopoietic stem cells : Self-renewing or aging?

    NARCIS (Netherlands)

    de Haan, G

    2002-01-01

    Stem cells are defined by their extensive self-renewal properties, and yet there is abundant evidence of erosion of stem cell functioning during aging. Whereas intracellular repair and protection mechanisms determine the lifespan of an individual cell, here an argument is made that somatic stem

  6. 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.

  7. Cellular memory and, hematopoietic stem cell aging

    NARCIS (Netherlands)

    Kamminga, Leonie M.; de Haan, Gerald

    Hematopoietic stem cells (HSCs) balance self-renewal and differentiation in order to sustain lifelong blood production and simultaneously maintain the HSC pool. However, there is clear evidence that HSCs are subject to quantitative and qualitative exhaustion. In this review, we briefly discuss

  8. Erythrocyte aging in sickle cell disease.

    NARCIS (Netherlands)

    Bosman, G.J.C.G.M.

    2004-01-01

    Physiological removal of old erythrocytes from the circulation by macrophages is initiated by binding of autologous IgG to senescent cell antigen (SCA). SCA is generated from the anion exchanger band 3. This process is accompanied by a number of alterations in the function and structure of band 3.

  9. 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.

  10. Cell ageing: a flourishing field for neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    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

  11. 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

  12. 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.

  13. 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.

  14. Osteopontin attenuates aging-associated phenotypes of hematopoietic stem cells.

    Science.gov (United States)

    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.

  15. Hyaluronan in aged collagen matrix increases prostate epithelial cell proliferation

    Science.gov (United States)

    Damodarasamy, Mamatha; Vernon, Robert B.; Chan, Christina K.; Plymate, Stephen R.; Wight, Thomas N.

    2015-01-01

    The extracellular matrix (ECM) of the prostate, which is comprised primarily of collagen, becomes increasingly disorganized with age, a property that may influence the development of hyperplasia and cancer. Collageous ECM extracted from the tails of aged mice exhibits many characteristics of collagen in aged tissues, including the prostate. When polymerized into a 3-dimensional (3D) gel, these collagen extracts can serve as models for the study of specific cell-ECM interactions. In the present study, we examined the behaviors of human prostatic epithelial cell lines representing normal prostate epithelial cells (PEC), benign prostatic hyperplasia (BPH-1), and adenocarcinoma (LNCaP) cultured in contact with 3D gels made from collagen extracts of young and aged mice. We found that proliferation of PEC, BPH-1, and LNCaP cells were all increased by culture on aged collagen gels relative to young collagen gels. In examining age-associated differences in the composition of the collagen extracts, we found that aged and young collagen had a similar amount of several collagen-associated ECM components, but aged collagen had a much greater content of the glycosaminoglycan hyaluronan (HA) than young collagen. The addition of HA (of similar size and concentration to that found in aged collagen extracts) to cells placed in young collagen elicited significantly increased proliferation in BPH-1 cells, but not in PEC or LNCaP cells, relative to controls not exposed to HA. Of note, histochemical analyses of human prostatic tissues showed significantly higher expression of HA in BPH and prostate cancer stroma relative to stroma of normal prostate. Collectively, these results suggest that changes in ECM involving increased levels of HA contribute to the growth of prostatic epithelium with aging. PMID:25124870

  16. Cellular and epigenetic drivers of stem cell ageing.

    Science.gov (United States)

    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.

  17. Recent advances in the cell biology of aging.

    Science.gov (United States)

    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.

  18. Development and aging of a brain neural stem cell niche.

    Science.gov (United States)

    Conover, Joanne C; Todd, Krysti L

    2017-08-01

    In the anterior forebrain, along the lateral wall of the lateral ventricles, a neurogenic stem cell niche is found in a region referred to as the ventricular-subventricular zone (V-SVZ). In rodents, robust V-SVZ neurogenesis provides new neurons to the olfactory bulb throughout adulthood; however, with increasing age stem cell numbers are reduced and neurogenic capacity is significantly diminished, but new olfactory bulb neurons continue to be produced even in old age. Humans, in contrast, show little to no new neurogenesis after two years of age and whether V-SVZ neural stem cells persist in the adult human brain remains unclear. Here, we review functional and organizational differences in the V-SVZ stem cell niche of mice and humans, and examine how aging affects the V-SVZ niche and its associated functions. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. 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...

  20. Cell-Nonautonomous Mechanisms Underlying Cellular and Organismal Aging.

    Science.gov (United States)

    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.

  1. 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. PMID:26732838

  2. 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.)

  3. 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

  4. Induced Pluripotent Stem Cell Derived Mesenchymal Stem Cells for Attenuating Age-Related Bone Loss

    Science.gov (United States)

    2012-07-01

    Mesenchymal stem cell (MSC) differentiation towards the bone forming osteoblastic lineage decreases as a function of age and may contribute to age-related...problem of age-related reduced availability of MSC we propose to examine the bone anabolic potential of induced pluripotent stem cell (iPS) derived MSC

  5. Aging of marrow stromal (skeletal) stem cells and their contribution to age-related bone loss

    DEFF Research Database (Denmark)

    Bellantuono, Ilaria; Aldahmash, Abdullah; Kassem, Moustapha

    2009-01-01

    Marrow stromal cells (MSC) are thought to be stem cells with osteogenic potential and therefore responsible for the repair and maintenance of the skeleton. Age related bone loss is one of the most prevalent diseases in the elder population. It is controversial whether MSC undergo a process of agi...

  6. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  8. 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.

  9. 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.

  10. 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)

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

    Science.gov (United States)

    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.

  12. Accumulation of senescent cells in mitotic tissue of aging primates.

    Science.gov (United States)

    Jeyapalan, Jessie C; Ferreira, Mark; Sedivy, John M; Herbig, Utz

    2007-01-01

    Cellular senescence, a stress induced growth arrest of somatic cells, was first documented in cell cultures over 40 years ago, however its physiological significance has only recently been demonstrated. Using novel biomarkers of cellular senescence we examined whether senescent cells accumulate in tissues from baboons of ages encompassing the entire lifespan of this species. We show that dermal fibroblasts, displaying markers of senescence such as telomere damage, active checkpoint kinase ATM, high levels of heterochromatin proteins and elevated levels of p16, accumulate in skin biopsies from baboons with advancing age. The number of dermal fibroblasts containing damaged telomeres reaches a value of over 15% of total fibroblasts, whereas 80% of cells contain high levels of the heterochromatin protein HIRA. In skeletal muscle, a postmitotic tissue, only a small percentage of myonuclei containing damaged telomeres were detected regardless of animal age. The presence of senescent cells in mitotic tissues might therefore be a contributing factor to aging and age related pathology and provides further evidence that cellular senescence is a physiological event.

  13. 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.

  14. 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.

  15. Aging increases cell-to-cell transcriptional variability upon immune stimulation.

    Science.gov (United States)

    Martinez-Jimenez, Celia Pilar; Eling, Nils; Chen, Hung-Chang; Vallejos, Catalina A; Kolodziejczyk, Aleksandra A; Connor, Frances; Stojic, Lovorka; Rayner, Timothy F; Stubbington, Michael J T; Teichmann, Sarah A; de la Roche, Maike; Marioni, John C; Odom, Duncan T

    2017-03-31

    Aging is characterized by progressive loss of physiological and cellular functions, but the molecular basis of this decline remains unclear. We explored how aging affects transcriptional dynamics using single-cell RNA sequencing of unstimulated and stimulated naïve and effector memory CD4 + T cells from young and old mice from two divergent species. In young animals, immunological activation drives a conserved transcriptomic switch, resulting in tightly controlled gene expression characterized by a strong up-regulation of a core activation program, coupled with a decrease in cell-to-cell variability. Aging perturbed the activation of this core program and increased expression heterogeneity across populations of cells in both species. These discoveries suggest that increased cell-to-cell transcriptional variability will be a hallmark feature of aging across most, if not all, mammalian tissues. Copyright © 2017, American Association for the Advancement of Science.

  16. Critical survey on electrode aging in molten carbonate fuel cells

    Energy Technology Data Exchange (ETDEWEB)

    Kinoshita, K.

    1979-12-01

    To evaluate potential electrodes for molten carbonate fuel cells, we reviewed the literature pertaining to these cells and interviewed investigators working in fuel cell technology. In this critical survey, the effect of three electrode aging processes - corrosion or oxidation, sintering, and poisoning - on these potential fuel-cell electrodes is presented. It is concluded that anodes of stabilized nickel and cathodes of lithium-doped NiO are the most promising electrode materials for molten carbonate fuel cells, but that further research and development of these electrodes are needed. In particular, the effect of contaminants such as H/sub 2/S and HCl on the nickel anode must be investigated, and methods to improve the physical strength and to increase the conductivity of NiO cathodes must be explored. Recommendations are given on areas of applied electrode research that should accelerate the commercialization of the molten carbonate fuel cell. 153 references.

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

    Science.gov (United States)

    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.

  18. Intrinsically photosensitive retinal ganglion cell function in relation to age

    DEFF Research Database (Denmark)

    Herbst, Kristina; Sander, Birgit; Lund-Andersen, Henrik

    2012-01-01

    The activity of melanopsin containing intrinsically photosensitive ganglion retinal cells (ipRGC) can be assessed by a means of pupil responses to bright blue (appr.480 nm) light. Due to age related factors in the eye, particularly, structural changes of the lens, less light reaches retina. The aim...... of this study was to examine how age and in vivo measured lens transmission of blue light might affect pupil light responses, in particular, mediated by the ipRGC....

  19. 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.)

  20. Transplantation of retinal pigment epithelial cells - a possible future treatment for age-related macular degeneration

    DEFF Research Database (Denmark)

    Wiencke, Anne Katrine

    2001-01-01

    ophthalmology, age-related macular degeneration, transplantation, retinal pigment epithelial cells, treatment......ophthalmology, age-related macular degeneration, transplantation, retinal pigment epithelial cells, treatment...

  1. Transplantation of retinal pigment epithelial cells - a possible future treatment for age-related macular degeneration

    DEFF Research Database (Denmark)

    Wiencke, Anne Katrine

    2001-01-01

    ophthalmology, age-related macular degeneration, retinal pigment epithelial cells, transplantation, treatment......ophthalmology, age-related macular degeneration, retinal pigment epithelial cells, transplantation, treatment...

  2. 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.

  3. High Plasticity of New Granule Cells in the Aging Hippocampus

    Directory of Open Access Journals (Sweden)

    Mariela F. Trinchero

    2017-10-01

    Full Text Available Summary: During aging, the brain undergoes changes that impair cognitive capacity and circuit plasticity, including a marked decrease in production of adult-born hippocampal neurons. It is unclear whether development and integration of those new neurons are also affected by age. Here, we show that adult-born granule cells (GCs in aging mice are scarce and exhibit slow development, but they display a remarkable potential for structural plasticity. Retrovirally labeled 3-week-old GCs in middle-aged mice were small, underdeveloped, and disconnected. Neuronal development and integration were accelerated by voluntary exercise or environmental enrichment. Similar effects were observed via knockdown of Lrig1, an endogenous negative modulator of neurotrophin receptors. Consistently, blocking neurotrophin signaling by Lrig1 overexpression abolished the positive effects of exercise. These results demonstrate an unparalleled degree of plasticity in the aging brain mediated by neurotrophins, whereby new GCs remain immature until becoming rapidly recruited to the network by activity. : Trinchero et al. show that development of new granule cells born in the adult hippocampus is strongly influenced by age. In the aging hippocampus, new neurons remain immature for prolonged intervals, yet voluntary exercise triggers their rapid growth and functional synaptogenesis. This extensive structural remodeling is mediated by neurotrophins. Keywords: adult neurogenesis, dentate gyrus, functional integration, neurotrophins, synaptogenesis, exercise

  4. 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

  5. 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.

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

    Science.gov (United States)

    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.

  7. Aging: a portrait from gene expression profile in blood cells.

    Science.gov (United States)

    Calabria, Elisa; Mazza, Emilia Maria Cristina; Dyar, Kenneth Allen; Pogliaghi, Silvia; Bruseghini, Paolo; Morandi, Carlo; Salvagno, Gian Luca; Gelati, Matteo; Guidi, Gian Cesare; Bicciato, Silvio; Schiaffino, Stefano; Schena, Federico; Capelli, Carlo

    2016-08-01

    The availability of reliable biomarkers of aging is important not only to monitor the effect of interventions and predict the timing of pathologies associated with aging but also to understand the mechanisms and devise appropriate countermeasures. Blood cells provide an easily available tissue and gene expression profiles from whole blood samples appear to mirror disease states and some aspects of the aging process itself. We report here a microarray analysis of whole blood samples from two cohorts of healthy adult and elderly subjects, aged 43±3 and 68±4 years, respectively, to monitor gene expression changes in the initial phase of the senescence process. A number of significant changes were found in the elderly compared to the adult group, including decreased levels of transcripts coding for components of the mitochondrial respiratory chain, which correlate with a parallel decline in the maximum rate of oxygen consumption (VO2max), as monitored in the same subjects. In addition, blood cells show age-related changes in the expression of several markers of immunosenescence, inflammation and oxidative stress. These findings support the notion that the immune system has a major role in tissue homeostasis and repair, which appears to be impaired since early stages of the aging process.

  8. 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.

  9. Microglial cell dysregulation in Brain Aging and Neurodegeneration.

    Directory of Open Access Journals (Sweden)

    Rommy eVon Bernhardi

    2015-07-01

    Full Text Available Aging is the main risk factor for neurodegenerative diseases. In aging, microglia undergo phenotypic changes compatible with their activation. Glial activation can lead to neuroinflammation, which is increasingly accepted as part of the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD. We hypothesize that in aging, aberrant microglia activation leads to a deleterious environment and neurodegeneration. In aged mice, microglia exhibit an increased expression of cytokines and an exacerbated inflammatory response to pathological changes. Whereas LPS increases nitric oxide secretion in microglia from young mice, induction of reactive oxygen species (ROS predominates in older mice. Furthermore, there is accumulation of DNA oxidative damage in mitochondria of microglia during aging, and also an increased intracellular ROS production. Increased ROS activates the redox-sensitive nuclear factor kappa B, which promotes more neuroinflammation, and can be translated in functional deficits, such as cognitive impairment. Mitochondria-derived ROS and cathepsin B, are also necessary for the microglial cell production of interleukin-1β, a key inflammatory cytokine. Interestingly, whereas the regulatory cytokine TGFβ1 is also increased in the aged brain, neuroinflammation persists. Assessing this apparent contradiction, we have reported that TGFβ1 induction and activation of Smad3 signaling after inflammatory stimulation are reduced in adult mice. Other protective functions, such as phagocytosis, although observed in aged animals, become not inducible by inflammatory stimuli and TGFβ1. Here, we discuss data suggesting that mitochondrial and endolysosomal dysfunction could at least partially mediate age-associated microglial cell changes, and, together with the impairment of the TGFβ1-Smad3 pathway, could result in a reduction of protective activation and a facilitation of cytotoxic activation of microglia, resulting in the

  10. Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging.

    Science.gov (United States)

    Zhang, Weiqi; Li, Jingyi; Suzuki, Keiichiro; Qu, Jing; Wang, Ping; Zhou, Junzhi; Liu, Xiaomeng; Ren, Ruotong; Xu, Xiuling; Ocampo, Alejandro; Yuan, Tingting; Yang, Jiping; Li, Ying; Shi, Liang; Guan, Dee; Pan, Huize; Duan, Shunlei; Ding, Zhichao; Li, Mo; Yi, Fei; Bai, Ruijun; Wang, Yayu; Chen, Chang; Yang, Fuquan; Li, Xiaoyu; Wang, Zimei; Aizawa, Emi; Goebl, April; Soligalla, Rupa Devi; Reddy, Pradeep; Esteban, Concepcion Rodriguez; Tang, Fuchou; Liu, Guang-Hui; Belmonte, Juan Carlos Izpisua

    2015-06-05

    Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1α and nuclear lamina-heterochromatin anchoring protein LAP2β. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging. Copyright © 2015, American Association for the Advancement of Science.

  11. Effect of aging and oral tolerance on dendritic cell function

    Directory of Open Access Journals (Sweden)

    P.U. Simioni

    2010-01-01

    Full Text Available Oral tolerance can be induced in some mouse strains by gavage or spontaneous ingestion of dietary antigens. In the present study, we determined the influence of aging and oral tolerance on the secretion of co-stimulatory molecules by dendritic cells (DC, and on the ability of DC to induce proliferation and cytokine secretion by naive T cells from BALB/c and OVA transgenic (DO11.10 mice. We observed that oral tolerance could be induced in BALB/c mice (N = 5 in each group of all ages (8, 20, 40, 60, and 80 weeks old, although a decline in specific antibody levels was observed in the sera of both tolerized and immunized mice with advancing age (40 to 80 weeks old. DC obtained from young, adult and middle-aged (8, 20, and 40 weeks old tolerized mice were less efficient (65, 17 and 20%, respectively than DC from immunized mice (P < 0.05 in inducing antigen-specific proliferation of naive T cells from both BALB/c and DO11.10 young mice, or in stimulating IFN-g, IL-4 and IL-10 production. However, TGF-β levels were significantly elevated in co-cultures carried out with DC from tolerant mice (P < 0.05. DC from both immunized and tolerized old and very old (60 and 80 weeks old mice were equally ineffective in inducing T cell proliferation and cytokine production (P < 0.05. A marked reduction in CD86+ marker expression was observed in DC isolated from both old and tolerized mice (75 and 50%, respectively. The results indicate that the aging process does not interfere with the establishment of oral tolerance in BALB/c mice, but reduces DC functions, probably due to the decline of the expression of the CD86 surface marker.

  12. Acrylamide induces accelerated endothelial aging in a human cell model.

    Science.gov (United States)

    Sellier, Cyril; Boulanger, Eric; Maladry, François; Tessier, Frédéric J; Lorenzi, Rodrigo; Nevière, Rémi; Desreumaux, Pierre; Beuscart, Jean-Baptiste; Puisieux, François; Grossin, Nicolas

    2015-09-01

    Acrylamide (AAM) has been recently discovered in food as a Maillard reaction product. AAM and glycidamide (GA), its metabolite, have been described as probably carcinogenic to humans. It is widely established that senescence and carcinogenicity are closely related. In vitro, endothelial aging is characterized by replicative senescence in which primary cells in culture lose their ability to divide. Our objective was to assess the effects of AAM and GA on human endothelial cell senescence. Human umbilical vein endothelial cells (HUVECs) cultured in vitro were used as model. HUVECs were cultured over 3 months with AAM or GA (1, 10 or 100 μM) until growth arrest. To analyze senescence, β-galactosidase activity and telomere length of HUVECs were measured by cytometry and semi-quantitative PCR, respectively. At all tested concentrations, AAM or GA reduced cell population doubling compared to the control condition (p < 0.001). β-galactosidase activity in endothelial cells was increased when exposed to AAM (≥10 μM) or GA (≥1 μM) (p < 0.05). AAM (≥10 μM) or GA (100 μM) accelerated telomere shortening in HUVECs (p < 0.05). In conclusion, in vitro chronic exposure to AAM or GA at low concentrations induces accelerated senescence. This result suggests that an exposure to AAM might contribute to endothelial aging. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Systemic Problems: A perspective on stem cell aging and rejuvenation.

    Science.gov (United States)

    Conboy, Irina M; Conboy, Michael J; Rebo, Justin

    2015-10-01

    This review provides balanced analysis of the advances in systemic regulation of young and old tissue stem cells and suggests strategies for accelerating development of therapies to broadly combat age-related tissue degenerative pathologies. Many highlighted recent reports on systemic tissue rejuvenation combine parabiosis with a "silver bullet" putatively responsible for the positive effects. Attempts to unify these papers reflect the excitement about this experimental approach and add value in reproducing previous work. At the same time, defined molecular approaches, which are "beyond parabiosis" for the rejuvenation of multiple old organs represent progress toward attenuating or even reversing human tissue aging.

  14. 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.

  15. Regenerative Potential of Mesenchymal Stromal Cells: Age-Related Changes

    Directory of Open Access Journals (Sweden)

    Flavia Bruna

    2016-01-01

    Full Text Available Preclinical and clinical studies have shown that a therapeutic effect results from mesenchymal stromal cells (MSCs transplant. No systematic information is currently available regarding whether donor age modifies MSC regenerative potential on cutaneous wound healing. Here, we evaluate whether donor age influences this potential. Two different doses of bone marrow MSCs (BM-MSCs from young, adult, or old mouse donors or two doses of their acellular derivatives mesenchymal stromal cells (acd-MSCs were intradermally injected around wounds in the midline of C57BL/6 mice. Every two days, wound healing was macroscopically assessed (wound closure and microscopically assessed (reepithelialization, dermal-epidermal junction, skin appendage regeneration, granulation tissue, leukocyte infiltration, and density dermal collagen fibers after 12 days from MSC transplant. Significant differences in the wound closure kinetic, quality, and healing of skin regenerated were observed in lesions which received BM-MSCs from different ages or their acd-MSCs compared to lesions which received vehicle. Nevertheless, our data shows that adult’s BM-MSCs or their acd-MSCs were the most efficient for recovery of most parameters analyzed. Our data suggest that MSC efficacy was negatively affected by donor age, where the treatment with adult’s BM-MSCs or their acd-MSCs in cutaneous wound promotes a better tissue repair/regeneration. This is due to their paracrine factors secretion.

  16. Effect of aging and oral tolerance on dendritic cell function.

    Science.gov (United States)

    Simioni, P U; Fernandes, L G R; Gabriel, D L; Tamashiro, W M S C

    2010-01-01

    Oral tolerance can be induced in some mouse strains by gavage or spontaneous ingestion of dietary antigens. In the present study, we determined the influence of aging and oral tolerance on the secretion of co-stimulatory molecules by dendritic cells (DC), and on the ability of DC to induce proliferation and cytokine secretion by naive T cells from BALB/c and OVA transgenic (DO11.10) mice. We observed that oral tolerance could be induced in BALB/c mice (N = 5 in each group) of all ages (8, 20, 40, 60, and 80 weeks old), although a decline in specific antibody levels was observed in the sera of both tolerized and immunized mice with advancing age (40 to 80 weeks old). DC obtained from young, adult and middle-aged (8, 20, and 40 weeks old) tolerized mice were less efficient (65, 17 and 20%, respectively) than DC from immunized mice (P stimulating IFN-g, IL-4 and IL-10 production. However, TGF-beta levels were significantly elevated in co-cultures carried out with DC from tolerant mice (P production (P oral tolerance in BALB/c mice, but reduces DC functions, probably due to the decline of the expression of the CD86 surface marker.

  17. T Follicular Helper Cells and B Cell Dysfunction in Aging and HIV-1 Infection.

    Science.gov (United States)

    Pallikkuth, Suresh; de Armas, Lesley; Rinaldi, Stefano; Pahwa, Savita

    2017-01-01

    T follicular helper (Tfh) cells are a subset of CD4 T cells that provide critical signals to antigen-primed B cells in germinal centers to undergo proliferation, isotype switching, and somatic hypermutation to generate long-lived plasma cells and memory B cells during an immune response. The quantity and quality of Tfh cells therefore must be tightly controlled to prevent immune dysfunction in the form of autoimmunity and, on the other hand, immune deficiency. Both Tfh and B cell perturbations appear during HIV infection resulting in impaired antibody responses to vaccines such as seasonal trivalent influenza vaccine, also seen in biologic aging. Although many of the HIV-associated defects improve with antiretroviral therapy (ART), excess immune activation and antigen-specific B and T cell responses including Tfh function are still impaired in virologically controlled HIV-infected persons on ART. Interestingly, HIV infected individuals experience increased risk of age-associated pathologies. This review will discuss Tfh and B cell dysfunction in HIV infection and highlight the impact of chronic HIV infection and aging on Tfh-B cell interactions.

  18. Ageing combines CD4 T cell lymphopenia in secondary lymphoid organs and T cell accumulation in gut associated lymphoid tissue

    OpenAIRE

    Martinet , Kim ,; Bloquet , Stéphane; Bourgeois , Christine

    2014-01-01

    International audience; BackgroundCD4 T cell lymphopenia is an important T cell defect associated to ageing. Higher susceptibility to infections, cancer, or autoimmune pathologies described in aged individuals is thought to partly rely on T cell lymphopenia. We hypothesize that such diverse effects may reflect anatomical heterogeneity of age related T cell lymphopenia. Indeed, no data are currently available on the impact of ageing on T cell pool recovered from gut associated lymphoid tissue ...

  19. 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.

  20. Increased genome instability is not accompanied by sensitivity to DNA damaging agents in aged yeast cells

    NARCIS (Netherlands)

    Novarina, Daniele; Mavrova, Sara N.; Janssens, Georges E.; Rempel, Irina L.; Veenhoff, Liesbeth M.; Chang, Michael

    The budding yeast Saccharomyces cerevisiae divides asymmetrically, producing a new daughter cell from the original mother cell. While daughter cells are born with a full lifespan, a mother cell ages with each cell division and can only generate on average 25 daughter cells before dying. Aged yeast

  1. The impact of metabolism on aging and cell size in single yeast cells

    NARCIS (Netherlands)

    Huberts, Daphne

    2015-01-01

    The aim of this thesis was to determine how metabolism affects yeast aging in single yeast cells using a novel microfluidic device. We first review how cells are able to sense nutrients in their environment and then describe the use of the microfluidic dissection platform that greatly improves our

  2. Age and radiation sensitivity of rat mammary clonogenic cells

    International Nuclear Information System (INIS)

    Shimada, Yoshiya; Yasukawa-Barnes, J.; Kim, R.Y.; Gould, M.N.; Clifton, K.H.

    1994-01-01

    The relative risk of breast cancer is very high among women who were exposed to ionizing radiation during or before puberty. In the current studies, the surviving fractions of clonogenic mammary cells of groups of virgin rats were estimated after single exposures to 137 Cs γ rays at intervals from 1 to 12 weeks after birth. The radiosensitivity of clonogens from prepubertal rats was high and changed with the onset of puberty at between 4 and 6 weeks of age. By this time, the increase in the size of the clonogenic cell subpopulation was slowing and differentiation of terminal mammary end buds and alveolar structures was occurring. Analysis of the relationship of clonogen survival and radiation dose according to the α/β model showed that the exponential αD term predominated at the second and fourth weeks of age. By the eighth week of age, the βD 2 term had come to predominate and the survival curve had a pronounced initial convex shoulder. Further experiments are required to determine whether there is an association between the high sensitivity of the prepubertal and pubertal mammary clonogens to radiation killing and a high susceptibility to radiogenic initiation of cancer. 24 refs., 4 figs., 1 tab

  3. Apple Can Act as Anti-Aging on Yeast Cells

    Directory of Open Access Journals (Sweden)

    Vanessa Palermo

    2012-01-01

    Full Text Available In recent years, epidemiological and biochemical studies have shown that eating apples is associated with reduction of occurrence of cancer, degenerative, and cardiovascular diseases. This association is often attributed to the presence of antioxidants such as ascorbic acid (vitamin C and polyphenols. The substances that hinder the presence of free radicals are also able to protect cells from aging. In our laboratory we used yeast, a unicellular eukaryotic organism, to determine in vivo efficacy of entire apples and their components, such as flesh, skin and polyphenolic fraction, to influence aging and oxidative stress. Our results indicate that all the apple components increase lifespan, with the best result given by the whole fruit, indicating a cooperative role of all apple components.

  4. Inexhaustible hair-cell regeneration in young and aged zebrafish

    Directory of Open Access Journals (Sweden)

    Filipe Pinto-Teixeira

    2015-07-01

    Full Text Available Animals have evolved two general strategies to counter injury and maintain physiological function. The most prevalent is protection by isolating vital organs into body cavities. However, protection is not optimal for sensory systems because their external components need to be exposed to the environment to fulfill their receptive function. Thus, a common strategy to maintain sensory abilities against persistent environmental insult involves repair and regeneration. However, whether age or frequent injuries affect the regenerative capacity of sensory organs remains unknown. We have found that neuromasts of the zebrafish lateral line regenerate mechanosensory hair cells after recurrent severe injuries and in adulthood. Moreover, neuromasts can reverse transient imbalances of Notch signaling that result in defective organ proportions during repair. Our results reveal inextinguishable hair-cell regeneration in the lateral line, and suggest that the neuromast epithelium is formed by plastic territories that are maintained by continuous intercellular communication.

  5. Hemoglobin redox reactions and red blood cell aging.

    Science.gov (United States)

    Rifkind, Joseph M; Nagababu, Enika

    2013-06-10

    The physiological mechanism(s) for recognition and removal of red blood cells (RBCs) from circulation after 120 days of its lifespan is not fully understood. Many of the processes thought to be associated with the removal of RBCs involve oxidative stress. We have focused on hemoglobin (Hb) redox reactions, which is the major source of RBC oxidative stress. The importance of Hb redox reactions have been shown to originate in large parts from the continuous slow autoxidation of Hb producing superoxide and its dramatic increase under hypoxic conditions. In addition, oxidative stress has been shown to be associated with redox reactions that originate from Hb reactions with nitrite and nitric oxide (NO) and the resultant formation of highly toxic peroxynitrite when NO reacts with superoxide released during Hb autoxidation. The interaction of Hb, particularly under hypoxic conditions with band 3 of the RBC membrane is critical for the generating the RBC membrane changes that trigger the removal of cells from circulation. These changes include exposure of antigenic sites, increased calcium leakage into the RBC, and the resultant leakage of potassium out of the RBC causing cell shrinkage and impaired deformability. The need to understand the oxidative damage to specific membrane proteins that result from redox reactions occurring when Hb is bound to the membrane. Proteomic studies that can pinpoint the specific proteins damaged under different conditions will help elucidate the cellular aging processes that result in cells being removed from circulation.

  6. The nucleolus: a paradigm for cell proliferation and aging

    Directory of Open Access Journals (Sweden)

    Comai L.

    1999-01-01

    Full Text Available The nucleolus is the cellular site of ribosome biosynthesis. At this site, active ribosomal DNA (rDNA genes are rapidly transcribed by RNA polymerase I (pol I molecules. Recent advances in our understanding of the pol I transcription system have indicated that regulation of ribosomal RNA (rRNA synthesis is a critical factor in cell growth. Importantly, the same signaling networks that control cell growth and proliferation and are deregulated in cancer appear to control pol I transcription. Therefore, the study of the biochemical basis for growth regulation of pol I transcription can provide basic information about the nuclear signaling network. Hopefully, this information may facilitate the search for drugs that can inhibit the growth of tumor cells by blocking pol I activation. In addition to its function in ribosome biogenesis, recent studies have revealed the prominent role of the nucleolus in cell senescence. These findings have stimulated a new wave of research on the functional relationship between the nucleolus and aging. The aim of this review is to provide an overview of some current topics in the area of nucleolus biology, and it has been written for a general readership.

  7. Blood cell mitochondrial DNA content and premature ovarian aging.

    Directory of Open Access Journals (Sweden)

    Marco Bonomi

    Full Text Available Primary ovarian insufficiency (POI is a critical fertility defect characterized by an anticipated and silent impairment of the follicular reserve, but its pathogenesis is largely unexplained. The frequent maternal inheritance of POI together with a remarkable dependence of ovarian folliculogenesis upon mitochondrial biogenesis and bioenergetics suggested the possible involvement of a generalized mitochondrial defect. Here, we verified the existence of a significant correlation between blood and ovarian mitochondrial DNA (mtDNA content in a group of women undergoing ovarian hyperstimulation (OH, and then aimed to verify whether mtDNA content was significantly altered in the blood cells of POI women. We recruited 101 women with an impaired ovarian reserve: 59 women with premature ovarian failure (POF and 42 poor responders (PR to OH. A Taqman copy number assay revealed a significant mtDNA depletion (P<0.001 in both POF and PR women in comparison with 43 women of similar age and intact ovarian reserve, or 53 very old women with a previous physiological menopause. No pathogenic variations in the mitochondrial DNA polymerase γ (POLG gene were detected in 57 POF or PR women with low blood mtDNA content. In conclusion, blood cell mtDNA depletion is a frequent finding among women with premature ovarian aging, suggesting that a still undetermined but generalized mitochondrial defect may frequently predispose to POI which could then be considered a form of anticipated aging in which the ovarian defect may represent the first manifestation. The determination of mtDNA content in blood may become an useful tool for the POI risk prediction.

  8. Cell cycle phase of nondividing cells in aging human cell cultures determined by DNA content and chromosomal constitution

    International Nuclear Information System (INIS)

    Yanishevsky, R.M.

    1975-01-01

    Human diploid cell cultures, strain WI-38, have a finite proliferative capacity and have been proposed as a model of biological aging. To identify the cell cycle phase of the nondividing cells, cultures of various ages were exposed to 3 Hdt for 48 hours to label dividing cells, then the cycle phase was identified for individual cells by one of two methods, and finally, the proliferative status of the same cells was scored by autoradiographic evidence of 3 HdT uptake. The methods to identify the cycle phase were: determination of DNA strain content by Feulgen scanning cytophotometry, and determination of chromosome constitution by the technique of premature chromosome condensation (PCC). Preliminary experiments showed the effect of continuous exposure to various levels of 3 HdT on cell growth. High levels of 3 HdT inhibited cell cycle traverse: the cell number and labeling index curves reached a plateau; the cell volume increased; the cells accumulated with 4C DNA contents and it appeared that they blocked in G 2 phase. This pattern is consistent with a radiation effect. (U.S.)

  9. Epigenetic Control of Stem Cell Potential During Homeostasis, Aging, and Disease

    Science.gov (United States)

    Beerman, Isabel; Rossi, Derrick J.

    2015-01-01

    Stem cell decline is an important cellular driver of aging-associated pathophysiology in multiple tissues. Epigenetic regulation is central to establishing and maintaining stem cell function, and emerging evidence indicates that epigenetic dysregulation contributes to the altered potential of stem cells during aging. Unlike terminally differentiated cells, the impact of epigenetic dysregulation in stem cells is propagated beyond self; alterations can be heritably transmitted to differentiated progeny, in addition to being perpetuated and amplified within the stem cell pool through self-renewal divisions. This review focuses on recent studies examining epigenetic regulation of tissue-specific stem cells in homeostasis, aging, and aging-related disease. PMID:26046761

  10. Effects of age, replicative lifespan and growth rate of human nucleus pulposus cells on selecting age range for cell-based biological therapies for degenerative disc diseases.

    Science.gov (United States)

    Lee, J S; Lee, S M; Jeong, S W; Sung, Y G; Lee, J H; Kim, K W

    2016-07-01

    Autologous disc cell implantation, growth factors and gene therapy appear to be promising therapies for disc regeneration. Unfortunately, the replicative lifespan and growth kinetics of human nucleus pulposus (NP) cells related to host age are unclear. We investigated the potential relations among age, replicative lifespan and growth rate of NP cells, and determined the age range that is suitable for cell-based biological therapies for degenerative disc diseases. We used NP tissues classified by decade into five age groups: 30s, 40s, 50s, 60s and 70s. The mean cumulative population doubling level (PDL) and population doubling rate (PDR) of NP cells were assessed by decade. We also investigated correlations between cumulative PDL and age, and between PDR and age. The mean cumulative PDL and PDR decreased significantly in patients in their 60s. The mean cumulative PDL and PDR in the younger groups (30s, 40s and 50s) were significantly higher than those in the older groups (60s and 70s). There also were significant negative correlations between cumulative PDL and age, and between PDR and age. We found that the replicative lifespan and growth rate of human NP cells decreased with age. The replicative potential of NP cells decreased significantly in patients 60 years old and older. Young individuals less than 60 years old may be suitable candidates for NP cell-based biological therapies for treating degenerative disc diseases.

  11. Planarians as a model of aging to study the interaction between stem cells and senescent cells in vivo

    Directory of Open Access Journals (Sweden)

    Patrick M. Perrigue

    2015-12-01

    Full Text Available The depletion of stem cell pools and the accumulation of senescent cells in animal tissues are linked to aging. Planarians are invertebrate flatworms and are unusual in that their stem cells, called neoblasts, are constantly replacing old and dying cells. By eliminating neoblasts in worms via irradiation, the biological principles of aging are exposed in the absence of wound healing and regeneration, making planaria a powerful tool for aging research.

  12. Aging

    International Nuclear Information System (INIS)

    Sasaki, Hideo; Kodama, Kazunori; Yamada, Michiko

    1991-01-01

    The hypothesis that exposure to ionizing radiation accelerates the aging process has been actively investigated at ABCC-RERF since 1958, when longitudinal cohort studies of the Adult Health Study (AHS) and the Life Span Study (LSS) were initiated. In their 1975 overall review of aging studies related to the atomic bomb (A-bomb) survivors, Finch and Beebe concluded that while most studies had shown no correlation between aging and radiation exposure, they had not involved the large numbers of subjects required to provide strong evidence for or against the hypothesis. Extending LSS mortality data up to 1978 did not alter the earlier conclusion that any observed life-shortening was associated primarily with cancer induction rather than with any nonspecific cause. The results of aging studies conducted during the intervening 15 years using data from the same populations are reviewed in the present paper. Using clinical, epidemiological, and laboratory techniques, a broad spectrum of aging parameters have been studied, such as postmortem morphological changes, tests of functional capacity, physical tests and measurements, laboratory tests, tissue changes, and morbidity. With respect to the aging process, the overall results have not been consistent and are generally thought to show no relation to radiation exposure. Although some preliminary results suggest a possible radiation-induced increase in atherosclerotic diseases and acceleration of aging in the T-cell-related immune system, further study is necessary to confirm these findings. In the future, applying the latest gerontological study techniques to data collected from subjects exposed 45 years ago to A-bomb radiation at relatively young ages will present a new body of data relevant to the study of late radiation effects. (author) 103 refs

  13. SHIP1-expressing mesenchymal stem cells regulate hematopoietic stem cell homeostasis and lineage commitment during aging.

    Science.gov (United States)

    Iyer, Sonia; Brooks, Robert; Gumbleton, Matthew; Kerr, William G

    2015-05-01

    Hematopoietic stem cell (HSC) self-renewal and lineage choice are subject to intrinsic control. However, this intrinsic regulation is also impacted by external cues provided by niche cells. There are multiple cellular components that participate in HSC support with the mesenchymal stem cell (MSC) playing a pivotal role. We had previously identified a role for SH2 domain-containing inositol 5'-phosphatase-1 (SHIP1) in HSC niche function through analysis of mice with germline or induced SHIP1 deficiency. In this study, we show that the HSC compartment expands significantly when aged in a niche that contains SHIP1-deficient MSC; however, this expanded HSC compartment exhibits a strong bias toward myeloid differentiation. In addition, we show that SHIP1 prevents chronic G-CSF production by the aging MSC compartment. These findings demonstrate that intracellular signaling by SHIP1 in MSC is critical for the control of HSC output and lineage commitment during aging. These studies increase our understanding of how myeloid bias occurs in aging and thus could have implications for the development of myeloproliferative disease in aging.

  14. Dietary macronutrients and the aging liver sinusoidal endothelial cell.

    Science.gov (United States)

    Cogger, Victoria Carroll; Mohamad, Mashani; Solon-Biet, Samantha Marie; Senior, Alistair M; Warren, Alessandra; O'Reilly, Jennifer Nicole; Tung, Bui Thanh; Svistounov, Dmitri; McMahon, Aisling Clare; Fraser, Robin; Raubenheimer, David; Holmes, Andrew J; Simpson, Stephen James; Le Couteur, David George

    2016-05-01

    Fenestrations are pores within the liver sinusoidal endothelial cells (LSECs) that line the sinusoids of the highly vascularized liver. Fenestrations facilitate the transfer of substrates between blood and hepatocytes. With pseudocapillarization of the hepatic sinusoid in old age, there is a loss of fenestrations. LSECs are uniquely exposed to gut-derived dietary and microbial substrates delivered by the portal circulation to the liver. Here we studied the effect of 25 diets varying in content of macronutrients and energy on LSEC fenestrations using the Geometric Framework method in a large cohort of mice aged 15 mo. Macronutrient distribution rather than total food or energy intake was associated with changes in fenestrations. Porosity and frequency were inversely associated with dietary fat intake, while fenestration diameter was inversely associated with protein or carbohydrate intake. Fenestrations were also linked to diet-induced changes in gut microbiome, with increased fenestrations associated with higher abundance of Firmicutes and reduced abundance of Bacteroidetes Diet-induced changes in levels of several fatty acids (C16:0, C19:0, and C20:4) were also significantly inversely associated with fenestrations, suggesting a link between dietary fat and modulation of lipid rafts in the LSECs. Diet influences fenestrations and these data reflect both the key role of the LSECs in clearing gut-derived molecules from the vascular circulation and the impact these molecules have on LSEC morphology. Copyright © 2016 the American Physiological Society.

  15. Robust nuclear lamina-based cell classification of aging and senescent cells.

    Science.gov (United States)

    Righolt, Christiaan H; van 't Hoff, Merel L R; Vermolen, Bart J; Young, Ian T; Raz, Vered

    2011-12-01

    Changes in the shape of the nuclear lamina are exhibited in senescent cells, as well as in cells expressing mutations in lamina genes. To identify cells with defects in the nuclear lamina we developed an imaging method that quantifies the intensity and curvature of the nuclear lamina. We show that this method accurately describes changes in the nuclear lamina. Spatial changes in nuclear lamina coincide with redistribution of lamin A proteins and local reduction in protein mobility in senescent cell. We suggest that local accumulation of lamin A in the nuclear envelope leads to bending of the structure. A quantitative distinction of the nuclear lamina shape in cell populations was found between fresh and senescent cells, and between primary myoblasts from young and old donors. Moreover, with this method mutations in lamina genes were significantly distinct from cells with wild-type genes. We suggest that this method can be applied to identify abnormal cells during aging, in in vitro propagation, and in lamina disorders.

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

    Directory of Open Access Journals (Sweden)

    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

  17. 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.

  18. Homeostatic migration and distribution of innate immune cells in primary and secondary lymphoid organs with ageing.

    Science.gov (United States)

    Nikolich-Žugich, J; Davies, J S

    2017-03-01

    Ageing of the innate and adaptive immune system, collectively termed immune senescence, is a complex process. One method to understand the components of ageing involves dissociating the effects of ageing on the cells of the immune system, on the microenvironment in lymphoid organs and tissues where immune cells reside and on the circulating factors that interact with both immune cells and their microenvironment. Heterochronic parabiosis, a surgical union of two organisms of disparate ages, is ideal for this type of study, as it has the power to dissociate the age of the cell and the age of the microenvironment into which the cell resides or is migrating. So far, however, it has been used sparingly to study immune ageing. Here we review the limited literature on homeostatic innate immune cell trafficking in ageing in the absence of chronic inflammation. We also review our own recent data on trafficking of innate immune subsets between primary and secondary lymphoid organs in heterochronic parabiosis. We found no systemic bias in retention or acceptance of neutrophils, macrophages, dendritic cells or natural killer cells with ageing in primary and secondary lymphoid organs. We conclude that these four innate immune cell types migrate to and populate lymphoid organs (peripheral lymph nodes, spleen and bone marrow), regardless of their own age and of the age of lymphoid organs. © 2017 British Society for Immunology.

  19. Signaling pathway activation drift during aging: Hutchinson-Gilford Progeria Syndrome fibroblasts are comparable to normal middle-age and old-age cells.

    Science.gov (United States)

    Aliper, Alexander M; Csoka, Antonei Benjamin; Buzdin, Anton; Jetka, Tomasz; Roumiantsev, Sergey; Moskalev, Alexy; Zhavoronkov, Alex

    2015-01-01

    For the past several decades, research in understanding the molecular basis of human aging has progressed significantly with the analysis of premature aging syndromes. Progerin, an altered form of lamin A, has been identified as the cause of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), and may be a contributing causative factor in normal aging. However, the question of whether HGPS actually recapitulates the normal aging process at the cellular and organismal level, or simply mimics the aging phenotype is widely debated. In the present study we analyzed publicly available microarray datasets for fibroblasts undergoing cellular aging in culture, as well as fibroblasts derived from young, middle-age, and old-age individuals, and patients with HGPS. Using GeroScope pathway analysis and drug discovery platform we analyzed the activation states of 65 major cellular signaling pathways. Our analysis reveals that signaling pathway activation states in cells derived from chronologically young patients with HGPS strongly resemble cells taken from normal middle-aged and old individuals. This clearly indicates that HGPS may truly represent accelerated aging, rather than being just a simulacrum. Our data also points to potential pathways that could be targeted to develop drugs and drug combinations for both HGPS and normal aging.

  20. Ageing combines CD4 T cell lymphopenia in secondary lymphoid organs and T cell accumulation in gut associated lymphoid tissue.

    Science.gov (United States)

    Martinet, Kim Zita; Bloquet, Stéphane; Bourgeois, Christine

    2014-01-01

    CD4 T cell lymphopenia is an important T cell defect associated to ageing. Higher susceptibility to infections, cancer, or autoimmune pathologies described in aged individuals is thought to partly rely on T cell lymphopenia. We hypothesize that such diverse effects may reflect anatomical heterogeneity of age related T cell lymphopenia. Indeed, no data are currently available on the impact of ageing on T cell pool recovered from gut associated lymphoid tissue (GALT), a crucial site of CD4 T cell accumulation. Primary, secondary and tertiary lymphoid organs of C57BL/6 animals were analysed at three intervals of ages: 2 to 6 months (young), 10 to 14 months (middle-aged) and 22 to 26 months (old). We confirmed that ageing preferentially impacted CD4 T cell compartment in secondary lymphoid organs. Importantly, a different picture emerged from gut associated mucosal sites: during ageing, CD4 T cell accumulation was progressively developing in colon and small intestine lamina propria and Peyer's patches. Similar trend was also observed in middle-aged SJL/B6 F1 mice. Interestingly, an inverse correlation was detected between CD4 T cell numbers in secondary lymphoid organs and colonic lamina propria of C57BL/6 mice whereas no increase in proliferation rate of GALT CD4 T cells was detected. In contrast to GALT, no CD4 T cell accumulation was detected in lungs and liver in middle-aged animals. Finally, the concomitant accumulation of CD4 T cell in GALT and depletion in secondary lymphoid organs during ageing was detected both in male and female animals. Our data thus demonstrate that T cell lymphopenia in secondary lymphoid organs currently associated to ageing is not sustained in gut or lung mucosa associated lymphoid tissues or non-lymphoid sites such as the liver. The inverse correlation between CD4 T cell numbers in secondary lymphoid organs and colonic lamina propria and the absence of overt proliferation in GALT suggest that marked CD4 T cell decay in secondary

  1. γ/δ T cell subsets in human aging using the classical α/β T cell model.

    Science.gov (United States)

    Vasudev, Anusha; Ying, Crystal Tan Tze; Ayyadhury, Shamini; Puan, Kia Joo; Andiappan, Anand Kumar; Nyunt, Ma Shwe Zin; Shadan, Nurhidaya Binte; Mustafa, Seri; Low, Ivy; Rotzschke, Olaf; Fulop, Tamas; Ng, Tze Pin; Larbi, Anis

    2014-10-01

    Aging is associated with an increased susceptibility to infections and diseases. It has also been associated with reduced functionality and altered distribution of immune cells, especially T cells. Whereas classical α/β T cells, especially CD8(+) T cells, were shown to be highly susceptible to aging, the effects of viral persistent stimulations on the fate of γ/δ T cells are much less documented. Healthy, elderly individuals of Chinese ethnical background were recruited under the aegis of SLAS-II. In this observational study, γ/δ T cell populations were characterized by flow cytometry and compared with the α/β CD4(+) and CD8(+) T cells in elderly and young controls. In our study, we identified a reduced frequency of γ/δ T cells but not α/β T cells with aging. The classical markers of α/β T cell aging, including CD28, CD27, and CD57, did not prove significant for γ/δ T cells. The extreme range of expression of these markers in γ/δ T cells was responsible for the lack of relationship between γ/δ T cell subsets, CD4/CD8 ratio, and anti-CMV titers that was significant for α/β T cells and, especially, CD8(+) T cells. Although markers of aging for γ/δ T cells are not clearly identified, our data collectively suggest that the presence of CD27 γ/δ T cells is associated with markers of α/β T cell aging. © 2014 Society for Leukocyte Biology.

  2. Age-Related Change in Vestibular Ganglion Cell Populations in Individuals With Presbycusis and Normal Hearing.

    Science.gov (United States)

    Gluth, Michael B; Nelson, Erik G

    2017-04-01

    We sought to establish that the decline of vestibular ganglion cell counts uniquely correlates with spiral ganglion cell counts, cochlear hair cell counts, and hearing phenotype in individuals with presbycusis. The relationship between aging in the vestibular system and aging in the cochlea is a topic of ongoing investigation. Histopathologic age-related changes the vestibular system may mirror what is seen in the cochlea, but correlations with hearing phenotype and the impact of presbycusis are not well understood. Vestibular ganglion cells, spiral ganglion cells, and cochlear hair cells were counted in specimens from individuals with presbycusis and normal hearing. These were taken from within a large collection of processed human temporal bones. Correlations between histopathology and hearing phenotype were investigated. Vestibular ganglion cell counts were positively correlated with spiral ganglion cell counts and cochlear hair cell counts and were negatively correlated with hearing phenotype. There was no statistical evidence on linear regression to suggest that the relationship between age and cell populations differed significantly according to whether presbycusis was present or not. Superior vestibular ganglion cells were more negatively correlated with age than inferior ganglion cells. No difference in vestibular ganglion cells was noted based on sex. Vestibular ganglion cell counts progressively deteriorate with age, and this loss correlates closely with changes in the cochlea, as well as hearing phenotype. However, these correlations do not appear to be unique in individuals with presbycusis as compared with those with normal hearing.

  3. Microglial cell dysregulation in brain aging and neurodegeneration

    OpenAIRE

    von Bernhardi, Rommy; Eugen?n-von Bernhardi, Laura; Eugen?n, Jaime

    2015-01-01

    Aging is the main risk factor for neurodegenerative diseases. In aging, microglia undergoes phenotypic changes compatible with their activation. Glial activation can lead to neuroinflammation, which is increasingly accepted as part of the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). We hypothesize that in aging, aberrant microglia activation leads to a deleterious environment and neurodegeneration. In aged mice, microglia exhibit an increased expression of c...

  4. Increased Arf/p53 activity in stem cells, aging and cancer.

    Science.gov (United States)

    Carrasco-Garcia, Estefania; Moreno, Manuel; Moreno-Cugnon, Leire; Matheu, Ander

    2017-04-01

    Arf/p53 pathway protects the cells against DNA damage induced by acute stress. This characteristic is the responsible for its tumor suppressor activity. Moreover, it regulates the chronic type of stress associated with aging. This is the basis of its anti-aging activity. Indeed, increased gene dosage of Arf/p53 displays elongated longevity and delayed aging. At a cellular level, it has been recently shown that increased dosage of Arf/p53 delays age-associated stem cell exhaustion and the subsequent decline in tissue homeostasis and regeneration. However, p53 can also promote aging if constitutively activated. In this context, p53 reduces tissue regeneration, which correlates with premature exhaustion of stem cells. We discuss here the current evidence linking the Arf/p53 pathway to the processes of aging and cancer through stem cell regulation. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  5. Proteomics and aging : studying the influence of aging on endothelial cells and human plasma

    NARCIS (Netherlands)

    Eman, M.R.

    2007-01-01

    In general, human aging is considered one of the most complex and less-well understood process in biology. In this thesis the possibilities of proteomics technology in the field of aging were explored. The complexity of the aging process was supposed to accompanied by relatively subtle proteome

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

    Science.gov (United States)

    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.

  7. Enrichment for Th1 cells in the Mel-14+ CD4+ T cell fraction in aged mice

    NARCIS (Netherlands)

    Dobber, R.; Tielemans, M.; Nagelkerken, L.

    1995-01-01

    CD4+ T cells from young and aged mice were sorted into Mel-14+ cells which are regarded as naive cells and Mel-14- cells which are regarded as memory cells. These subsets were stimulated in short-time cultures with anti-CD3 or anti-CD3/anti-CD28 in order to determine the presence of Th1 and/or Th2

  8. Stem cell metabolism in tissue development and aging

    Science.gov (United States)

    Shyh-Chang, Ng; Daley, George Q.; Cantley, Lewis C.

    2013-01-01

    Recent advances in metabolomics and computational analysis have deepened our appreciation for the role of specific metabolic pathways in dictating cell fate. Once thought to be a mere consequence of the state of a cell, metabolism is now known to play a pivotal role in dictating whether a cell proliferates, differentiates or remains quiescent. Here, we review recent studies of metabolism in stem cells that have revealed a shift in the balance between glycolysis, mitochondrial oxidative phosphorylation and oxidative stress during the maturation of adult stem cells, and during the reprogramming of somatic cells to pluripotency. These insights promise to inform strategies for the directed differentiation of stem cells and to offer the potential for novel metabolic or pharmacological therapies to enhance regeneration and the treatment of degenerative disease. PMID:23715547

  9. Delayed animal aging through the recovery of stem cell senescence by platelet rich plasma.

    Science.gov (United States)

    Liu, Hen-Yu; Huang, Chiung-Fang; Lin, Tzu-Chieh; Tsai, Ching-Yu; Tina Chen, Szu-Yu; Liu, Alice; Chen, Wei-Hong; Wei, Hong-Jian; Wang, Ming-Fu; Williams, David F; Deng, Win-Ping

    2014-12-01

    Aging is related to loss of functional stem cell accompanying loss of tissue and organ regeneration potentials. Previously, we demonstrated that the life span of ovariectomy-senescence accelerated mice (OVX-SAMP8) was significantly prolonged and similar to that of the congenic senescence-resistant strain of mice after platelet rich plasma (PRP)/embryonic fibroblast transplantation. The aim of this study is to investigate the potential of PRP for recovering cellular potential from senescence and then delaying animal aging. We first examined whether stem cells would be senescent in aged mice compared to young mice. Primary adipose derived stem cells (ADSCs) and bone marrow derived stem cells (BMSCs) were harvested from young and aged mice, and found that cell senescence was strongly correlated to animal aging. Subsequently, we demonstrated that PRP could recover cell potential from senescence, such as promote cell growth (cell proliferation and colony formation), increase osteogenesis, decrease adipogenesis, restore cell senescence related markers and resist the oxidative stress in stem cells from aged mice. The results also showed that PRP treatment in aged mice could delay mice aging as indicated by survival, body weight and aging phenotypes (behavior and gross morphology) in term of recovering the cellular potential of their stem cells compared to the results on aged control mice. In conclusion these findings showed that PRP has potential to delay aging through the recovery of stem cell senescence and could be used as an alternative medicine for tissue regeneration and future rejuvenation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Aging impairs transcriptional regulation of vascular endothelial growth factor in human microvascular endothelial cells: implications for angiogenesis and cell survival.

    Science.gov (United States)

    Ahluwalia, A; Jones, M K; Szabo, S; Tarnawski, A S

    2014-04-01

    In some tissues, aging impairs angiogenesis and reduces expression of vascular endothelial growth factor A (VEGF), a fundamental regulator of angiogenesis. We previously examined angiogenesis in aging and young gastric mucosa in vivo and in vitro and showed that an imbalance between expressions of VEGF (pro-angiogenic factor) and endostatin (anti-angiogenic protein) results in an aging-related impairment of angiogenesis in rats. However, the human relevance of these findings, and whether these mechanisms apply to endothelial cells derived from other tissues, is not clear. Since P-STAT3 and P-CREB are transcription factors that, in association with HIF-1α, can activate VEGF gene expression in some cells (e.g., liver cancer cells, vascular smooth muscle cells), we examined the expression of these two proteins in human dermal microvascular endothelial cells (HMVECs) derived from aging and neonatal individuals. We examined and quantified in vitro angiogenesis, expression of VEGF, P-STAT3, P-CREB and importin-α in HMVECs isolated from neonates (neonatal) and a 66 year old subject (aging). We also examined the effects of treatment with exogenous VEGF and endostatin on in vitro angiogenesis in these cells. Endothelial cells isolated from aging individuals had impaired angiogenesis (vs. neonatal endothelial cells) and reduced expression of VEGF mRNA and protein. Aged HMVECs also had reduced importin-α expression, and reduced expression and nuclear translocation of P-STAT3 and P-CREB. Reduced VEGF gene expression in aged HMVECs strongly correlated with the decreased levels of P-STAT3, P-CREB and importin-α in these cells. Our study clearly demonstrates that endothelial cells from aging individuals have impaired angiogenesis and reduced expression of VEGF likely due to impaired nuclear transport of P-STAT3 and P-CREB transcription factors in these cells.

  11. Aging impairs recipient T cell intrinsic and extrinsic factors in response to transplantation.

    Directory of Open Access Journals (Sweden)

    Hua Shen

    Full Text Available As increasing numbers of older people are listed for solid organ transplantation, there is an urgent need to better understand how aging modifies alloimmune responses. Here, we investigated whether aging impairs the ability of donor dendritic cells or recipient immunity to prime alloimmune responses to organ transplantation.Using murine experimental models, we found that aging impaired the host environment to expand and activate antigen specific CD8(+ T cells. Additionally, aging impaired the ability of polyclonal T cells to induce acute allograft rejection. However, the alloimmune priming capability of donor dendritic cells was preserved with aging.Aging impairs recipient responses, both T cell intrinsic and extrinsic, in response to organ transplantation.

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

    Science.gov (United States)

    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.

  13. Aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors.

    Science.gov (United States)

    Henry, Curtis J; Casás-Selves, Matias; Kim, Jihye; Zaberezhnyy, Vadym; Aghili, Leila; Daniel, Ashley E; Jimenez, Linda; Azam, Tania; McNamee, Eoin N; Clambey, Eric T; Klawitter, Jelena; Serkova, Natalie J; Tan, Aik Choon; Dinarello, Charles A; DeGregori, James

    2015-12-01

    The incidence of cancer is higher in the elderly; however, many of the underlying mechanisms for this association remain unexplored. Here, we have shown that B cell progenitors in old mice exhibit marked signaling, gene expression, and metabolic defects. Moreover, B cell progenitors that developed from hematopoietic stem cells (HSCs) transferred from young mice into aged animals exhibited similar fitness defects. We further demonstrated that ectopic expression of the oncogenes BCR-ABL, NRAS(V12), or Myc restored B cell progenitor fitness, leading to selection for oncogenically initiated cells and leukemogenesis specifically in the context of an aged hematopoietic system. Aging was associated with increased inflammation in the BM microenvironment, and induction of inflammation in young mice phenocopied aging-associated B lymphopoiesis. Conversely, a reduction of inflammation in aged mice via transgenic expression of α-1-antitrypsin or IL-37 preserved the function of B cell progenitors and prevented NRAS(V12)-mediated oncogenesis. We conclude that chronic inflammatory microenvironments in old age lead to reductions in the fitness of B cell progenitor populations. This reduced progenitor pool fitness engenders selection for cells harboring oncogenic mutations, in part due to their ability to correct aging-associated functional defects. Thus, modulation of inflammation--a common feature of aging--has the potential to limit aging-associated oncogenesis.

  14. Deficiency in DNA damage response of enterocytes accelerates intestinal stem cell aging in Drosophila.

    Science.gov (United States)

    Park, Joung-Sun; Jeon, Ho-Jun; Pyo, Jung-Hoon; Kim, Young-Shin; Yoo, Mi-Ae

    2018-03-07

    Stem cell dysfunction is closely linked to tissue and organismal aging and age-related diseases, and heavily influenced by the niche cells' environment. The DNA damage response (DDR) is a key pathway for tissue degeneration and organismal aging; however, the precise protective role of DDR in stem cell/niche aging is unclear. The Drosophila midgut is an excellent model to study the biology of stem cell/niche aging because of its easy genetic manipulation and its short lifespan. Here, we showed that deficiency of DDR in Drosophila enterocytes (ECs) accelerates intestinal stem cell (ISC) aging. We generated flies with knockdown of Mre11 , Rad50 , Nbs1 , ATM , ATR , Chk1 , and Chk2 , which decrease the DDR system in ECs. EC-specific DDR depletion induced EC death, accelerated the aging of ISCs, as evidenced by ISC hyperproliferation, DNA damage accumulation, and increased centrosome amplification, and affected the adult fly's survival. Our data indicated a distinct effect of DDR depletion in stem or niche cells on tissue-resident stem cell proliferation. Our findings provide evidence of the essential role of DDR in protecting EC against ISC aging, thus providing a better understanding of the molecular mechanisms of stem cell/niche aging.

  15. Combining magnetic sorting of mother cells and fluctuation tests to analyze genome instability during mitotic cell aging in Saccharomyces cerevisiae.

    Science.gov (United States)

    Patterson, Melissa N; Maxwell, Patrick H

    2014-10-16

    Saccharomyces cerevisiae has been an excellent model system for examining mechanisms and consequences of genome instability. Information gained from this yeast model is relevant to many organisms, including humans, since DNA repair and DNA damage response factors are well conserved across diverse species. However, S. cerevisiae has not yet been used to fully address whether the rate of accumulating mutations changes with increasing replicative (mitotic) age due to technical constraints. For instance, measurements of yeast replicative lifespan through micromanipulation involve very small populations of cells, which prohibit detection of rare mutations. Genetic methods to enrich for mother cells in populations by inducing death of daughter cells have been developed, but population sizes are still limited by the frequency with which random mutations that compromise the selection systems occur. The current protocol takes advantage of magnetic sorting of surface-labeled yeast mother cells to obtain large enough populations of aging mother cells to quantify rare mutations through phenotypic selections. Mutation rates, measured through fluctuation tests, and mutation frequencies are first established for young cells and used to predict the frequency of mutations in mother cells of various replicative ages. Mutation frequencies are then determined for sorted mother cells, and the age of the mother cells is determined using flow cytometry by staining with a fluorescent reagent that detects bud scars formed on their cell surfaces during cell division. Comparison of predicted mutation frequencies based on the number of cell divisions to the frequencies experimentally observed for mother cells of a given replicative age can then identify whether there are age-related changes in the rate of accumulating mutations. Variations of this basic protocol provide the means to investigate the influence of alterations in specific gene functions or specific environmental conditions on

  16. Anti-aging effects of vitamin C on human pluripotent stem cell-derived cardiomyocytes.

    Science.gov (United States)

    Kim, Yoon Young; Ku, Seung-Yup; Huh, Yul; Liu, Hung-Ching; Kim, Seok Hyun; Choi, Young Min; Moon, Shin Yong

    2013-10-01

    Human pluripotent stem cells (hPSCs) have arisen as a source of cells for biomedical research due to their developmental potential. Stem cells possess the promise of providing clinicians with novel treatments for disease as well as allowing researchers to generate human-specific cellular metabolism models. Aging is a natural process of living organisms, yet aging in human heart cells is difficult to study due to the ethical considerations regarding human experimentation as well as a current lack of alternative experimental models. hPSC-derived cardiomyocytes (CMs) bear a resemblance to human cardiac cells and thus hPSC-derived CMs are considered to be a viable alternative model to study human heart cell aging. In this study, we used hPSC-derived CMs as an in vitro aging model. We generated cardiomyocytes from hPSCs and demonstrated the process of aging in both human embryonic stem cell (hESC)- and induced pluripotent stem cell (hiPSC)-derived CMs. Aging in hESC-derived CMs correlated with reduced membrane potential in mitochondria, the accumulation of lipofuscin, a slower beating pattern, and the downregulation of human telomerase RNA (hTR) and cell cycle regulating genes. Interestingly, the expression of hTR in hiPSC-derived CMs was not significantly downregulated, unlike in hESC-derived CMs. In order to delay aging, vitamin C was added to the cultured CMs. When cells were treated with 100 μM of vitamin C for 48 h, anti-aging effects, specifically on the expression of telomere-related genes and their functionality in aging cells, were observed. Taken together, these results suggest that hPSC-derived CMs can be used as a unique human cardiomyocyte aging model in vitro and that vitamin C shows anti-aging effects in this model.

  17. A systematic review on the role of environmental toxicants in stem cells aging.

    Science.gov (United States)

    Hodjat, Mahshid; Rezvanfar, Mohammad Amin; Abdollahi, Mohammad

    2015-12-01

    Stem cells are an important target for environmental toxicants. As they are the main source for replenishing of organs in the body, any changes in their normal function could affect the regenerative potential of organs, leading to the appearance of age-related disease and acceleration of the aging process. Environmental toxicants could exert their adverse effect on stem cell function via multiple cellular and molecular mechanisms, resulting in changes in the stem cell differentiation fate and cell transformation, and reduced self-renewal capacity, as well as induction of stress-induced cellular senescence. The present review focuses on the effect of environmental toxicants on stem cell function associated with the aging process. We categorized environmental toxicants according to their preferred molecular mechanism of action on stem cells, including changes in genomic, epigenomic, and proteomic levels and enhancing oxidative stress. Pesticides, tobacco smoke, radiation and heavy metals are well-studied toxicants that cause stem cell dysfunction via induction of oxidative stress. Transgenerational epigenetic changes are the most important effects of a variety of toxicants on germ cells and embryos that are heritable and could affect health in the next several generations. A better understanding of the underlying mechanisms of toxicant-induced stem cell aging will help us to develop therapeutic intervention strategies against environmental aging. Meanwhile, more efforts are required to find the direct in vivo relationship between adverse effect of environmental toxicants and stem cell aging, leading to organismal aging. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Aged induced pluripotent stem cell (iPSCs) as a new cellular model for studying premature aging.

    Science.gov (United States)

    Petrini, Stefania; Borghi, Rossella; D'Oria, Valentina; Restaldi, Fabrizia; Moreno, Sandra; Novelli, Antonio; Bertini, Enrico; Compagnucci, Claudia

    2017-05-31

    Nuclear integrity and mechanical stability of the nuclear envelope (NE) are conferred by the nuclear lamina, a meshwork of intermediate filaments composed of A- and B-type lamins, supporting the inner nuclear membrane and playing a pivotal role in chromatin organization and epigenetic regulation. During cell senescence, nuclear alterations also involving NE architecture are widely described. In the present study, we utilized induced pluripotent stem cells (iPSCs) upon prolonged in vitro culture as a model to study aging and investigated the organization and expression pattern of NE major constituents. Confocal and four-dimensional imaging combined with molecular analyses, showed that aged iPSCs are characterized by nuclear dysmorphisms, nucleoskeletal components (lamin A/C-prelamin isoforms, lamin B1, emerin, and nesprin-2) imbalance, leading to impaired nucleo-cytoplasmic MKL1 shuttling, actin polymerization defects, mitochondrial dysfunctions, SIRT7 downregulation and NF-kBp65 hyperactivation. The observed age-related NE features of iPSCs closely resemble those reported for premature aging syndromes (e.g., Hutchinson-Gilford progeria syndrome) and for somatic cell senescence. These findings validate the use of aged iPSCs as a suitable cellular model to study senescence and for investigating therapeutic strategies aimed to treat premature aging.

  19. Increased centrosome amplification in aged stem cells of the Drosophila midgut

    International Nuclear Information System (INIS)

    Park, Joung-Sun; Pyo, Jung-Hoon; Na, Hyun-Jin; Jeon, Ho-Jun; Kim, Young-Shin; Arking, Robert; Yoo, Mi-Ae

    2014-01-01

    Highlights: • Increased centrosome amplification in ISCs of aged Drosophila midguts. • Increased centrosome amplification in ISCs of oxidative stressed Drosophila midguts. • Increased centrosome amplification in ISCs by overexpression of PVR, EGFR, and AKT. • Supernumerary centrosomes can be responsible for abnormal ISC polyploid cells. • Supernumerary centrosomes can be a useful marker for aging stem cells. - Abstract: Age-related changes in long-lived tissue-resident stem cells may be tightly linked to aging and age-related diseases such as cancer. Centrosomes play key roles in cell proliferation, differentiation and migration. Supernumerary centrosomes are known to be an early event in tumorigenesis and senescence. However, the age-related changes of centrosome duplication in tissue-resident stem cells in vivo remain unknown. Here, using anti-γ-tubulin and anti-PH3, we analyzed mitotic intestinal stem cells with supernumerary centrosomes in the adult Drosophila midgut, which may be a versatile model system for stem cell biology. The results showed increased centrosome amplification in intestinal stem cells of aged and oxidatively stressed Drosophila midguts. Increased centrosome amplification was detected by overexpression of PVR, EGFR, and AKT in intestinal stem cells/enteroblasts, known to mimic age-related changes including hyperproliferation of intestinal stem cells and hyperplasia in the midgut. Our data show the first direct evidence for the age-related increase of centrosome amplification in intestinal stem cells and suggest that the Drosophila midgut is an excellent model for studying molecular mechanisms underlying centrosome amplification in aging adult stem cells in vivo

  20. Increased centrosome amplification in aged stem cells of the Drosophila midgut

    Energy Technology Data Exchange (ETDEWEB)

    Park, Joung-Sun; Pyo, Jung-Hoon; Na, Hyun-Jin; Jeon, Ho-Jun; Kim, Young-Shin [Department of Molecular Biology, Pusan National University, Busan 609-735 (Korea, Republic of); Arking, Robert, E-mail: aa2210@wayne.edu [Department of Biological Sciences, Wayne State University, Detroit, MI 48202 (United States); Yoo, Mi-Ae, E-mail: mayoo@pusan.ac.kr [Department of Molecular Biology, Pusan National University, Busan 609-735 (Korea, Republic of)

    2014-07-25

    Highlights: • Increased centrosome amplification in ISCs of aged Drosophila midguts. • Increased centrosome amplification in ISCs of oxidative stressed Drosophila midguts. • Increased centrosome amplification in ISCs by overexpression of PVR, EGFR, and AKT. • Supernumerary centrosomes can be responsible for abnormal ISC polyploid cells. • Supernumerary centrosomes can be a useful marker for aging stem cells. - Abstract: Age-related changes in long-lived tissue-resident stem cells may be tightly linked to aging and age-related diseases such as cancer. Centrosomes play key roles in cell proliferation, differentiation and migration. Supernumerary centrosomes are known to be an early event in tumorigenesis and senescence. However, the age-related changes of centrosome duplication in tissue-resident stem cells in vivo remain unknown. Here, using anti-γ-tubulin and anti-PH3, we analyzed mitotic intestinal stem cells with supernumerary centrosomes in the adult Drosophila midgut, which may be a versatile model system for stem cell biology. The results showed increased centrosome amplification in intestinal stem cells of aged and oxidatively stressed Drosophila midguts. Increased centrosome amplification was detected by overexpression of PVR, EGFR, and AKT in intestinal stem cells/enteroblasts, known to mimic age-related changes including hyperproliferation of intestinal stem cells and hyperplasia in the midgut. Our data show the first direct evidence for the age-related increase of centrosome amplification in intestinal stem cells and suggest that the Drosophila midgut is an excellent model for studying molecular mechanisms underlying centrosome amplification in aging adult stem cells in vivo.

  1. Preferential retrotransposition in aging yeast mother cells is correlated with increased genome instability.

    Science.gov (United States)

    Patterson, Melissa N; Scannapieco, Alison E; Au, Pak Ho; Dorsey, Savanna; Royer, Catherine A; Maxwell, Patrick H

    2015-10-01

    Retrotransposon expression or mobility is increased with age in multiple species and could promote genome instability or altered gene expression during aging. However, it is unclear whether activation of retrotransposons during aging is an indirect result of global changes in chromatin and gene regulation or a result of retrotransposon-specific mechanisms. Retromobility of a marked chromosomal Ty1 retrotransposon in Saccharomyces cerevisiae was elevated in mother cells relative to their daughter cells, as determined by magnetic cell sorting of mothers and daughters. Retromobility frequencies in aging mother cells were significantly higher than those predicted by cell age and the rate of mobility in young populations, beginning when mother cells were only several generations old. New Ty1 insertions in aging mothers were more strongly correlated with gross chromosome rearrangements than in young cells and were more often at non-preferred target sites. Mother cells were more likely to have high concentrations and bright foci of Ty1 Gag-GFP than their daughter cells. Levels of extrachromosomal Ty1 cDNA were also significantly higher in aged mother cell populations than their daughter cell populations. These observations are consistent with a retrotransposon-specific mechanism that causes retrotransposition to occur preferentially in yeast mother cells as they begin to age, as opposed to activation by phenotypic changes associated with very old age. These findings will likely be relevant for understanding retrotransposons and aging in many organisms, based on similarities in regulation and consequences of retrotransposition in diverse species. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Adipose-derived mesenchymal stromal cells from aged patients with coronary artery disease keep mesenchymal stromal cell properties but exhibit characteristics of aging and have impaired angiogenic potential.

    Science.gov (United States)

    Efimenko, Anastasia; Dzhoyashvili, Nina; Kalinina, Natalia; Kochegura, Tatiana; Akchurin, Renat; Tkachuk, Vsevolod; Parfyonova, Yelena

    2014-01-01

    Tissue regeneration is impaired in aged individuals. Adipose-derived mesenchymal stromal cells (ADSCs), a promising source for cell therapy, were shown to secrete various angiogenic factors and improve vascularization of ischemic tissues. We analyzed how patient age affected the angiogenic properties of ADSCs. ADSCs were isolated from subcutaneous fat tissue of patients with coronary artery disease (CAD; n = 64, 43-77 years old) and without CAD (n = 31, 2-82 years old). ADSC phenotype characterized by flow cytometry was CD90(+)/CD73(+)/CD105(+)/CD45(-)/CD31(-) for all samples, and these cells were capable of adipogenic and osteogenic differentiation. ADSCs from aged patients had shorter telomeres (quantitative reverse transcription polymerase chain reaction) and a tendency to attenuated telomerase activity. ADSC-conditioned media (ADSC-CM) stimulated capillary-like tube formation by endothelial cells (EA.hy926), and this effect significantly decreased with the age of patients both with and without CAD. Angiogenic factors (vascular endothelial growth factor, placental growth factor, hepatocyte growth factor, angiopoetin-1, and angiogenin) in ADSC-CM measured by enzyme-linked immunosorbent assay significantly decreased with patient age, whereas levels of antiangiogenic factors thrombospondin-1 and endostatin did not. Expression of angiogenic factors in ADSCs did not change with patient age (real-time polymerase chain reaction); however, gene expression of factors related to extracellular proteolysis (urokinase and its receptor, plasminogen activator inhibitor-1) and urokinase-type plasminogen activator receptor surface expression increased in ADSCs from aged patients with CAD. ADSCs from aged patients both with and without CAD acquire aging characteristics, and their angiogenic potential declines because of decreasing proangiogenic factor secretion. This could restrict the effectiveness of autologous cell therapy with ADSCs in aged patients.

  3. The emerging age of cell-free synthetic biology.

    Science.gov (United States)

    Smith, Mark Thomas; Wilding, Kristen M; Hunt, Jeremy M; Bennett, Anthony M; Bundy, Bradley C

    2014-08-25

    The engineering of and mastery over biological parts has catalyzed the emergence of synthetic biology. This field has grown exponentially in the past decade. As increasingly more applications of synthetic biology are pursued, more challenges are encountered, such as delivering genetic material into cells and optimizing genetic circuits in vivo. An in vitro or cell-free approach to synthetic biology simplifies and avoids many of the pitfalls of in vivo synthetic biology. In this review, we describe some of the innate features that make cell-free systems compelling platforms for synthetic biology and discuss emerging improvements of cell-free technologies. We also select and highlight recent and emerging applications of cell-free synthetic biology. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  4. Aging impairs long-term hematopoietic regeneration after autologous stem cell transplantation

    NARCIS (Netherlands)

    Woolthuis, Carolien M; Mariani, Niccoló; Verkaik-Schakel, Rikst Nynke; Brouwers-Vos, Annet Z.; Schuringa, Jan Jacob; Vellenga, Edo; de Wolf, Joost T M; Huls, Gerwin

    Most of our knowledge of the effects of aging on the hematopoietic system comes from studies in animal models. In this study, to explore potential effects of aging on human hematopoietic stem and progenitor cells (HSPCs), we evaluated CD34(+) cells derived from young (<35 years) and old (>60 years)

  5. Impaired hematopoietic stem cell functioning after serial transplantation and during normal aging

    NARCIS (Netherlands)

    Kamminga, LM; Van Os, R; Ausema, A; Noach, EJK; Weersing, E; Dontje, B; Vellenga, E; De Haan, G

    Adult somatic stem cells possess extensive self-renewal capacity, as their primary role is to replenish aged and functionally impaired tissues. We have previously shown that the stem cell pool in short-lived DBA/2 (D2) mice is reduced during aging, in contrast to long-lived C57BL/6 (136) mice. This

  6. 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.

  7. Numeric and volumetric changes in Leydig cells during aging of rats.

    Science.gov (United States)

    Neves, Bruno Vinicius Duarte; Lorenzini, Fernando; Veronez, Djanira; Miranda, Eduardo Pereira de; Neves, Gabriela Duarte; Fraga, Rogério de

    2017-10-01

    To analyze the effects of aging in rats on the nuclear volume, cytoplasmic volume, and total volume of Leydig cells, as well as their number. Seventy-two Wistar rats were divided into six subgroups of 12 rats, which underwent right orchiectomy at 3, 6, 9, 12, 18, and 24 months of age. The weight and volume of the resected testicles were assessed. A stereological study of Leydig cells was conducted, which included measurements of cell number and nuclear, cytoplasmic, and total cell volumes. The weight and volume of the resected testicles showed reductions with age. Only the subgroup composed of 24-month old rats showed a decrease in the nuclear volume of Leydig cells. Significant reductions in the cytoplasmic volume and total volume of Leydig cells were observed in 18- and 24-month old rats. The number of Leydig cells did not vary significantly with age. Aging in rats resulted in reduction of the nuclear, cytoplasmic, and total cell volumes of Leydig cells. There was no change in the total number of these cells during aging.

  8. Clonal reversal of ageing-associated stem cell lineage bias via a pluripotent intermediate

    DEFF Research Database (Denmark)

    Wahlestedt, Martin; Erlandsson, Eva; Kristiansen, Trine

    2017-01-01

    Ageing associates with significant alterations in somatic/adult stem cells and therapies to counteract these might have profound benefits for health. In the blood, haematopoietic stem cell (HSC) ageing is linked to several functional shortcomings. However, besides the recent realization...... with the generation of induced pluripotent stem (iPS) cells. This allows us to specifically focus on aged HSCs presenting with a pronounced lineage skewing, a hallmark of HSC ageing. Functional and molecular evaluations reveal haematopoiesis from these iPS clones to be indistinguishable from that associating...

  9. Aging-Induced Stem Cell Mutations as Drivers for Disease and Cancer

    Science.gov (United States)

    Adams, Peter D.; Jasper, Heinrich; Rudolph, K. Lenhard

    2015-01-01

    Aging is characterized by a decrease in genome integrity, impaired organ maintenance, and an increased risk of cancer, which coincide with clonal dominance of expanded mutant stem and progenitor cell populations in aging tissues, such as the intestinal epithelium, the hematopoietic system, and the male germline. Here we discuss possible explanations for age-associated increases in the initiation and/or progression of mutant stem/progenitor clones and highlight the roles of stem cell quiescence, replication-associated DNA damage, telomere shortening, epigenetic alterations, and metabolic challenges as determinants of stem cell mutations and clonal dominance in aging. PMID:26046760

  10. Intrinsic and extrinsic contributors to defective CD8+ T cell responses with aging.

    Science.gov (United States)

    Jergović, Mladen; Smithey, Megan J; Nikolich-Žugich, Janko

    2018-05-01

    Aging has a profound effect on the immune system, and both innate and adaptive arms of the immune system show functional decline with age. In response to infection with intracellular microorganisms, old animals mobilize decreased numbers of antigen-specific CD8+ T cells with reduced production of effector molecules and impaired cytolytic activity. However, the CD8+ T cell-intrinsic contribution to, and molecular mechanisms behind, these defects remain unclear. In this review we will discuss the mechanistic contributions of age related changes in the CD8+ T cell pool and the relative roles of intrinsic functional defects in aged CD8+ T cells vs. defects in the aged environment initiating the CD8+ T cell response. Copyright © 2018 Elsevier Inc. All rights reserved.

  11. Epigenetic mechanisms of peptidergic regulation of gene expression during aging of human cells.

    Science.gov (United States)

    Ashapkin, V V; Linkova, N S; Khavinson, V Kh; Vanyushin, B F

    2015-03-01

    Expression levels of genes encoding specific transcription factors and other functionally important proteins vary upon aging of pancreatic and bronchial epithelium cell cultures. The peptides KEDW and AEDL tissue-specifically affect gene expression in pancreatic and bronchial cell cultures, respectively. It is established in this work that the DNA methylation patterns of the PDX1, PAX6, NGN3, NKX2-1, and SCGB1A1 gene promoter regions change upon aging in pancreatic and bronchial cell cultures in correlation with variations in their expression levels. Thus, stable changes in gene expression upon aging of cell cultures could be caused by changes in their promoter methylation patterns. The methylation patterns of the PAX4 gene in pancreatic cells as well as those of the FOXA1, SCGB3A2, and SFTPA1 genes in bronchial cells do not change upon aging and are unaffected by peptides, whereas their expression levels change in both cases. The promoter region of the FOXA2 gene in pancreatic cells contains a small number of methylated CpG sites, their methylation levels being affected by cell culture aging and KEDW, though without any correlation with gene expression levels. The promoter region of the FOXA2 gene is completely unmethylated in bronchial cells irrespective of cell culture age and AEDL action. Changes in promoter methylation might be the cause of age- and peptide-induced variations in expression levels of the PDX1, PAX6, and NGN3 genes in pancreatic cells and NKX2-1 and SCGB1A1 genes in bronchial cells. Expression levels of the PAX4 and FOXA2 genes in pancreatic cells and FOXA1, FOXA2, SCGB3A2, and SFTPA1 genes in bronchial cells seem to be controlled by some other mechanisms.

  12. Stem Cell-Specific Mechanisms Ensure Genomic Fidelity within HSCs and upon Aging of HSCs

    Directory of Open Access Journals (Sweden)

    Bettina M. Moehrle

    2015-12-01

    Full Text Available Whether aged hematopoietic stem and progenitor cells (HSPCs have impaired DNA damage repair is controversial. Using a combination of DNA mutation indicator assays, we observe a 2- to 3-fold increase in the number of DNA mutations in the hematopoietic system upon aging. Young and aged hematopoietic stem cells (HSCs and hematopoietic progenitor cells (HPCs do not show an increase in mutation upon irradiation-induced DNA damage repair, and young and aged HSPCs respond very similarly to DNA damage with respect to cell-cycle checkpoint activation and apoptosis. Both young and aged HSPCs show impaired activation of the DNA-damage-induced G1-S checkpoint. Induction of chronic DNA double-strand breaks by zinc-finger nucleases suggests that HSPCs undergo apoptosis rather than faulty repair. These data reveal a protective mechanism in both the young and aged hematopoietic system against accumulation of mutations in response to DNA damage.

  13. 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

  14. Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells

    DEFF Research Database (Denmark)

    Dokkedahl, Karin Stenderup; Justesen, Jeannette; Clausen, Christian

    2003-01-01

    Age-related decrease in bone formation is well described. However, the cellular causes are not known. Thus, we have established cultures of bone marrow stromal cells (MSC) from young (aged 18-29 years, n = 6) and old (aged 68-81 years, n = 5) donors. MSC were serially passaged until reaching maxi...

  15. Progressive alterations in multipotent hematopoietic progenitors underlie lymphoid cell loss in aging.

    Science.gov (United States)

    Young, Kira; Borikar, Sneha; Bell, Rebecca; Kuffler, Lauren; Philip, Vivek; Trowbridge, Jennifer J

    2016-10-17

    Declining immune function with age is associated with reduced lymphoid output of hematopoietic stem cells (HSCs). Currently, there is poor understanding of changes with age in the heterogeneous multipotent progenitor (MPP) cell compartment, which is long lived and responsible for dynamically regulating output of mature hematopoietic cells. In this study, we observe an early and progressive loss of lymphoid-primed MPP cells (LMPP/MPP4) with aging, concomitant with expansion of HSCs. Transcriptome and in vitro functional analyses at the single-cell level reveal a concurrent increase in cycling of aging LMPP/MPP4 with loss of lymphoid priming and differentiation potential. Impaired lymphoid differentiation potential of aged LMPP/MPP4 is not rescued by transplantation into a young bone marrow microenvironment, demonstrating cell-autonomous changes in the MPP compartment with aging. These results pinpoint an age and cellular compartment to focus further interrogation of the drivers of lymphoid cell loss with aging. © 2016 Young et al.

  16. From Hayflick to Walford: the role of T cell replicative senescence in human aging.

    Science.gov (United States)

    Effros, Rita B

    2004-06-01

    The immunologic theory of aging, proposed more than 40 years ago by Roy Walford, suggests that the normal process of aging in man and in animals is pathogenetically related to faulty immunological processes. Since that time, research on immunological aging has undergone extraordinary expansion, leading to new information in areas spanning from molecular biology and cell signaling to large-scale clinical studies. Investigation in this area has also provided unexpected insights into HIV disease, many aspects of which represent accelerated immunological aging. This article describes the initial insights and vision of Roy Walford into one particular facet of human immunological aging, namely, the potential relevance of the well-studied human fibroblast replicative senescence model, initially developed by Leonard Hayflick, to cells of the immune system. Extensive research on T cell senescence in cell culture has now documented changes in vitro that closely mirror alterations occurring during in vivo aging in humans, underscoring the biological significance of T cell replicative senescence. Moreover, the inclusion of high proportions of putatively senescent T cells in the 'immune risk phenotype' that is associated with early mortality in octogenarians provides initial clinical confirmation of both the immunologic theory of aging and the role of the T cell Hayflick Limit in human aging, two areas of gerontological research pioneered by Roy Walford.

  17. Long live the liver: immunohistochemical and stereological study of hepatocytes, liver sinusoidal endothelial cells, Kupffer cells and hepatic stellate cells of male and female rats throughout ageing.

    Science.gov (United States)

    Marcos, Ricardo; Correia-Gomes, Carla

    2016-12-01

    Male/female differences in enzyme activity and gene expression in the liver are known to be attenuated with ageing. Nevertheless, the effect of ageing on liver structure and quantitative cell morphology remains unknown. Male and female Wistar rats aged 2, 6, 12 and 18 months were examined by means of stereological techniques and immunohistochemical tagging of hepatocytes (HEP), liver sinusoidal endothelial cells (LSEC), Kupffer cells (KC) and hepatic stellate cells (HSC) in order to assess the total number and number per gram of these cells throughout life. The mean cell volume of HEP and HSC, the lobular position and the collagen content of the liver were also evaluated with stereological techniques. The number per gram of HSC was similar for both genders and was maintained throughout ageing. The mean volume of HSC was also conserved but differences in the cell body and lobular location were observed. Statistically significant gender differences in HEP were noted in young rats (females had smaller and more binucleated HEP) but were attenuated with ageing. The same occurred for KC and LSEC, since the higher number per gram in young females disappeared in older animals. Liver collagen increased with ageing but only in males. Thus, the numbers of these four cell types are related throughout ageing, with well-defined cell ratios. The shape and lobular position of HSC change with ageing in both males and females. Gender dimorphism in HEP, KC and LSEC of young rat liver disappears with ageing.

  18. Aging of bone marrow mesenchymal stromal/stem cells: Implications on autologous regenerative medicine.

    Science.gov (United States)

    Charif, N; Li, Y Y; Targa, L; Zhang, L; Ye, J S; Li, Y P; Stoltz, J F; Han, H Z; de Isla, N

    2017-01-01

    With their proliferation, differentiation into specific cell types, and secretion properties, mesenchymal stromal/stem cells (MSC) are very interesting tools to be used in regenerative medicine. Bone marrow (BM) was the first MSC source characterized. In the frame of autologous MSC therapy, it is important to detect donor's parameters affecting MSC potency. Age of the donors appears as one parameter that could greatly affect MSC properties. Moreover, in vitro cell expansion is needed to obtain the number of cells necessary for clinical developments. It will lead to in vitro cell aging that could modify cell properties. This review recapitulates several studies evaluating the effect of in vitro and in vivo MSC aging on cell properties.

  19. Hypothalamic stem cells control ageing speed partly through exosomal miRNAs.

    Science.gov (United States)

    Zhang, Yalin; Kim, Min Soo; Jia, Baosen; Yan, Jingqi; Zuniga-Hertz, Juan Pablo; Han, Cheng; Cai, Dongsheng

    2017-08-03

    It has been proposed that the hypothalamus helps to control ageing, but the mechanisms responsible remain unclear. Here we develop several mouse models in which hypothalamic stem/progenitor cells that co-express Sox2 and Bmi1 are ablated, as we observed that ageing in mice started with a substantial loss of these hypothalamic cells. Each mouse model consistently displayed acceleration of ageing-like physiological changes or a shortened lifespan. Conversely, ageing retardation and lifespan extension were achieved in mid-aged mice that were locally implanted with healthy hypothalamic stem/progenitor cells that had been genetically engineered to survive in the ageing-related hypothalamic inflammatory microenvironment. Mechanistically, hypothalamic stem/progenitor cells contributed greatly to exosomal microRNAs (miRNAs) in the cerebrospinal fluid, and these exosomal miRNAs declined during ageing, whereas central treatment with healthy hypothalamic stem/progenitor cell-secreted exosomes led to the slowing of ageing. In conclusion, ageing speed is substantially controlled by hypothalamic stem cells, partially through the release of exosomal miRNAs.

  20. Molecular mechanisms of anti-aging hormetic effects of mild heat stress on human cells

    DEFF Research Database (Denmark)

    Rattan, Suresh I S; Eskildsen-Helmond, Yvonne E G; Beedholm, Rasmus

    2004-01-01

    of cellular responsiveness to mild and severe heat stress. Furthermore, we are also undertaking comparative studies using non-aging immortal cell lines, such as SV40-transformed human fibroblasts, spontaneous osteosarcoma cells, and telomerase-immortalized human bone marrow cells for establishing differences...

  1. Changes in Circulating B Cell Subsets Associated with Aging and Acute SIV Infection in Rhesus Macaques.

    Science.gov (United States)

    Chang, W L William; Gonzalez, Denise F; Kieu, Hung T; Castillo, Luis D; Messaoudi, Ilhem; Shen, Xiaoying; Tomaras, Georgia D; Shacklett, Barbara L; Barry, Peter A; Sparger, Ellen E

    2017-01-01

    Aging and certain viral infections can negatively impact humoral responses in humans. To further develop the nonhuman primate (NHP) model for investigating B cell dynamics in human aging and infectious disease, a flow cytometric panel was developed to characterize circulating rhesus B cell subsets. Significant differences between human and macaque B cells included the proportions of cells within IgD+ and switched memory populations and a prominent CD21-CD27+ unswitched memory population detected only in macaques. We then utilized the expanded panel to analyze B cell alterations associated with aging and acute simian immunodeficiency virus (SIV) infection in the NHP model. In the aging study, distinct patterns of B cell subset frequencies were observed for macaques aged one to five years compared to those between ages 5 and 30 years. In the SIV infection study, B cell frequencies and absolute number were dramatically reduced following acute infection, but recovered within four weeks of infection. Thereafter, the frequencies of activated memory B cells progressively increased; these were significantly correlated with the magnitude of SIV-specific IgG responses, and coincided with impaired maturation of anti-SIV antibody avidity, as previously reported for HIV-1 infection. These observations further validate the NHP model for investigation of mechanisms responsible for B cells alterations associated with immunosenescence and infectious disease.

  2. Single-Cell Analysis of Human Pancreas Reveals Transcriptional Signatures of Aging and Somatic Mutation Patterns.

    Science.gov (United States)

    Enge, Martin; Arda, H Efsun; Mignardi, Marco; Beausang, John; Bottino, Rita; Kim, Seung K; Quake, Stephen R

    2017-10-05

    As organisms age, cells accumulate genetic and epigenetic errors that eventually lead to impaired organ function or catastrophic transformation such as cancer. Because aging reflects a stochastic process of increasing disorder, cells in an organ will be individually affected in different ways, thus rendering bulk analyses of postmitotic adult cells difficult to interpret. Here, we directly measure the effects of aging in human tissue by performing single-cell transcriptome analysis of 2,544 human pancreas cells from eight donors spanning six decades of life. We find that islet endocrine cells from older donors display increased levels of transcriptional noise and potential fate drift. By determining the mutational history of individual cells, we uncover a novel mutational signature in healthy aging endocrine cells. Our results demonstrate the feasibility of using single-cell RNA sequencing (RNA-seq) data from primary cells to derive insights into genetic and transcriptional processes that operate on aging human tissue. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Irradiated stem cells and ageing of the haematopoietic system

    Czech Academy of Sciences Publication Activity Database

    Vávrová, J.; Šinkorová, Z.; Řezáčová, M.; Tichý, Adam; Filip, S.; Mokrý, J.; Lukášová, Emilie

    2012-01-01

    Roč. 51, č. 2 (2012), s. 205-213 ISSN 0301-634X Institutional research plan: CEZ:AV0Z50040702 Institutional support: RVO:68081707 Keywords : Irradiation * Ageing of haematopoiesis * Anaemia Subject RIV: BO - Biophysics Impact factor: 1.754, year: 2012

  4. Polycomb group proteins in hematopoietic stem cell aging and malignancies

    NARCIS (Netherlands)

    Klauke, Karin; de Haan, Gerald

    Protection of the transcriptional "stemness" network is important to maintain a healthy hematopoietic stem cells (HSCs) compartment during the lifetime of the organism. Recent evidence shows that fundamental changes in the epigenetic status of HSCs might be one of the driving forces behind many

  5. Chromatin Structure in Cell Differentiation, Aging and Cancer

    NARCIS (Netherlands)

    S. Kheradmand Kia (Sima)

    2009-01-01

    textabstractChromatin is the structure that the eukaryotic genome is packaged into, allowing over a metre of DNA to fit into the small volume of the nucleus. It is composed of DNA and proteins, most of which are histones. This DNA-protein complex is the template for a number of essential cell

  6. TGFβ lengthens the G1 phase of stem cells in aged mouse brain.

    Science.gov (United States)

    Daynac, Mathieu; Pineda, Jose R; Chicheportiche, Alexandra; Gauthier, Laurent R; Morizur, Lise; Boussin, François D; Mouthon, Marc-André

    2014-12-01

    Neurogenesis decreases during aging causing a progressive cognitive decline but it is still controversial whether proliferation defects in neurogenic niches result from a loss of neural stem cells or from an impairment of their progression through the cell cycle. Using an accurate fluorescence-activated cell sorting technique, we show that the pool of neural stem cells is maintained in the subventricular zone of middle-aged mice while they have a reduced proliferative potential eventually leading to the subsequent decrease of their progeny. In addition, we demonstrate that the G1 phase is lengthened during aging specifically in activated stem cells, but not in transit-amplifying cells, and directly impacts on neurogenesis. Finally, we report that inhibition of TGFβ signaling restores cell cycle progression defects in stem cells. Our data highlight the significance of cell cycle dysregulation in stem cells in the aged brain and provide an attractive foundation for the development of anti-TGFβ regenerative therapies based on stimulating endogenous neural stem cells. © 2014 AlphaMed Press.

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

    Directory of Open Access Journals (Sweden)

    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.

  8. Modulation of dendritic cell and T cell cross-talk during aging: The potential role of checkpoint inhibitory molecules.

    Science.gov (United States)

    Gardner, Joanne K; Mamotte, Cyril D S; Jackaman, Connie; Nelson, Delia J

    2017-09-01

    Dendritic cells (DCs) undergo continuous changes throughout life, and there is evidence that elderly DCs have a reduced capacity to stimulate T cells, which may contribute to impaired anti-tumour immune responses in elderly people with cancer. Changes in checkpoint inhibitory molecules/pathways during aging may be one mechanism that impairs the ability of elderly DCs to activate T cells. However, little is currently known regarding the combined effects of aging and cancer on DC and T cell inhibitory molecules/pathways. In this review, we discuss our current understanding of the influence of aging and cancer on key DC and T cell inhibitory molecules/pathways, the potential underlying cellular and molecular mechanisms contributing to their modulation, and the possibility of therapeutically targeting inhibitory molecules in elderly cancer patients. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Airborne polycyclic aromatic hydrocarbons trigger human skin cells aging through aryl hydrocarbon receptor.

    Science.gov (United States)

    Qiao, Yuan; Li, Qiang; Du, Hong-Yang; Wang, Qiao-Wei; Huang, Ye; Liu, Wei

    2017-07-01

    Accumulating evidence suggests that polycyclic aromatic hydrocarbons (PAH) which adsorbed on the surface of ambient air particulate matters (PM), are the major toxic compound to cause cardiovascular and respiratory diseases, even cancer. However, its detrimental effects on human skin cell remain unclear. Here, we demonstrated that SRM1649b, a reference urban dust material of PAH, triggers human skin cells aging through cell cycle arrest, cell growth inhibition and apoptosis. Principally, SRM1649b facilitated Aryl hydrocarbon receptor (AhR) translocated into nucleus, subsequently activated ERK/MAPK signaling pathway, and upregulated aging-related genes expression. Most important, we found that AhR antagonist efficiently revert the aging of skin cells. Thus our novel findings firstly revealed the mechanism of skin aging under PAH contamination and provided potential strategy for clinical application. Copyright © 2017. Published by Elsevier Inc.

  10. Age-related changes in the endocytic capacity of rat liver Kupffer and endothelial cells

    International Nuclear Information System (INIS)

    Brouwer, A.; Barelds, R.J.; Knook, D.L.

    1985-01-01

    There are many indications that the functional capacity of the reticuloendothelial system (RES) declines with age. The aim of this study was to investigate the cellular basis of age-related changes in the clearance function of the RES. The experiments were focused mainly on Kupffer and endothelial cells of the liver which represent a major part of the RES and are primarily responsible for clearance of colloidal material from the circulation. The clearance capacity of the RES was tested clinically and experimentally by intravenous injection of colloids, such as radiolabeled heat-aggregated colloidal albumin. Age-related changes in the endocytosis of 125 I-labeled colloidal albumin (CA) in rats were determined by clearance and organ distribution of different doses of intravenously injected CA, uptake of CA by Kupffer and endothelial liver cells in vivo as determined after isolation of the cells from injected rats and kinetic studies on CA uptake by Kupffer cells in culture. The results show that, at a low dose, the clearance of CA is primarily determined by liver blood flow. At a higher saturating dose, plasma clearance and uptake by the liver are not significantly decreased with age. Endocytosis by endothelial cells, which accounts for about 60% of that of the whole liver, is also unchanged with age. In contrast, a significant decrease in endocytic capacity was observed for Kupffer cells in vivo. This age-related functional decline was also observed in Kupffer cells which were isolated from rats of different ages and maintained in culture

  11. Involvement of p53 and Bcl-2 in sensory cell degeneration in aging rat cochleae.

    Science.gov (United States)

    Xu, Yang; Yang, Wei Ping; Hu, Bo Hua; Yang, Shiming; Henderson, Donald

    2017-06-01

    p53 and Bcl-2 (B-cell lymphoma 2) are involved in the process of sensory cell degeneration in aging cochleae. To determine molecular players in age-related hair cell degeneration, this study examined the changes in p53 and Bcl-2 expression at different stages of apoptotic and necrotic death of hair cells in aging rat cochleae. Young (3-4 months) and aging (23-24 months) Fisher 344/NHsd rats were used. The thresholds of the auditory brainstem response (ABR) were measured to determine the auditory function. Immunolabeling was performed to determine the expression of p53 and Bcl-2 proteins in the sensory epithelium. Propidium iodide staining was performed to determine the morphologic changes in hair cell nuclei. Aging rats exhibited a significant elevation in ABR thresholds at all tested frequencies (p aging hair cells showing the early signs of apoptotic changes in their nuclei. The Bcl-2 expression increase was also observed in hair cells displaying early signs of necrosis. As the hair cell degenerative process advanced, p53 and Bcl-2 immunoreactivity became reduced or absent. In the areas where no detectable nuclear staining was present, p53 and Bcl-2 immunoreactivity was absent.

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

    Science.gov (United States)

    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.

  13. Comparison of tumour age response to radiation for cells derived from tissue culture or solid tumours

    International Nuclear Information System (INIS)

    Keng, P.C.; Siemann, D.W.; Rochester Univ., NY; Rochester Univ., NY; Wheeler, K.T.

    1984-01-01

    Direct comparison of the cell age response of 9L and KHT tumour cells derived either from tissue culture or solid tumours was achieved. Cells from dissociated KHT and 9L tumours (the latter implanted either subcutaneously or intracerebrally) and cells from tissue culture were separated into homogenous sized populations by centrifugal elutriation. In both tumour models these homogeneous sized populations correspond to populations enriched at different stages of the cell cycle. The survival of these elutriated cell populations was measured after a single dose of Cs-137 gamma rays. For cells isolated from 9L solid tumours, there was little variation in radiosensitivity throughout the cell cycle; however, a very small but significant increase in resistance was found in late G 1 cells. This lack of a large variation in radiosensitivity through the cell cycle for 9L cells from solid tumours also was seen in 9L cells growing in monolayer tissue culture. When similar experiments were performed using the KHT sarcoma tumour model, the results showed that KHT cells in vitro exhibited a fairly conventional increase in radioresistance in both mid G 1 and late S. However, the cell age response of KHT cells from solid tumours was different; particularly in the late S and G 2 + M phases. (author)

  14. 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.

  15. Stem cell therapies in preclinical models of stroke. Is the aged brain microenvironment refractory to cell therapy?

    Science.gov (United States)

    Sandu, Raluca Elena; Balseanu, Adrian Tudor; Bogdan, Catalin; Slevin, Mark; Petcu, Eugen; Popa-Wagner, Aurel

    2017-08-01

    Stroke is a devastating disease demanding vigorous search for new therapies. Initial enthusiasm to stimulate restorative processes in the ischemic brain by means of cell-based therapies has meanwhile converted into a more balanced view recognizing impediments that may be related to unfavorable age-associated environments. Recent results using a variety of drug, cell therapy or combination thereof suggest that, (i) treatment with Granulocyte-Colony Stimulating Factor (G-CSF) in aged rats has primarily a beneficial effect on functional outcome most likely via supportive cellular processes such as neurogenesis; (ii) the combination therapy, G-CSF with mesenchymal cells (G-CSF+BM-MSC or G-CSF+BM-MNC) did not further improve behavioral indices, neurogenesis or infarct volume as compared to G-CSF alone in aged animals; (iii) better results with regard to integration of transplanted cells in the aged rat environment have been obtained using iPS of human origin; (iv) mesenchymal cells may be used as drug carriers for the aged post-stroke brains. While the middle aged brain does not seem to impair drug and cell therapies, in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be carried out for a much longer time. Copyright © 2017. Published by Elsevier Inc.

  16. Electron microscopic radioautographic studies on macromolecular synthesis in mitochondria of animal cells in aging

    International Nuclear Information System (INIS)

    Nagata, Tetsuji

    2010-01-01

    Study aging changes of intramitochondrial DNA, RNA, protein synthesis of mouse organs during the development and aging, 30 groups of developing and aging mice (3 individuals each), from fetal day 19 to postnatal newborn at day 1, 3, 9, 14 and adult at month 1, 2, 6, 12 to 24, were injected with either 3 H-thymidine, 3 H-uriidine, or 3 H-leucine, sacrificed 1 h later and liver, adrenal, lung and testis tissues observed by electron microscopic radioautography. Accordingly, numbers of mitochondria per cell profile area, numbers of labeled mitochondria and the mitochondrial labeling index labeled with 3 H-labeled precursors showing DNA, RNA, protein synthesis in these cells (hepatocytes, 3 zones of the adrenal cortices - zona glomerulosa, fasciculata and reticularis -, adrenal medullary cells, pulmonary cells and testis cells) were counted per cells and compared among the respective developing and aging groups. The numbers of mitochondria in these cells increased from fetal day 19 to postnatal month 1 and 2. However, the numbers of labeled mitochondria and the labeling indices of intramitochondrial DNA, RNA, protein syntheses incorporating the 3 H-labeled precursors in the described tissue cells increased from fetal day 19 to postnatal month 1 and decreased to month 24. These data support that the activity of intramitochnodrial DNA, RNA, protein syntheses in cells of these tissues increased and decreased by development and aging in mice. The intramitochondrial DNA, RNA and protein syntheses in some other organs were also reviewed and discussed. (author)

  17. Electron microscopic radioautographic studies on macromolecular synthesis in mitochondria of animal cells in aging

    Energy Technology Data Exchange (ETDEWEB)

    Nagata, Tetsuji, E-mail: nagata@kowagakuen.ac.j [Shinshu Univ. School of Medicine, Matsumoto (Japan). Dept. of Anatomy and Cell Biology

    2010-07-01

    Study aging changes of intramitochondrial DNA, RNA, protein synthesis of mouse organs during the development and aging, 30 groups of developing and aging mice (3 individuals each), from fetal day 19 to postnatal newborn at day 1, 3, 9, 14 and adult at month 1, 2, 6, 12 to 24, were injected with either {sup 3}H-thymidine, {sup 3}H-uriidine, or {sup 3}H-leucine, sacrificed 1 h later and liver, adrenal, lung and testis tissues observed by electron microscopic radioautography. Accordingly, numbers of mitochondria per cell profile area, numbers of labeled mitochondria and the mitochondrial labeling index labeled with {sup 3}H-labeled precursors showing DNA, RNA, protein synthesis in these cells (hepatocytes, 3 zones of the adrenal cortices - zona glomerulosa, fasciculata and reticularis -, adrenal medullary cells, pulmonary cells and testis cells) were counted per cells and compared among the respective developing and aging groups. The numbers of mitochondria in these cells increased from fetal day 19 to postnatal month 1 and 2. However, the numbers of labeled mitochondria and the labeling indices of intramitochondrial DNA, RNA, protein syntheses incorporating the {sup 3}H-labeled precursors in the described tissue cells increased from fetal day 19 to postnatal month 1 and decreased to month 24. These data support that the activity of intramitochnodrial DNA, RNA, protein syntheses in cells of these tissues increased and decreased by development and aging in mice. The intramitochondrial DNA, RNA and protein syntheses in some other organs were also reviewed and discussed. (author)

  18. Differences of isolated dental stem cells dependent on donor age and consequences for autologous tooth replacement.

    Science.gov (United States)

    Kellner, Manuela; Steindorff, Marina M; Strempel, Jürgen F; Winkel, Andreas; Kühnel, Mark P; Stiesch, Meike

    2014-06-01

    Autologous therapy via stem cell-based tissue regeneration is an aim to rebuild natural teeth. One option is the use of adult stem cells from the dental pulp (DPSCs), which have been shown to differentiate into several types of tissue in vitro and in vivo, especially into tooth-like structures. DPSCs are mainly isolated from the dental pulp of third molars routinely extracted for orthodontic reasons. Due to the extraction of third molars at various phases of life, DPSCs are isolated at different developmental stages of the tooth. The present study addressed the question whether DPSCs from patients of different ages were similar in their growth characteristics with respect to the stage of tooth development. Therefore DPSCs from third molars of 12-30 year-old patients were extracted, and growth characteristics, e.g. doubling time and maximal cell division potential were analysed. In addition, pulp and hard dental material weight were recorded. Irrespective of the age of patients almost all isolated cells reached 40-60 generations with no correlation between maximal cell division potential and patient age. Cells from patients <22 years showed a significantly faster doubling time than the cells from patients ≥22 years. The age of patients at the time of stem cell isolation is not a crucial factor concerning maximal cell division potential, but does have an impact on the doubling time. However, differences in individuals regarding growth characteristics were more pronounced than age-dependent differences. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Origin of the effects of cell cycle age on radiation sensitivity

    International Nuclear Information System (INIS)

    Nelson, J.M.; Braby, L.A.; Metting, N.F.; Roesch, W.C.

    1987-01-01

    The observed differences in radiation sensitivity as a function of cell age could reflect either differences in cellular capacity to remove different types of damage, or differences in damage production. The authors used centrifugal elutriation methods to produce enriched populations of G/sub 1/-, S-, and G/sub 2/-phase cells from stationary phase CHO cultures. Recognizing the imperfect correlation between cell age and cross-sectional area (the criterion upon which the separation process is based) flow-cytometric methods were used to measure cellular DNA content and determine cell age distributions. Split-dose repair kinetics were then determined for cells in different phases of the cycle. The authors find no striking differences in total repair, indicating that damage is removed at generally the same rate and with essentially the same efficiency, throughout the cell cycle. This suggests that changes in the production of damage are likely responsible for the change in sensitivity

  20. The kinetics of epithelial cell generation: its relevance to cancer and ageing.

    Science.gov (United States)

    Morris, J A

    1999-07-07

    A hierarchical model of epithelial cell generation is proposed, in which even in extreme old age mature epithelial cells in humans are only a limited number of cell divisions from the zygote (60-120). This contrasts with conventional models in which regularly cycling stem cells can be several thousands of cell divisions from the zygote. The hierarchical model is supported by data on the rate of telomere shortening both in vivo and in vitro, and by data on the rate of synonymous substitutions in Y-linked, X-linked and autosomal genes in rodents. Limiting the number of cell generations leads to a vast reduction in the risk of cancer and reduces the rate of ageing. It is suggested that longer-lived animals need stricter control of the hierarchy than do shorter-lived animals and this difference has implications for theories of ageing. Copyright 1999 Academic Press.

  1. Sox10 expressing cells in the lateral wall of the aged mouse and human cochlea.

    Directory of Open Access Journals (Sweden)

    Xinping Hao

    Full Text Available Age-related hearing loss (presbycusis is a common human disorder, affecting one in three Americans aged 60 and over. Previous studies have shown that presbyacusis is associated with a loss of non-sensory cells in the cochlear lateral wall. Sox10 is a transcription factor crucial to the development and maintenance of neural crest-derived cells including some non-sensory cell types in the cochlea. Mutations of the Sox10 gene are known to cause various combinations of hearing loss and pigmentation defects in humans. This study investigated the potential relationship between Sox10 gene expression and pathological changes in the cochlear lateral wall of aged CBA/CaJ mice and human temporal bones from older donors. Cochlear tissues prepared from young adult (1-3 month-old and aged (2-2.5 year-old mice, and human temporal bone donors were examined using quantitative immunohistochemical analysis and transmission electron microscopy. Cells expressing Sox10 were present in the stria vascularis, outer sulcus and spiral prominence in mouse and human cochleas. The Sox10(+ cell types included marginal and intermediate cells and outer sulcus cells, including those that border the scala media and those extending into root processes (root cells in the spiral ligament. Quantitative analysis of immunostaining revealed a significant decrease in the number of Sox10(+ marginal cells and outer sulcus cells in aged mice. Electron microscopic evaluation revealed degenerative alterations in the surviving Sox10(+ cells in aged mice. Strial marginal cells in human cochleas from donors aged 87 and older showed only weak immunostaining for Sox10. Decreases in Sox10 expression levels and a loss of Sox10(+ cells in both mouse and human aged ears suggests an important role of Sox10 in the maintenance of structural and functional integrity of the lateral wall. A loss of Sox10(+ cells may also be associated with a decline in the repair capabilities of non-sensory cells in the

  2. 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

  3. 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.)

  4. 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.

  5. Human epithelial cells increase their rigidity with ageing in vitro: direct measurements

    International Nuclear Information System (INIS)

    Berdyyeva, Tamara K; Woodworth, Craig D; Sokolov, Igor

    2005-01-01

    The decrease in elasticity of epithelial tissues with ageing contributes to many human diseases. This change was previously attributed to increased crosslinking of extracellular matrix proteins. Here we show that individual human epithelial cells also become significantly more rigid during ageing in vitro. Using atomic force microscopy (AFM), we found that the Young's modulus of viable cells was consistently increased two- to four-fold in older versus younger cells. Direct visualization of the cytoskeleton using a novel method involving the AFM suggested that increased rigidity of ageing cells was due to a higher density of cytoskeletal fibres. Our results identify a unique mechanism that might contribute to the age-related loss of elasticity in epithelial tissues

  6. Aging increases microglial proliferation, delays cell migration, and decreases cortical neurogenesis after focal cerebral ischemia.

    Science.gov (United States)

    Moraga, Ana; Pradillo, Jesús M; García-Culebras, Alicia; Palma-Tortosa, Sara; Ballesteros, Ivan; Hernández-Jiménez, Macarena; Moro, María A; Lizasoain, Ignacio

    2015-05-10

    Aging is not just a risk factor of stroke, but it has also been associated with poor recovery. It is known that stroke-induced neurogenesis is reduced but maintained in the aged brain. However, there is no consensus on how neurogenesis is affected after stroke in aged animals. Our objective is to determine the role of aging on the process of neurogenesis after stroke. We have studied neurogenesis by analyzing proliferation, migration, and formation of new neurons, as well as inflammatory parameters, in a model of cerebral ischemia induced by permanent occlusion of the middle cerebral artery in young- (2 to 3 months) and middle-aged mice (13 to 14 months). Aging increased both microglial proliferation, as shown by a higher number of BrdU(+) cells and BrdU/Iba1(+) cells in the ischemic boundary and neutrophil infiltration. Interestingly, aging increased the number of M1 monocytes and N1 neutrophils, consistent with pro-inflammatory phenotypes when compared with the alternative M2 and N2 phenotypes. Aging also inhibited (subventricular zone) SVZ cell proliferation by decreasing both the number of astrocyte-like type-B (prominin-1(+)/epidermal growth factor receptor (EGFR)(+)/nestin(+)/glial fibrillary acidic protein (GFAP)(+) cells) and type-C cells (prominin-1(+)/EGFR(+)/nestin(-)/Mash1(+) cells), and not affecting apoptosis, 1 day after stroke. Aging also inhibited migration of neuroblasts (DCX(+) cells), as indicated by an accumulation of neuroblasts at migratory zones 14 days after injury; consistently, aged mice presented a smaller number of differentiated interneurons (NeuN(+)/BrdU(+) and GAD67(+) cells) in the peri-infarct cortical area 14 days after stroke. Our data confirm that stroke-induced neurogenesis is maintained but reduced in aged animals. Importantly, we now demonstrate that aging not only inhibits proliferation of specific SVZ cell subtypes but also blocks migration of neuroblasts to the damaged area and decreases the number of new interneurons in

  7. Age-related changes in CD8 T cell homeostasis and immunity to infection.

    Science.gov (United States)

    Nikolich-Žugich, Janko; Li, Gang; Uhrlaub, Jennifer L; Renkema, Kristin R; Smithey, Megan J

    2012-10-01

    Studies of CD8 T cell responses to vaccination or infection with various pathogens in both animal models and human subjects have revealed a markedly consistent array of age-related defects. In general, recent work shows that aged CD8 T cell responses are decreased in magnitude, and show poor differentiation into effector cells, with a reduced arsenal of effector functions. Here we review potential mechanisms underlying these defects. We specifically address phenotypic and numeric changes to the naïve CD8 T cell precursor pool, the impact of persistent viral infection(s) and inflammation, and contributions of the aging environment in which these cells are activated. Copyright © 2012 Elsevier Ltd. All rights reserved.

  8. Radiosensitivity of spermatogenous epithelium stem cells of mice of different strains and age

    International Nuclear Information System (INIS)

    Konoplyannikova, O.A.; Konoplyannikov, A.G.

    1988-01-01

    In experiments on CBA and BALB/c male mices (3 months of age) and F 1 (CBAxC57BL/6) hybrides (at the age of 3, 12, and 24 months) a difference was noted in the radiosensitivity of spermatogenous epithelium stem cells displayed by the changes in their colony-forming ability to testicular tubules 42 days following local 60 Co-γ-irradiation. The older the hybrid mice the smaller was the number of spermatogenous epithelium stem cells

  9. Age

    Science.gov (United States)

    ... adults? How can you reduce anesthesia risks in older patients? Age Age may bring wisdom but it also brings ... Ask your physician to conduct a pre-surgery cognitive test — an assessment of your mental function. The physician can use the results as a ...

  10. Aging impairs double-strand break repair by homologous recombination in Drosophila germ cells.

    Science.gov (United States)

    Delabaere, Laetitia; Ertl, Henry A; Massey, Dashiell J; Hofley, Carolyn M; Sohail, Faraz; Bienenstock, Elisa J; Sebastian, Hans; Chiolo, Irene; LaRocque, Jeannine R

    2017-04-01

    Aging is characterized by genome instability, which contributes to cancer formation and cell lethality leading to organismal decline. The high levels of DNA double-strand breaks (DSBs) observed in old cells and premature aging syndromes are likely a primary source of genome instability, but the underlying cause of their formation is still unclear. DSBs might result from higher levels of damage or repair defects emerging with advancing age, but repair pathways in old organisms are still poorly understood. Here, we show that premeiotic germline cells of young and old flies have distinct differences in their ability to repair DSBs by the error-free pathway homologous recombination (HR). Repair of DSBs induced by either ionizing radiation (IR) or the endonuclease I-SceI is markedly defective in older flies. This correlates with a remarkable reduction in HR repair measured with the DR-white DSB repair reporter assay. Strikingly, most of this repair defect is already present at 8 days of age. Finally, HR defects correlate with increased expression of early HR components and increased recruitment of Rad51 to damage in older organisms. Thus, we propose that the defect in the HR pathway for germ cells in older flies occurs following Rad51 recruitment. These data reveal that DSB repair defects arise early in the aging process and suggest that HR deficiencies are a leading cause of genome instability in germ cells of older animals. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  11. Stem cell therapies in preclinical models of stroke associated with aging

    Directory of Open Access Journals (Sweden)

    Aurel ePopa-Wagner

    2014-11-01

    Full Text Available Stroke has limited treatment options, demanding a vigorous search for new therapeutic strategies. Initial enthusiasm to stimulate restorative processes in the ischemic brain by means of cell-based therapies has meanwhile converted into a more balanced view recognizing impediments related to unfavorable environments that are in part related to aging processes. Since stroke afflicts mostly the elderly, it is highly desirable and clinically important to test the efficacy of cell therapies in aged brain microenvironments. Although widely believed to be refractory to regeneration, recent studies using both neural precursor cells and bone marrow-derived mesenchymal stem cells for stroke therapy suggest that the aged rat brain is not refractory to cell-based therapy, and that it also supports plasticity and remodeling. Yet, important differences exist in the aged compared with young brain, i.e., the accelerated progression of ischemic injury to brain infarction, the reduced rate of endogenous neurogenesis and the delayed initiation of neurological recovery. Pitfalls in the development of cell-based therapies may also be related to age-associated comorbidities, e.g., diabetes or hyperlipidemia, which may result in maladaptive or compromised brain remodeling, respectively. These age-related aspects should be carefully considered in the clinical translation of restorative therapies.

  12. Aging-associated oxidative stress inhibits liver progenitor cell activation in mice.

    Science.gov (United States)

    Cheng, Yiji; Wang, Xue; Wang, Bei; Zhou, Hong; Dang, Shipeng; Shi, Yufang; Hao, Li; Luo, Qingquan; Jin, Min; Zhou, Qianjun; Zhang, Yanyun

    2017-04-29

    Recent studies have discovered aging-associated changes of adult stem cells in various tissues and organs, which potentially contribute to the organismal aging. However, aging-associated changes of liver progenitor cells (LPCs) remain elusive. Employing young (2-month-old) and old (24-month-old) mice, we found diverse novel alterations in LPC activation during aging. LPCs in young mice could be activated and proliferate upon liver injury, whereas the counterparts in old mice failed to respond and proliferate, leading to the impaired liver regeneration. Surprisingly, isolated LPCs from young and old mice did not exhibit significant difference in their clonogenic and proliferative capacity. Later, we uncovered that the decreased activation and proliferation of LPCs were due to excessive reactive oxygen species produced by neutrophils infiltrated into niche, which was resulted from chemokine production from activated hepatic stellate cells during aging. This study demonstrates aging-associated changes in LPC activation and reveals critical roles for the stem cell niche, including neutrophils and hepatic stellate cells, in the negative regulation of LPCs during aging.

  13. 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

  14. Pink1 and Parkin regulate Drosophila intestinal stem cell proliferation during stress and aging.

    Science.gov (United States)

    Koehler, Christopher L; Perkins, Guy A; Ellisman, Mark H; Jones, D Leanne

    2017-08-07

    Intestinal stem cells (ISCs) maintain the midgut epithelium in Drosophila melanogaster Proper cellular turnover and tissue function rely on tightly regulated rates of ISC division and appropriate differentiation of daughter cells. However, aging and epithelial injury cause elevated ISC proliferation and decreased capacity for terminal differentiation of daughter enteroblasts (EBs). The mechanisms causing functional decline of stem cells with age remain elusive; however, recent findings suggest that stem cell metabolism plays an important role in the regulation of stem cell activity. Here, we investigate how alterations in mitochondrial homeostasis modulate stem cell behavior in vivo via RNA interference-mediated knockdown of factors involved in mitochondrial dynamics. ISC/EB-specific knockdown of the mitophagy-related genes Pink1 or Parkin suppresses the age-related loss of tissue homeostasis, despite dramatic changes in mitochondrial ultrastructure and mitochondrial damage in ISCs/EBs. Maintenance of tissue homeostasis upon reduction of Pink1 or Parkin appears to result from reduction of age- and stress-induced ISC proliferation, in part, through induction of ISC senescence. Our results indicate an uncoupling of cellular, tissue, and organismal aging through inhibition of ISC proliferation and provide insight into strategies used by stem cells to maintain tissue homeostasis despite severe damage to organelles. © 2017 Koehler et al.

  15. Human Neural Stem Cell Aging Is Counteracted by α-Glycerylphosphorylethanolamine.

    Science.gov (United States)

    Daniele, Simona; Da Pozzo, Eleonora; Iofrida, Caterina; Martini, Claudia

    2016-07-20

    Neural stem cells (NSCs) represent a subpopulation of cells, located in specific regions of the adult mammalian brain, with the ability of self-renewing and generating neurons and glia. In aged NSCs, modifications in the amount and composition of membrane proteins/lipids, which lead to a reduction in membrane fluidity and cholinergic activities, have been reported. In this respect, molecules that are effective at normalizing the membrane composition and cholinergic signaling could counteract stem cell aging. α-Glycerylphosphorylethanolamine (GPE), a nootropic drug, plays a role in phospholipid biosynthesis and acetylcholine release. Herein, GPE was assayed on human NSC cultures and on hydroxyurea-aged cells. Using cell counting, colorimetric, and fluorimetric analyses, immunoenzymatic assays, and real time PCR experiments, NSC culture proliferation, senescence, reactive oxygen species, and ADP/ATP levels were assessed. Aged NSCs exhibited cellular senescence, decreased proliferation, and an impairment in mitochondrial metabolism. These changes included a substantial induction in the nuclear factor NF-κB, a key inflammatory mediator. GPE cell treatment significantly protected the redox state and functional integrity of mitochondria, and counteracted senescence and NF-κB activation. In conclusion, our data show the beneficial properties of GPE in this model of stem cell aging.

  16. Anti-aging Effect of Transplanted Amniotic Membrane Mesenchymal Stem Cells in a Premature Aging Model of Bmi-1 Deficiency

    Science.gov (United States)

    Xie, Chunfeng; Jin, Jianliang; Lv, Xianhui; Tao, Jianguo; Wang, Rong; Miao, Dengshun

    2015-01-01

    To determine whether transplanted amniotic membrane mesenchymal stem cells (AMSCs) ameliorated the premature senescent phenotype of Bmi-1-deficient mice, postnatal 2-day-old Bmi-1−/− mice were injected intraperitoneally with the second-passage AMSCs from amniotic membranes of β-galactosidase (β-gal) transgenic mice or wild-type (WT) mice labeled with DiI. Three reinjections were given, once every seven days. Phenotypes of 5-week-old β-gal+ AMSC-transplanted or 6-week-old DiI+ AMSC-transplanted Bmi-1−/− mice were compared with vehicle-transplanted Bmi-1−/− and WT mice. Vehicle-transplanted Bmi-1−/− mice displayed growth retardation and premature aging with decreased cell proliferation and increased cell apoptosis; a decreased ratio and dysmaturity of lymphocytic series; premature osteoporosis with reduced osteogenesis and increased adipogenesis; redox imbalance and DNA damage in multiple organs. Transplanted AMSCs carried Bmi-1 migrated into multiple organs, proliferated and differentiated into multiple tissue cells, promoted growth and delayed senescence in Bmi-1−/− transplant recipients. The dysmaturity of lymphocytic series were ameliorated, premature osteoporosis were rescued by promoting osteogenesis and inhibiting adipogenesis, the oxidative stress and DNA damage in multiple organs were inhibited by the AMSC transplantation in Bmi-1−/− mice. These findings indicate that AMSC transplantation ameliorated the premature senescent phenotype of Bmi-1-deficient mice and could be a novel therapy to delay aging and prevent aging-associated degenerative diseases. PMID:26370922

  17. γ-irradiation-induced oxidative stress and aging of cultured endothelial cells

    International Nuclear Information System (INIS)

    Van Uye, A.; Agay, D.; Drouet, M.; Chancerelle, Y.; Mathieu, J.; Kergonou, J.F.; Mestries, J.C.

    1995-01-01

    The aim of this work was to study aging of cultured vascular cells. In order to induce an oxidative stress, which is known to participate in aging process, we apply γ-induced peroxidation and is revealed by indirect immunofluorescence. (author)

  18. The association between Neovascular Age-related Macular Degeneration and Regulatory T cells in peripheral blood

    DEFF Research Database (Denmark)

    Madelung, Christopher Fugl; Falk, Mads; Sørensen, Torben Lykke

    2015-01-01

    PURPOSE: To investigate regulatory T cells (Tregs) and subsets of the Treg population in patients with neovascular age-related macular degeneration (AMD). PATIENTS AND METHODS: Twenty-one neovascular AMD cases and 12 age-matched controls without retinal pathology were selected. Patients were...

  19. Satellite cell frequency in cross-age transplanted rat extensor digitorum longus muscles

    Czech Academy of Sciences Publication Activity Database

    Rudež, M.; Carlson, B. M.; Sajko, Š.; Kubínová, Lucie; Wernig, A.; Eržen, I.

    2004-01-01

    Roč. 14, č. 3 (2004), s. 155-159 ISSN 1120-9992 Grant - others:European programme(XE) QLKG-1999-02034 Institutional research plan: CEZ:AV0Z5011922 Keywords : aging * confocal microscopy * satellite cell s Subject RIV: EA - Cell Biology

  20. Aging of hematopoietic stem cells : Intrinsic changes or micro-environmental effects?

    NARCIS (Netherlands)

    Woolthuis, Carolien M.; de Haan, Gerald; Huls, Gerwin

    During development hematopoietic stem cells (HSCs) expand in number and persist throughout life by undergoing self-renewing divisions. Nevertheless, the hematopoietic system does not escape the negative effects of aging, suggesting that self-renewal is not complete. A fundamental issue in stem cell

  1. Improving methodological strategies for statellite cells counting in human muscle during ageing

    Czech Academy of Sciences Publication Activity Database

    Sajko, Š.; Kubínová, Lucie; Kreft, M.; Dahmane, R.; Wernig, A.; Eržen, I.

    2002-01-01

    Roč. 21, č. 1 (2002), s. 7-12 ISSN 1580-3139 Grant - others:European programme(XE) QLKG-1999-02034 Institutional research plan: CEZ:AV0Z5011922 Keywords : ageing * immunohistochemistry * satellite cell s Subject RIV: EA - Cell Biology

  2. Fibroblast growth factors as regulators of stem cell self-renewal and aging

    NARCIS (Netherlands)

    Yeoh, Joyce S. G.; de Haan, Gerald

    Organ and tissue dysfunction which is readily observable during aging results from a loss of cellular homeostasis and reduced stem cell self-renewal. Over the past 10 years, studies have been aimed at delineating growth factors that will sustain and promote the self-renewal potential of stem cells

  3. 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.

  4. Accelerated aging and discharge of lithium/thionyl-chloride D cells

    Science.gov (United States)

    Cieslak, W. R.

    Lithium/Thionyl-Chloride spiral wound 'D' cells from a variety of suppliers have been evaluated. Abuse testing has been used to verify safety of the cells, and accelerated aging has been used to estimate their performance for long life projects.

  5. Accelerated aging and discharge of lithium/thionyl-chloride D'' cells

    Energy Technology Data Exchange (ETDEWEB)

    Cieslak, W.R.

    1991-01-01

    Lithium/Thionyl-Chloride spiral wound D'' cells from a variety of suppliers have been evaluated. Abuse testing has been used to verify safety of the cells, and accelerated aging has been used to estimate their performance for long life projects. 2 tabs.

  6. Targeting Senescent Cells : Possible Implications for Delaying Skin Aging: A Mini-Review

    NARCIS (Netherlands)

    Velarde, Michael C.; Demaria, Marco

    2016-01-01

    Senescent cells are induced by a wide variety of stimuli. They accumulate in several tissues during aging, including the skin. Senescent cells secrete proinflammatory cytokines, chemokines, growth factors, and proteases, a phenomenon called senescence-associated secretory phenotype (SASP), which are

  7. Stromal-epithelial interactions in aging and cancer: Senescent fibroblasts alter epithelial cell differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Parrinello, Simona; Coppe, Jean-Philippe; Krtolica, Ana; Campisi, Judith

    2004-07-14

    Cellular senescence suppresses cancer by arresting cells at risk for malignant tumorigenesis. However, senescent cells also secrete molecules that can stimulate premalignant cells to proliferate and form tumors, suggesting the senescence response is antagonistically pleiotropic. We show that premalignant mammary epithelial cells exposed to senescent human fibroblasts in mice irreversibly lose differentiated properties, become invasive and undergo full malignant transformation. Moreover, using cultured mouse or human fibroblasts and non-malignant breast epithelial cells, we show that senescent fibroblasts disrupt epithelial alveolar morphogenesis, functional differentiation, and branching morphogenesis. Further, we identify MMP-3 as the major factor responsible for the effects of senescent fibroblasts on branching morphogenesis. Our findings support the idea that senescent cells contribute to age-related pathology, including cancer, and describe a new property of senescent fibroblasts--the ability to alter epithelial differentiation--that might also explain the loss of tissue function and organization that is a hallmark of aging.

  8. Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion.

    Science.gov (United States)

    Stearns-Reider, Kristen M; D'Amore, Antonio; Beezhold, Kevin; Rothrauff, Benjamin; Cavalli, Loredana; Wagner, William R; Vorp, David A; Tsamis, Alkiviadis; Shinde, Sunita; Zhang, Changqing; Barchowsky, Aaron; Rando, Thomas A; Tuan, Rocky S; Ambrosio, Fabrisia

    2017-06-01

    Age-related declines in skeletal muscle regeneration have been attributed to muscle stem cell (MuSC) dysfunction. Aged MuSCs display a fibrogenic conversion, leading to fibrosis and impaired recovery after injury. Although studies have demonstrated the influence of in vitro substrate characteristics on stem cell fate, whether and how aging of the extracellular matrix (ECM) affects stem cell behavior has not been investigated. Here, we investigated the direct effect of the aged muscle ECM on MuSC lineage specification. Quantification of ECM topology and muscle mechanical properties reveals decreased collagen tortuosity and muscle stiffening with increasing age. Age-related ECM alterations directly disrupt MuSC responses, and MuSCs seeded ex vivo onto decellularized ECM constructs derived from aged muscle display increased expression of fibrogenic markers and decreased myogenicity, compared to MuSCs seeded onto young ECM. This fibrogenic conversion is recapitulated in vitro when MuSCs are seeded directly onto matrices elaborated by aged fibroblasts. When compared to young fibroblasts, fibroblasts isolated from aged muscle display increased nuclear levels of the mechanosensors, Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ), consistent with exposure to a stiff microenvironment in vivo. Accordingly, preconditioning of young fibroblasts by seeding them onto a substrate engineered to mimic the stiffness of aged muscle increases YAP/TAZ nuclear translocation and promotes secretion of a matrix that favors MuSC fibrogenesis. The findings here suggest that an age-related increase in muscle stiffness drives YAP/TAZ-mediated pathogenic expression of matricellular proteins by fibroblasts, ultimately disrupting MuSC fate. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  9. L-carnitine significantly decreased aging of rat adipose tissue-derived mesenchymal stem cells.

    Science.gov (United States)

    Mobarak, Halimeh; Fathi, Ezzatollah; Farahzadi, Raheleh; Zarghami, Nosratollah; Javanmardi, Sara

    2017-03-01

    Mesenchymal stem cells are undifferentiated cells that have the ability to divide continuously and tissue regeneration potential during the transplantation. Aging and loss of cell survival, is one of the main problems in cell therapy. Since the production of free radicals in the aging process is effective, the use of antioxidant compounds can help in scavenging free radicals and prevent the aging of cells. The aim of this study is evaluate the effects of L-carnitine (LC) on proliferation and aging of rat adipose tissue-derived mesenchymal stem cells (rADSC). rADSCs were isolated from inguinal region of 5 male Rattus rats. Oil red-O, alizarin red-S and toluidine blue staining were performed to evaluate the adipogenic, osteogenic and chondrogenic differentiation of rADSCs, respectively. Flow cytometric analysis was done for investigating the cell surface markers. The methyl thiazol tetrazolium (MTT) method was used to determine the cell proliferation of rADSCs following exposure to different concentrations of LC. rADSCs aging was evaluated by beta-galactosidase staining. The results showed significant proliferation of rADSCs 48 h after treatment with concentrations of 0.2 mM LC. In addition, in the presence of 0.2 mM LC, rADSCs appeared to be growing faster than control group and 0.2 mM LC supplementation could significantly decrease the population doubling time and aging of rADSCs. It seems that LC would be a good antioxidant to improve lifespan of rADSCs due to the decrease in aging.

  10. Age and gender-related differences in mitral cells of olfactory bulb

    International Nuclear Information System (INIS)

    Haq, I.H.; Tahir, M.

    2008-01-01

    To investigate the age and gender-related differences in mitral cells of the human cadaveric olfactory bulbs. Sixty olfactory bulbs, 30 each from male and female (age 20-76 years) human cadavers divided into six groups of age and gender-wise were collected from the mortuary of the King Edward Medical University, Lahore. Mitral cells were counted and their diameter was calculated from 10 micro m thick cresyl violet stained histological sections. Statistical analysis was done using ANOVA for age-related differences and independent t-test for gender-related differences. There was significant reduction in the number of mitral cells and diameter of their nuclei with age. There was significant decrease in the number of mitral cells in males, between groups I and II (p < 0.001); II and III (p < 0.001); and I and III (p < 0.001); statistically significant decrease also occurred in females, between groups IV and V (p < 0.001); V and VI (p < 0.001); and IV and VI (p < 0.001). In most cases, the distance between individual mitral cells was seen to be much greater than in younger group. In group VI, few mitral cells were observed in the cell layer. There was also significant decrease in the diameter of mitral cell nuclei in males, between groups I and III (p < 0.001); and II and III (p < 0.010); in females, between groups IV and VI (p < 0.001); and V and VI (p < 0.001). No gender-related differences were observed. The number of mitral cells and diameter of their nuclei decreased with advancing age. (author)

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

    Science.gov (United States)

    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.

  12. Circadian rhythm of the Leydig cells endocrine function is attenuated during aging.

    Science.gov (United States)

    Baburski, Aleksandar Z; Sokanovic, Srdjan J; Bjelic, Maja M; Radovic, Sava M; Andric, Silvana A; Kostic, Tatjana S

    2016-01-01

    Although age-related hypofunction of Leydig cells is well illustrated across species, its circadian nature has not been analyzed. Here we describe changes in circadian behavior in Leydig cells isolated from adult (3-month) and aged (18- and 24-month) rats. The results showed reduced circadian pattern of testosterone secretion in both groups of aged rats despite unchanged LH circadian secretion. Although arrhythmic, the expression of Insl3, another secretory product of Leydig cells, was decreased in both groups. Intracellular cAMP and most important steroidogenic genes (Star, Cyp11a1 and Cyp17a1), together with positive steroidogenic regulator (Nur77), showed preserved circadian rhythm in aging although rhythm robustness and expression level were attenuated in both aged groups. Aging compromised cholesterol mobilization and uptake by Leydig cells: the oscillatory transcription pattern of genes encoding HDL-receptor (Scarb1), hormone sensitive lipase (Lipe, enzyme that converts cholesterol esters from lipid droplets into free cholesterol) and protein responsible for forming the cholesterol esters (Soat2) were flattened in 24-month group. The majority of examined clock genes displayed circadian behavior in expression but only a few of them (Bmal1, Per1, Per2, Per3 and Rev-Erba) were reduced in 24-month-old group. Furthermore, aging reduced oscillatory expression pattern of Sirt1 and Nampt, genes encoding key enzymes that connect cellular metabolism and circadian network. Altogether circadian amplitude of Leydig cell's endocrine function decreased during aging. The results suggest that clock genes are more resistant to aging than genes involved in steroidogenesis supporting the hypothesis about peripheral clock involvement in rhythm maintenance during aging. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Aging differentially affects male and female neural stem cell neurogenic properties

    Directory of Open Access Journals (Sweden)

    Jay Waldron

    2010-09-01

    Full Text Available Jay Waldron1, Althea McCourty1, Laurent Lecanu1,21The Research Institute of the McGill University Health Centre, Montreal, Canada; 2Department of Medicine, McGill University, Montreal, Quebec, CanadaPurpose: Neural stem cell transplantation as a brain repair strategy is a very promising technology. However, despite many attempts, the clinical success remains very deceiving. Despite clear evidence that sexual dimorphism rules many aspects of human biology, the occurrence of a sex difference in neural stem cell biology is largely understudied. Herein, we propose to determine whether gender is a dimension that drives the fate of neural stem cells through aging. Should it occur, we believe that neural stem cell sexual dimorphism and its variation during aging should be taken into account to refine clinical approaches of brain repair strategies.Methods: Neural stem cells were isolated from the subventricular zone of three- and 20-month-old male and female Long-Evans rats. Expression of the estrogen receptors, ERα and ERβ, progesterone receptor, androgen receptor, and glucocorticoid receptor was analyzed and quantified by Western blotting on undifferentiated neural stem cells. A second set of neural stem cells was treated with retinoic acid to trigger differentiation, and the expression of neuronal, astroglial, and oligodendroglial markers was determined using Western blotting.Conclusion: We provided in vitro evidence that the fate of neural stem cells is affected by sex and aging. Indeed, young male neural stem cells mainly expressed markers of neuronal and oligodendroglial fate, whereas young female neural stem cells underwent differentiation towards an astroglial phenotype. Aging resulted in a lessened capacity to express neuron and astrocyte markers. Undifferentiated neural stem cells displayed sexual dimorphism in the expression of steroid receptors, in particular ERα and ERβ, and the expression level of several steroid receptors increased

  14. Aging

    International Nuclear Information System (INIS)

    Finch, S.C.; Beebe, G.W.

    1975-01-01

    The hypothesis that ionizing radiation accelerates natural aging has been under investigation at the Atomic Bomb Casualty Commission since 1959. Postmortem observations of morphologic and chemical changes, tests of functional capacity, physical tests and measurements, clinical laboratory tests, tissue changes, morbidity, and mortality have all been examined by ABCC investigators interested in this hypothesis. These studies have been beset with conceptual difficulties centered on the definition and measurement of aging. An empirical approach early led to the calculation of an index of physiologic age as a linear combination of age-related tests of various organ systems. Most studies have been negative but have not involved the large numbers that might be required to provide strong evidence for or against the hypothesis. Mortality, however, has been examined on the basis of a large sample and over the period 1950-1972 had provided no support for the hypothesis of radiation-accelerated aging. Ionizing radiation dose, of course shorten human life, but its life-shortening effect appears to be the result of specific radiation-induced disease, especially neoplasms. The hypothesis is now much less attractive than it was 10-20 years ago but still has some value in stimulating research on aging. The experience of the A-bomb survivors provides an unusual opportunity for a definitive test of the hypothesis. (auth.)

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

    Directory of Open Access Journals (Sweden)

    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.

  16. The Fountain of Stem Cell-Based Youth? Online Portrayals of Anti-Aging Stem Cell Technologies.

    Science.gov (United States)

    Rachul, Christen M; Percec, Ivona; Caulfield, Timothy

    2015-08-01

    The hype surrounding stem cell science has created a market opportunity for the cosmetic industry. Cosmetic and anti-aging products and treatments that make claims regarding stem cell technology are increasingly popular, despite a lack of evidence for safety and efficacy of such products. This study explores how stem cell-based products and services are portrayed to the public through online sources, in order to gain insight into the key messages available to consumers. A content analysis of 100 web pages was conducted to examine the portrayals of stem cell-based cosmetic and anti-aging products and treatments. A qualitative discourse analysis of one web page further examined how language contributes to the portrayals of these products and treatments to public audiences. The majority of web pages portrayed stem cell-based products as ready for public use. Very few web pages substantiated claims with scientific evidence, and even fewer mentioned any risks or limitations associated with stem cell science. The discourse analysis revealed that the framing and use of metaphor obscures the certainty of the efficacy of and length of time for stem cell-based anti-aging technology to be publicly available. This study highlights the need to educate patients and the public on the current limits of stem cell applications in this context. In addition, generating scientific evidence for stem cell-based anti-aging and aesthetic applications is needed for optimizing benefits and minimizing adverse effects for the public. Having more evidence on efficacy and risks will help to protect patients who are eagerly seeking out these treatments. © 2015 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com.

  17. Aging effects on intestinal homeostasis associated with expansion and dysfunction of intestinal epithelial stem cells.

    Science.gov (United States)

    Moorefield, Emily C; Andres, Sarah F; Blue, R Eric; Van Landeghem, Laurianne; Mah, Amanda T; Santoro, M Agostina; Ding, Shengli

    2017-08-29

    Intestinal epithelial stem cells (IESCs) are critical to maintain intestinal epithelial function and homeostasis. We tested the hypothesis that aging promotes IESC dysfunction using old (18-22 months) and young (2-4 month) Sox9-EGFP IESC reporter mice. Different levels of Sox9-EGFP permit analyses of active IESC (Sox9-EGFP Low ), activatable reserve IESC and enteroendocrine cells (Sox9-EGFP High ), Sox9-EGFP Sublow progenitors, and Sox9-EGFP Negative differentiated lineages. Crypt-villus morphology, cellular composition and apoptosis were measured by histology. IESC function was assessed by crypt culture, and proliferation by flow cytometry and histology. Main findings were confirmed in Lgr5-EGFP and Lgr5-LacZ mice. Aging-associated gene expression changes were analyzed by Fluidigm mRNA profiling. Crypts culture from old mice yielded fewer and less complex enteroids. Histology revealed increased villus height and Paneth cells per crypt in old mice. Old mice showed increased numbers and hyperproliferation of Sox9-EGFP Low IESC and Sox9-EGFP High cells. Cleaved caspase-3 staining demonstrated increased apoptotic cells in crypts and villi of old mice. Gene expression profiling revealed aging-associated changes in mRNAs associated with cell cycle, oxidative stress and apoptosis specifically in IESC. These findings provide new, direct evidence for aging associated IESC dysfunction, and define potential biomarkers and targets for translational studies to assess and maintain IESC function during aging.

  18. Changes in chromatin structure during the aging of cell cultures as revealed by differential scanning calorimetry

    International Nuclear Information System (INIS)

    Almagor, M.; Cole, R.D.

    1989-01-01

    Nuclei from cultured human cells were examined by differential scanning calorimetry. Their melting profiles revealed four structural transitions at 60, 76, 88, and 105 degrees C (transitions I-IV, respectively). In immortalized (i.e., tumor) cell cultures and in normal cell cultures of low passage number, melting profiles were dominated by the 105 degrees C transition (transition IV), but in vitro aging of normal and Werner syndrome cells was associated with a marked decrease in transition IV followed by an increase in transition III at the expense of transition IV. At intermediate times in the aging process, much DNA melted at a temperature range (95-102 degrees C) intermediate between transitions III and IV, and this is consistent with the notion that aging of cell cultures is accompanied by an increase in single-strand character of the DNA. Calorimetric changes were observed in the melting profile of nuclei from UV-irradiated tumor cells that resembled the age-induced intermediate melting of chromatin. It is suggested that aging is accompanied by an increase in single-stranded character of the DNA in chromatin, which lowers its melting temperature, followed by strand breaks in the DNA that destroy its supercoiling potential

  19. Environmental stress, ageing and glial cell senescence: a novel mechanistic link to Parkinson's disease?

    Science.gov (United States)

    Chinta, S J; Lieu, C A; Demaria, M; Laberge, R-M; Campisi, J; Andersen, J K

    2013-05-01

    Exposure to environmental toxins is associated with a variety of age-related diseases including cancer and neurodegeneration. For example, in Parkinson's disease (PD), chronic environmental exposure to certain toxins has been linked to the age-related development of neuropathology. Neuronal damage is believed to involve the induction of neuroinflammatory events as a consequence of glial cell activation. Cellular senescence is a potent anti-cancer mechanism that occurs in a number of proliferative cell types and causes the arrest of proliferation of cells at risk of malignant transformation following exposure to potentially oncogenic stimuli. With age, senescent cells accumulate and express a senescence-associated secretory phenotype (SASP; that is the robust secretion of many inflammatory cytokines, growth factors and proteases). Whereas cell senescence in peripheral tissues has been causally linked to a number of age-related pathologies, little is known about the induction of cellular senescence and the SASP in the brain. On the basis of recently reported findings, we propose that environmental stressors associated with PD may act in part by eliciting senescence and the SASP within non neuronal glial cells in the ageing brain, thus contributing to the characteristic decline in neuronal integrity that occurs in this disorder. © 2013 The Association for the Publication of the Journal of Internal Medicine.

  20. Environmental stress, ageing and glial cell senescence: a novel mechanistic link to Parkinson’s disease?

    Science.gov (United States)

    Chinta, Shankar J; Lieu, Christopher A; DeMaria, Marco; Laberge, Remi-Martin; Campisi, Judith; Andersen, Julie K

    2013-01-01

    Exposure to environmental toxins is associated with a variety of age-related diseases including cancer and neurodegeneration. For example, in Parkinson’s disease (PD), chronic environmental exposure to certain toxins has been linked to the age-related development of neuropathology. Neuronal damage is believed to involve the induction of neuroinflammatory events as a consequence of glial cell activation. Cellular senescence is a potent anti-cancer mechanism that occurs in a number of proliferative cell types and causes the arrest of proliferation of cells at risk of malignant transformation following exposure to potentially oncogenic stimuli. With age, senescent cells accumulate and express a senescence-associated secretory phenotype (SASP; i.e. the robust secretion of many inflammatory cytokines, growth factors and proteases). Whereas cell senescence in peripheral tissues has been causally linked to a number of age-related pathologies, little is known about the induction of cellular senescence and the SASP in the brain. Based on recently reported findings, we propose that environmental stressors associated with PD may act in part by eliciting senescence and the SASP within non-neuronal glial cells in the ageing brain, thus contributing to the characteristic decline in neuronal integrity that occurs in this disorder. PMID:23600398

  1. 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

  2. Sparing of extraocular muscle in aging and muscular dystrophies: A myogenic precursor cell hypothesis

    Energy Technology Data Exchange (ETDEWEB)

    Kallestad, Kristen M.; Hebert, Sadie L.; McDonald, Abby A.; Daniel, Mark L.; Cu, Sharon R.; McLoon, Linda K., E-mail: mcloo001@tc.umn.edu

    2011-04-01

    The extraocular muscles (EOM) are spared from pathology in aging and many forms of muscular dystrophy. Despite many studies, this sparing remains an enigma. The EOM have a distinct embryonic lineage compared to somite-derived muscles, and we have shown that they continuously remodel throughout life, maintaining a population of activated satellite cells even in aging. These data suggested the hypothesis that there is a population of myogenic precursor cells (mpcs) in EOM that is different from those in limb, with either elevated numbers of stem cells and/or mpcs with superior proliferative capacity compared to mpcs in limb. Using flow cytometry, EOM and limb muscle mononuclear cells were compared, and a number of differences were seen. Using two different cell isolation methods, EOM have significantly more mpcs per mg muscle than limb skeletal muscle. One specific subpopulation significantly increased in EOM compared to limb was positive for CD34 and negative for Sca-1, M-cadherin, CD31, and CD45. We named these the EOMCD34 cells. Similar percentages of EOMCD34 cells were present in both newborn EOM and limb muscle. They were retained in aged EOM, whereas the population decreased significantly in adult limb muscle and were extremely scarce in aged limb muscle. Most importantly, the percentage of EOMCD34 cells was elevated in the EOM from both the mdx and the mdx/utrophin{sup -/-} (DKO) mouse models of DMD and extremely scarce in the limb muscles of these mice. In vitro, the EOMCD34 cells had myogenic potential, forming myotubes in differentiation media. After determining a media better able to induce proliferation in these cells, a fusion index was calculated. The cells isolated from EOM had a 40% higher fusion index compared to the same cells isolated from limb muscle. The EOMCD34 cells were resistant to both oxidative stress and mechanical injury. These data support our hypothesis that the EOM may be spared in aging and in muscular dystrophies due to a

  3. Sparing of extraocular muscle in aging and muscular dystrophies: A myogenic precursor cell hypothesis

    International Nuclear Information System (INIS)

    Kallestad, Kristen M.; Hebert, Sadie L.; McDonald, Abby A.; Daniel, Mark L.; Cu, Sharon R.; McLoon, Linda K.

    2011-01-01

    The extraocular muscles (EOM) are spared from pathology in aging and many forms of muscular dystrophy. Despite many studies, this sparing remains an enigma. The EOM have a distinct embryonic lineage compared to somite-derived muscles, and we have shown that they continuously remodel throughout life, maintaining a population of activated satellite cells even in aging. These data suggested the hypothesis that there is a population of myogenic precursor cells (mpcs) in EOM that is different from those in limb, with either elevated numbers of stem cells and/or mpcs with superior proliferative capacity compared to mpcs in limb. Using flow cytometry, EOM and limb muscle mononuclear cells were compared, and a number of differences were seen. Using two different cell isolation methods, EOM have significantly more mpcs per mg muscle than limb skeletal muscle. One specific subpopulation significantly increased in EOM compared to limb was positive for CD34 and negative for Sca-1, M-cadherin, CD31, and CD45. We named these the EOMCD34 cells. Similar percentages of EOMCD34 cells were present in both newborn EOM and limb muscle. They were retained in aged EOM, whereas the population decreased significantly in adult limb muscle and were extremely scarce in aged limb muscle. Most importantly, the percentage of EOMCD34 cells was elevated in the EOM from both the mdx and the mdx/utrophin -/- (DKO) mouse models of DMD and extremely scarce in the limb muscles of these mice. In vitro, the EOMCD34 cells had myogenic potential, forming myotubes in differentiation media. After determining a media better able to induce proliferation in these cells, a fusion index was calculated. The cells isolated from EOM had a 40% higher fusion index compared to the same cells isolated from limb muscle. The EOMCD34 cells were resistant to both oxidative stress and mechanical injury. These data support our hypothesis that the EOM may be spared in aging and in muscular dystrophies due to a subpopulation of

  4. Seismic-fragility tests of new and accelerated-aged Class 1E battery cells

    International Nuclear Information System (INIS)

    Bonzon, L.L.; Janis, W.J.; Black, D.A.; Paulsen, G.A.

    1987-01-01

    The seismic-fragility response of naturally-aged nuclear station safety-related batteries is of interest for two reasons: (1) to determine actual failure modes and thresholds and (2) to determine the validity of using the electrical capacity of individual cells as an indicator of the potential survivability of a battery given a seismic event. Prior reports in this series discussed the seismic-fragility tests and results for three specific naturally-aged cell types: 12-year old NCX-2250, 10-year old LCU-13, and 10-year old FHC-19. This report focuses on the complementary approach, namely, the seismic-fragility response of accelerated-aged batteries. Of particular interest is the degree to which such approaches accurately reproduce the actual failure modes and thresholds. In these tests the significant aging effects observed, in terms of seismic survivability, were: embrittlement of cell cases, positive bus material and positive plate grids; and excessive sulphation of positive plate active material causing hardening and expansion of positive plates. The IEEE Standard 535 accelerated aging method successfully reproduced seismically significant aging effects in new cells but accelerated grid embrittlement an estimated five years beyond the conditional age of other components

  5. Reduced reactivation from dormancy but maintained lineage choice of human mesenchymal stem cells with donor age.

    Directory of Open Access Journals (Sweden)

    Verena Dexheimer

    Full Text Available UNLABELLED: Mesenchymal stem cells (MSC are promising for cell-based regeneration therapies but up to date it is still controversial whether their function is maintained throughout ageing. Aim of this study was to address whether frequency, activation in vitro, replicative function, and in vitro lineage choice of MSC is maintained throughout ageing to answer the question whether MSC-based regeneration strategies should be restricted to younger individuals. MSC from bone marrow aspirates of 28 donors (5-80 years were characterized regarding colony-forming unit-fibroblast (CFU-F numbers, single cell cloning efficiency (SSCE, osteogenic, adipogenic and chondrogenic differentiation capacity in vitro. Alkaline phosphatase (ALP activity, mineralization, Oil Red O content, proteoglycan- and collagen type II deposition were quantified. While CFU-F frequency was maintained, SSCE and early proliferation rate decreased significantly with advanced donor age. MSC with higher proliferation rate before start of induction showed stronger osteogenic, adipogenic and chondrogenic differentiation. MSC with high osteogenic capacity underwent better chondrogenesis and showed a trend to better adipogenesis. Lineage choice was, however, unaltered with age. CONCLUSION: Ageing influenced activation from dormancy and replicative function of MSC in a way that it may be more demanding to mobilize MSC to fast cell growth at advanced age. Since fast proliferation came along with high multilineage capacity, the proliferation status of expanded MSC rather than donor age may provide an argument to restrict MSC-based therapies to certain individuals.

  6. Stem cells in degenerative orthopaedic pathologies: effects of aging on therapeutic potential.

    Science.gov (United States)

    Atesok, Kivanc; Fu, Freddie H; Sekiya, Ichiro; Stolzing, Alexandra; Ochi, Mitsuo; Rodeo, Scott A

    2017-02-01

    The purpose of this study was to summarize the current evidence on the use of stem cells in the elderly population with degenerative orthopaedic pathologies and to highlight the pathophysiologic mechanisms behind today's therapeutic challenges in stem cell-based regeneration of destructed tissues in the elderly patients with osteoarthritis (OA), degenerative disc disease (DDD), and tendinopathies. Clinical and basic science studies that report the use of stem cells in the elderly patients with OA, DDD, and tendinopathies were identified using a PubMed search. The studies published in English have been assessed, and the best and most recent evidence was included in the current study. Evidence suggests that, although short-term results regarding the effects of stem cell therapy in degenerative orthopaedic pathologies can be promising, stem cell therapies do not appear to reverse age-related tissue degeneration. Causes of suboptimal outcomes can be attributed to the decrease in the therapeutic potential of aged stem cell populations and the regenerative capacity of these cells, which might be negatively influenced in an aged microenvironment within the degenerated tissues of elderly patients with OA, DDD, and tendinopathies. Clinical protocols guiding the use of stem cells in the elderly patient population are still under development, and high-level randomized controlled trials with long-term outcomes are lacking. Understanding the consequences of age-related changes in stem cell function and responsiveness of the in vivo microenvironment to stem cells is critical when designing cell-based therapies for elderly patients with degenerative orthopaedic pathologies.

  7. Immune Checkpoint Function of CD85j in CD8 T Cell Differentiation and Aging

    Directory of Open Access Journals (Sweden)

    Claire E. Gustafson

    2017-06-01

    Full Text Available Aging is associated with an increased susceptibility to infection and a failure to control latent viruses thought to be driven, at least in part, by alterations in CD8 T cell function. The aging T cell repertoire is characterized by an accumulation of effector CD8 T cells, many of which express the negative regulatory receptor CD85j. To define the biological significance of CD85j expression on CD8 T cells and to address the question whether presence of CD85j in older individuals is beneficial or detrimental for immune function, we examined the specific attributes of CD8 T cells expressing CD85j as well as the functional role of CD85j in antigen-specific CD8 T cell responses during immune aging. Here, we show that CD85j is mainly expressed by terminally differentiated effector (TEMRAs CD8 T cells, which increase with age, in cytomegalovirus (CMV infection and in males. CD85j+ CMV-specific cells demonstrate clonal expansion. However, TCR diversity is similar between CD85j+ and CD85j− compartments, suggesting that CD85j does not directly impact the repertoire of antigen-specific cells. Further phenotypic and functional analyses revealed that CD85j identifies a specific subset of CMV-responsive CD8 T cells that coexpress a marker of senescence (CD57 but retain polyfunctional cytokine production and expression of cytotoxic mediators. Blocking CD85j binding enhanced proliferation of CMV-specific CD8 T cells upon antigen stimulation but did not alter polyfunctional cytokine production. Taken together, these data demonstrate that CD85j characterizes a population of “senescent,” but not exhausted antigen-specific effector CD8 T cells and indicates that CD85j is an important checkpoint regulator controlling expansion of virus-specific T cells during aging. Inhibition of CD85j activity may be a mechanism to promote stronger CD8 T cell effector responses during immune aging.

  8. Oxidative stress and age-related changes in T cells: is thalassemia a model of accelerated immune system aging?

    Science.gov (United States)

    Ghatreh-Samani, Mahdi; Esmaeili, Nafiseh; Soleimani, Masoud; Asadi-Samani, Majid; Ghatreh-Samani, Keihan; Shirzad, Hedayatolah

    2016-01-01

    Iron overload in β-thalassemia major occurs mainly due to blood transfusion, an essential treatment for β-thalassemia major patients, which results in oxidative stress. It has been thought that oxidative stress causes elevation of immune system senescent cells. Under this condition, cells normally enhance in aging, which is referred to as premature immunosenescence. Because there is no animal model for immunosenescence, most knowledge on the immunosenescence pattern is based on induction of immunosenescence. In this review, we describe iron overload and oxidative stress in β-thalassemia major patients and how they make these patients a suitable human model for immunosenescence. We also consider oxidative stress in some kinds of chronic virus infections, which induce changes in the immune system similar to β-thalassemia major. In conclusion, a therapeutic approach used to improve the immune system in such chronic virus diseases, may change the immunosenescence state and make life conditions better for β-thalassemia major patients.

  9. Immunofluorescence Analysis of Testicular Biopsies With Germ Cell and Sertoli Cell Markers Shows Significant MVH Negative Germ Cell Depletion With Older Age of Orchidopexy

    DEFF Research Database (Denmark)

    Li, Ruili; Thorup, Jørgen Mogens; Sun, Cong

    2014-01-01

    Undescended testis is the most common defect in newborn boys. It is associated with increased risks of infertility and testicular malignancy due to abnormal germ cell development in these testes. Early surgery may limit such risks. The aim of our study was to analyse germ cell development verses ...... age of orchidopexy using a germ cell marker and a Sertoli cell marker on testicular biopsies.......Undescended testis is the most common defect in newborn boys. It is associated with increased risks of infertility and testicular malignancy due to abnormal germ cell development in these testes. Early surgery may limit such risks. The aim of our study was to analyse germ cell development verses...

  10. Influence of age on the proliferation and peripheralization of thymic T cells

    International Nuclear Information System (INIS)

    Hirokawa, K.; Utsuyama, M.; Katsura, Y.; Sado, T.

    1988-01-01

    Bone marrow cells obtained from B10.Thy-1.1 mice (H-2b, Thy-1.1) were injected directly into the thymus of C57BL/6 mice (H-2b,Thy 1.2) of various ages. Thymocyte precursors in the injected donor-bone marrow cells could proliferate in the thymic microenvironment in the following manner: first, preferentially proliferating into the subcapsular cortex; and second, spreading to the whole layer of the cortex, a portion of them gradually moving into the medulla. The proliferation of donor-type thymocytes was most pronounced when intrathymic injection of bone marrow cells (ITB) was performed in newborn mice and especially prominent in week-old mice; it took approximately ten weeks for donor-type thymocytes to finish the whole course of proliferation, differentiation, and emigration to the periphery. When ITB was performed in mice 4 weeks of age and older, the proliferation of donor-type thymocytes was retarded at onset, less pronounced in magnitude, and disappeared earlier. Emigration of donor-type T cells from the thymus to the peripheral lymphoid tissues occurred most rapidly when ITB was performed in newborn mice, and these T cells continued to reside thereafter in the peripheral lymphoid tissues. However, when ITB was performed in mice 4 weeks of age and older, the number of emigrated T cells in the spleen decreased (about a tenth of that in newborn mice) and, moreover, these T cells resided only transiently in the spleen. It was suggested that T cells emigrating from the thymus of mice from newborn to 2 weeks of age are long-lived, whereas those from the thymus in mice 4 weeks of age and older are short-lived. However, when 4-week-old young adult mice were treated by irradiation or hydrocortisone, the thymic capacity was enhanced in terms of proliferation and peripheralization of thymocytes, and emigrated T cells became long-lived

  11. Age-related changes in expression of the neural cell adhesion molecule in skeletal muscle

    DEFF Research Database (Denmark)

    Andersson, A M; Olsen, M; Zhernosekov, D

    1993-01-01

    Neural cell adhesion molecule (NCAM) is expressed by muscle and involved in muscle-neuron and muscle-muscle cell interactions. The expression in muscle is regulated during myogenesis and by the state of innervation. In aged muscle, both neurogenic and myogenic degenerative processes occur. We here...... report quantitative and qualitative changes in NCAM protein and mRNA forms during aging in normal rat skeletal muscle. Determination of the amount of NCAM by e.l.i.s.a. showed that the level decreased from perinatal to adult age, followed by a considerable increase in 24-month-old rat muscle. Thus NCAM...... concentration in aged muscle was sixfold higher than in young adult muscle. In contrast with previous reports, NCAM polypeptides of 200, 145, 125 and 120 kDa were observed by immunoblotting throughout postnatal development and aging, the relative proportions of the individual NCAM polypeptides remaining...

  12. Effects of spermatozoa-oviductal cell coincubation time and oviductal cell age on spermatozoa-oviduct interactions.

    Science.gov (United States)

    Aldarmahi, Ahmed; Elliott, Sarah; Russell, Jean; Fazeli, Alireza

    2014-01-01

    The oviduct plays a crucial role in sperm storage, maintenance of sperm viability and sperm transport to the site of fertilisation. The aim of the present study was to investigate the effects of oviductal cell culture passage number, oviductal cell age and spermatozoa-oviduct coincubation times on gene expression in oviductal cells. Immortalised oviductal epithelial cells (OPEC) obtained from two different cell passages (36 and 57) were subcultured three times with and without spermatozoa for 24 h (control group). In a second study, OPEC were cocultured with spermatozoa for different time intervals (0, 4, 12 and 24 h). Expression of adrenomedullin (ADM), heat shock 70 kDa protein 8 (HSPA8) and prostaglandin E synthase (PGES) in OPEC was measured by quantitative polymerase chain reaction. The expression of ADM and HSPA8 was decreased significantly in OPEC cells from Passage 57, particularly in the later subculture group. These effects on HSPA8, but not ADM, expression in OPEC were further altered after coculture with spermatozoa for 24 h. We also demonstrated that spermatozoa-oviduct coculture for 12 and 24 h resulted in significantly higher expression of ADM, HSPA8 and PGES in OPEC. Overall, the data suggest that the OPEC lose some of their properties as a result of oviductal cell aging and that there are spermatozoa-oviduct interactions leading to increased oviductal cell gene expression.

  13. NF-κB activation impairs somatic cell reprogramming in ageing.

    Science.gov (United States)

    Soria-Valles, Clara; Osorio, Fernando G; Gutiérrez-Fernández, Ana; De Los Angeles, Alejandro; Bueno, Clara; Menéndez, Pablo; Martín-Subero, José I; Daley, George Q; Freije, José M P; López-Otín, Carlos

    2015-08-01

    Ageing constitutes a critical impediment to somatic cell reprogramming. We have explored the regulatory mechanisms that constitute age-associated barriers, through derivation of induced pluripotent stem cells (iPSCs) from individuals with premature or physiological ageing. We demonstrate that NF-κB activation blocks the generation of iPSCs in ageing. We also show that NF-κB repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-κB hyperactivation impairs the generation of iPSCs by eliciting the reprogramming repressor DOT1L, which reinforces senescence signals and downregulates pluripotency genes. Genetic and pharmacological NF-κB inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Néstor-Guillermo progeria syndrome and Hutchinson-Gilford progeria syndrome patients, as well as from normal aged donors. Finally, we demonstrate that DOT1L inhibition in vivo extends lifespan and ameliorates the accelerated ageing phenotype of progeroid mice, supporting the interest of studying age-associated molecular impairments to identify targets of rejuvenation strategies.

  14. Influence of exercise and aging on extracellular matrix composition in the skeletal muscle stem cell niche.

    Science.gov (United States)

    Garg, Koyal; Boppart, Marni D

    2016-11-01

    Skeletal muscle is endowed with a remarkable capacity for regeneration, primarily due to the reserve pool of muscle resident satellite cells. The satellite cell is the physiologically quiescent muscle stem cell that resides beneath the basal lamina and adjacent to the sarcolemma. The anatomic location of satellite cells is in close proximity to vasculature where they interact with other muscle resident stem/stromal cells (e.g., mesenchymal stem cells and pericytes) through paracrine mechanisms. This mini-review describes the components of the muscle stem cell niche, as well as the influence of exercise and aging on the muscle stem cell niche. Although exercise promotes ECM reorganization and stem cell accumulation, aging is associated with dense ECM deposition and loss of stem cell function resulting in reduced regenerative capacity and strength. An improved understanding of the niche elements will be valuable to inform the development of therapeutic interventions aimed at improving skeletal muscle regeneration and adaptation over the life span. Copyright © 2016 the American Physiological Society.

  15. 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.

  16. Cyclophilin D links programmed cell death and organismal aging in Podospora anserina.

    Science.gov (United States)

    Brust, Diana; Daum, Bertram; Breunig, Christine; Hamann, Andrea; Kühlbrandt, Werner; Osiewacz, Heinz D

    2010-10-01

    Cyclophilin D (CYPD) is a mitochondrial peptidyl prolyl-cis,trans-isomerase involved in opening of the mitochondrial permeability transition pore (mPTP). CYPD abundance increases during aging in mammalian tissues and in the aging model organism Podospora anserina. Here, we show that treatment of the P. anserina wild-type with low concentrations of the cyclophilin inhibitor cyclosporin A (CSA) extends lifespan. Transgenic strains overexpressing PaCypD are characterized by reduced stress tolerance, suffer from pronounced mitochondrial dysfunction and are characterized by accelerated aging and induction of cell death. Treatment with CSA leads to correction of mitochondrial function and lifespan to that of the wild-type. In contrast, PaCypD deletion strains are not affected by CSA within the investigated concentration range and show increased resistance against inducers of oxidative stress and cell death. Our data provide a mechanistic link between programmed cell death (PCD) and organismal aging and bear implications for the potential use of CSA to intervene into biologic aging. © 2010 The Authors Aging Cell © 2010 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

  17. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.

    Science.gov (United States)

    Baar, Marjolein P; Brandt, Renata M C; Putavet, Diana A; Klein, Julian D D; Derks, Kasper W J; Bourgeois, Benjamin R M; Stryeck, Sarah; Rijksen, Yvonne; van Willigenburg, Hester; Feijtel, Danny A; van der Pluijm, Ingrid; Essers, Jeroen; van Cappellen, Wiggert A; van IJcken, Wilfred F; Houtsmuller, Adriaan B; Pothof, Joris; de Bruin, Ron W F; Madl, Tobias; Hoeijmakers, Jan H J; Campisi, Judith; de Keizer, Peter L J

    2017-03-23

    The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging Xpd TTD/TTD and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. The aged brain: genesis and fate of residual progenitor cells in the subventricular zone

    Directory of Open Access Journals (Sweden)

    Vivian eCapilla-Gonzalez

    2015-09-01

    Full Text Available Neural stem cells persist in the adult mammalian brain through life. The subventricular zone is the largest source of stem cells in the nervous system, and continuously generates new neuronal and glial cells involved in brain regeneration. During aging, the germinal potential of the subventricular zone suffers a widespread decline, but the causes of this turn down are not fully understood. This review provides a compilation of the current knowledge about the age-related changes in the neural stem cell population, as well as the fate of the newly generated cells in the aged brain. It is known that the neurogenic capacity is clearly disrupted during aging, while the production of oligodendroglial cells is not compromised. Interestingly, the human brain seems to primarily preserve the ability to produce new oligodendrocytes instead of neurons, which could be related to the development of neurological disorders. Further studies in this matter are required to improve our understanding and the current strategies for fighting neurological diseases associated with senescence.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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

  1. Intervention of oxygen-control ability to radiation sensitivity, cell aging and cell transformation

    International Nuclear Information System (INIS)

    Yoshii, Hanako; Watanabe, Masami

    2009-01-01

    Oxygen is essential for life, and cells have therefore developed numerous adaptive responses to oxygen change. Here, we examined the difference in oxygen-control functions of human (HE), mouse (ME), and Syrian hamster embryo (SHE) cells cultured under different oxygen conditions (0.5%, 2% and 20%), and also examined whether oxygen tensions contributed to cellular lifespan and transformation. HE cells had their replicative lifespan slightly extended under hypoxic (0.5% and 2% oxygen) conditions, but were not immortalized under any of the oxygen concentrations. On the other hand, although ME cells cultured under 20% oxygen tension decreased their proliferation potency temporarily at early stage, all rodent cells were immortalized and acquired anchorage-independency, regardless of oxygen tension. These results suggest that cellular oxygen control function is related to sensitivities cellular immortalization and transformation. To understand intervention of oxygen control ability on cellular immortalization and transformation, we examined the intracellular oxidative level, mitochondria functions and radiation sensitivity. Intracellular oxidative levels of hypoxically cultured rodent cells were significantly enhanced. Mitochondrial membrane potential was altered depend on oxygen tensions, but the change was not parallel to mitochondria number in rodent cells. ME cells were particularly sensitive to oxygen change, and showed a clear oxygen effect on the X-ray survival. However, there was no difference in frequency of radiation-induced micronuclei between HE and ME cells. These results suggest that the response to oxygen change differs markedly in HE and rodent cells. (author)

  2. Loss of CD34 expression in aging human choriocapillaris endothelial cells.

    Directory of Open Access Journals (Sweden)

    Elliott H Sohn

    Full Text Available Structural and gene expression changes in the microvasculature of the human choroid occur during normal aging and age-related macular degeneration (AMD. In this study, we sought to determine the impact of aging and AMD on expression of the endothelial cell glycoprotein CD34. Sections from 58 human donor eyes were categorized as either young (under age 40, age-matched controls (> age 60 without AMD, or AMD affected (>age 60 with early AMD, geographic atrophy, or choroidal neovascularization. Dual labeling of sections with Ulex europaeus agglutinin-I lectin (UEA-I and CD34 antibodies was performed, and the percentage of capillaries labeled with UEA-I but negative for anti-CD34 was determined. In addition, published databases of mouse and human retinal pigment epithelium-choroid were evaluated and CD34 expression compared between young and old eyes. Immunohistochemical studies revealed that while CD34 and UEA-I were colocalized in young eyes, there was variable loss of CD34 immunoreactivity in older donor eyes. While differences between normal aging and AMD were not significant, the percentage of CD34 negative capillaries in old eyes, compared to young eyes, was highly significant (p = 3.8×10(-6. Endothelial cells in neovascular membranes were invariably CD34 positive. Published databases show either a significant decrease in Cd34 (mouse or a trend toward decreased CD34 (human in aging. These findings suggest that UEA-I and endogenous alkaline phosphatase activity are more consistent markers of aging endothelial cells in the choroid, and suggest a possible mechanism for the increased inflammatory milieu in the aging choroid.

  3. Human T cell aging and the impact of persistent viral infections

    Directory of Open Access Journals (Sweden)

    Tamas eFulop

    2013-09-01

    Full Text Available Aging is associated with a dysregulation of the immune response, loosely termed immunosenescence. Each part of the immune system is influenced to some extent by the aging process. However, adaptive immunity seems more extensively affected and among all participating cells it is the T cells that are most altered. There is a large body of experimental work devoted to the investigation of age-associated differences in T cell phenotypes and functions in young and old individuals, but few longitudinal studies in humans actually delineating changes at the level of the individual. In most studies, the number and proportion of late-differentiated T cells, especially CD8+ T cells, is reported to be higher in the elderly than in the young. Limited longitudinal studies suggest that accumulation of these cells is a dynamic process and does indeed represent an age-associated change. Accumulations of such late-stage cells may contribute to the enhanced systemic pro-inflammatory milieu commonly seen in older people. We do not know exactly what causes these observed changes, but an understanding of the possible causes is now beginning to emerge. A favored hypothesis is that these events are at least partly due to the effects of the maintenance of essential immune surveillance against persistent viral infections, notably Cytomegalovirus (CMV, which may exhaust the immune system over time. It is still a matter of debate as to whether these changes are compensatory and beneficial or pathological and detrimental to the proper functioning of the immune system and whether they impact longevity. Here, we will review present knowledge of T cell changes with aging and their relation to chronic viral and possibly other persistent infections.

  4. Perspectives of Stem Cell-Based Therapy for Age-Related Retinal Degenerative Diseases.

    Science.gov (United States)

    Holan, Vladimir; Hermankova, Barbora; Kossl, Jan

    2017-09-01

    Retinal degenerative diseases, which include age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy, and glaucoma, mostly affect the elderly population and are the most common cause of decreased quality of vision or even blindness. So far, there is no satisfactory treatment protocol to prevent, stop, or cure these disorders. A great hope and promise for patients suffering from retinal diseases is represented by stem cell-based therapy that could replace diseased or missing retinal cells and support regeneration. In this respect, mesenchymal stem cells (MSCs) that can be obtained from the particular patient and used as autologous cells have turned out to be a promising stem cell type for treatment. Here we show that MSCs can differentiate into cells expressing markers of retinal cells, inhibit production of pro-inflammatory cytokines by retinal tissue, and produce a number of growth and neuroprotective factors for retinal regeneration. All of these properties make MSCs a prospective cell type for cell-based therapy of age-related retinal degenerative diseases.

  5. Aging-related impairments of hippocampal mossy fibers synapses on CA3 pyramidal cells.

    Science.gov (United States)

    Villanueva-Castillo, Cindy; Tecuatl, Carolina; Herrera-López, Gabriel; Galván, Emilio J

    2017-01-01

    The network interaction between the dentate gyrus and area CA3 of the hippocampus is responsible for pattern separation, a process that underlies the formation of new memories, and which is naturally diminished in the aged brain. At the cellular level, aging is accompanied by a progression of biochemical modifications that ultimately affects its ability to generate and consolidate long-term potentiation. Although the synapse between dentate gyrus via the mossy fibers (MFs) onto CA3 neurons has been subject of extensive studies, the question of how aging affects the MF-CA3 synapse is still unsolved. Extracellular and whole-cell recordings from acute hippocampal slices of aged Wistar rats (34 ± 2 months old) show that aging is accompanied by a reduction in the interneuron-mediated inhibitory mechanisms of area CA3. Several MF-mediated forms of short-term plasticity, MF long-term potentiation and at least one of the critical signaling cascades necessary for potentiation are also compromised in the aged brain. An analysis of the spontaneous glutamatergic and gamma-aminobutyric acid-mediated currents on CA3 cells reveal a dramatic alteration in amplitude and frequency of the nonevoked events. CA3 cells also exhibited increased intrinsic excitability. Together, these results demonstrate that aging is accompanied by a decrease in the GABAergic inhibition, reduced expression of short- and long-term forms of synaptic plasticity, and increased intrinsic excitability. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Periplasmic Acid Stress Increases Cell Division Asymmetry (Polar Aging of Escherichia coli.

    Directory of Open Access Journals (Sweden)

    Michelle W Clark

    Full Text Available Under certain kinds of cytoplasmic stress, Escherichia coli selectively reproduce by distributing the newer cytoplasmic components to new-pole cells while sequestering older, damaged components in cells inheriting the old pole. This phenomenon is termed polar aging or cell division asymmetry. It is unknown whether cell division asymmetry can arise from a periplasmic stress, such as the stress of extracellular acid, which is mediated by the periplasm. We tested the effect of periplasmic acid stress on growth and division of adherent single cells. We tracked individual cell lineages over five or more generations, using fluorescence microscopy with ratiometric pHluorin to measure cytoplasmic pH. Adherent colonies were perfused continually with LBK medium buffered at pH 6.00 or at pH 7.50; the external pH determines periplasmic pH. In each experiment, cell lineages were mapped to correlate division time, pole age and cell generation number. In colonies perfused at pH 6.0, the cells inheriting the oldest pole divided significantly more slowly than the cells inheriting the newest pole. In colonies perfused at pH 7.50 (near or above cytoplasmic pH, no significant cell division asymmetry was observed. Under both conditions (periplasmic pH 6.0 or pH 7.5 the cells maintained cytoplasmic pH values at 7.2-7.3. No evidence of cytoplasmic protein aggregation was seen. Thus, periplasmic acid stress leads to cell division asymmetry with minimal cytoplasmic stress.

  7. 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.

  8. Compound effects of aging and experimental FSGS on glomerular epithelial cells.

    Science.gov (United States)

    Schneider, Remington R S; Eng, Diana G; Kutz, J Nathan; Sweetwyne, Mariya T; Pippin, Jeffrey W; Shankland, Stuart J

    2017-02-17

    Advanced age portends a poorer prognosis in FSGS. To understand the impact of age on glomerular podocytes and parietal epithelial cells (PECs), experimental FSGS was induced in 3m-old mice (20-year old human age) and 27m-old mice (78-year old human age) by abruptly depleting podocytes with a cytopathic anti-podocyte antibody. Despite similar binding of the disease-inducing antibody, podocyte density was lower in aged FSGS mice compared to young FSGS mice. Activated PEC density was higher in aged versus young FSGS mice, as was the percentage of total activated PECs. Additionally, the percentage of glomeruli containing PECs with evidence of phosphorylated ERK and EMT was higher in aged FSGS mice. Extracellular matrix, measured by collagen IV and silver staining, was higher in aged FSGS mice along Bowman's capsule. However, collagen IV accumulation in the glomerular tufts alone and in glomeruli with both tuft and Bowman's capsule accumulation were similar in young FSGS and aged FSGS mice. Thus, the major difference in collagen IV staining in FSGS was along Bowman's capsule in aged mice. The significant differences in podocytes, PECs and extracellular matrix accumulation between young mice and old mice with FSGS might explain the differences in outcomes in FSGS based on age.

  9. Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices

    Science.gov (United States)

    Tremblay, Marie-Ève; Zettel, Martha L.; Ison, James R.; Allen, Paul D.; Majewska, Ania K.

    2011-01-01

    Normal aging is often accompanied by a progressive loss of receptor sensitivity in hearing and vision, whose consequences on cellular function in cortical sensory areas have remained largely unknown. By examining the primary auditory (A1) and visual (V1) cortices in two inbred strains of mice undergoing either age-related loss of audition (C57BL/6J) or vision (CBA/CaJ), we were able to describe cellular and subcellular changes that were associated with normal aging (occurring in A1 and V1 of both strains) or specifically with age-related sensory loss (only in A1 of C57BL/6J or V1 of CBA/CaJ), using immunocytochemical electron microscopy and light microscopy. While the changes were subtle in neurons, glial cells and especially microglia were transformed in aged animals. Microglia became more numerous and irregularly distributed, displayed more variable cell body and process morphologies, occupied smaller territories, and accumulated phagocytic inclusions that often displayed ultrastructural features of synaptic elements. Additionally, evidence of myelination defects were observed, and aged oligodendrocytes became more numerous and were more often encountered in contiguous pairs. Most of these effects were profoundly exacerbated by age-related sensory loss. Together, our results suggest that the age-related alteration of glial cells in sensory cortical areas can be accelerated by activity-driven central mechanisms that result from an age-related loss of peripheral sensitivity. In light of our observations, these age-related changes in sensory function should be considered when investigating cellular, cortical and behavioral functions throughout the lifespan in these commonly used C57BL/6J and CBA/CaJ mouse models. PMID:22223464

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

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    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.

  11. DETERMINANTS OF RED-BLOOD-CELL DEFORMABILITY IN RELATION TO CELL AGE

    NARCIS (Netherlands)

    BOSCH, FH; WERRE, JM; ROERDINKHOLDERSTOELWINDER, B; HULS, T; WILLEKENS, FLA; WICHERS, G; HALIE, MR

    Red blood cell (RBC) deformability was determined with an ektacytometer in fractions separated on the basis of differences in cell volume or density. Deformability was measured with ektacytometry (rpm-scan and osmo-scan). We studied three groups of RBC fractions:l. By counterflow centrifugation we

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

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    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

  13. Pre-mRNA Processing Is Partially Impaired in Satellite Cell Nuclei from Aged Muscles

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    Manuela Malatesta

    2010-01-01

    Full Text Available Satellite cells are responsible for the capacity of mature mammalian skeletal muscles to repair and maintain mass. During aging, skeletal muscle mass as well as the muscle strength and endurance progressively decrease, leading to a condition termed sarcopenia. The causes of sarcopenia are manifold and remain to be completely elucidated. One of them could be the remarkable decline in the efficiency of muscle regeneration; this has been associated with decreasing amounts of satellite cells, but also to alterations in their activation, proliferation, and/or differentiation. In this study, we investigated the satellite cell nuclei of biceps and quadriceps muscles from adult and old rats; morphometry and immunocytochemistry at light and electron microscopy have been combined to assess the organization of the nuclear RNP structural constituents involved in different steps of mRNA formation. We demonstrated that in satellite cells the RNA pathways undergo alterations during aging, possibly hampering their responsiveness to muscle damage.

  14. 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.

  15. 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.

  16. Impact of age-related neuroglial cell responses on hippocampal deterioration

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    Joseph O Ojo

    2015-04-01

    Full Text Available Aging is one of the greatest risk factors for the development of sporadic age-related neurodegenerative diseases and neuroinflammation is a common feature of this disease phenotype. In the immunoprivileged brain, neuroglial cells, which mediate neuroinflammatory responses, are influenced by the physiological factors in the microenvironment of the central nervous system (CNS. These physiological factors include but are not limited to cell-to-cell communication involving cell adhesion molecules, neuronal electrical activity and neurotransmitter and neuromodulator action. However, despite this dynamic control of neuroglial activity, in the healthy aged brain there is an alteration in the underlying neuroinflammatory response notably seen in the hippocampus, typified by astrocyte/microglia activation and increased pro-inflammatory cytokine production and signalling. Normally, these changes occur without any concurrent pathology, however, they can correlate with deteriorations in hippocampal or cognitive function. In this review we examine two important phenomenons, firstly the relationship between age-related brain deterioration (focusing on hippocampal function and underlying neuroglial response(s, and secondly how the latter affects molecular and cellular processes within the hippocampus that makes it vulnerable to age-related cognitive decline.

  17. The generation of oligodendroglial cells is preserved in the rostral migratory stream during aging

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    Vivian eCapilla-Gonzalez

    2013-09-01

    Full Text Available The subventricular zone (SVZ is the largest source of newly generated cells in the adult mammalian brain. SVZ-derived neuroblasts migrate via the rostral migratory stream (RMS to the olfactory bulb (OB, where they differentiate into mature neurons. Additionally, a small proportion of SVZ-derived cells contribute to the generation of myelinating oligodendrocytes. The production of new cells in the SVZ decreases during aging, affecting the incorporation of new neurons into the OB. However, the age-related changes that occur across the RMS are not fully understood. In this study we evaluate how aging affects the cellular organization of migrating neuroblast chains, the proliferation, and the fate of the newly generated cells in the SVZ-OB system. By using electron microscopy and immunostaining, we found that the RMS path becomes discontinuous and its cytoarchitecture is disorganized in aged mice (24-month-old mice. Subsequently, OB neurogenesis was impaired in the aged brain while the production of oligodendrocytes was not compromised. These findings provide new insight into oligodendrocyte preservation throughout life. Further exploration of this matter could help the development of new strategies to prevent neurological disorders associated with senescence.

  18. 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.

  19. 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.

  20. The extraocular muscle stem cell niche is resistant to ageing and disease

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    Luigi eFormicola

    2014-12-01

    Full Text Available Specific muscles are spared in many degenerative myopathies. Most notably, the extraocular muscles (EOMs do not show clinical signs of late stage myopathies including the accumulation of fibrosis and fat. It has been proposed that an altered stem cell niche underlies the resistance of EOMs in these pathologies, however, to date, no reports have provided a detailed characterization of the EOM stem cell niche. PW1/Peg3 is expressed in progenitor cells in all adult tissues including satellite cells and a subset of interstitial non-satellite cell progenitors in muscle. These PW1-positive interstitial cells (PICs include a fibroadipogenic progenitor population (FAPs that give rise to fat and fibrosis in late stage myopathies. PICs/FAPs are mobilized following injury and FAPs exert a promyogenic role upon myoblasts in vitro but require the presence of a minimal population of satellite cells in vivo. We and others recently described that FAPs express promyogenic factors while satellite cells express antimyogenic factors suggesting that PICs/FAPs act as support niche cells in skeletal muscle through paracrine interactions. We analyzed the EOM stem cell niche in young adult and aged wild-type mice and found that the balance between PICs and satellite cells within the EOM stem cell niche is maintained throughout life. Moreover, in the adult mdx mouse model for Duchenne muscular dystrophy, the EOM stem cell niche is unperturbed compared to normal mice, in contrast to Tibialis Anterior (TA muscle, which displays signs of ongoing degeneration/regeneration. Regenerating mdx TA shows increased levels of both PICs and satellite cells, comparable to normal unaffected EOMs. We propose that the increase in PICs that we observe in normal EOMs contributes to preserving the integrity of the myofibers and satellite cells. Our data suggest that molecular cues regulating muscle regeneration are intrinsic properties of EOMs.

  1. Chemotherapy and Stem Cell Transplantation Increase p16INK4a Expression, a Biomarker of T-cell Aging

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    William A. Wood

    2016-09-01

    Full Text Available The expression of markers of cellular senescence increases exponentially in multiple tissues with aging. Age-related physiological changes may contribute to adverse outcomes in cancer survivors. To investigate the impact of high dose chemotherapy and stem cell transplantation on senescence markers in vivo, we collected blood and clinical data from a cohort of 63 patients undergoing hematopoietic cell transplantation. The expression of p16INK4a, a well-established senescence marker, was determined in T-cells before and 6 months after transplant. RNA sequencing was performed on paired samples from 8 patients pre- and post-cancer therapy. In patients undergoing allogeneic transplant, higher pre-transplant p16INK4a expression was associated with a greater number of prior cycles of chemotherapy received (p = 0.003, prior autologous transplantation (p = 0.01 and prior exposure to alkylating agents (p = 0.01. Transplantation was associated with a marked increase in p16INK4a expression 6 months following transplantation. Patients receiving autologous transplant experienced a larger increase in p16INK4a expression (3.1-fold increase, p = 0.002 than allogeneic transplant recipients (1.9-fold increase, p = 0.0004. RNA sequencing of T-cells pre- and post- autologous transplant or cytotoxic chemotherapy demonstrated increased expression of transcripts associated with cellular senescence and physiological aging. Cytotoxic chemotherapy, especially alkylating agents, and stem cell transplantation strongly accelerate expression of a biomarker of molecular aging in T-cells.

  2. The glia doctrine: addressing the role of glial cells in healthy brain ageing.

    Science.gov (United States)

    Nagelhus, Erlend A; Amiry-Moghaddam, Mahmood; Bergersen, Linda H; Bjaalie, Jan G; Eriksson, Jens; Gundersen, Vidar; Leergaard, Trygve B; Morth, J Preben; Storm-Mathisen, Jon; Torp, Reidun; Walhovd, Kristine B; Tønjum, Tone

    2013-10-01

    Glial cells in their plurality pervade the human brain and impact on brain structure and function. A principal component of the emerging glial doctrine is the hypothesis that astrocytes, the most abundant type of glial cells, trigger major molecular processes leading to brain ageing. Astrocyte biology has been examined using molecular, biochemical and structural methods, as well as 3D brain imaging in live animals and humans. Exosomes are extracelluar membrane vesicles that facilitate communication between glia, and have significant potential for biomarker discovery and drug delivery. Polymorphisms in DNA repair genes may indirectly influence the structure and function of membrane proteins expressed in glial cells and predispose specific cell subgroups to degeneration. Physical exercise may reduce or retard age-related brain deterioration by a mechanism involving neuro-glial processes. It is most likely that additional information about the distribution, structure and function of glial cells will yield novel insight into human brain ageing. Systematic studies of glia and their functions are expected to eventually lead to earlier detection of ageing-related brain dysfunction and to interventions that could delay, reduce or prevent brain dysfunction. Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  3. Perspectives of Stem Cell-Based Therapy for Age-Related Retinal Degenerative Diseases

    Czech Academy of Sciences Publication Activity Database

    Holáň, Vladimír; Heřmánková, Barbora; Kössl, Jan

    2017-01-01

    Roč. 26, č. 9 (2017), s. 1538-1541 ISSN 0963-6897 R&D Projects: GA ČR(CZ) GA17-04800S; GA MŠk(CZ) ED1.1.00/02.0109; GA MŠk(CZ) LO1309 Institutional support: RVO:68378041 Keywords : age-related retinal degenerative diseases * mesenchymal stem cells * stem cell therapy Subject RIV: FF - HEENT, Dentistry OBOR OECD: Ophthalmology Impact factor: 3.006, year: 2016

  4. [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.

  5. Impact of age and gender interaction on circulating endothelial progenitor cells in healthy subjects.

    Science.gov (United States)

    Rousseau, Alexandra; Ayoubi, Fida; Deveaux, Christel; Charbit, Beny; Delmau, Catherine; Christin-Maitre, Sophie; Jaillon, Patrice; Uzan, Georges; Simon, Tabassome

    2010-02-01

    To assess the level of circulating endothelial progenitor cells (CEPC) in cycling women compared with men and menopausal women. Controlled clinical study. Healthy, nonsmoking volunteers. Twelve women, aged 18-40 years, with regular menstrual cycles, 12 menopausal women, and two groups of 12 age-matched men were recruited. Women did not receive any hormone therapy. Collection of 20 mL of peripheral blood. The number of CEPC, defined as (Lin-/7AAD-/CD34+/CD133+/KDR+) cells per 10(6) mononuclear cells (MNC), was measured by flow cytometry. The number of CEPC was significantly higher in cycling women than in age-matched men and menopausal women (26.5 per 10(6) MNC vs. 10.5 per 10(6) MNC vs. 10 per 10(6) MNC, respectively). The number of CEPC was similar in menopausal women, age-matched, and young men. The number of CEPC is influenced by an age-gender interaction. This phenomenon may explain in part the better vascular repair and relative cardiovascular protection in younger women as compared with age-matched men. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  6. Renal cell carcinoma in India demonstrates early age of onset & a late stage of presentation

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    Shalini Agnihotri

    2014-01-01

    Full Text Available Background & objectives: Clinical spectrum of most of the diseases in developing countries is different from the west. Similarly whether renal cell carcinomas (RCC in a developing country like India is seen in the same spectrum in relation to the age at presentation as in the west is not described in the literature. This study was carried out to investigate the spectrum of RCC in India with regards to age of onset, stage at presentation and survival. Methods: Patients with renal tumour, treated between January 2000 to December 2012 in a tertiary care hospital in north India, were analyzed for age at presentation, clinical features and histopathological characteristics. Clinical diagnosis was made by contrast enhanced computerized tomography (CECT scans and/or magnetic resonance imaging (MRI. Renal masses diagnosed as angiomyolipoma, infective masses and hydatid cysts were excluded from the analysis. Impact of various age groups on gender, tumour size, TNM stage, Fuhrman grade, histopathological subtypes, lymph node, inferior vena cava (IVC involvement and survival was analyzed. Patients were grouped in five age groups i.e. ≤39, 40-49, 50-59, 60-69 and more than 70 yr of age. Results: Of the total 617 patients with 617 renal tumours (2 patients had bilateral tumours but only the larger tumour was considered clinically suspected as RCC, 586 had epithelial cell tumour and the remaining 31 had non epithelial cell tumour. The mean tumour size was 8.08±3.5 cm (median 7, range 1-25 cm. Tumour of less than 4 cm size was present in only 10.4 per cent patients. The mean age at diagnosis was 55.15±13.34 (median 56, range 14-91 yr years. A total of 30.03 per cent of renal tumours presented in patients younger than 50 yr of age. Though there was no difference in stage, Fuhrman′s grade, IVC involvement and lymph nodal spread among various age groups, younger patients had higher proportion of non clear cell RCC and only 48.59 per cent of them presented

  7. Age-associated distribution of normal B-cell and plasma cell subsets in peripheral blood

    NARCIS (Netherlands)

    Blanco, E. (Elena); M. Perez-Andres; Arriba-Méndez, S. (Sonia); Contreras-Sanfeliciano, T. (Teresa); I. Criado (Ignacio); Pelak, O. (Ondrej); Serra-Caetano, A. (Ana); A. Romero (Alfonso); N. Puig (Noemí); Remesal, A. (Ana); Torres Canizales, J. (Juan); E. Lopez-Granados (Eduardo); T. Kalina (Tomas); Sousa, A.E. (Ana E.); M.C. van Zelm (Menno); M. van der Burg (Mirjam); J.J.M. van Dongen (Jacques); Orfao, A. (Alberto)

    2018-01-01

    textabstractBackground: Humoral immunocompetence develops stepwise throughout life and contributes to individual susceptibility to infection, immunodeficiency, autoimmunity, and neoplasia. Immunoglobulin heavy chain (IgH) isotype serum levels can partly explain such age-related differences, but

  8. DNA damage, metabolism and aging in pro-inflammatory T cells: Rheumatoid arthritis as a model system.

    Science.gov (United States)

    Li, Yinyin; Goronzy, Jörg J; Weyand, Cornelia M

    2018-05-01

    The aging process is the major driver of morbidity and mortality, steeply increasing the risk to succumb to cancer, cardiovascular disease, infection and neurodegeneration. Inflammation is a common denominator in age-related pathologies, identifying the immune system as a gatekeeper in aging overall. Among immune cells, T cells are long-lived and exposed to intense replication pressure, making them sensitive to aging-related abnormalities. In successful T cell aging, numbers of naïve cells, repertoire diversity and activation thresholds are preserved as long as possible; in maladaptive T cell aging, protective T cell functions decline and pro-inflammatory effector cells are enriched. Here, we review in the model system of rheumatoid arthritis (RA) how maladaptive T cell aging renders the host susceptible to chronic, tissue-damaging inflammation. In T cells from RA patients, known to be about 20years pre-aged, three interconnected functional domains are altered: DNA damage repair, metabolic activity generating energy and biosynthetic precursor molecules, and shaping of plasma membranes to promote T cell motility. In each of these domains, key molecules and pathways have now been identified, including the glycolytic enzymes PFKFB3 and G6PD; the DNA repair molecules ATM, DNA-PKcs and MRE11A; and the podosome marker protein TKS5. Some of these molecules may help in defining targetable pathways to slow the T cell aging process. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Trends in cell phone use among children in the Danish national birth cohort at ages 7 and 11 years.

    Science.gov (United States)

    Sudan, Madhuri; Olsen, Jørn; Sigsgaard, Torben; Kheifets, Leeka

    2016-11-01

    We prospectively examined trends in cell phone use among children in the Danish National Birth Cohort. Cell phone use was assessed at ages 7 and 11 years, and we examined use patterns by age, by year of birth, and in relation to specific individual characteristics. There was an increase in cell phone use from age 7 (37%) to 11 years (94%). There was a clear pattern of greater reported cell phone use among children at age 7 years with later birth year, but this trend disappeared at age 11. Girls and those who used phones at age 7 talked more often and for longer durations at age 11 years. Low socio-economic status and later year of birth were associated with voice calls at age 7 but not at age 11 years. At age 11 most used cell phones for texting and gaming more than for voice calls. Further, children who started using cell phones at age 7 years were more likely to be heavy cell phone voice users at age 11 years, making early use a marker for higher cumulative exposure regardless of year of birth. As cell phone technology continues to advance, new use patterns will continue to emerge, and exposure assessment research among children must reflect these trends.

  10. Association between age and repair of oxidatively damaged DNA in human peripheral blood mononuclear cells

    DEFF Research Database (Denmark)

    Løhr, Mille; Jensen, Annie; Eriksen, Louise

    2015-01-01

    damaged DNA in peripheral blood mononuclear cells (PBMCs). We isolated PBMCs from subjects aged 18-83 years, as part of a health survey of the Danish population that focussed on lifestyle factors. The level of DNA repair activity was measured as incisions on potassium bromate-damaged DNA by the comet...... assay. There was an inverse association between age and DNA repair activity with a 0.65% decline in activity per year from age 18 to 83 (95% confidence interval: 0.16-1.14% per year). Univariate regression analysis also indicated inverse associations between DNA repair activity and waist-hip ratio (P...

  11. Toward an understanding of mechanism of aging-induced oxidative stress in human mesenchymal stem cells.

    Science.gov (United States)

    Benameur, Laila; Charif, Naceur; Li, Yueying; Stoltz, Jean-François; de Isla, Natalia

    2015-01-01

    Under physiological conditions, there is a production of limited range of free radicals. However, when the cellular antioxidant defence systems, overwhelm and fail to reverse back the free radicals to their normal basal levels, there is a creation of a condition of redox disequilibrium termed "oxidative stress", which is implicated in a very wide spectrum of genetic, metabolic, and cellular responses. The excess of free radicals can, cause unfavourable molecular alterations to biomolecules through oxidation of lipids, proteins, RNA and DNA, that can in turn lead to mutagenesis, carcinogenesis, and aging. Mesenchymal stem cells (MSCs) have been proven to be a promising source of cells for regenerative medicine, and to be useful in the treatment of pathologies in which tissue damage is linked to oxidative stress. Moreover, MSCs appeared to efficiently manage oxidative stress and to be more resistant to oxidative insult than normal somatic cells, making them an interesting and testable model for the role of oxidative stress in the aging process. In addition, aging is accompanied by a progressive decline in stem cell function, resulting in less effective tissue homeostasis and repair. Also, there is an obvious link between intracellular reactive oxygen species levels and cellular senescence. To date, few studies have investigated the promotion of aging by oxidative stress on human MSCs, and the mechanism by which oxidative stress induce stem cell aging is poorly understood. In this context, the aim of this review is to gain insight the current knowledge about the molecular mechanisms of aging-induced oxidative stress in human MSCs.

  12. Augmented vascular smooth muscle cell stiffness and adhesion when hypertension is superimposed on aging.

    Science.gov (United States)

    Sehgel, Nancy L; Sun, Zhe; Hong, Zhongkui; Hunter, William C; Hill, Michael A; Vatner, Dorothy E; Vatner, Stephen F; Meininger, Gerald A

    2015-02-01

    Hypertension and aging are both recognized to increase aortic stiffness, but their interactions are not completely understood. Most previous studies have attributed increased aortic stiffness to changes in extracellular matrix proteins that alter the mechanical properties of the vascular wall. Alternatively, we hypothesized that a significant component of increased vascular stiffness in hypertension is due to changes in the mechanical and adhesive properties of vascular smooth muscle cells, and that aging would augment the contribution from vascular smooth muscle cells when compared with the extracellular matrix. Accordingly, we studied aortic stiffness in young (16-week-old) and old (64-week-old) spontaneously hypertensive rats and Wistar-Kyoto wild-type controls. Systolic and pulse pressures were significantly increased in young spontaneously hypertensive rats when compared with young Wistar-Kyoto rats, and these continued to rise in old spontaneously hypertensive rats when compared with age-matched controls. Excised aortic ring segments exhibited significantly greater elastic moduli in both young and old spontaneously hypertensive rats versus Wistar-Kyoto rats. were isolated from the thoracic aorta, and stiffness and adhesion to fibronectin were measured by atomic force microscopy. Hypertension increased both vascular smooth muscle cell stiffness and vascular smooth muscle cell adhesion, and these increases were both augmented with aging. By contrast, hypertension did not affect histological measures of aortic collagen and elastin, which were predominantly changed by aging. These findings support the concept that stiffness and adhesive properties of vascular smooth muscle cells are novel mechanisms contributing to the increased aortic stiffness occurring with hypertension superimposed on aging. © 2014 American Heart Association, Inc.

  13. 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.

  14. Age-dependent change in biological characteristics of stem cells in radiation-induced mammary carcinogenesis

    International Nuclear Information System (INIS)

    Shimada, Yoshiya; Nishimura, Mayumi; Kakinuma, Shizuko; Imaoka, Tatsuhiko; Yasukawa-Barnes, Jane; Gould, Michael N.; Clifton, Kelly H.

    2003-01-01

    If you ask what types of cells are the targets for carcinogenesis, a popular answer would be that cancer arises from stem cells. Stem cells are cells that are capable of both self-renewal and generation of differentiated progenies. If the hypothesis of 'cancer as stem cell disease' is correct, the risk of carcinogenesis should be a function of the number of stem cells and their responsiveness of carcinogen-induced damage. In the present study, we addressed the feasibility of this hypothesis using the rat mammary carcinogenesis model. One of the important conclusions emerging from studies on atomic bomb survivors concerns age-related changes in the susceptibility to breast cancer. The relative risk of breast cancer is very high among women exposed to ionizing radiation before or during puberty, and it decreases thereafter. Little information is available, however, on age-related changes in the radiobiological nature of mammary stem cells. We examined age-associated changes in the number of mammary stem-like cells (clonogens) and their susceptibility to radiation in terms of cell death and carcinogenic initiation frequency. The results were as follows. (1) During the prepubertal period, the total number of mammary clonogens per rat increased exponentially with a population doubling time of ∼4 days. After puberty, the doubling time lengthened to ∼30 days. The total number of clonogens in abdominal and inguinal mammary glands was ∼200 in 2-week-old rats, while it was ∼5600 in 8-week-old rats. (2) The survival curves of clonogenic cells after irradiation indicated that radiation sensitivity of the cells before and during puberty was much higher than after puberty. (3) The initiation frequency of the clonogens from prepubertal rats after 5 Gy irradiation was four times higher than that of the clonogens from post-pubertal rats. These results suggest that changes in the number of stem cells and their radiobiological characteristics underlie the age

  15. Age-dependent change in biological characteristics of stem cells in radiation-induced mammary carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Shimada, Yoshiya; Nishimura, Mayumi; Kakinuma, Shizuko; Imaoka, Tatsuhiko [National Institute of Radiological Sciences, Anagawa, Chiba (Japan); Yasukawa-Barnes, Jane; Gould, Michael N.; Clifton, Kelly H. [Univ. of Wisconsin, Department of Human Oncology, Madison, WI (United States)

    2003-07-01

    If you ask what types of cells are the targets for carcinogenesis, a popular answer would be that cancer arises from stem cells. Stem cells are cells that are capable of both self-renewal and generation of differentiated progenies. If the hypothesis of 'cancer as stem cell disease' is correct, the risk of carcinogenesis should be a function of the number of stem cells and their responsiveness of carcinogen-induced damage. In the present study, we addressed the feasibility of this hypothesis using the rat mammary carcinogenesis model. One of the important conclusions emerging from studies on atomic bomb survivors concerns age-related changes in the susceptibility to breast cancer. The relative risk of breast cancer is very high among women exposed to ionizing radiation before or during puberty, and it decreases thereafter. Little information is available, however, on age-related changes in the radiobiological nature of mammary stem cells. We examined age-associated changes in the number of mammary stem-like cells (clonogens) and their susceptibility to radiation in terms of cell death and carcinogenic initiation frequency. The results were as follows. (1) During the prepubertal period, the total number of mammary clonogens per rat increased exponentially with a population doubling time of {approx}4 days. After puberty, the doubling time lengthened to {approx}30 days. The total number of clonogens in abdominal and inguinal mammary glands was {approx}200 in 2-week-old rats, while it was {approx}5600 in 8-week-old rats. (2) The survival curves of clonogenic cells after irradiation indicated that radiation sensitivity of the cells before and during puberty was much higher than after puberty. (3) The initiation frequency of the clonogens from prepubertal rats after 5 Gy irradiation was four times higher than that of the clonogens from post-pubertal rats. These results suggest that changes in the number of stem cells and their radiobiological characteristics

  16. Impact of NBTI Aging on the Single-Event Upset of SRAM Cells

    CERN Document Server

    Bagatin, M; Gerardin, Simone; Paccagnella, Alessandro; Bagatin, Marta

    2010-01-01

    We analyzed the impact of negative bias temperature instability (NBTI) on the single-event upset rate of SRAM cells through experiments and SPICE simulations. We performed critical charge simulations introducing different degradation patterns in the cells, in three technology nodes, from 180 to 90 nm. The simulations results were checked with alpha-particle and heavy-ion irradiations on a 130-nm technology. Both simulations and experimental results show that NBTI degradation does not significantly affect the single-event upset SRAM cell rate as long as the parametric drift induced by aging is within 10\\%.

  17. Cell population data in neonates: differences by age group and associations with perinatal factors.

    Science.gov (United States)

    Lee, J; Kim, S Y; Lee, W; Han, K; Sung, I K

    2015-10-01

    Cell population data (CPD) describe physical parameters of white blood cell subpopulations and are reported to be of some value in the diagnosis of sepsis in neonates. Before using the CPD for diagnosing sepsis, the baseline features of the CPD distribution in healthy neonates should be clarified. The aim of this study was to compare the CPD distributions of healthy neonates and other age groups and to identify perinatal factors that are associated with changes in the CPD distribution of healthy neonates. The CPD distribution of 69 samples from term neonates was compared with adolescents and adults. The CPD distribution of 163 samples from healthy neonates was analyzed in association with perinatal factors, including gestational age, chronologic age, birthweight, delivery mode, premature rupture of membranes, diabetes, and pregnancy-induced hypertension. The CPD distribution for term neonates was significantly different from those in adolescents and adults. The mean lymphocyte volume showed a negative correlation with gestational age at birth (r = -0.305; P group than in the normal delivery group. The small for gestational age (SGA) group had smaller mean neutrophil volume and mean monocyte volume than the appropriate for gestational age group. The CPD distribution of healthy neonates differed from those of adolescents or adults, and the differences were associated with gestational age, delivery mode, and being SGA. © 2015 John Wiley & Sons Ltd.

  18. A micro-Raman spectroscopic investigation of leukemic U-937 cells in aged cultures

    Science.gov (United States)

    Fazio, Enza; Trusso, Sebastiano; Franco, Domenico; Nicolò, Marco Sebastiano; Allegra, Alessandro; Neri, Fortunato; Musolino, Caterina; Guglielmino, Salvatore P. P.

    2016-04-01

    Recently it has been shown that micro-Raman spectroscopy combined with multivariate analysis is able to discriminate among different types of tissues and tumoral cells by the detection of significant alterations and/or reorganizations of complex biological molecules, such as nucleic acids, lipids and proteins. Moreover, its use, being in principle a non-invasive technique, appears an interesting clinical tool for the evaluation of the therapeutical effects and of the disease progression. In this work we analyzed molecular changes in aged cultures of leukemia model U937 cells with respect to fresh cultures of the same cell line. In fact, structural variations of individual neoplastic cells on aging may lead to a heterogeneous data set, therefore falsifying confidence intervals, increasing error levels of analysis and consequently limiting the use of Raman spectroscopy analysis. We found that the observed morphological changes of U937 cells corresponded to well defined modifications of the Raman contributions in selected spectral regions, where markers of specific functional groups, useful to characterize the cell state, are present. A detailed subcellular analysis showed a change in cellular organization as a function of time, and correlated to a significant increase of apoptosis levels. Besides the aforementioned study, Raman spectra were used as input for principal component analysis (PCA) in order to detect and classify spectral changes among U937 cells.

  19. Seismic fragility testing of naturally-aged, safety-related, class 1E battery cells

    International Nuclear Information System (INIS)

    Bonzon, L.L.; Hente, D.B.; Kukreti, B.M.; Schendel, J.S.; Black, D.A.; Paulsen, G.D.; Tulk, J.D.; Janis, W.J.; Aucoin, B.D.

    1984-01-01

    The concern over seismic susceptibility of naturally-aged lead-acid batteries used for safety-related emergency power in nuclear power stations was brought about by battery problems that periodically had been reported in Licensee Event Reports (LERs). The Turkey Point Station had reported cracked and buckled plates in several cells in October 1974 (LER 75-5). The Fitzpatrick Station had reported cracked battery cell cases in October 1977 (LER 77-55) and again in September 1979 (LER 79-59). The Browns Ferry Station had reported a cracked cell leaking a small quantity of electrolyte in July 1981 (LER 81-42). The Indian Point Station had reported cracked and leaking cells in both February (LER 82-7) and April 1982 (LER 82-16); both of these LERs indicated the cracked cells were due to expansion (i.e., growth) of the positive plates

  20. Epigenetic control of hematopoietic stem cell aging - The case of Ezh2

    NARCIS (Netherlands)

    de Haan, Gerald; Gerrits, Alice; Kanz, L; Weisel, KC; Dick, JE; Fibbe, WE

    2007-01-01

    Hematopoietic stem cells have potent, but not unlimited, selfrenewal potential. The mechanisms that restrict selfrenewal are likely to play a role during aging. Recent data suggest that the regulation of histone modifications by Polycomb group genes may be of crucial relevance to balance selfrenewal

  1. TH1 and TH2 cell polarization increases with aging and is modulated by zinc supplementation

    OpenAIRE

    2008-01-01

    TH1 and TH2 cell polarization increases with aging and is modulated by zinc supplementation correspondence: Corresponding author. Tel.: +49 241 8080208; fax: +49 241 8082613. (Rink, Lothar) (Rink, Lothar) Institute of Immunology, University Hospital, RWTH Aachen University - Aachen--> - GERMANY (Uciechowski, Peter) Institute of Immunology, University Hospital, RWTH Aachen University - Aachen--> - GERMAN...

  2. Age, gender, and percentage of circulating osteoprogenitor (COP) cells: The COP Study.

    Science.gov (United States)

    Gunawardene, Piumali; Al Saedi, Ahmed; Singh, Lakshman; Bermeo, Sandra; Vogrin, Sara; Phu, Steven; Suriyaarachchi, Pushpa; Pignolo, Robert J; Duque, Gustavo

    2017-10-01

    Circulating osteoprogenitor (COP) cells are blood-borne cells which express a variety of osteoblastic markers and are able to form bone nodules in vivo. Whereas a high percentage of COP cells (%COP) is associated with vascular calcification, low %COP has been associated with disability and frailty. However, the reference range of %COP in age- and gender-matching populations, and the age-related changes in %COP remain unknown. A cross-sectional study was undertaken in 144 healthy volunteers in Western Sydney (20-90year-old, 10 male and 10 female subjects per decade). %COP was quantified by flow cytometry. A high inter-and intra-rater reliability was found. In average, in this healthy population average of %COP was 0.42. There was no significant difference in %COP among the age groups. Similarly, no significant difference was found in %COP with gender, weight, height or BMI. In addition, we identified a normal reference range of %COP of 0.1-3.8%. In conclusion, in addition to the identification of steady levels of COP cells with age, we also identified a normal reference range of %COP, which could be used in future studies looking at musculoskeletal diseases in older populations. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Neural stem cells improve neuronal survival in cultured postmortem brain tissue from aged and Alzheimer patients

    NARCIS (Netherlands)

    Wu, L.; Sluiter, A.A.; Guo, Ho Fu; Balesar, R. A.; Swaab, D. F.; Zhou, Jiang Ning; Verwer, R. W H

    Neurodegenerative diseases are progressive and incurable and are becoming ever more prevalent. To study whether neural stem cell can reactivate or rescue functions of impaired neurons in the human aging and neurodegenerating brain, we co-cultured postmortem slices from Alzheimer patients and control

  4. Aging- and Senescence-associated Changes of Mesenchymal Stromal Cells in Myelodysplastic Syndromes.

    Science.gov (United States)

    Mattiucci, Domenico; Maurizi, Giulia; Leoni, Pietro; Poloni, Antonella

    2018-01-01

    Hematopoietic stem and progenitor cells reside within the bone marrow (BM) microenvironment. By a well-balanced interplay between self-renewal and differentiation, they ensure a lifelong supply of mature blood cells. Physiologically, multiple different cell types contribute to the regulation of stem and progenitor cells in the BM microenvironment by cell-extrinsic and cell-intrinsic mechanisms. During the last decades, mesenchymal stromal cells (MSCs) have been identified as one of the main cellular components of the BM microenvironment holding an indispensable role for normal hematopoiesis. During aging, MSCs diminish their functional and regenerative capacities and in some cases encounter replicative senescence, promoting inflammation and cancer progression. It is now evident that alterations in specific stromal cells that comprise the BM microenvironment can contribute to hematologic malignancies, and there is growing interest regarding the contribution of MSCs to the pathogenesis of myelodysplastic syndromes (MDSs), a clonal hematological disorder, occurring mostly in the elderly, characterized by ineffective hematopoiesis and increased tendency to acute myeloid leukemia evolution. The pathogenesis of MDS has been associated with specific genetic and epigenetic events occurring both in hematopoietic stem cells (HSCs) and in the whole BM microenvironment with an aberrant cross talk between hematopoietic elements and stromal compartment. This review highlights the role of MSCs in MDS showing functional and molecular alterations such as altered cell-cycle regulation with impaired proliferative potential, dysregulated cytokine secretion, and an abnormal gene expression profile. Here, the current knowledge of impaired functional properties of both aged MSCs and MSCs in MDS have been described with a special focus on inflammation and senescence induced changes in the BM microenvironment. Furthermore, a better understanding of aberrant BM microenvironment could

  5. Using measures of single-cell physiology and physiological state to understand organismic aging.

    Science.gov (United States)

    Mendenhall, Alexander; Driscoll, Monica; Brent, Roger

    2016-02-01

    Genetically identical organisms in homogeneous environments have different lifespans and healthspans. These differences are often attributed to stochastic events, such as mutations and 'epimutations', changes in DNA methylation and chromatin that change gene function and expression. But work in the last 10 years has revealed differences in lifespan- and health-related phenotypes that are not caused by lasting changes in DNA or identified by modifications to DNA or chromatin. This work has demonstrated persistent differences in single-cell and whole-organism physiological states operationally defined by values of reporter gene signals in living cells. While some single-cell states, for example, responses to oxygen deprivation, were defined previously, others, such as a generally heightened ability to make proteins, were, revealed by direct experiment only recently, and are not well understood. Here, we review technical progress that promises to greatly increase the number of these measurable single-cell physiological variables and measureable states. We discuss concepts that facilitate use of single-cell measurements to provide insight into physiological states and state transitions. We assert that researchers will use this information to relate cell level physiological readouts to whole-organism outcomes, to stratify aging populations into groups based on different physiologies, to define biomarkers predictive of outcomes, and to shed light on the molecular processes that bring about different individual physiologies. For these reasons, quantitative study of single-cell physiological variables and state transitions should provide a valuable complement to genetic and molecular explanations of how organisms age. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

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

    Directory of Open Access Journals (Sweden)

    Carl Johan Drott

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

  7. Cell-autonomous mechanisms of chronological aging in the yeast Saccharomyces cerevisiae

    Directory of Open Access Journals (Sweden)

    Anthony Arlia-Ciommo

    2014-05-01

    Full Text Available A body of evidence supports the view that the signaling pathways governing cellular aging – as well as mechanisms of their modulation by longevity-extending genetic, dietary and pharmacological interventions - are conserved across species. The scope of this review is to critically analyze recent advances in our understanding of cell-autonomous mechanisms of chronological aging in the budding yeast Saccharomyces cerevisiae. Based on our analysis, we propose a concept of a biomolecular network underlying the chronology of cellular aging in yeast. The concept posits that such network progresses through a series of lifespan checkpoints. At each of these checkpoints, the intracellular concentrations of some key intermediates and products of certain metabolic pathways - as well as the rates of coordinated flow of such metabolites within an intricate network of intercompartmental communications - are monitored by some checkpoint-specific ′′master regulator′′ proteins. The concept envisions that a synergistic action of these master regulator proteins at certain early-life and late-life checkpoints modulates the rates and efficiencies of progression of such processes as cell metabolism, growth, proliferation, stress resistance, macromolecular homeostasis, survival and death. The concept predicts that, by modulating these vital cellular processes throughout lifespan (i.e., prior to an arrest of cell growth and division, and following such arrest, the checkpoint-specific master regulator proteins orchestrate the development and maintenance of a pro- or anti-aging cellular pattern and, thus, define longevity of chronologically aging yeast.

  8. Cell-autonomous mechanisms of chronological aging in the yeast Saccharomyces cerevisiae.

    Science.gov (United States)

    Arlia-Ciommo, Anthony; Leonov, Anna; Piano, Amanda; Svistkova, Veronika; Titorenko, Vladimir I

    2014-05-27

    A body of evidence supports the view that the signaling pathways governing cellular aging - as well as mechanisms of their modulation by longevity-extending genetic, dietary and pharmacological interventions - are conserved across species. The scope of this review is to critically analyze recent advances in our understanding of cell-autonomous mechanisms of chronological aging in the budding yeast Saccharomyces cerevisiae . Based on our analysis, we propose a concept of a biomolecular network underlying the chronology of cellular aging in yeast. The concept posits that such network progresses through a series of lifespan checkpoints. At each of these checkpoints, the intracellular concentrations of some key intermediates and products of certain metabolic pathways - as well as the rates of coordinated flow of such metabolites within an intricate network of intercompartmental communications - are monitored by some checkpoint-specific "master regulator" proteins. The concept envisions that a synergistic action of these master regulator proteins at certain early-life and late-life checkpoints modulates the rates and efficiencies of progression of such processes as cell metabolism, growth, proliferation, stress resistance, macromolecular homeostasis, survival and death. The concept predicts that, by modulating these vital cellular processes throughout lifespan (i.e., prior to an arrest of cell growth and division, and following such arrest), the checkpoint-specific master regulator proteins orchestrate the development and maintenance of a pro- or anti-aging cellular pattern and, thus, define longevity of chronologically aging yeast.

  9. Telomerase Protects Werner Syndrome Lineage-Specific Stem Cells from Premature Aging

    Directory of Open Access Journals (Sweden)

    Hoi-Hung Cheung

    2014-04-01

    Full Text Available Werner syndrome (WS patients exhibit premature aging predominantly in mesenchyme-derived tissues, but not in neural lineages, a consequence of telomere dysfunction and accelerated senescence. The cause of this lineage-specific aging remains unknown. Here, we document that reprogramming of WS fibroblasts to pluripotency elongated telomere length and prevented telomere dysfunction. To obtain mechanistic insight into the origin of tissue-specific aging, we differentiated iPSCs to mesenchymal stem cells (MSCs and neural stem/progenitor cells (NPCs. We observed recurrence of premature senescence associated with accelerated telomere attrition and defective synthesis of the lagging strand telomeres in MSCs, but not in NPCs. We postulate this “aging” discrepancy is regulated by telomerase. Expression of hTERT or p53 knockdown ameliorated the accelerated aging phenotypein MSC, whereas inhibition of telomerase sensitized NPCs to DNA damage. Our findings unveil a role for telomerase in the protection of accelerated aging in a specific lineage of stem cells.

  10. Age-related effect of cell death on fiber morphology and number in tongue muscle.

    Science.gov (United States)

    Kletzien, Heidi; Hare, Allison J; Leverson, Glen; Connor, Nadine P

    2018-01-01

    Multiple pathways may exist for age-related tongue muscle degeneration. Cell death is one mechanism contributing to muscle atrophy and decreased function. We hypothesized with aging, apoptosis, and apoptotic regulators would be increased, and muscle fiber size and number would be reduced in extrinsic tongue muscles. Cell death indices, expression of caspase-3 and Bcl-2, and measures of muscle morphology and number were determined in extrinsic tongue muscles of young and old rats. Significant increases in cell death, caspase-3, and Bcl-2 were observed in all extrinsic tongue muscles along with reductions in muscle fiber number in old rats. We demonstrated that apoptosis indices increase with age in lingual muscles and that alterations in apoptotic regulators may be associated with age-related degeneration in muscle fiber size and number. These observed apoptotic processes may be detrimental to muscle function, and may contribute to degradation of cranial functions with age. Muscle Nerve 57: E29-E37, 2018. © 2017 Wiley Periodicals, Inc.

  11. Age-old wisdom concerning cell-based therapies with added knowledge in the stem cell era: our perspectives

    Directory of Open Access Journals (Sweden)

    Preethy S

    2013-04-01

    Full Text Available Senthilkumar Preethy,1,2 Sudhakar John,1 Jegatheesan Saravana Ganesh,1 Thangavelu Srinivasan,1 Hiroshi Terunuma,3 Masaru Iwasaki,4 Samuel J Abraham1,4 1Nichi-In Centre for Regenerative Medicine, 2Hope Foundation Trust, Chennai, India; 3Biotherapy Institute of Japan, Tokyo, 4Yamanashi University School of Medicine, Chuo, Japan Abstract: Among the various strategies providing a cure for illness, cell-based therapies have caught the attention of the world with the advent of the "stem cell" era. Our inherent understanding indicates that stem cells have been in existence since the birth of multicellular organisms. However, the formal discovery of stem cells in the last century, followed by their intricate and extensive analysis, has led to clinical and translational efforts with the aim of using them in the treatment of conditions which don't have a definitive therapeutic strategy, has fueled our interest and expectations. Technological advances in our ability to study their cellular components in depth, along with surface markers and other finer constituents, that were unknown until last century, have improved our understanding, leading to several novel applications. This has created a need to establish guidelines, and in that process, there are expressed understandings and views which describe cell therapy along lines similar to that of biologic products, drugs, and devices. However, the age-old wisdom of using cells as tools for curing illness should not be misled by recent knowledge, to make cell therapy using highly complex stem cells equal to factory-synthesized and reproducible chemical compounds, drugs, or devices. This article analyses the differences between these two entities from various perspectives. Keywords: cell transplantation, drugs, regenerative medicine, stem cells

  12. Methodological study of aging effects on fuel cells using X-ray synchrotron radiography and tomography

    International Nuclear Information System (INIS)

    Arlt, Tobias

    2012-01-01

    In the present work, new and advanced methods for the investigation of methanol and hydrogen powered fuel cells were analyzed. Synchrotron radiography and tomography were applied to investigate materials and transport processes in operating fuel cells ''in-situ'' and non-destructively. The corrosion of ruthenium is a key issue during aging of direct methanol fuel cells (DMFC). Therefore the influence of different aging processes on the distribution of ruthenium is of great interesting. An imaging method based on X-ray absorption spectroscopy (XAS) was applied to investigate the changes in the distribution of fuel cell catalysts three-dimensionally. Using monoenergetic synchrotron radiation it was shown that the distribution of ruthenium (Ru) in the anode catalyst changes after application of an accelerated aging procedure. A strong influence on the flowfield and the gas diffusion layer structures on the Ru distribution were found in the gas diffusion electrode at the anode side. Additionally some ruthenium moves through the membrane from the anode to the cathode. The redistribution caused by the accelerated aging procedure strongly differs from that obtained after aging under realistic stack operation (here over 1700 h) of a fuel cell in a pallet transporter. For the tomographic investigations samples were taken out from a stack operation in aged membrane electrode assembly (MEA) and were analyzed ex-situ. It was shown that the Ru redistribution can be attributed to mass transport processes (CO 2 and H 2 O) in the gas diffusion layer (GDL). Other high energy resolved measurements showed that the strength of the oxidation of ruthenium and platinum depends on the spatial distribution of the ruthenium. Last mentioned - also for the platinum catalyst - could be given quantitatively by means of this newly developed method. In the second part of this work high temperature polymer electrolyte fuel cells (HT-PEFC) were investigated. No liquid water can

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  14. Mechanisms of Heshouwuyin in regulating apoptosis of testicular cells in aging rats through mitochondrial pathway.

    Science.gov (United States)

    Chen, Jingbo; Wang, Yujuan; Hui, Chenhong; Xi, Yao; Liu, Xiang; Qi, Feng; Liu, Haokun; Wang, Zhenshan; Niu, Siyun

    2016-09-01

    Polygonum multiflorum has important effects on anti-aging and immunity enhancement. Many traditional Chinese medicine preparations based on Polygonum multiflorum are widely used for the clinical prevention and treatment of aging. However the mechanisms of these herb mixtures are often unknown. This study investigates the effect of Heshouwuyin, a Chinese herbal compound for invigorating the kidney, on the regulation of testicular cells apoptosis in aging rats. In this study, 18-month-old Wistar rats served as a model of natural aging and 12-month-old rats served as a young control group. Heshouwuyin group 1 and group 2 were comprised 18-month-old rats given Heshouwuyin intragastrically for 60 days and 30 days respectively. Then testes of the young control group were isolated in the age of 12 months, the other three groups were in the age of 18 months. TUNEL assay showed that the rate of testicular cell apoptosis was obviously higher and Flow cytometry analysis showed that the rate of cell proliferation was significantly lower in the natural aging group than in the young control group and that intervention with Heshouwuyin could reverse this phenomenon. Therefore, we further applied microarray analysis to screen out differentially expressed genes regulated by Heshouwuyin and related to cell apoptosis. The expression of these genes was observed by quantitative fluorescence PCR, immunofluorescence staining, and western blot. The results showed that the expression of 14-3-3σ was significantly lower and that the expression of DR6, BAX, caspase-3 and Cytc were significantly higher in the natural aging group than in the young control group, but intervention with Heshouwuyin significantly reversed this phenomenon. Moreover, the curative efficacy of Heshouwuyin after 60 days was better than that of Heshouwuyin after 30 days. Our study suggests that Heshouwuyin has anti-aging effects on the testis by means of inhibiting the occurrence of apoptosis in spermatogenic

  15. Strengthening of the DNA-protein complex during stationary phase aging of cell cultures

    International Nuclear Information System (INIS)

    Khokhlov, A.N.; Chirkova, E.Yu.; Gorin, A.I.

    1986-01-01

    The possibility of accumulation of cross-linkages in the DNA-protein complex was studied during stationary phase aging of cells in culture. Chinese hamster cells were used in the experiments, along with human fibroblasts. 3 H-thymidine, 14 C-valine, and 14 C-leucine were added to the medium. The quantity of protein firmly bound with DNA was judged from the value of the coefficient 14 C/ 3 H determined with allowance for penetration of counting from the 14 C-channel into the 3 H-channel. The authors maintain that the results presented in this paper provide further evidence of the value of stationary phase cell cultures for the study of the mechanisms of aging and also of some of the general principles underlying hereditary pathology

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

    Directory of Open Access Journals (Sweden)

    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.

  17. Modeling and Analysis of a Nonlinear Age-Structured Model for Tumor Cell Populations with Quiescence

    Science.gov (United States)

    Liu, Zijian; Chen, Jing; Pang, Jianhua; Bi, Ping; Ruan, Shigui

    2018-05-01

    We present a nonlinear first-order hyperbolic partial differential equation model to describe age-structured tumor cell populations with proliferating and quiescent phases at the avascular stage in vitro. The division rate of the proliferating cells is assumed to be nonlinear due to the limitation of the nutrient and space. The model includes a proportion of newborn cells that enter directly the quiescent phase with age zero. This proportion can reflect the effect of treatment by drugs such as erlotinib. The existence and uniqueness of solutions are established. The local and global stabilities of the trivial steady state are investigated. The existence and local stability of the positive steady state are also analyzed. Numerical simulations are performed to verify the results and to examine the impacts of parameters on the nonlinear dynamics of the model.

  18. Donor age of human platelet lysate affects proliferation and differentiation of mesenchymal stem cells.

    Directory of Open Access Journals (Sweden)

    Michael Lohmann

    Full Text Available The regenerative potential declines upon aging. This might be due to cell-intrinsic changes in stem and progenitor cells or to influences by the microenvironment. Mesenchymal stem cells (MSC raise high hopes in regenerative medicine. They are usually culture expanded in media with fetal calf serum (FCS or other serum supplements such as human platelet lysate (HPL. In this study, we have analyzed the impact of HPL-donor age on culture expansion. 31 single donor derived HPLs (25 to 57 years old were simultaneously compared for culture of MSC. Proliferation of MSC did not reveal a clear association with platelet counts of HPL donors or growth factors concentrations (PDGF-AB, TGF-β1, bFGF, or IGF-1, but it was significantly higher with HPLs from younger donors (45 years. Furthermore, HPLs from older donors increased activity of senescence-associated beta-galactosidase (SA-βgal. HPL-donor age did not affect the fibroblastoid colony-forming unit (CFU-f frequency, immunophenotype or induction of adipogenic differentiation, whereas osteogenic differentiation was significantly lower with HPLs from older donors. Concentrations of various growth factors (PDGF-AB, TGF-β1, bFGF, IGF-1 or hormones (estradiol, parathormone, leptin, 1,25 vitamin D3 were not associated with HPL-donor age or MSC growth. Taken together, our data support the notion that aging is associated with systemic feedback mechanisms acting on stem and progenitor cells, and this is also relevant for serum supplements in cell culture: HPLs derived from younger donors facilitate enhanced expansion and more pronounced osteogenic differentiation.

  19. Donor Age of Human Platelet Lysate Affects Proliferation and Differentiation of Mesenchymal Stem Cells

    Science.gov (United States)

    Lohmann, Michael; Walenda, Gudrun; Hemeda, Hatim; Joussen, Sylvia; Drescher, Wolf; Jockenhoevel, Stefan; Hutschenreuter, Gabriele; Zenke, Martin; Wagner, Wolfgang

    2012-01-01

    The regenerative potential declines upon aging. This might be due to cell-intrinsic changes in stem and progenitor cells or to influences by the microenvironment. Mesenchymal stem cells (MSC) raise high hopes in regenerative medicine. They are usually culture expanded in media with fetal calf serum (FCS) or other serum supplements such as human platelet lysate (HPL). In this study, we have analyzed the impact of HPL-donor age on culture expansion. 31 single donor derived HPLs (25 to 57 years old) were simultaneously compared for culture of MSC. Proliferation of MSC did not reveal a clear association with platelet counts of HPL donors or growth factors concentrations (PDGF-AB, TGF-β1, bFGF, or IGF-1), but it was significantly higher with HPLs from younger donors (45 years). Furthermore, HPLs from older donors increased activity of senescence-associated beta-galactosidase (SA-βgal). HPL-donor age did not affect the fibroblastoid colony-forming unit (CFU-f) frequency, immunophenotype or induction of adipogenic differentiation, whereas osteogenic differentiation was significantly lower with HPLs from older donors. Concentrations of various growth factors (PDGF-AB, TGF-β1, bFGF, IGF-1) or hormones (estradiol, parathormone, leptin, 1,25 vitamin D3) were not associated with HPL-donor age or MSC growth. Taken together, our data support the notion that aging is associated with systemic feedback mechanisms acting on stem and progenitor cells, and this is also relevant for serum supplements in cell culture: HPLs derived from younger donors facilitate enhanced expansion and more pronounced osteogenic differentiation. PMID:22662236

  20. Changes in glomerular parietal epithelial cells in mouse kidneys with advanced age

    Science.gov (United States)

    Roeder, Sebastian S.; Stefanska, Ania; Eng, Diana G.; Kaverina, Natalya; Sunseri, Maria W.; McNicholas, Bairbre A.; Rabinovitch, Peter; Engel, Felix B.; Daniel, Christoph; Amann, Kerstin; Lichtnekert, Julia; Pippin, Jeffrey W.

    2015-01-01

    Kidney aging is accompanied by characteristic changes in the glomerulus, but little is known about the effect of aging on glomerular parietal epithelial cells (PECs), nor if the characteristic glomerular changes in humans and rats also occur in very old mice. Accordingly, a descriptive analysis was undertaken in 27-mo-old C57B6 mice, considered advanced age. PEC density was significantly lower in older mice compared with young mice (aged 3 mo), and the decrease was more pronounced in juxtamedullary glomeruli compared with outer cortical glomeruli. In addition to segmental and global glomerulosclerosis in older mice, staining for matrix proteins collagen type IV and heparan sulfate proteoglycan were markedly increased in Bowman's capsules of older mouse glomeruli, consistent with increased extracellular matrix production by PECs. De novo staining for CD44, a marker of activated and profibrotic PECs, was significantly increased in aged glomeruli. CD44 staining was more pronounced in the juxtamedullary region and colocalized with phosphorylated ERK. Additionally, a subset of aged PECs de novo expressed the epithelial-to-mesenchymal transition markers α-smooth muscle and vimentin, with no changes in epithelial-to-mesenchymal transition markers E-cadherin and β-catenin. The mural cell markers neural/glial antigen 2, PDGF receptor-β, and CD146 as well as Notch 3 were also substantially increased in aged PECs. These data show that mice can be used to better understand the aging kidney and that PECs undergo substantial changes, especially in juxtamedullary glomeruli, that may participate in the overall decline in glomerular structure and function with advancing age. PMID:26017974

  1. Changes in glomerular parietal epithelial cells in mouse kidneys with advanced age.

    Science.gov (United States)

    Roeder, Sebastian S; Stefanska, Ania; Eng, Diana G; Kaverina, Natalya; Sunseri, Maria W; McNicholas, Bairbre A; Rabinovitch, Peter; Engel, Felix B; Daniel, Christoph; Amann, Kerstin; Lichtnekert, Julia; Pippin, Jeffrey W; Shankland, Stuart J

    2015-07-15

    Kidney aging is accompanied by characteristic changes in the glomerulus, but little is known about the effect of aging on glomerular parietal epithelial cells (PECs), nor if the characteristic glomerular changes in humans and rats also occur in very old mice. Accordingly, a descriptive analysis was undertaken in 27-mo-old C57B6 mice, considered advanced age. PEC density was significantly lower in older mice compared with young mice (aged 3 mo), and the decrease was more pronounced in juxtamedullary glomeruli compared with outer cortical glomeruli. In addition to segmental and global glomerulosclerosis in older mice, staining for matrix proteins collagen type IV and heparan sulfate proteoglycan were markedly increased in Bowman's capsules of older mouse glomeruli, consistent with increased extracellular matrix production by PECs. De novo staining for CD44, a marker of activated and profibrotic PECs, was significantly increased in aged glomeruli. CD44 staining was more pronounced in the juxtamedullary region and colocalized with phosphorylated ERK. Additionally, a subset of aged PECs de novo expressed the epithelial-to-mesenchymal transition markers α-smooth muscle and vimentin, with no changes in epithelial-to-mesenchymal transition markers E-cadherin and β-catenin. The mural cell markers neural/glial antigen 2, PDGF receptor-β, and CD146 as well as Notch 3 were also substantially increased in aged PECs. These data show that mice can be used to better understand the aging kidney and that PECs undergo substantial changes, especially in juxtamedullary glomeruli, that may participate in the overall decline in glomerular structure and function with advancing age. Copyright © 2015 the American Physiological Society.

  2. Bisphenol A Disrupts Transcription and Decreases Viability in Aging Vascular Endothelial Cells

    Science.gov (United States)

    Ribeiro-Varandas, Edna; Pereira, H. Sofia; Monteiro, Sara; Neves, Elsa; Brito, Luísa; Boavida Ferreira, Ricardo; Viegas, Wanda; Delgado, Margarida

    2014-01-01

    Bisphenol A (BPA) is a widely utilized endocrine disruptor capable of mimicking endogenous hormones, employed in the manufacture of numerous consumer products, thereby interfering with physiological cellular functions. Recent research has shown that BPA alters epigenetic cellular mechanisms in mammals and may be correlated to enhanced cellular senescence. Here, the effects of BPA at 10 ng/mL and 1 µg/mL, concentrations found in human samples, were analyzed on HT29 human colon adenocarcinona cell line and Human Umbilical Vein Endothelial Cells (HUVEC). Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) transcriptional analysis of the Long Interspersed Element-1 (LINE-1) retroelement showed that BPA induces global transcription deregulation in both cell lines, although with more pronounced effects in HUVEC cells. Whereas there was an increase in global transcription in HT29 exclusively after 24 h of exposure, this chemical had prolonged effects on HUVEC. Immunoblotting revealed that this was not accompanied by alterations in the overall content of H3K9me2 and H3K4me3 epigenetic marks. Importantly, cell viability assays and transcriptional analysis indicated that prolonged BPA exposure affects aging processes in senescent HUVEC. To our knowledge this is the first report that BPA interferes with senescence in primary vascular endothelial cells, therefore, suggesting its association to the etiology of age-related human pathologies, such as atherosclerosis. PMID:25207595

  3. The promise of human embryonic stem cells in aging-associated diseases

    Science.gov (United States)

    Yabut, Odessa; Bernstein, Harold S.

    2011-01-01

    Aging-associated diseases are often caused by progressive loss or dysfunction of cells that ultimately affect the overall function of tissues and organs. Successful treatment of these diseases could benefit from cell-based therapy that would regenerate lost cells or otherwise restore tissue function. Human embryonic stem cells (hESCs) promise to be an important therapeutic candidate in treating aging-associated diseases due to their unique capacity for self-renewal and pluripotency. To date, there are numerous hESC lines that have been developed and characterized. We will discuss how hESC lines are derived, their molecular and cellular properties, and how their ability to differentiate into all three embryonic germ layers is determined. We will also outline the methods currently employed to direct their differentiation into populations of tissue-specific, functional cells. Finally, we will highlight the general challenges that must be overcome and the strategies being developed to generate highly-purified hESC-derived cell populations that can safely be used for clinical applications. PMID:21566262

  4. The Citrus Flavanone Naringenin Protects Myocardial Cells against Age-Associated Damage

    Directory of Open Access Journals (Sweden)

    Eleonora Da Pozzo

    2017-01-01

    Full Text Available In recent years, the health-promoting effects of the citrus flavanone naringenin have been examined. The results have provided evidence for the modulation of some key mechanisms involved in cellular damage by this compound. In particular, naringenin has been revealed to have protective properties such as an antioxidant effect in cardiometabolic disorders. Very recently, beneficial effects of naringenin have been demonstrated in old rats. Because aging has been demonstrated to be directly related to the occurrence of cardiac disorders, in the present study, the ability of naringenin to prevent cardiac cell senescence was investigated. For this purpose, a cellular model of senescent myocardial cells was set up and evaluated using colorimetric, fluorimetric, and immunometric techniques. Relevant cellular senescence markers, such as X-gal staining, cell cycle regulator levels, and the percentage of cell cycle-arrested cells, were found to be reduced in the presence of naringenin. In addition, cardiac markers of aging-induced damage, including radical oxidative species levels, mitochondrial metabolic activity, mitochondrial calcium buffer capacity, and estrogenic signaling functions, were also modulated by the compound. These results suggested that naringenin has antiaging effects on myocardial cells.

  5. Female Aging Alters Expression of Human Cumulus Cells Genes that Are Essential for Oocyte Quality

    Directory of Open Access Journals (Sweden)

    Tamadir Al-Edani

    2014-01-01

    Full Text Available Impact of female aging is an important issue in human reproduction. There was a need for an extensive analysis of age impact on transcriptome profile of cumulus cells (CCs to link oocyte quality and developmental potential with patient’s age. CCs from patients of three age groups were analyzed individually using microarrays. RT-qPCR validation was performed on independent CC cohorts. We focused here on pathways affected by aging in CCs that may explain the decline of oocyte quality with age. In CCs collected from patients >37 years, angiogenic genes including ANGPTL4, LEPR, TGFBR3, and FGF2 were significantly overexpressed compared to patients of the two younger groups. In contrast genes implicated in TGF-β signaling pathway such as AMH, TGFB1, inhibin, and activin receptor were underexpressed. CCs from patients whose ages are between 31 and 36 years showed an overexpression of genes related to insulin signaling pathway such as IGFBP3, PIK3R1, and IGFBP5. A bioinformatic analysis was performed to identify the microRNAs that are potential regulators of the differentially expressed genes of the study. It revealed that the pathways impacted by age were potential targets of specific miRNAs previously identified in our CCs small RNAs sequencing.

  6. SV40-transformed human fibroblasts: evidence for cellular aging in pre-crisis cells.

    Science.gov (United States)

    Stein, G H

    1985-10-01

    Pre-crisis SV40-transformed human diploid fibroblast (HDF) cultures have a finite proliferative lifespan, but they do not enter a viable senescent state at end of lifespan. Little is known about either the mechanism for this finite lifespan in SV40-transformed HDF or its relationship to finite lifespan in normal HDF. Recently we proposed that in normal HDF the phenomena of finite lifespan and arrest in a viable senescent state depend on two separate processes: 1) an age-related decrease in the ability of the cells to recognize or respond to serum and/or other mitogens such that the cells become functionally mitogen-deprived at the end of lifespan; and 2) the ability of the cells to enter a viable, G1-arrested state whenever they experience mitogen deprivation. In this paper, data are presented that suggest that pre-crisis SV40-transformed HDF retain the first process described above, but lack the second process. It is shown that SV40-transformed HDF have a progressively decreasing ability to respond to serum as they age, but they continue to traverse the cell cycle at the end of lifespan. Concomitantly, the rate of cell death increases steadily toward the end of lifespan, thereby causing the total population to cease growing and ultimately to decline. Previous studies have shown that when SV40-transformed HDF are environmentally serum deprived, they likewise exhibit continued cell cycle traverse coupled with increased cell death. Thus, these results support the hypothesis that pre-crisis SV40-transformed HDF still undergo the same aging process as do normal HDF, but they end their lifespan in crisis rather than in the normal G1-arrested senescent state because they have lost their ability to enter a viable, G1-arrested state in response to mitogen deprivation.

  7. Combination Of Aging And Dimethylhydrazine Treatment Causes An Increase In The Stem Cell Population Of Rat Colonic Crypts

    OpenAIRE

    Levi, Edi; Misra, Sandhya; Du, Jianhua; Patel, Bhaumik B.; Majumdar, Adhip P. N.

    2009-01-01

    Aging is associated with increased incidence of colon cancers. It is also becoming evident that cancer stem cells (CSC) play a vital role in the pathogenesis and prognosis of colon cancer. Recently, we reported the presence of colon cancer stem-like cells in macroscopically normal mucosa in patients with adenomatous polyps and that they increase with aging, suggesting that aging may predispose the colon to carcinogenesis. In the current study we have examined the combined effects of aging and...

  8. Age and metabolic risk factors associated with oxidatively damaged DNA in human peripheral blood mononuclear cells

    DEFF Research Database (Denmark)

    Løhr, Mille; Jensen, Annie; Eriksen, Louise

    2015-01-01

    Aging is associated with oxidative stress-generated damage to DNA and this could be related to metabolic disturbances. This study investigated the association between levels of oxidatively damaged DNA in peripheral blood mononuclear cells (PBMCs) and metabolic risk factors in 1,019 subjects, aged...... 18-93 years. DNA damage was analyzed as strand breaks by the comet assay and levels of formamidopyrimidine (FPG-) and human 8-oxoguanine DNA glycosylase 1 (hOGG1)-sensitive sites There was an association between age and levels of FPG-sensitive sites for women, but not for men. The same tendency......, cholesterol and glycosylated hemoglobin (HbA1c). In the group of men, there were significant positive associations between alcohol intake, HbA1c and FPG-sensitive sites in multivariate analysis. The levels of metabolic risk factors were positively associated with age, yet only few subjects fulfilled all...

  9. Impaired succinic dehydrogenase activity of rat Purkinje cell mitochondria during aging.

    Science.gov (United States)

    Fattoretti, P; Bertoni-Freddari, C; Caselli, U; Paoloni, R; Meier-Ruge, W

    1998-03-16

    The perikaryal Purkinje cell mitochondria positive to the copper ferrocyanide histochemical reaction for succinic dehydrogenase (SDH) have been investigated by means of semiautomatic morphometric methods in rats of 3, 12 and 24 months of age. The number of organelles/microm3 of Purkinje cell cytoplasm (Numeric density: Nv), the average mitochondrial volume (V) and the mitochondrial volume fraction (Volume density: Vv) were the ultrastructural parameters taken into account. Nv was significantly higher at 12 than at 3 and 24 months of age. V was significantly decreased at 12 and 24 months of age, but no difference was envisaged between adult and old rats. Vv was significantly decreased in old animals vs. the other age groups. In young and old rats, the percentage of organelles larger than 0.32 microm3 was 13.5 and 11%, respectively, while these enlarged mitochondria accounted for less than 1% in the adult group. Since SDH activity is of critical importance when energy demand is high, the marked decrease of Vv supports an impaired capacity of the old Purkinje cells to match actual energy supply at sustained transmission of the nervous impulse. However, the high percentage of enlarged organelles found in old rats may witness a morphofunctional compensatory response.

  10. Increased Stiffness in Aged Skeletal Muscle Impairs Muscle Progenitor Cell Proliferative Activity.

    Directory of Open Access Journals (Sweden)

    Grégory Lacraz

    Full Text Available Skeletal muscle aging is associated with a decreased regenerative potential due to the loss of function of endogenous stem cells or myogenic progenitor cells (MPCs. Aged skeletal muscle is characterized by the deposition of extracellular matrix (ECM, which in turn influences the biomechanical properties of myofibers by increasing their stiffness. Since the stiffness of the MPC microenvironment directly impacts MPC function, we hypothesized that the increase in muscle stiffness that occurs with aging impairs the behavior of MPCs, ultimately leading to a decrease in regenerative potential.We showed that freshly isolated individual myofibers from aged mouse muscles contain fewer MPCs overall than myofibers from adult muscles, with fewer quiescent MPCs and more proliferative and differentiating MPCs. We observed alterations in cultured MPC behavior in aged animals, where the proliferation and differentiation of MPCs were lower and higher, respectively. These alterations were not linked to the intrinsic properties of aged myofibers, as shown by the similar values for the cumulative population-doubling values and fusion indexes. However, atomic force microscopy (AFM indentation experiments revealed a nearly 4-fold increase in the stiffness of the MPC microenvironment. We further showed that the increase in stiffness is associated with alterations to muscle ECM, including the accumulation of collagen, which was correlated with higher hydroxyproline and advanced glycation end-product content. Lastly, we recapitulated the impaired MPC behavior observed in aging using a hydrogel substrate that mimics the stiffness of myofibers.These findings provide novel evidence that the low regenerative potential of aged skeletal muscle is independent of intrinsic MPC properties but is related to the increase in the stiffness of the MPC microenvironment.

  11. A new human male diploid cell strain, TIG-7: its age-related changes and comparison with a matched female TIG-1 cell strain.

    Science.gov (United States)

    Yamamoto, K; Kaji, K; Kondo, H; Matsuo, M; Shibata, Y; Tasaki, Y; Utakoji, T; Ooka, H

    1991-01-01

    A new human diploid cell strain, TIG-7, which has the male karyotype, was established and characterized. Isozyme and histocompatibility typing of the cell strain was performed. The average in vitro life span of the cells is 73 population doublings. Changes in cell volume, doubling time, saturation density, the efficiency of cell attachment, plating efficiency, and relative DNA content were examined during in vitro cellular aging. Hydrocortisone slightly prolongs the life span of the cell strain when the hormone is administered to the cultures during middle passages. The age-related changes in the parameters of TIG-7 are not appreciably different from those of the previously established TIG-1 cell strain. These results show that this cell strain is useful for research on cellular aging; further profit is anticipated from research using a combination of these two sexually different cell strains.

  12. Depletion of Pax7+ satellite cells does not affect diaphragm adaptations to running in young or aged mice.

    Science.gov (United States)

    Murach, Kevin A; Confides, Amy L; Ho, Angel; Jackson, Janna R; Ghazala, Lina S; Peterson, Charlotte A; Dupont-Versteegden, Esther E

    2017-10-01

    Satellite cell depletion does not affect diaphragm adaptations to voluntary wheel running in young or aged mice. Satellite cell depletion early in life (4 months of age) has minimal effect on diaphragm phenotype by old age (24 months). Prolonged satellite cell depletion in the diaphragm does not result in excessive extracellular matrix accumulation, in contrast to what has been reported in hind limb muscles. Up-regulation of Pax3 mRNA+ cells after satellite cell depletion in young and aged mice suggests that Pax3+ cells may compensate for a loss of Pax7+ satellite cells in the diaphragm. Future investigations should focus on the role of Pax3+ cells in the diaphragm during adaptation to exercise and ageing. Satellite cell contribution to unstressed diaphragm is higher compared to hind limb muscles, which is probably attributable to constant activation of this muscle to drive ventilation. Whether satellite cell depletion negatively impacts diaphragm quantitative and qualitative characteristics under stressed conditions in young and aged mice is unknown. We therefore challenged the diaphragm with prolonged running activity in the presence and absence of Pax7+ satellite cells in young and aged mice using an inducible Pax7 CreER -R26R DTA model. Mice were vehicle (Veh, satellite cell-replete) or tamoxifen (Tam, satellite cell-depleted) treated at 4 months of age and were then allowed to run voluntarily at 6 months (young) and 22 months (aged). Age-matched, cage-dwelling, Veh- and Tam-treated mice without wheel access served as activity controls. Diaphragm muscles were analysed from young (8 months) and aged (24 months) mice. Satellite cell depletion did not alter diaphragm mean fibre cross-sectional area, fibre type distribution or extracellular matrix content in young or aged mice, regardless of running activity. Resting in vivo diaphragm function was also unaffected by satellite cell depletion. Myonuclear density was maintained in young satellite cell

  13. Impact of Type of Sport, Gender and Age on Red Blood Cell Deformability of Elite Athletes.

    Science.gov (United States)

    Tomschi, Fabian; Bloch, Wilhelm; Grau, Marijke

    2018-01-01

    Our objective was to detect possible differences in red blood cell (RBC) deformability of elite athletes performing different types of sports and being of different age and gender.182 athletes were included in this cross-sectional study. RBC deformability was measured using the laser-assisted optical rotational cell-analyzer. Maximal elongation index (EI  max ) and shear stress at half-maximum deformation (SS  1/2 ) were calculated. The ratio SS  1/2  /EI  max  (EI  Ratio ) was calculated with low values representing high RBC deformation. Hematocrit (Hct) and mean cellular volume (MCV) were determined in venous blood. Overall RBC deformability did not differ between male and female athletes but, when separated by age of the subjects, RBC deformability increased with age in male but not in female athletes. RBC deformability was lower in Combat sports compared other sport groups. Hct was higher in male compared to female athletes while no difference was observed for MCV. MCV and Hct increased with increasing age. A negative correlation was found between the EI  Ratio  and MCV and between EI  Ratio  and Hct. RBC deformability is influenced by age and endurance rate of the sport which suggests that the RBC system may adapt to changing conditions such as adolescence with the onset effects of sex hormones or physical exercise. © Georg Thieme Verlag KG Stuttgart · New York.

  14. Protein Carbamylation: A Marker Reflecting Increased Age-Related Cell Oxidation

    Directory of Open Access Journals (Sweden)

    Julia Carracedo

    2018-05-01

    Full Text Available Carbamylation is a post-translational modification of proteins that may partake in the oxidative stress-associated cell damage, and its increment has been recently proposed as a “hallmark of aging”. The molecular mechanisms associated with aging are related to an increased release of free radicals. We have studied whether carbamylated proteins from the peripheral blood of healthy subjects are related to oxidative damage and aging, taking into account the gender and the immune profile of the subjects. The study was performed in healthy human volunteers. The detection of protein carbamylation and malondialdehyde (MDA levels was evaluated using commercial kits. The immune profile was calculated using parameters of immune cell function. The results show that the individuals from the elderly group (60–79 years old have increased carbamylated protein and MDA levels. When considered by gender, only men between 60 and 79 years old showed significantly increased carbamylated proteins and MDA levels. When those subjects were classified by their immune profile, the carbamylated protein levels were higher in those with an older immune profile. In conclusion, the carbamylation of proteins in peripheral blood is related to age-associated oxidative damage and to an aging functional immunological signature. Our results suggest that carbamylated proteins may play an important role at the cellular level in the aging process.

  15. Age-Dependent Differences in Systemic and Cell-Autonomous Immunity to L. monocytogenes

    Directory of Open Access Journals (Sweden)

    Ashley M. Sherrid

    2013-01-01

    Full Text Available Host defense against infection can broadly be categorized into systemic immunity and cell-autonomous immunity. Systemic immunity is crucial for all multicellular organisms, increasing in importance with increasing cellular complexity of the host. The systemic immune response to Listeria monocytogenes has been studied extensively in murine models; however, the clinical applicability of these findings to the human newborn remains incompletely understood. Furthermore, the ability to control infection at the level of an individual cell, known as “cell-autonomous immunity,” appears most relevant following infection with L. monocytogenes; as the main target, the monocyte is centrally important to innate as well as adaptive systemic immunity to listeriosis. We thus suggest that the overall increased risk to suffer and die from L. monocytogenes infection in the newborn period is a direct consequence of age-dependent differences in cell-autonomous immunity of the monocyte to L. monocytogenes. We here review what is known about age-dependent differences in systemic innate and adaptive as well as cell-autonomous immunity to infection with Listeria monocytogenes.

  16. Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women.

    Science.gov (United States)

    White, Yvonne A R; Woods, Dori C; Takai, Yasushi; Ishihara, Osamu; Seki, Hiroyuki; Tilly, Jonathan L

    2012-02-26

    Germline stem cells that produce oocytes in vitro and fertilization-competent eggs in vivo have been identified in and isolated from adult mouse ovaries. Here we describe and validate a fluorescence-activated cell sorting-based protocol that can be used with adult mouse ovaries and human ovarian cortical tissue to purify rare mitotically active cells that have a gene expression profile that is consistent with primitive germ cells. Once established in vitro, these cells can be expanded for months and can spontaneously generate 35- to 50-μm oocytes, as determined by morphology, gene expression and haploid (1n) status. Injection of the human germline cells, engineered to stably express GFP, into human ovarian cortical biopsies leads to formation of follicles containing GFP-positive oocytes 1-2 weeks after xenotransplantation into immunodeficient female mice. Thus, ovaries of reproductive-age women, similar to adult mice, possess rare mitotically active germ cells that can be propagated in vitro as well as generate oocytes in vitro and in vivo.

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

    Science.gov (United States)

    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.

  18. Induced pluripotent stem cell-based therapy for age-related macular degeneration.

    Science.gov (United States)

    Bracha, Peter; Moore, Nicholas A; Ciulla, Thomas A

    2017-09-01

    In age-related macular degeneration (AMD), stem cells could possibly replace or regenerate disrupted pathologic retinal pigment epithelium (RPE), and produce supportive growth factors and cytokines such as brain-derived neurotrophic factor.  Induced pluripotent stem cells (iPSCs)-derived RPE was first subretinally transplanted in a neovascular AMD patient in 2014. Areas covered: Induced PSCs are derived from the introduction of transcription factors to adult cells under specific cell culture conditions, followed by differentiation into RPE cells. Induced PSC-derived RPE cells exhibit ion transport, membrane potential, polarized VEGF secretion and gene expression that is similar to native RPE. Despite having similar in vitro function, morphology, immunostaining and microscopic analysis, it remains to be seen if iPSC-derived RPE can replicate the myriad of in vivo functions, including immunomodulatory effects, of native RPE cells.  Historically, adjuvant RPE transplantation during CNV resections were technically difficult and complicated by immune rejection. Autologous iPSCs are hypothesized to reduce the risk of immune rejection, but their production is time-consuming and expensive.  Alternatively, allogenic transplantation using human leukocyte antigen (HLA)-matched iPSCs, similar to HLA-matched organ transplantation, is currently being investigated. Expert opinion: Challenges to successful transplantation with iPSCs include surgical technique, a pathologic subretinal microenvironment, possible immune rejection, and complications of immunosuppression.

  19. Aging studies on micro-fabricated alkali buffer-gas cells for miniature atomic clocks

    International Nuclear Information System (INIS)

    Abdullah, S.; Affolderbach, C.; Gruet, F.; Mileti, G.

    2015-01-01

    We report an aging study on micro-fabricated alkali vapor cells using neon as a buffer gas. An experimental atomic clock setup is used to measure the cell's intrinsic frequency, by recording the clock frequency shift at different light intensities and extrapolating to zero intensity. We find a drift of the cell's intrinsic frequency of (−5.2 ± 0.6) × 10 −11 /day and quantify deterministic variations in sources of clock frequency shifts due to the major physical effects to identify the most probable cause of the drift. The measured drift is one order of magnitude stronger than the total frequency variations expected from clock parameter variations and corresponds to a slow reduction of buffer gas pressure inside the cell, which is compatible with the hypothesis of loss of Ne gas from the cell due to its permeation through the cell windows. A negative drift on the intrinsic cell frequency is reproducible for another cell of the same type. Based on the Ne permeation model and the measured cell frequency drift, we determine the permeation constant of Ne through borosilicate glass as (5.7 ± 0.7) × 10 −22 m 2 s −1  Pa −1 at 81 °C. We propose this method based on frequency metrology in an alkali vapor cell atomic clock setup based on coherent population trapping for measuring permeation constants of inert gases

  20. Polarization Curve of a Non-Uniformly Aged PEM Fuel Cell

    Directory of Open Access Journals (Sweden)

    Andrei Kulikovsky

    2014-01-01

    Full Text Available We develop a semi-analytical model for polarization curve of a polymer electrolyte membrane (PEM fuel cell with distributed (aged along the oxygen channel MEA transport and kinetic parameters of the membrane–electrode assembly (MEA. We show that the curve corresponding to varying along the channel parameter, in general, does not reduce to the curve for a certain constant value of this parameter. A possibility to determine the shape of the deteriorated MEA parameter along the oxygen channel by fitting the model equation to the cell polarization data is demonstrated.

  1. Mesenchymal Stem Cells from Adipose Tissue in Clinical Applications for Dermatological Indications and Skin Aging

    Directory of Open Access Journals (Sweden)

    Meenakshi Gaur

    2017-01-01

    Full Text Available Operating at multiple levels of control, mesenchymal stem cells from adipose tissue (ADSCs communicate with organ systems to adjust immune response, provide signals for differentiation, migration, enzymatic reactions, and to equilibrate the regenerative demands of balanced tissue homeostasis. The identification of the mechanisms by which ADSCs accomplish these functions for dermatological rejuvenation and wound healing has great potential to identify novel targets for the treatment of disorders and combat aging. Herein, we review new insights into the role of adipose-derived stem cells in the maintenance of dermal and epidermal homeostasis, and recent advances in clinical applications of ADSCs related to dermatology.

  2. Age-related mitochondrial DNA depletion and the impact on pancreatic Beta cell function.

    Science.gov (United States)

    Nile, Donna L; Brown, Audrey E; Kumaheri, Meutia A; Blair, Helen R; Heggie, Alison; Miwa, Satomi; Cree, Lynsey M; Payne, Brendan; Chinnery, Patrick F; Brown, Louise; Gunn, David A; Walker, Mark

    2014-01-01

    Type 2 diabetes is characterised by an age-related decline in insulin secretion. We previously identified a 50% age-related decline in mitochondrial DNA (mtDNA) copy number in isolated human islets. The purpose of this study was to mimic this degree of mtDNA depletion in MIN6 cells to determine whether there is a direct impact on insulin secretion. Transcriptional silencing of mitochondrial transcription factor A, TFAM, decreased mtDNA levels by 40% in MIN6 cells. This level of mtDNA depletion significantly decreased mtDNA gene transcription and translation, resulting in reduced mitochondrial respiratory capacity and ATP production. Glucose-stimulated insulin secretion was impaired following partial mtDNA depletion, but was normalised following treatment with glibenclamide. This confirms that the deficit in the insulin secretory pathway precedes K+ channel closure, indicating that the impact of mtDNA depletion is at the level of mitochondrial respiration. In conclusion, partial mtDNA depletion to a degree comparable to that seen in aged human islets impaired mitochondrial function and directly decreased insulin secretion. Using our model of partial mtDNA depletion following targeted gene silencing of TFAM, we have managed to mimic the degree of mtDNA depletion observed in aged human islets, and have shown how this correlates with impaired insulin secretion. We therefore predict that the age-related mtDNA depletion in human islets is not simply a biomarker of the aging process, but will contribute to the age-related risk of type 2 diabetes.

  3. Age-Associated Decline in Thymic B Cell Expression of Aire and Aire-Dependent Self-Antigens

    Directory of Open Access Journals (Sweden)

    Sergio Cepeda

    2018-01-01

    Full Text Available Although autoimmune disorders are a significant source of morbidity and mortality in older individuals, the mechanisms governing age-associated increases in susceptibility remain incompletely understood. Central T cell tolerance is mediated through presentation of self-antigens by cells constituting the thymic microenvironment, including epithelial cells, dendritic cells, and B cells. Medullary thymic epithelial cells (mTECs and B cells express distinct cohorts of self-antigens, including tissue-restricted self-antigens (TRAs, such that developing T cells are tolerized to antigens from peripheral tissues. We find that expression of the TRA transcriptional regulator Aire, as well as Aire-dependent genes, declines with age in thymic B cells in mice and humans and that cell-intrinsic and cell-extrinsic mechanisms contribute to the diminished capacity of peripheral B cells to express Aire within the thymus. Our findings indicate that aging may diminish the ability of thymic B cells to tolerize T cells, revealing a potential mechanistic link between aging and autoimmunity.

  4. Use of Aromatase Inhibitors in Large Cell Calcifying Sertoli Cell Tumors: Effects on Gynecomastia, Growth Velocity, and Bone Age

    Science.gov (United States)

    Crocker, Melissa K.; Gourgari, Evgenia; Stratakis, Constantine A.

    2014-01-01

    Context: Large cell calcifying Sertoli cell tumors (LCCSCT) present in isolation or, especially in children, in association with Carney Complex (CNC) or Peutz-Jeghers Syndrome (PJS). These tumors overexpress aromatase (CYP19A1), which leads to increased conversion of delta-4-androstenedione to estrone and testosterone to estradiol. Prepubertal boys may present with growth acceleration, advanced bone age, and gynecomastia. Objective: To investigate the outcomes of aromatase inhibitor therapy (AIT) in prepubertal boys with LCCSCTs. Design: Case series of a very rare tumor and chart review of cases treated at other institutions. Setting: Tertiary care and referral center. Patients: Six boys, five with PJS and one with CNC, were referred to the National Institutes of Health for treatment of LCCSCT. All patients had gynecomastia, testicular enlargement, and advanced bone ages, and were being treated by their referring physicians with AIT. Interventions: Patients were treated for a total of 6–60 months on AIT. Main Outcome Measures: Height, breast tissue mass, and testicular size were all followed; physical examination, scrotal ultrasounds, and bone ages were obtained, and hormonal concentrations and tumor markers were measured. Results: Tumor markers were negative. All patients had decreases in breast tissue while on therapy. Height percentiles declined, and predicted adult height moved closer to midparental height as bone age advancement slowed. Testicular enlargement stabilized until entry into central puberty. Only one patient required unilateral orchiectomy. Conclusions: Patients with LCCSCT benefit from AIT with reduction and/or elimination of gynecomastia and slowing of linear growth and bone age advancement. Further study of long-term outcomes and safety monitoring are needed but these preliminary data suggest that mammoplasty and/or orchiectomy may be foregone in light of the availability of medical therapy. PMID:25226294

  5. Curcumin in Cell Death Processes: A Challenge for CAM of Age-Related Pathologies

    Directory of Open Access Journals (Sweden)

    S. Salvioli

    2007-01-01

    Full Text Available Curcumin, the yellow pigment from the rhizoma of Curcuma longa, is a widely studied phytochemical which has a variety of biological activities: anti-inflammatory and anti-oxidative. In this review we discuss the biological mechanisms and possible clinical effects of curcumin treatment on cancer therapy, and neurodegenerative diseases such as Alzheimer's Disease, with particular attention to the cell death processes induced by curcumin. Since oxidative stress and inflammation are major determinants of the aging process, we also argue that curcumin can have a more general effect that slows down the rate of aging. Finally, the effects of curcumin can be described as xenohormetic, since it activates a sort of stress response in mammalian cells.

  6. Circulating endothelial progenitor cells: a new approach to anti-aging medicine?

    Directory of Open Access Journals (Sweden)

    Patel Amit N

    2009-12-01

    Full Text Available Abstract Endothelial dysfunction is associated with major causes of morbidity and mortality, as well as numerous age-related conditions. The possibility of preserving or even rejuvenating endothelial function offers a potent means of preventing/treating some of the most fearful aspects of aging such as loss of mental, cardiovascular, and sexual function. Endothelial precursor cells (EPC provide a continual source of replenishment for damaged or senescent blood vessels. In this review we discuss the biological relevance of circulating EPC in a variety of pathologies in order to build the case that these cells act as an endogenous mechanism of regeneration. Factors controlling EPC mobilization, migration, and function, as well as therapeutic interventions based on mobilization of EPC will be reviewed. We conclude by discussing several clinically-relevant approaches to EPC mobilization and provide preliminary data on a food supplement, Stem-Kine, which enhanced EPC mobilization in human subjects.

  7. Cigarette Smoke-Induced Cell Death Causes Persistent Olfactory Dysfunction in Aged Mice

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    Rumi Ueha

    2018-06-01

    Full Text Available Introduction: Exposure to cigarette smoke is a cause of olfactory dysfunction. We previously reported that in young mice, cigarette smoke damaged olfactory progenitors and decreased mature olfactory receptor neurons (ORNs, then, mature ORNs gradually recovered after smoking cessation. However, in aged populations, the target cells in ORNs by cigarette smoke, the underlying molecular mechanisms by which cigarette smoke impairs the regenerative ORNs, and the degree of ORN regeneration after smoking cessation remain unclear.Objectives: To explore the effects of cigarette smoke on the ORN cell system using an aged mouse model of smoking, and to investigate the extent to which smoke-induced damage to ORNs recovers following cessation of exposure to cigarette smoke in aged mice.Methods: We intranasally administered a cigarette smoke solution (CSS to 16-month-old male mice over 24 days, then examined ORN existence, cell survival, changes of inflammatory cytokines in the olfactory epithelium (OE, and olfaction using histological analyses, gene analyses and olfactory habituation/dishabituation tests.Results: CSS administration reduced the number of mature ORNs in the OE and induced olfactory dysfunction. These changes coincided with an increase in the number of apoptotic cells and Tumor necrosis factor (TNF expression and a decrease in Il6 expression. Notably, the reduction in mature ORNs did not recover even on day 28 after cessation of treatment with CSS, resulting in persistent olfactory dysfunction.Conclusion: In aged mice, by increasing ORN death, CSS exposure could eventually overwhelm the regenerative capacity of the OE, resulting in continued reduction in the number of mature ORNs and olfactory dysfunction.

  8. Morphometric analysis of the folliculostellate cells and luteinizing hormone gonadotropic cells of the anterior pituitary of the men during the aging process.

    Science.gov (United States)

    Čukuranović Kokoris, Jovana; Jovanović, Ivan; Pantović, Vukica; Krstić, Miljan; Stanojković, Milica; Milošević, Verica; Ugrenović, Slađana; Stojanović, Vesna

    2017-02-01

    The aim of this research was to quantify the changes in the morphology and density of the anterior pituitary folliculostellate (FS) and luteinizing hormone (LH) cells. Material was tissue of the pituitary gland of the 14 male cadavers. Tissue slices were immunohistochemically stained with monoclonal anti-LH antibody and polyclonal anti-S100 antibody for the detection of LH and FS cells, respectively. Digital images of the stained slices were afterwards morphometrically analyzed by ImageJ. Results of the morphometric analysis showed significant increase of the FS cells volume density in cases older than 70 years. Volume density of the LH cells did not significantly change, whereas their area significantly increased with age. Nucleocytoplasmic ratio of the LH cells gradually decreased and became significant after the age of 70. Finally, volume density of the FS cell significantly correlated with LH cells area and nucleocytoplasmic ratio. From all above cited, we concluded that in men, density and size of the FS cells increase with age. Long-term hypertrophy of the LH cells results in their functional decline after the age of 70. Strong correlation between FS cells and LH cells morphometric parameters might point to age-related interaction between these two cell groups. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. 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.

  10. Maintenance of osteoblastic and adipocytic differentiation potential with age and osteoporosis in human marrow stromal cell cultures

    DEFF Research Database (Denmark)

    Justesen, J; Dokkedahl, Karin Stenderup; Eriksen, E F

    2002-01-01

    Osteoblasts and adipocytes share a common precursor cell in the bone marrow stroma, termed marrow stromal cell (MSC). As the volume of bone adipose tissue increases in vivo with age, we hypothesized that decreased bone formation observed during aging and in patients with osteoporosis (OP) is the ...

  11. Aging and cytomegalovirus (CMV) infection differentially and jointly affect distinct circulating T cell subsets in humans1

    Science.gov (United States)

    Wertheimer, Anne M.; Bennett, Michael S.; Park, Byung; Uhrlaub, Jennifer L.; Martinez, Carmine; Pulko, Vesna; Currier, Noreen L.; Nikolich-Zugich, Dragana; Kaye, Jeffrey; Nikolich-Zugich, Janko

    2014-01-01

    The impact of intrinsic aging upon human peripheral blood T-cell subsets remains incompletely quantified and understood. This impact must be distinguished from the influence of latent persistent microorganisms, particularly cytomegalovirus (CMV), which has been associated with age-related changes in the T cell pool. In a cross-sectional cohort of 152 CMV-negative individuals, aged 21–101 years, we found that aging correlated strictly to an absolute loss of naïve CD8, but not CD4, T cells, but, contrary to many reports, did not lead to an increase in memory T cell numbers. The loss of naïve CD8 T cells was not altered by CMV in 239 subjects (range 21–96 years) but the decline in CD4+ naïve cells showed significance in CMV+ individuals. These individuals also exhibited an absolute increase in the effector/effector memory CD4+ and CD8+ cells with age. That increase was seen mainly, if not exclusively, in older subjects with elevated anti-CMV Ab titers, suggesting that efficacy of viral control over time may determine the magnitude of CMV impact upon T cell memory, and perhaps upon immune defense. These findings provide important new insights into the age-related changes in the peripheral blood pool of older adults, demonstrating that aging and CMV exert both distinct and joint influence upon blood T cell homeostasis in humans. PMID:24501199

  12. Anti-Aging Effect of Siraitia grosuenorii by Enhancement of Hematopoietic Stem Cell Function.

    Science.gov (United States)

    Bai, Lin; Shi, Guiying; Yang, Yajun; Chen, Wei; Zhang, Lianfeng

    2016-01-01

    Anti-aging has always been a popular topic, and there are many claims about the existence of factors that can slow, stop, or even reverse the aging process. Siraitia grosuenorii, a local fruit in china, has been used for the treatment of gastritis, sore throats, and whooping cough in traditional Chinese medicine. The individuals who took the juice of Siraitia grosuenorii regularly had increased longevity in the Guangxi Province, which is located in the Southern part of China. In this paper, we fed mice with Siraitia grosuenorii for 10 months to identify the role of Siraitia grosuenorii in anti-aging and to investigate its corresponding mechanism. The results showed that mice fed with Siraitia grosuenorii displayed a slower aging process. The extension of the aging process was due to the enhanced function of HSCs. FACS analysis showed that the number of LSKs, LT-HSCs, ST-HSCs and MPPs from Siraitia grosuenorii mice was decreased. In vitro, a clonigenic assay showed that LT-HSCs from Siraitia grosuenorii mice increased the ability of self-renewal. Moreover, Siraitia grosuenorii mice maintained the quiescence of LSKs, decreased the level of ROS and reduced the amount of senescence associated β-gal positive cells. Furthermore, Siraitia grosuenorii mice decreased the expression of senescence-associated proteins. Siraitia grosuenorii maintained quiescence, decreased senescence and enhanced the function of HSCs, slowing the aging process of mice.

  13. Factors affecting red blood cell storage age at the time of transfusion.

    Science.gov (United States)

    Dzik, Walter H; Beckman, Neil; Murphy, Michael F; Delaney, Meghan; Flanagan, Peter; Fung, Mark; Germain, Marc; Haspel, Richard L; Lozano, Miguel; Sacher, Ronald; Szczepiorkowski, Zbigniew; Wendel, Silvano

    2013-12-01

    Clinical trials are investigating the potential benefit resulting from a reduced maximum storage interval for red blood cells (RBCs). The key drivers that determine RBC age at the time of issue vary among individual hospitals. Although progressive reduction in the maximum storage period of RBCs would be expected to result in smaller hospital inventories and reduced blood availability, the magnitude of the effect is unknown. Data on current hospital blood inventories were collected from 11 hospitals and three blood centers in five nations. A general predictive model for the age of RBCs at the time of issue was developed based on considerations of demand for RBCs in the hospital. Age of RBCs at issue is sensitive to the following factors: ABO group, storage age at the time of receipt by the hospital, the restock interval, inventory reserve, mean demand, and variation in demand. A simple model, based on hospital demand, may serve as the basis for examining factors affecting the storage age of RBCs in hospital inventories. The model suggests that the age of RBCs at the time of their issue to the patient depends on factors external to the hospital transfusion service. Any substantial change in the expiration date of stored RBCs will need to address the broad variation in demand for RBCs while attempting to balance considerations of availability and blood wastage. © 2013 American Association of Blood Banks.

  14. Paxillin and its role in the aging process of skin cells

    Directory of Open Access Journals (Sweden)

    Anna Skoczyńska

    2016-10-01

    Full Text Available Morphology of senescent cells is constantly changing at the molecular level, which in turn leads to disruption of their function. It is connected with reduced ability to synthesize extracellular matrix (ECM and leads to the dysfunction of integrin adhesion molecules and adhesion clusters. In skin, these factors cause a loss of communication between the extracellular matrix and fibroblasts. This contributes to the appearance of signs of aging. The aim of this study is to draw attention to the very important molecule such as paxillin, which is an adaptor protein with mass of 68 kDa. This family of proteins includes Hic-5, PaxB and leupaxin. Paxillin binds to actin-binding proteins such as vinculin, actopaxin, and kinases (e.g. Integrin-linked kinase (ILK. Moreover, it plays an important role in the integrity of the matrix, because it transduces transmembrane signaling between integrins and growth factors. Paxillin is a scaffold protein, activating the arrangement and organization of the cytoskeleton. Signaling through paxillin affects the long-term changes in gene expression, cell proliferation, and organization of the ECM. Correct functioning of the ECM is important for the wound healing processes and regeneration of tissues or tissue repair. Decrease or lack of paxillin expression results in changes in the structure and integrity of the ECM, which are manifested by aging of cells and organs. Restoration of the cellular matrix connections would be a significant element in the processes related to the anti-aging activities.

  15. Oocyte formation by mitotically-active germ cells purified from ovaries of reproductive age women

    Science.gov (United States)

    White, Yvonne A. R.; Woods, Dori C.; Takai, Yasushi; Ishihara, Osamu; Seki, Hiroyuki; Tilly, Jonathan L.

    2012-01-01

    Germline stem cells that produce oocytes in vitro and fertilization-competent eggs in vivo have been identified in and isolated from adult mouse ovaries. Here we describe and validate a FACS-based protocol that can be used with adult mouse ovaries and human ovarian cortical tissue to purify rare mitotically-active cells that exhibit a gene expression profile consistent with primitive germ cells. Once established in vitro, these cells can be expanded for months and spontaneously generate 35–50 µm oocytes, as determined by morphology, gene expression and attainment of haploid (1n) status. Injection of the human germline cells, engineered to stably express GFP, into human ovarian cortical biopsies leads to formation of follicles containing GFP-positive oocytes 1–2 weeks after xenotransplantation into immunodeficient female mice. Thus, ovaries of reproductive-age women, like adult mice, possess rare mitotically-active germ cells that can be propagated in vitro as well as generate oocytes in vitro and in vivo. PMID:22366948

  16. 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.

  17. An "age"-structured model of hematopoietic stem cell organization with application to chronic myeloid leukemia.

    Science.gov (United States)

    Roeder, Ingo; Herberg, Maria; Horn, Matthias

    2009-04-01

    Previously, we have modeled hematopoietic stem cell organization by a stochastic, single cell-based approach. Applications to different experimental systems demonstrated that this model consistently explains a broad variety of in vivo and in vitro data. A major advantage of the agent-based model (ABM) is the representation of heterogeneity within the hematopoietic stem cell population. However, this advantage comes at the price of time-consuming simulations if the systems become large. One example in this respect is the modeling of disease and treatment dynamics in patients with chronic myeloid leukemia (CML), where the realistic number of individual cells to be considered exceeds 10(6). To overcome this deficiency, without losing the representation of the inherent heterogeneity of the stem cell population, we here propose to approximate the ABM by a system of partial differential equations (PDEs). The major benefit of such an approach is its independence from the size of the system. Although this mean field approach includes a number of simplifying assumptions compared to the ABM, it retains the key structure of the model including the "age"-structure of stem cells. We show that the PDE model qualitatively and quantitatively reproduces the results of the agent-based approach.

  18. 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

    Science.gov (United States)

    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

  19. 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

  20. Is cell aging caused by respiration-dependent injury to the mitochondrial genome

    Science.gov (United States)

    Fleming, J. E.; Yengoyan, L. S.; Miquel, J.; Cottrell, S. F.; Economos, A. C.

    1982-01-01

    Though intrinsic mitochondrial aging has been considered before as a possible cause of cellular senescence, the mechanisms of such mitochondrial aging have remained obscure. In this article, the hypothesis of free-radical-induced inhibition of mitochondrial replenishment in fixed postmitotic cells is expanded. It is maintained that the respiration-dependent production of superoxide and hydroxyl radicals may not be fully counteracted, leading to a continuous production of lipoperoxides and malonaldehyde in actively respiring mitochondria. These compounds, in turn, can easily react with the mitochondrial DNA which is in close spatial relationship with the inner mitochondrial membrane, producing an injury that the mitochondria may be unable to counteract because of their apparent lack of adequate repair mechanisms. Mitochondrial division may thus be inhibited leading to age-related reduction of mitochondrial numbers, a deficit in energy production with a concomitant decrease in protein synthesis, deterioration of physiological performance, and, therefore, of organismic performance.

  1. The total number of Leydig and Sertoli cells in the testes of men across various age groups - a stereological study

    DEFF Research Database (Denmark)

    Petersen, Peter M; Seierøe, Karina; Pakkenberg, Bente

    2015-01-01

    is particularly sensitive to methodological problems. Therefore, using the optical fractionator technique and a sampling design specifically optimized for human testes, we estimated the total number of Sertoli and Leydig cells in the testes from 26 post mortem male subjects ranging in age from 16 to 80 years...... of Sertoli cells with age; no such decline was found for Leydig cells. Quantitative stereological analysis of post mortem tissue may help understand the influence of age or disease on the number of human testicular cells....

  2. The clock is ticking. Ageing of the circadian system: From physiology to cell cycle.

    Science.gov (United States)

    Terzibasi-Tozzini, Eva; Martinez-Nicolas, Antonio; Lucas-Sánchez, Alejandro

    2017-10-01

    The circadian system is the responsible to organise the internal temporal order in relation to the environment of every process of the organisms producing the circadian rhythms. These rhythms have a fixed phase relationship among them and with the environment in order to optimise the available energy and resources. From a cellular level, circadian rhythms are controlled by genetic positive and negative auto-regulated transcriptional and translational feedback loops, which generate 24h rhythms in mRNA and protein levels of the clock components. It has been described about 10% of the genome is controlled by clock genes, with special relevance, due to its implications, to the cell cycle. Ageing is a deleterious process which affects all the organisms' structures including circadian system. The circadian system's ageing may produce a disorganisation among the circadian rhythms, arrhythmicity and, even, disconnection from the environment, resulting in a detrimental situation to the organism. In addition, some environmental conditions can produce circadian disruption, also called chronodisruption, which may produce many pathologies including accelerated ageing. Finally, some strategies to prevent, palliate or counteract chronodisruption effects have been proposed to enhance the circadian system, also called chronoenhancement. This review tries to gather recent advances in the chronobiology of the ageing process, including cell cycle, neurogenesis process and physiology. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Enhanced taurine release in cell-damaging conditions in the developing and ageing mouse hippocampus.

    Science.gov (United States)

    Saransaari, P; Oja, S S

    1997-08-01

    Taurine has been shown to be essential for neuronal development and survival in the central nervous system. The release of preloaded [3H]taurine was studied in hippocampal slices from seven-day-, three-month- and 18-22-month-old mice in cell-damaging conditions. The slices were superfused in hypoxic, hypoglycemic and ischemic conditions and exposed to free radicals and oxidative stress. The release of taurine was greatly enhanced in the above conditions in all age groups, except in oxidative stress. The release was large in ischemia, particularly in the hippocampus of aged mice. Potassium stimulation was still able to release taurine in cell-damaging conditions in immature mice, whereas in adult and aged animals the release was so substantial that this additional stimulus failed to work. Taurine release was partially Ca2+-dependent in all cases. The massive release of the inhibitory amino acid taurine in ischemic conditions could act neuroprotectively, counteracting in several ways the effects of simultaneous release of excitatory amino acids. This protection could be of great importance in developing brain tissue, while also having an effect in aged brains.

  4. p66Shc Aging Protein in Control of Fibroblasts Cell Fate

    Directory of Open Access Journals (Sweden)

    Mariusz R. Wieckowski

    2011-08-01

    Full Text Available Reactive oxygen species (ROS are wieldy accepted as one of the main factors of the aging process. These highly reactive compounds modify nucleic acids, proteins and lipids and affect the functionality of mitochondria in the first case and ultimately of the cell. Any agent or genetic modification that affects ROS production and detoxification can be expected to influence longevity. On the other hand, genetic manipulations leading to increased longevity can be expected to involve cellular changes that affect ROS metabolism. The 66-kDa isoform of the growth factor adaptor Shc (p66Shc has been recognized as a relevant factor to the oxygen radical theory of aging. The most recent data indicate that p66Shc protein regulates life span in mammals and its phosphorylation on serine 36 is important for the initiation of cell death upon oxidative stress. Moreover, there is strong evidence that apart from aging, p66Shc may be implicated in many oxidative stress-associated pathologies, such as diabetes, mitochondrial and neurodegenerative disorders and tumorigenesis. This article summarizes recent knowledge about the role of p66Shc in aging and senescence and how this protein can influence ROS production and detoxification, focusing on studies performed on skin and skin fibroblasts.

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

    Science.gov (United States)

    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.

  6. Age-related macular degeneration is associated with increased proportion of CD56(+) T cells in peripheral blood

    DEFF Research Database (Denmark)

    Faber, Carsten; Singh, Amardeep; Krüger Falk, Mads

    2013-01-01

    PURPOSE: To examine the association between age-related changes in the T-cell compartment and prevalence of age-related macular degeneration (AMD). DESIGN: Case-control study. PARTICIPANTS: A total of 117 AMD cases and 106 controls were included prospectively. METHODS: Fresh-drawn peripheral blood...... samples were processed for flow cytometric analysis of T-cell populations. Plasma samples were analyzed for anti-cytomegalovirus (CMV) immunoglobulin (Ig)G and complement factor H (CFH) Y402H genotype. The diagnosis of AMD was made according to the Clinical Age-Related Maculopathy Staging System. MAIN...... OUTCOME MEASURES: Association between frequency of aged T cells and prevalence of AMD. RESULTS: The prevalence of AMD was associated with distinct age-related changes in the T-cell compartment. Specifically, the patients with AMD had an increased frequency of CD28(-) T cells that expressed the CD56...

  7. Age-related changes in rat bone-marrow mesenchymal stem cell plasticity

    Directory of Open Access Journals (Sweden)

    Chase P Bryant

    2011-10-01

    Full Text Available Abstract Background The efficacy of adult stem cells is known to be compromised as a function of age. This therefore raises questions about the effectiveness of autologous cell therapy in elderly patients. Results We demonstrated that the expression profile of stemness markers was altered in BM-MSCs derived from old rats. BM-MSCs from young rats (4 months expressed Oct-4, Sox-2 and NANOG, but we failed to detect Sox-2 and NANOG in BM-MSCs from older animals (15 months. Chondrogenic, osteogenic and adipogenic potential is compromised in old BM-MSCs. Stimulation with a cocktail mixture of bone morphogenetic protein (BMP-2, fibroblast growth factor (FGF-2 and insulin-like growth factor (IGF-1 induced cardiomyogenesis in young BM-MSCs but not old BM-MSCs. Significant differences in the expression of gap junction protein connexin-43 were observed between young and old BM-MSCs. Young and old BM-MSCs fused with neonatal ventricular cardiomyocytes in co-culture and expressed key cardiac transcription factors and structural proteins. Cells from old animals expressed significantly lower levels of VEGF, IGF, EGF, and G-CSF. Significantly higher levels of DNA double strand break marker γ-H2AX and diminished levels of telomerase activity were observed in old BM-MSCs. Conclusion The results suggest age related differences in the differentiation capacity of BM-MSCs. These changes may affect the efficacy of BM-MSCs for use in stem cell therapy.

  8. Evaluation of Experimental Parameters in the Accelerated Aging of Closed-Cell Foam Insulation

    Energy Technology Data Exchange (ETDEWEB)

    Stovall, Therese K [ORNL; Vanderlan, Michael [ORNL; Atchley, Jerald Allen [ORNL

    2012-12-01

    The thermal conductivity of many closed-cell foam insulation products changes over time as production gases diffuse out of the cell matrix and atmospheric gases diffuse into the cells. Thin slicing has been shown to be an effective means of accelerating this process in such a way as to produce meaningful results. Efforts to produce a more prescriptive version of the ASTM C1303 standard test method led to the ruggedness test described here. This test program included the aging of full size insulation specimens for time periods of five years for direct comparison to the predicted results. Experimental parameters under investigation include: slice thickness, slice origin (at the surface or from the core of the slab), thin slice stack composition, product facings, original product thickness, product density, and product type. The test protocol has been completed and this report provides a detailed evaluation of the impact of the test parameters on the accuracy of the 5-year thermal conductivity prediction.

  9. Piwi Is Required to Limit Exhaustion of Aging Somatic Stem Cells

    Directory of Open Access Journals (Sweden)

    Pedro Sousa-Victor

    2017-09-01

    Full Text Available Sophisticated mechanisms that preserve genome integrity are critical to ensure the maintenance of regenerative capacity while preventing transformation of somatic stem cells (SCs, yet little is known about mechanisms regulating genome maintenance in these cells. Here, we show that intestinal stem cells (ISCs induce the Argonaute family protein Piwi in response to JAK/STAT signaling during acute proliferative episodes. Piwi function is critical to ensure heterochromatin maintenance, suppress retrotransposon activation, and prevent DNA damage in homeostasis and under regenerative pressure. Accordingly, loss of Piwi results in the loss of actively dividing ISCs and their progenies by apoptosis. We further show that Piwi expression is sufficient to allay age-related retrotransposon expression, DNA damage, apoptosis, and mis-differentiation phenotypes in the ISC lineage, improving epithelial homeostasis. Our data identify a role for Piwi in the regulation of somatic SC function, and they highlight the importance of retrotransposon control in somatic SC maintenance.

  10. Skeletal Muscle Regeneration, Repair and Remodelling in Aging: The Importance of Muscle Stem Cells and Vascularization.

    Science.gov (United States)

    Joanisse, Sophie; Nederveen, Joshua P; Snijders, Tim; McKay, Bryon R; Parise, Gianni

    2017-01-01

    Sarcopenia is the age-related loss of skeletal muscle mass and strength. Ultimately, sarcopenia results in the loss of independence, which imposes a large financial burden on healthcare systems worldwide. A critical facet of sarcopenia is the diminished ability for aged muscle to regenerate, repair and remodel. Over the years, research has focused on elucidating underlying mechanisms of sarcopenia and the impaired ability of muscle to respond to stimuli with aging. Muscle-specific stem cells, termed satellite cells (SC), play an important role in maintaining muscle health throughout the lifespan. It is well established that SC are essential in skeletal muscle regeneration, and it has been hypothesized that a reduction and/or dysregulation of the SC pool, may contribute to accelerated loss of skeletal muscle mass that is observed with advancing age. The preservation of skeletal muscle tissue and its ability to respond to stimuli may be impacted by reduced SC content and impaired function observed with aging. Aging is also associated with a reduction in capillarization of skeletal muscle. We have recently demonstrated that the distance between type II fibre-associated SC and capillaries is greater in older compared to younger adults. The greater distance between SC and capillaries in older adults may contribute to the dysregulation in SC activation ultimately impairing muscle's ability to remodel and, in extreme circumstances, regenerate. This viewpoint will highlight the importance of optimal SC activation in addition to skeletal muscle capillarization to maximize the regenerative potential of skeletal muscle in older adults. © 2016 S. Karger AG, Basel.

  11. Recovery of aging-related size increase of skin epithelial cells: in vivo mouse and in vitro human study.

    Directory of Open Access Journals (Sweden)

    Igor Sokolov

    Full Text Available The size increase of skin epithelial cells during aging is well-known. Here we demonstrate that treatment of aging cells with cytochalasin B substantially decreases cell size. This decrease was demonstrated on a mouse model and on human skin cells in vitro. Six nude mice were treated by topical application of cytochalasin B on skin of the dorsal left midsection for 140 days (the right side served as control for placebo treatment. An average decrease in cell size of 56±16% resulted. A reduction of cell size was also observed on primary human skin epithelial cells of different in vitro age (passages from 1 to 8. A cell strain obtained from a pool of 6 human subjects was treated with cytochalasin B in vitro for 12 hours. We observed a decrease in cell size that became statistically significant and reached 20-40% for cells of older passage (6-8 passages whereas no substantial change was observed for younger cells. These results may be important for understanding the aging processes, and for cosmetic treatment of aging skin.

  12. Advanced glycation end-products (AGEs acutely impair Ca2+ signalling in bovine aortic endothelial cells

    Directory of Open Access Journals (Sweden)

    Nadim eNaser

    2013-03-01

    Full Text Available Post-translational modification of proteins in diabetes, including formation of advanced glycation end products (AGEs are believed to contribute to vascular dysfunction and disease. Impaired function of the endothelium is an early indicator of vascular dysfunction in diabetes and as many endothelial cell processes are dependent upon intracellular [Ca2+] and Ca2+ signalling, the aim of this study was to examine the acute effects of AGEs on Ca2+ signalling in bovine aortic endothelial cells (BAEC. Ca2+ signalling was studied using the fluorescent indicator dye Fura2-AM. AGEs were generated by incubating bovine serum albumin with 0 - 250 mM glucose or glucose-6-phosphate for 0 to 120 days at 37ºC. Under all conditions, the main AGE species generated was carboxymethyl lysine (CML as assayed using both GC-MS and HPLC. In Ca2+-replete solution, exposure of BAEC to AGEs for 5 min caused an elevation in basal [Ca2+] and attenuated the increase in intracellular [Ca2+] caused by ATP (100 µM. In the absence of extracellular Ca2+, exposure of BAEC to AGEs for 5 min caused an elevation in basal [Ca2+] and attenuated subsequent intracellular Ca2+ release caused by ATP, thapsigargin (0.1 µM and ionomycin (3 µM, but AGEs did not affect extracellular Ca2+ entry induced by the re-addition of Ca2+ to the bathing solution in the presence of any of these agents. The anti-oxidant α-lipoic acid (2 µM and NAD(PH oxidase inhibitors apocynin (500 µM and diphenyleneiodonium (DPI, 1 µM abolished these effects of AGEs on BAECs, as did the IP3 receptor antagonist xestospongin C (1 µM. In summary, AGEs caused an acute depletion of Ca2+ from the intracellular store in BAECs, such that the Ca2+ signal stimulated by the subsequent application other agents acting upon this store is reduced. The mechanism may involve generation of ROS from NAD(PH oxidase and possible activation of the IP3 receptor.

  13. The impact of ageing on natural killer cell function and potential consequences for health in older adults.

    Science.gov (United States)

    Hazeldine, Jon; Lord, Janet M

    2013-09-01

    Forming the first line of defence against virally infected and malignant cells, natural killer (NK) cells are critical effector cells of the innate immune system. With age, significant impairments have been reported in the two main mechanisms by which NK cells confer host protection: direct cytotoxicity and the secretion of immunoregulatory cytokines and chemokines. In elderly subjects, decreased NK cell activity has been shown to be associated with an increased incidence and severity of viral infection, highlighting the clinical implications that age-associated changes in NK cell biology have on the health of older adults. However, is an increased susceptibility to viral infection the only consequence of these age-related changes in NK cell function? Recently, evidence has emerged that has shown that in addition to eliminating transformed cells, NK cells are involved in many other biological processes such as immune regulation, anti-microbial immune responses and the recognition and elimination of senescent cells, novel functions that involve NK-mediated cytotoxicity and/or cytokine production. Thus, the decrease in NK cell function that accompanies physiological ageing is likely to have wider implications for the health of older adults than originally thought. Here, we give a detailed description of the changes in NK cell biology that accompany human ageing and propose that certain features of the ageing process such as: (i) the increased reactivation rates of latent Mycobacterium tuberculosis, (ii) the slower resolution of inflammatory responses and (iii) the increased incidence of bacterial and fungal infection are attributable in part to an age-associated decline in NK cell function. Copyright © 2013 Elsevier B.V. All rights reserved.

  14. Effects of external pressure on the performance and ageing of single-layer lithium-ion pouch cells

    Science.gov (United States)

    Mussa, Abdilbari Shifa; Klett, Matilda; Lindbergh, Göran; Lindström, Rakel Wreland

    2018-05-01

    The effects of external compression on the performance and ageing of NMC(1/3)/Graphite single-layer Li-ion pouch cells are investigated using a spring-loaded fixture. The influence of pressure (0.66, 0.99, 1.32, and 1.98 MPa) on impedance is characterized in fresh cells that are subsequently cycled at the given pressure levels. The aged cells are analyzed for capacity fade and impedance rise at the cell and electrode level. The effect of pressure distribution that may occur in large-format cells or in a battery pack is simulated using parallel connected cells. The results show that the kinetic and mass transport resistance increases with pressure in a fresh cell. An optimum pressure around 1.3 MPa is shown to be beneficial to reduce cyclable-lithium loss during cycling. The minor active mass losses observed in the electrodes are independent of the ageing pressure, whereas ageing pressure affects the charge transfer resistance of both NMC and graphite electrodes and the ohmic resistance of the cell. Pressure distribution induces current distribution but the enhanced current throughput at lower pressures cell does not accelerate its ageing. Conclusions from this work can explain some of the discrepancies in non-uniform ageing reported in the literature and indicate coupling between electrochemistry and mechanics.

  15. Age of red blood cells and mortality in the critically ill

    LENUS (Irish Health Repository)

    Pettila, Ville

    2011-04-15

    Abstract Introduction In critically ill patients, it is uncertain whether exposure to older red blood cells (RBCs) may contribute to mortality. We therefore aimed to evaluate the association between the age of RBCs and outcome in a large unselected cohort of critically ill patients in Australia and New Zealand. We hypothesized that exposure to even a single unit of older RBCs may be associated with an increased risk of death. Methods We conducted a prospective, multicenter observational study in 47 ICUs during a 5-week period between August 2008 and September 2008. We included 757 critically ill adult patients receiving at least one unit of RBCs. To test our hypothesis we compared hospital mortality according to quartiles of exposure to maximum age of RBCs without and with adjustment for possible confounding factors. Results Compared with other quartiles (mean maximum red cell age 22.7 days; mortality 121\\/568 (21.3%)), patients treated with exposure to the lowest quartile of oldest RBCs (mean maximum red cell age 7.7 days; hospital mortality 25\\/189 (13.2%)) had an unadjusted absolute risk reduction in hospital mortality of 8.1% (95% confidence interval = 2.2 to 14.0%). After adjustment for Acute Physiology and Chronic Health Evaluation III score, other blood component transfusions, number of RBC transfusions, pretransfusion hemoglobin concentration, and cardiac surgery, the odds ratio for hospital mortality for patients exposed to the older three quartiles compared with the lowest quartile was 2.01 (95% confidence interval = 1.07 to 3.77). Conclusions In critically ill patients, in Australia and New Zealand, exposure to older RBCs is independently associated with an increased risk of death.

  16. Parvalbumin-expressing ependymal cells in rostral lateral ventricle wall adhesions contribute to aging-related ventricle stenosis in mice.

    Science.gov (United States)

    Filice, Federica; Celio, Marco R; Babalian, Alexandre; Blum, Walter; Szabolcsi, Viktoria

    2017-10-15

    Aging-associated ependymal-cell pathologies can manifest as ventricular gliosis, ventricle enlargement, or ventricle stenosis. Ventricle stenosis and fusion of the lateral ventricle (LV) walls is associated with a massive decline of the proliferative capacities of the stem cell niche in the affected subventricular zone (SVZ) in aging mice. We examined the brains of adult C57BL/6 mice and found that ependymal cells located in the adhesions of the medial and lateral walls of the rostral LVs upregulated parvalbumin (PV) and displayed reactive phenotype, similarly to injury-reactive ependymal cells. However, PV+ ependymal cells in the LV-wall adhesions, unlike injury-reactive ones, did not express glial fibrillary acidic protein. S100B+/PV+ ependymal cells found in younger mice diminished in the LV-wall adhesions throughout aging. We found that periventricular PV-immunofluorescence showed positive correlation to the grade of LV stenosis in nonaged mice (wall adhesions and LV stenosis was significantly lower in mid-aged (>10-month-old) PV-knock out (PV-KO) mice. This suggests an involvement of PV+ ependymal cells in aging-associated ventricle stenosis. Additionally, we observed a time-shift in microglial activation in the LV-wall adhesions between age-grouped PV-KO and wild-type mice, suggesting a delay in microglial activation when PV is absent from ependymal cells. Our findings implicate that compromised ependymal cells of the adhering ependymal layers upregulate PV and display phenotype shift to "reactive" ependymal cells in aging-related ventricle stenosis; moreover, they also contribute to the progression of LV-wall fusion associated with a decline of the affected SVZ-stem cell niche in aged mice. © 2017 Wiley Periodicals, Inc.

  17. Age adjusted hematopoietic stem cell transplant comorbidity index predicts survival in a T-cell depleted cohort.

    Science.gov (United States)

    Saeed, Hayder; Yalamanchi, Swati; Liu, Meng; Van Meter, Emily; Gul, Zartash; Monohan, Gregory; Howard, Dianna; Hildebrandt, Gerhard C; Herzig, Roger

    2018-02-01

    Allogeneic hematopoietic stem cell transplant (HCT) continues to evolve with the treatment in higher risk patient population. This practice mandates stringent update and validation of risk stratification prior to undergoing such a complex and potentially fatal procedure. We examined the adoption of the new comorbidity index (HCT-CI/Age) proposed by the Seattle group after the addition of age variable and compared it to the pre-transplant assessment of mortality (PAM) that already incorporates age as part of its evaluation criteria. A retrospective analysis of adult patients who underwent HCT at our institution from January 2010 through August 2014 was performed. Kaplan-Meier's curve, log-rank tests, Cox model and Pearson correlation was used in the analysis. Of the 114 patients that underwent allogeneic transplant in our institution, 75.4% were ≥40 years old. More than 58% had a DLCO ≤80%. Although scores were positively correlated (correlation coefficient 0.43, p < 0.001), HCT-CI/Age more accurately predicted 2-year overall survival (OS) and non-relapse mortality (NRM) in patients with lower (0-4) and higher (5-7) scores (52% and 36% versus 24% and 76%, p = 0.004, 0.003 respectively). PAM score did not reach statistical significance for difference in OS nor NRM between the low (<24) and high-risk (≥24) groups (p = 0.19 for both). Despite our small sample population, HCT-CI/Age was more discriminative to identify patients with poor outcome that might benefit from intensified management strategies or other therapeutic approaches rather than allogeneic HCT. Copyright © 2018. Published by Elsevier B.V.

  18. Red blood cell aging markers during storage in citrate-phosphate-dextrose-saline-adenine-glucose-mannitol.

    Science.gov (United States)

    Antonelou, Marianna H; Kriebardis, Anastasios G; Stamoulis, Konstantinos E; Economou-Petersen, Effrosini; Margaritis, Lukas H; Papassideri, Issidora S

    2010-02-01

    It has been suggested that red blood cell (RBC) senescence is accelerated under blood bank conditions, although neither protein profile of RBC aging nor the impact of additive solutions on it have been studied in detail. RBCs and vesicles derived from RBCs in both citrate-phosphate-dextrose (CPD)-saline-adenine-glucose-mannitol (SAGM) and citrate-phosphate-dextrose-adenine (CPDA) were evaluated for the expression of cell senescence markers (vesiculation, protein aggregation, degradation, activation, oxidation, and topology) through immunoblotting technique and immunofluorescence or immunoelectron microscopy study. A group of cellular stress proteins exhibited storage time- and storage medium-related changes in their membrane association and exocytosis. The extent, the rate, and the expression of protein oxidation, Fas oligomerization, caspase activation, and protein modifications in Band 3, hemoglobin, and immunoglobulin G were less conspicuous and/or exhibited significant time retardation under storage in CPD-SAGM, compared to the CPDA storage. There was evidence for the localization of activated caspases near to the membrane of both cells and vesicles. We provide circumstantial evidence for a lower protein oxidative damage in CPD-SAGM-stored RBCs compared to the CPDA-stored cells. The different expression patterns of the senescence markers in the RBCs seem to be accordingly related to the oxidative stress management of the cells. We suggest that the storage of RBCs in CPD-SAGM might be more alike the in vivo RBC aging process, compared to storage in CPDA, since it is characterized by a slower stimulation of the recognition signaling pathways that are already known to trigger the erythrophagocytosis of senescent RBCs.

  19. Aging effects of plasma polymerized ethylenediamine (PPEDA) thin films on cell-adhesive implant coatings

    International Nuclear Information System (INIS)

    Testrich, H.; Rebl, H.; Finke, B.; Hempel, F.; Nebe, B.; Meichsner, J.

    2013-01-01

    Thin plasma polymer films from ethylenediamine were deposited on planar substrates placed on the powered electrode of a low pressure capacitively coupled 13.56 MHz discharge. The chemical composition of the plasma polymer films was analyzed by Fourier Transform Infrared Reflection Absorption Spectroscopy (FT-IRRAS) as well as by X-ray photoelectron spectroscopy (XPS) after derivatization of the primary amino groups. The PPEDA films undergo an alteration during the storage in ambient air, particularly, due to reactions with oxygen. The molecular changes in PPEDA films were studied over a long-time period of 360 days. Simultaneously, the adhesion of human osteoblast-like cells MG-63 (ATCC) was investigated on PPEDA coated corundum blasted titanium alloy (Ti-6Al-4V), which is applied as implant material in orthopedic surgery. The cell adhesion was determined by flow cytometry and the cell shape was analyzed by scanning electron microscopy. Compared to uncoated reference samples a significantly enhanced cell adhesion and proliferation were measured for PPEDA coated samples, which have been maintained after long-time storage in ambient air and additional sterilization by γ−irradiation. - Highlights: • Development of cell-adhesive nitrogen-rich coatings for biomedical applications. • Plasma polymer films from low pressure 13.56 MHz discharge in argon-ethylenediamine. • Enhanced osteoblast adhesion/proliferation on coated implant material (Ti-6Al-4V). • Despite film aging over 360 days the enhanced cell adhesion of the coating remains. • No influence of additional y-sterilization on the enhanced cell adhesion

  20. Patient-specific age: the other side of the coin in advanced mesenchymal stem cell therapy

    Directory of Open Access Journals (Sweden)

    Magdalena Maria Schimke

    2015-12-01

    Full Text Available Multipotential mesenchymal stromal cells (MSC are present as a rare subpopulation within any type of stroma in the body of higher animals. Prominently, MSC have been recognized to reside in perivascular locations, supposedly maintaining blood vessel integrity. During tissue damage and injury, MSC/pericytes become activated, evade from their perivascular niche and are thus assumed to support wound healing and tissue regeneration.In vitro MSC exhibit demonstrated capabilities to differentiate into a wide variety of tissue cell types. Hence, many MSC-based therapeutic approaches have been performed to address bone, cartilage or heart regeneration. Furthermore, prominent studies showed efficacy of ex vivo expanded MSC to countervail graft-versus-host-disease. Therefore, additional fields of application are presently conceived, in which MSC-based therapies potentially unfold beneficial effects, such as amelioration of non-healing conditions after tendon or spinal cord injury, as well as neuropathies. Working along these lines, MSC-based scientific research has been forged ahead to prominently occupy the clinical stage.Aging is to a great deal stochastic by nature bringing forth changes in an individual fashion. Yet, is aging of stem cells or/and their corresponding niche considered a determining factor for outcome and success of clinical therapies?

  1. The changes of stage distribution of seminiferous epithelium cycle and its correlations with Leydig cell stereological parameters in aging men.

    Science.gov (United States)

    Huang, Rui; Zhu, Wei-Jie; Li, Jing; Gu, Yi-Qun

    2014-12-01

    To evaluate the changes of stage distribution of seminiferous epithelium cycle and its correlations with Leydig cell stereological parameters in aging men. Point counting method was used to analyze the stereological parameters of Leydig cells. The stage number of seminiferous epithelium cycle was calculated in the same testicular tissue samples which were used for Leydig cell stereological analysis. The aging group had shown more severe pathological changes as well as higher pathologic scores than the young group. Compared with the control group, the volume density (VV) and surface density (NA) of Leydig cells in the aging group were increased significantly. The stage number of seminiferous epithelium cycle in the aging group was decreased coincidently compared to the young group. Leydig cell Vv in the young group has a positive relationship with stages I, II, III, V and VI of seminiferous epithelium cycle, and Leydig cell NA and numerical density (NV) were positively related to stage IV. However, only the correlation between NV and stage II was found in the aging group. The stage number of seminiferous epithelium cycle was decreased in aging testes. Changes in the stage distribution in aging testes were related to the Leydig cell stereological parameters which presented as a sign of morphological changes. Copyright © 2014 Elsevier GmbH. All rights reserved.

  2. Combination of aging and dimethylhydrazine treatment causes an increase in cancer-stem cell population of rat colonic crypts.

    Science.gov (United States)

    Levi, Edi; Misra, Sandhya; Du, Jianhua; Patel, Bhaumik B; Majumdar, Adhip P N

    2009-07-31

    Aging is associated with increased incidence of colon cancers. It is also becoming evident that cancer stem cells (CSC) play a vital role in the pathogenesis and prognosis of colon cancer. Recently, we reported the presence of colon cancer stem-like cells in macroscopically normal mucosa in patients with adenomatous polyps and that they increase with aging, suggesting that aging may predispose the colon to carcinogenesis. In the current study we have examined the combined effects of aging and carcinogen exposure on the status of colon CSCs in an experimental model. We used young (4-6 months) and aged (22-24 months) rats and exposed them to the carcinogen, dimethylhydroxide (DMH). We investigated the expression of colon cancer stem cell markers, CD44, CD166, EpCam, and ALDH1 as well as EGFR expression in normal colonic crypt epithelium following carcinogen treatment. Our results demonstrate that aging per se or carcinogen treatment alone causes an increase in the number of colon cancer stems cells, as evidenced by increased immunoreactive-CSC-markers positive cells in the colonic mucosa. In aged rats, carcinogen exposure results in a more pronounced increase in colon cancer stem cells. Our study shows that in aging colon the effects of carcinogens are more pronounced, and an increase in colon CSCs is one of the earliest changes preceding tumor development. Moreover, the current investigation of the use of a panel of immunohistochemical markers of colon CSC can potentially serve as a prognostic marker during screening for colon cancer.

  3. 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.

  4. T-cell differentiation and CD56+ levels in polypoidal choroidal vasculopathy and neovascular age-related macular degeneration.

    Science.gov (United States)

    Subhi, Yousif; Nielsen, Marie Krogh; Molbech, Christopher Rue; Oishi, Akio; Singh, Amardeep; Nissen, Mogens Holst; Sørensen, Torben Lykke

    2017-11-20

    Polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (AMD) are prevalent age-related diseases characterized by exudative changes in the macula. Although they share anatomical and clinical similarities, they are also distinctly characterized by their own features, e.g. vascular abnormalities in PCV and drusen-mediated progression in neovascular AMD. PCV remains etiologically uncharacterized, and ongoing discussion is whether PCV and neovascular AMD share the same etiology or constitute two substantially different diseases. In this study, we investigated T-cell differentiation and aging profile in human patients with PCV, patients with neovascular AMD, and age-matched healthy control individuals. Fresh venous blood was prepared for flow cytometry to investigate CD4 + and CD8 + T-cell differentiation (naïve, central memory, effector memory, effector memory CD45ra + ), loss of differentiation markers CD27 and CD28, and expression of aging marker CD56. Patients with PCV were similar to the healthy controls in all aspects. In patients with neovascular AMD we found significantly accelerated T-cell differentiation (more CD28 - CD27 - cells) and aging (more CD56 + cells) in the CD8 + T-cell compartment. These findings suggest that PCV and neovascular AMD are etiologically different in terms of T cell immunity, and that neovascular AMD is associated with T-cell immunosenescence.

  5. [Experimental study on aging effect of Angelica sinensis polysaccharides combined with cytarabine on human leukemia KG1alpha cell lines].

    Science.gov (United States)

    Xu, Chun-Yan; Geng, Shan; Liu, Jun; Zhu, Jia-Hong; Zhang, Xian-Ping; Jiang, Rong; Wang, Ya-Ping

    2014-04-01

    The latest findings of our laboratory showed that Angelica sinensis polysaccharide (ASP) showed a definite effect in regulating the aging of hematopoietic stem cells. Leukemia is a type of malignant hematopoietic tumor in hematopoietic stem cells. There have been no relevant reports about ASP's effect in regulating the aging of leukemia cells. In this study, human acute myeloid leukemia (AML) KG1alpha cell lines in logarithmic growth phase were taken as the study object, and were divided into the ASP group, the cytarabine (Ara-C) group, the ASP + Ara-C group and the control group. The groups were respectively treated with different concentration of ASP, Ara-C and ASP + Ara-C for different periods, with the aim to study the effect of ASP combined with Ara-C in regulating the aging of human acute myeloid leukemia KG1alpha cell lines and its relevant mechanism. The results showed that ASP, Ara-C and ASP + Ara-C could obviously inhibit KG1alpha cell proliferation in vitro, block the cells in G0/G1 phase. The cells showed the aging morphological feature. The percentage of positive stained aging cells was dramatically increased, and could significantly up-regulate the expression of aging-related proteins P16 and RB, which were more obvious in the ASP + Ara-C group. In conclusion, the aging mechanism of KG1alpha cell induced by ASP and Ara-C may be related to the regulation of the expression of aging-related proteins, suggesting that the combined administration of ASP and anticancer drugs plays a better role in the treatment of leukemia .

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

    Science.gov (United States)

    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

  7. 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.

  8. Oral cavity squamous cell carcinoma in 260 patients aged 80 years or more

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    Ortholan, Cecile; Lusinchi, Antoine; Italiano, Antoine; Bensadoun, Rene-Jean; Auperin, Anne; Poissonnet, Gilles; Bozec, Alexandre; Arriagada, Rodrigo; Temam, Stephane; Benezery, Karen; Thariat, Juliette; Tao Yungan; Janot, Francois; Mamelle, Gerard; Vallicioni, Jacques; Follana, Philippe; Peyrade, Frederic; Sudaka, Anne; Bourhis, Jean; Dassonville, Olivier

    2009-01-01

    Purpose: We report the experience of two French cancer centers in the treatment of oral cavity squamous cell carcinoma (SCC) in patients aged ≥80 years. Materials and methods: Two hundred and sixty patients aged ≥80 years with a primary oral cavity SCC were included in this retrospective analysis. Results: Sex ratio was near to 1. Tobacco or alcohol intoxication was the main risk factor for 66% of men and 16% of women and leukoplakia, lichen planus, or oral traumatism for 55% of women and 11% of men (p < 0.0001). Two hundred patients received a loco-regional (LR) treatment with a curative intent (surgery and/or radiotherapy), 29 with a palliative intent and 31 did not receive a LR treatment. Curative treatments were initially planned to be adapted to age in 118 patients (59%). The median disease-specific survival (DSS) was 29 months. In multivariate analysis, the independent prognostic factors for DSS were stage (HR = 0.42 [0.24-0.72]), age (HR = 0.43 [0.24-0.75]) and performance status (HR = 0.50 [0.27-0.95]). The median overall survival (OS) was 14 months. In multivariate analysis, the independent prognostic factors for OS were age (HR = 0.52 [0.35-0.79]), stage (HR = 0.56 [0.38-0.84]), tumor differentiation (HR = 0.60 [0.33-0.93]) and performance status (HR = 0.6 [0.37-0.97]). In patients treated with a curative intent, treatment adapted to age was not associated with a decreased overall survival or disease-specific survival as compared with the standard treatment. However, prophylactic lymph node treatment in stages I-II tumors decreased the rate of nodal recurrence from 38% to 6% (p = 0.01). Conclusion: This study emphasizes the need for prospective evaluation of standard and adapted schedules in elderly patients with oral cavity cancer.

  9. Low-level laser therapy: Effects on human face aged skin and cell viability of HeLa cells exposed to UV radiation

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    Mezghani Sana

    2015-01-01

    Full Text Available Chronic and excessive exposure to UV radiation leads to photoaging and photocarcinogenesis. Adequate protection of the skin against the deleterious effects of UV irradiation is essential. Low-level laser therapy (LLLT is a light source in the red to near-infrared range that has been accepted in a variety of medical applications. In this study, we explored the effect of LLLT in human face aged skin and the cell viability of HeLa cells exposed to UV radiation. We found that LLLT significantly reduced visible wrinkles and the loss of firmness of facial skin in aging subjects. Additionally, treatment of cultured HeLa cells with LLLT prior to or post UVA or UVB exposure significantly protected cells from UV-mediated cell death. All results showed the beneficial effects of LLLT on relieving signs of skin aging and its prevention and protection of the cell viability against UV-induced damage.

  10. Dietary restriction improves repopulation but impairs lymphoid differentiation capacity of hematopoietic stem cells in early aging

    Science.gov (United States)

    Tang, Duozhuang; Tao, Si; Chen, Zhiyang; Koliesnik, Ievgen Oleksandrovich; Calmes, Philip Gerald; Hoerr, Verena; Han, Bing; Gebert, Nadja; Zörnig, Martin; Löffler, Bettina

    2016-01-01

    Dietary restriction (DR) improves health, delays tissue aging, and elongates survival in flies and worms. However, studies on laboratory mice and nonhuman primates revealed ambiguous effects of DR on lifespan despite improvements in health parameters. In this study, we analyzed consequences of adult-onset DR (24 h to 1 yr) on hematopoietic stem cell (HSC) function. DR ameliorated HSC aging phenotypes, such as the increase in number of HSCs and the skewing toward myeloid-biased HSCs during aging. Furthermore, DR increased HSC quiescence and improved the maintenance of the repopulation capacity of HSCs during aging. In contrast to these beneficial effects, DR strongly impaired HSC differentiation into lymphoid lineages and particularly inhibited the proliferation of lymphoid progenitors, resulting in decreased production of peripheral B lymphocytes and impaired immune function. The study shows that DR-dependent suppression of growth factors and interleukins mediates these divergent effects caused by DR. Supplementation of insulin-like growth factor 1 partially reverted the DR-induced quiescence of HSCs, whereas IL-6/IL-7 substitutions rescued the impairment of B lymphopoiesis exposed to DR. Together, these findings delineate positive and negative effects of long-term DR on HSC functionality involving distinct stress and growth signaling pathways. PMID:26951333

  11. Red blood cell distribution width: Genetic evidence for aging pathways in 116,666 volunteers.

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    Luke C Pilling

    Full Text Available Variability in red blood cell volumes (distribution width, RDW increases with age and is strongly predictive of mortality, incident coronary heart disease and cancer. We investigated inherited genetic variation associated with RDW in 116,666 UK Biobank human volunteers.A large proportion RDW is explained by genetic variants (29%, especially in the older group (60+ year olds, 33.8%, <50 year olds, 28.4%. RDW was associated with 194 independent genetic signals; 71 are known for conditions including autoimmune disease, certain cancers, BMI, Alzheimer's disease, longevity, age at menopause, bone density, myositis, Parkinson's disease, and age-related macular degeneration. Exclusion of anemic participants did not affect the overall findings. Pathways analysis showed enrichment for telomere maintenance, ribosomal RNA, and apoptosis. The majority of RDW-associated signals were intronic (119 of 194, including SNP rs6602909 located in an intron of oncogene GAS6, an eQTL in whole blood.Although increased RDW is predictive of cardiovascular outcomes, this was not explained by known CVD or related lipid genetic risks, and a RDW genetic score was not predictive of incident disease. The predictive value of RDW for a range of negative health outcomes may in part be due to variants influencing fundamental pathways of aging.

  12. Angelica Sinensis Polysaccharide Prevents Hematopoietic Stem Cells Senescence in D-Galactose-Induced Aging Mouse Model

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    Xinyi Mu

    2017-01-01

    Full Text Available Age-related regression in hematopoietic stem/progenitor cells (HSC/HPCs limits replenishment of the blood and immune system and hence contributes to hematopoietic diseases and declined immunity. In this study, we employed D-gal-induced aging mouse model and observed the antiaging effects of Angelica Sinensis Polysaccharide (ASP, a major active ingredient in dong quai (Chinese Angelica Sinensis, on the Sca-1+ HSC/HPCs in vivo. ASP treatment prevents HSC/HPCs senescence with decreased AGEs levels in the serum, reduced SA-β-Gal positive cells, and promoted CFU-Mix formation in the D-gal administrated mouse. We further found that multiple mechanisms were involved: (1 ASP treatment prevented oxidative damage as total antioxidant capacity was increased and levels of reactive oxygen species (ROS, 8-OHdG, and 4-HNE were declined, (2 ASP reduced the expression of γ-H2A.X which is a DNA double strand breaks (DSBs marker and decreased the subsequent ectopic expressions of effectors in p16Ink4a-RB and p19Arf-p21Cip1/Waf senescent pathways, and (3 ASP inhibited the excessive activation of Wnt/β-catenin signaling in aged HSC/HPCs, as the expressions of β-catenin, phospho-GSK-3β, and TCF-4 were decreased, and the cyto-nuclear translocation of β-catenin was inhibited. Moreover, compared with the positive control of Vitamin E, ASP exhibited a better antiaging effect and a weaker antioxidation ability, suggesting a novel protective role of ASP in the hematopoietic system.

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

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    Miguel Foronda

    2014-07-01

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

  14. Age-Dependent Schwann Cell Phenotype Regulation Following Peripheral Nerve Injury.

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    Chen, Wayne A; Luo, T David; Barnwell, Jonathan C; Smith, Thomas L; Li, Zhongyu

    2017-12-01

    Schwann cells are integral to the regenerative capacity of the peripheral nervous system, which declines after adolescence. The mechanisms underlying this decline are poorly understood. This study sought to compare the protein expression of Notch, c-Jun, and Krox-20 after nerve crush injury in adolescent and young adult rats. We hypothesized that these Schwann cell myelinating regulatory factors are down-regulated after nerve injury in an age-dependent fashion. Adolescent (2 months old) and young adult (12 months old) rats (n = 48) underwent sciatic nerve crush injury. Protein expression of Notch, c-Jun, and Krox-20 was quantified by Western blot analysis at 1, 3, and 7 days post-injury. Functional recovery was assessed in a separate group of animals (n = 8) by gait analysis (sciatic functional index) and electromyography (compound motor action potential) over an 8-week post-injury period. Young adult rats demonstrated a trend of delayed onset of the dedifferentiating regulatory factors, Notch and c-Jun, corresponding to the delayed functional recovery observed in young adult rats compared to adolescent rats. Compound motor action potential area was significantly greater in adolescent rats relative to young adult rats, while amplitude and velocity trended toward statistical significance. The process of Schwann cell dedifferentiation following peripheral nerve injury shows different trends with age. These trends of delayed onset of key regulatory factors responsible for Schwann cell myelination may be one of many possible factors mediating the significant differences in functional recovery between adolescent and young adult rats following peripheral nerve injury.

  15. Age-related declines and disease-associated variation in immune cell telomere length in a wild mammal.

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    Christopher Beirne

    Full Text Available Immunosenescence, the deterioration of immune system capability with age, may play a key role in mediating age-related declines in whole-organism performance, but the mechanisms that underpin immunosenescence are poorly understood. Biomedical research on humans and laboratory models has documented age and disease related declines in the telomere lengths of leukocytes ('immune cells', stimulating interest their having a potentially general role in the emergence of immunosenescent phenotypes. However, it is unknown whether such observations generalise to the immune cell populations of wild vertebrates living under ecologically realistic conditions. Here we examine longitudinal changes in the mean telomere lengths of immune cells in wild European badgers (Meles meles. Our findings provide the first evidence of within-individual age-related declines in immune cell telomere lengths in a wild vertebrate. That the rate of age-related decline in telomere length appears to be steeper within individuals than at the overall population level raises the possibility that individuals with short immune cell telomeres and/or higher rates of immune cell telomere attrition may be selectively lost from this population. We also report evidence suggestive of associations between immune cell telomere length and bovine tuberculosis infection status, with individuals detected at the most advanced stage of infection tending to have shorter immune cell telomeres than disease positive individuals. While male European badgers are larger and show higher rates of annual mortality than females, we found no evidence of a sex difference in either mean telomere length or the average rate of within-individual telomere attrition with age. Our findings lend support to the view that age-related declines in the telomere lengths of immune cells may provide one potentially general mechanism underpinning age-related declines in immunocompetence in natural populations.

  16. 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.

  17. Anti-aging effect of adipose-derived stem cells in a mouse model of skin aging induced by D-galactose.

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    Shengchang Zhang

    Full Text Available INTRODUCTION: Glycation products accumulate during aging of slowly renewing tissue, including skin, and are suggested as an important mechanism underlying the skin aging process. Adipose-derived cells are widely used in the clinic to treat ischemic diseases and enhance wound healing. Interestingly, adipose-derived stem cells (ASCs are also effective in anti-aging therapy, although the mechanism underlying their effects remains unknown. The purpose of the present study was to examine the anti-aging effect of ASCs in a D-galactose-induced aging animal model and to clarify the underlying mechanism. MATERIALS AND METHODS: Six-week-old nude mice were subcutaneously injected with D-gal daily for 8 weeks. Two weeks after completion of treatment, mice were randomized to receive subcutaneous injections of 106 green fluorescent protein (GFP-expressing ASCs, aminoguanidine (AG or phosphate-buffered saline (PBS. Control mice received no treatment. We examined tissue histology and determined the activity of senescence-associated molecular markers such as superoxide dismutase (SOD and malondialdehyde (MDA. RESULTS: Transplanted ASCs were detectable for 14 days and their GFP signal disappeared at day 28 after injection. ASCs inhibited advanced glycation end product (AGE levels in our animal model as well as increased the SOD level and decreased the MDA level, all of which act to reverse the aging phenotype in a similar way to AG, an inhibitor of AGE formation. Furthermore, ASCs released angiogenic factors in vivo such as vascular endothelial growth factor, suggesting a skin trophic effect. CONCLUSIONS: These results demonstrate that ASCs may contribute to the regeneration of skin during aging. In addition, the data shows that ASCs provide a functional benefit by glycation suppression, antioxidation, and trophic effects in a mouse model of aging.

  18. Inverse associations between obesity indicators and thymic T-cell production levels in aging atomic-bomb survivors.

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    Kengo Yoshida

    Full Text Available Reduction of the naive T-cell population represents a deteriorating state in the immune system that occurs with advancing age. In animal model studies, obesity compromises the T-cell immune system as a result of enhanced adipogenesis in primary lymphoid organs and systemic inflammation. In this study, to test the hypothesis that obesity may contribute to the aging of human T-cell immunity, a thousand atomic-bomb survivors were examined for obesity status and ability to produce naive T cells, i.e., T-cell receptor excision circle (TREC numbers in CD4 and CD8 T cells. The number of TRECs showed a strong positive correlation with naive T cell numbers, and lower TREC numbers were associated with higher age. We found that the TREC number was inversely associated with levels of obesity indicators (BMI, hemoglobin A1c and serum CRP levels. Development of type-2 diabetes and fatty liver was also associated with lower TREC numbers. This population study suggests that obesity with enhanced inflammation is involved in aging of the human T-cell immune system. Given the fact that obesity increases the risk of numerous age-related diseases, attenuated immune competence is a possible mechanistic link between obesity and disease development among the elderly.

  19. Inverse associations between obesity indicators and thymic T-cell production levels in aging atomic-bomb survivors.

    Science.gov (United States)

    Yoshida, Kengo; Nakashima, Eiji; Kubo, Yoshiko; Yamaoka, Mika; Kajimura, Junko; Kyoizumi, Seishi; Hayashi, Tomonori; Ohishi, Waka; Kusunoki, Yoichiro

    2014-01-01

    Reduction of the naive T-cell population represents a deteriorating state in the immune system that occurs with advancing age. In animal model studies, obesity compromises the T-cell immune system as a result of enhanced adipogenesis in primary lymphoid organs and systemic inflammation. In this study, to test the hypothesis that obesity may contribute to the aging of human T-cell immunity, a thousand atomic-bomb survivors were examined for obesity status and ability to produce naive T cells, i.e., T-cell receptor excision circle (TREC) numbers in CD4 and CD8 T cells. The number of TRECs showed a strong positive correlation with naive T cell numbers, and lower TREC numbers were associated with higher age. We found that the TREC number was inversely associated with levels of obesity indicators (BMI, hemoglobin A1c) and serum CRP levels. Development of type-2 diabetes and fatty liver was also associated with lower TREC numbers. This population study suggests that obesity with enhanced inflammation is involved in aging of the human T-cell immune system. Given the fact that obesity increases the risk of numerous age-related diseases, attenuated immune competence is a possible mechanistic link between obesity and disease development among the elderly.

  20. Arginase-II Promotes Tumor Necrosis Factor-α Release From Pancreatic Acinar Cells Causing β-Cell Apoptosis in Aging.

    Science.gov (United States)

    Xiong, Yuyan; Yepuri, Gautham; Necetin, Sevil; Montani, Jean-Pierre; Ming, Xiu-Fen; Yang, Zhihong

    2017-06-01

    Aging is associated with glucose intolerance. Arginase-II (Arg-II), the type-II L -arginine-ureahydrolase, is highly expressed in pancreas. However, its role in regulation of pancreatic β-cell function is not known. Here we show that female (not male) mice deficient in Arg-II (Arg-II -/- ) are protected from age-associated glucose intolerance and reveal greater glucose induced-insulin release, larger islet size and β-cell mass, and more proliferative and less apoptotic β-cells compared with the age-matched wild-type (WT) controls. Moreover, Arg-II is mainly expressed in acinar cells and is upregulated with aging, which enhances p38 mitogen-activated protein kinase (p38 MAPK) activation and release of tumor necrosis factor-α (TNF-α). Accordingly, conditioned medium of isolated acinar cells from old WT (not Arg-II -/- ) mice contains higher TNF-α levels than the young mice and stimulates β-cell apoptosis and dysfunction, which are prevented by a neutralizing anti-TNF-α antibody. In acinar cells, our study demonstrates an age-associated Arg-II upregulation, which promotes TNF-α release through p38 MAPK leading to β-cell apoptosis, insufficient insulin secretion, and glucose intolerance in female rather than male mice. © 2017 by the American Diabetes Association.

  1. Cytokine-induced activation of glial cells in the mouse brain is enhanced at an advanced age.

    Science.gov (United States)

    Deng, X-H; Bertini, G; Xu, Y-Z; Yan, Z; Bentivoglio, M

    2006-08-25

    Numerous neurological diseases which include neuroinflammatory components exhibit an age-related prevalence. The aging process is characterized by an increase of inflammatory mediators both systemically and in the brain, which may prime glial cells. However, little information is available on age-related changes in the glial response of the healthy aging brain to an inflammatory challenge. This problem was here examined using a mixture of the proinflammatory cytokines interferon-gamma and tumor necrosis factor-alpha, which was injected intracerebroventricularly in young (2-3.5 months), middle-aged (10-11 months) and aged (18-21 months) mice. Vehicle (phosphate-buffered saline) was used as control. After a survival of 1 or 2 days (all age groups) or 4 days (young and middle-aged animals), immunohistochemically labeled astrocytes and microglia were investigated both qualitatively and quantitatively. In all age groups, astrocytes were markedly activated in periventricular as well as in deeper brain regions 2 days following cytokine treatment, whereas microglia activation was already evident at 24 h. Interestingly, cytokine-induced activation of both astrocytes and microglia was significantly more marked in the brain of aged animals, in which it included numerous ameboid microglia, than of younger age groups. Moderate astrocytic activation was also seen in the hippocampal CA1 field of vehicle-treated aged mice. FluoroJade B histochemistry and the terminal deoxynucleotidyl transferase-mediated UTP nick-end labeling technique, performed at 2 days after cytokine administration, did not reveal ongoing cell death phenomena in young or aged animals. This indicated that glial cell changes were not secondary to neuronal death. Altogether, the findings demonstrate for the first time enhanced activation of glial cells in the old brain, compared with young and middle-aged subjects, in response to cytokine exposure. Interestingly, the results also suggest that such enhancement

  2. Adipogenic differentiation and EGFP gene transfection of amniotic fluid-derived stem cells from goat fetus at terminal gestational age.

    Science.gov (United States)

    He, Xiao-Ying; Zheng, Yue-Mao; Qiu, Shuang; Qi, Ying-Pei; Zhang, Yong

    2011-08-01

    The aims of this study were to determine whether stem cells could be isolated from amniotic fluid of goat fetus at terminal gestational age and to determine if these stem cells could differentiate into adipogenic cells and be transfected with a reporter gene, EGFP (enhanced green fluorescent protein). The stem cells were isolated from amniotic fluid of goat fetus at terminal gestational age, induced to differentiate into adipogenic cells in vitro and transfected with the EGFP gene using lipofection. Markers associated with undifferentiated AFS (amniotic fluid-derived stem) cells were tested by RT (reverse transcription)-PCR. The results demonstrated that AFS cells could be isolated from amniotic fluid of goat fetus at terminal gestational age and could differentiate into adipogenic cells. The EGFP gene was transfected into AFS cells successfully. EGFP gene transfection efficiency of the three groups of transgenic AFS cells were 26.0, 29.9 and 30.5%, respectively. Both transgenic and wild-type AFS cells could express Hes1 (hairy and enhancer of split 1), Oct4 (octamer-binding protein 4) and Nanog.

  3. Dynamic activation of basilar membrane macrophages in response to chronic sensory cell degeneration in aging mouse cochleae.

    Science.gov (United States)

    Frye, Mitchell D; Yang, Weiping; Zhang, Celia; Xiong, Binbin; Hu, Bo Hua

    2017-02-01

    In the sensory epithelium, macrophages have been identified on the scala tympani side of the basilar membrane. These basilar membrane macrophages are the spatially closest immune cells to sensory cells and are able to directly respond to and influence sensory cell pathogenesis. While basilar membrane macrophages have been studied in acute cochlear stresses, their behavior in response to chronic sensory cell degeneration is largely unknown. Here we report a systematic observation of the variance in phenotypes, the changes in morphology and distribution of basilar membrane tissue macrophages in different age groups of C57BL/6J mice, a mouse model of age-related sensory cell degeneration. This study reveals that mature, fully differentiated tissue macrophages, not recently infiltrated monocytes, are the major macrophage population for immune responses to chronic sensory cell death. These macrophages display dynamic changes in their numbers and morphologies as age increases, and the changes are related to the phases of sensory cell degeneration. Notably, macrophage activation precedes sensory cell pathogenesis, and strong macrophage activity is maintained until sensory cell degradation is complete. Collectively, these findings suggest that mature tissue macrophages on the basilar membrane are a dynamic group of cells that are capable of vigorous adaptation to changes in the local sensory epithelium environment influenced by sensory cell status. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. DNA Methylation Patterns in Cord Blood of Neonates Across Gestational Age: Association With Cell-Type Proportions.

    Science.gov (United States)

    Braid, Susan M; Okrah, Kwame; Shetty, Amol; Corrada Bravo, Hector

    A statistical methodology is available to estimate the proportion of cell types (cellular heterogeneity) in adult whole blood specimens used in epigenome-wide association studies (EWAS). However, there is no methodology to estimate the proportion of cell types in umbilical cord blood (also a heterogeneous tissue) used in EWAS. The objectives of this study were to determine whether differences in DNA methylation (DNAm) patterns in umbilical cord blood are the result of blood cell type proportion changes that typically occur across gestational age and to demonstrate the effect of cell type proportion confounding by comparing preterm infants exposed and not exposed to antenatal steroids. We obtained DNAm profiles of cord blood using the Illumina HumanMethylation27k BeadChip array for 385 neonates from the Boston Birth Cohort. We estimated cell type proportions for six cell types using the deconvolution method developed by . The cell type proportion estimates segregated into two groups that were significantly different by gestational age, indicating that gestational age was associated with cell type proportion. Among infants exposed to antenatal steroids, the number of differentially methylated CpGs dropped from 127 to 1 after controlling for cell type proportion. EWAS utilizing cord blood are confounded by cell type proportion. Careful study design including correction for cell type proportion and interpretation of results of EWAS using cord blood are critical.

  5. Age-related changes in humoral and cell-mediated immunity in Down syndrome children living at home.

    Science.gov (United States)

    Lockitch, G; Singh, V K; Puterman, M L; Godolphin, W J; Sheps, S; Tingle, A J; Wong, F; Quigley, G

    1987-11-01

    Abnormalities of humoral and cell-mediated immunity have been described in Down syndrome but reported findings have been inconsistent. Confounding factors have included age, institutional versus home life, hepatitis B antigenemia, and zinc deficiency. To clarify this problem, we studied 64 children with Down syndrome (DS) compared with an age-matched control group. All children had always lived at home. All the DS children were negative for hepatitis B surface antigen. Serum zinc concentration in the DS group was on average 12 micrograms/dl lower than age-matched control children. They also had significantly lower levels of immunoglobulin M, total lymphocyte count, T and B lymphocytes, and T helper and suppressor cells. In vitro lymphocyte response to phytohemagglutinin and concanavalin A was significantly reduced at all ages in the DS group. Lymphocyte response to pokeweed mitogen increased with age in control children but decreased in the DS children. By 18 yr, the mean response for DS was 60000 cpm lower than controls. The DS group had significantly higher concentrations of immunoglobulins A and G than controls and the difference increased with age. Complement fractions C3 and C4 were also higher in the DS group at all ages. The number of HNK-1 positive cells was higher in the DS group than controls at all ages. When hepatitis and institutionalization are excluded as confounding factors, DS children still differ in both humoral and cell-mediated immunity from an age-matched control group.

  6. Aging of the T cell compartment in mice and humans: from no naïve expectations to foggy memories

    Science.gov (United States)

    Nikolich-Žugich, Janko

    2014-01-01

    Until the mid-20th century, infectious diseases were the major cause of morbidity and mortality in humans. Massive vaccination campaigns, antibiotics, antivirals and advanced public health measures drastically reduced sickness and death of infections in children and younger adults. Older adults (>65yr of age), however, remain vulnerable to infections, and to date infectious diseases remain amongst the top 5–10 causes of death in this population. The aging of the immune system, often referred to as immune senescence, is the key phenomenon underlying this vulnerability. This review centers on age-related changes in T cells, which are dramatically and reproducibly altered with aging. I will discuss changes in T cell production, maintenance, function and response to latent persistent infection, particularly against the cytomegalovirus (CMV), that exerts profound influence on the aging T cell pool, concluding with a brief list of measures to improve immune function in older adults. PMID:25193936

  7. Cold hypersensitivity increases with age in mice with sickle cell disease

    Science.gov (United States)

    Zappia, Katherine J.; Garrison, Sheldon R.; Hillery, Cheryl A.; Stucky, Cheryl L.

    2014-01-01

    Sickle cell disease (SCD) is associated with acute vaso-occlusive crises that trigger painful episodes and frequently involves ongoing, chronic pain. Additionally, both humans and mice with SCD experience heighted cold sensitivity. However, studies have not addressed the mechanism(s) underlying the cold sensitization, nor its progression with age. Here we measured thermotaxis behavior in young and aged mice with severe SCD. Sickle mice had a marked increase in cold sensitivity measured by a cold preference test. Further, cold hypersensitivity worsened with advanced age. We assessed whether enhanced peripheral input contributes to the chronic cold pain behavior by recording from C fibers, many of which are cold-sensitive, in skin-nerve preparations. We observed that C fibers from sickle mice displayed a shift to warmer (more sensitive) cold-detection thresholds. To address mechanisms underlying the cold sensitization in primary afferent neurons, we quantified mRNA expression levels for ion channels thought to be involved in cold detection. These included the Transient Receptor Potential Melastatin 8 (Trpm8) and TRP Ankyrin 1 (Trpa1) channels, as well as the two-pore domain potassium channels, TREK-1 (Kcnk2), TREK-2 (Kcnk4), and TRAAK (Kcnk10). Surprisingly, transcript expression levels of all of these channels were comparable between sickle and control mice. We further examined transcript expression of 83 additional pain-related genes and found increased mRNA levels for endothelin 1 and tachykinin receptor 1. These factors may contribute to hypersensitivity in sickle mice at both the afferent and behavioral levels. Sensory neurons from sickle cell disease mice are sensitized to cold, mirroring behavioral observations, and have increased expression of endothelin 1 and tachykinin receptor 1. PMID:24953902

  8. Mesenchymal stem cell-derived inflammatory fibroblasts mediate interstitial fibrosis in the aging heart.

    Science.gov (United States)

    Trial, JoAnn; Entman, Mark L; Cieslik, Katarzyna A

    2016-02-01

    Pathologic fibrosis in the aging mouse heart is associated with dysregulated resident mesenchymal stem cells (MSC) arising from reduced stemness and aberrant differentiation into dysfunctional inflammatory fibroblasts. Fibroblasts derived from aging MSC secrete higher levels of 1) collagen type 1 (Col1) that directly contributes to fibrosis, 2) monocyte chemoattractant protein-1 (MCP-1) that attracts leukocytes from the blood and 3) interleukin-6 (IL-6) that facilitates transition of monocytes into myeloid fibroblasts. The transcriptional activation of these proteins is controlled via the farnesyltransferase (FTase)-Ras-Erk pathway. The intrinsic change in the MSC phenotype acquired by advanced age is specific for the heart since MSC originating from bone wall (BW-MSC) or fibroblasts derived from them were free of these defects. The potential therapeutic interventions other than clinically approved strategies based on findings presented in this review are discussed as well. This article is a part of a Special Issue entitled "Fibrosis and Myocardial Remodeling". Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. EGFR regulation of colon cancer stem-like cells during aging and in response to the colonic carcinogen dimethylhydrazine.

    Science.gov (United States)

    Nautiyal, Jyoti; Du, Jianhua; Yu, Yingjie; Kanwar, Shailender S; Levi, Edi; Majumdar, Adhip P N

    2012-04-01

    One of the most consistent pathological conditions in the gastrointestinal tract with advancing age is malignancy, particularly gastrointestinal cancers, the incidence of which increases sharply with aging. Although the reasons for the age-related rise in colorectal cancer are not fully understood, we hypothesize that aging increases susceptibility of the colon to carcinogen(s)/toxicant(s), leading to an increase in cancer stem-like cells (CSLCs) that express cancer stem cell markers, in the colonic mucosa. The current study demonstrates that aging is associated with increased expression of several colon CSLC markers [CD44, CD166, and aldehyde dehydrogenase 1 (ALDH-1)] and a higher proportion of cells expressing these markers. Aging is also accompanied by increased expression of miR-21 in colon. These increases are further increased in response to the colonic carcinogen dimethylhydrazine (DMH). Aging is also associated with increased tyrosine-phosphorylated epidermal growth factor receptor (EGFR). Inhibition of EGFR using the EGFR inhibitor cetuximab abrogated the age-related increase in CD166 and ALDH-1 as well as miRNA (miR)-21. Our results provide new evidence that aging and DMH are associated with increases in CSLC biomarkers and miR21, each of which have been linked to colorectal cancer. EGFR inhibition attenuates these changes, indicating a role for EGFR in age- and mutagen-associated changes in CSLCs.

  10. Requirement of ATR for maintenance of intestinal stem cells in aging Drosophila.

    Science.gov (United States)

    Park, Joung-Sun; Na, Hyun-Jin; Pyo, Jung-Hoon; Jeon, Ho-Jun; Kim, Young-Shin; Yoo, Mi-Ae

    2015-05-01

    The stem cell genomic stability forms the basis for robust tissue homeostasis, particularly in high-turnover tissues. For the genomic stability, DNA damage response (DDR) is essential. This study was focused on the role of two major DDR-related factors, ataxia telangiectasia-mutated (ATM) and ATM- and RAD3-related (ATR) kinases, in the maintenance of intestinal stem cells (ISCs) in the adultDrosophila midgut. We explored the role of ATM and ATR, utilizing immunostaining with an anti-pS/TQ antibody as an indicator of ATM/ATR activation, γ-irradiation as a DNA damage inducer, and the UAS/GAL4 system for cell type-specific knockdown of ATM, ATR, or both during adulthood. The results showed that the pS/TQ signals got stronger with age and after oxidative stress. The pS/TQ signals were found to be more dependent on ATR rather than on ATM in ISCs/enteroblasts (EBs). Furthermore, an ISC/EB-specific knockdown of ATR, ATM, or both decreased the number of ISCs and oxidative stress-induced ISC proliferation. The phenotypic changes that were caused by the ATR knockdown were more pronounced than those caused by the ATM knockdown; however, our data indicate that ATR and ATM are both needed for ISC maintenance and proliferation; ATR seems to play a bigger role than does ATM.

  11. The ageing phenome: caloric restriction and hormones promote neural cell survival, growth, and de-differentiation.

    Science.gov (United States)

    Timiras, Paola S; Yaghmaie, Farzin; Saeed, Omar; Thung, Elaine; Chinn, Garrett

    2005-01-01

    The phenome represents the observable properties of an organism that have developed under the continued influences of both genome and environmental factors. Phenotypic properties are expressed through the functions of cells, organs and body systems that operate optimally, close to equilibrium. In complex organisms, maintenance of the equilibrium is achieved by the interplay of several regulatory mechanisms. In the elderly, dynamic instability may lead to progressive loss of normal function, failure of adaptation and increased pathology. Extensive research (reported elsewhere in this journal) has demonstrated that genetic manipulations of endocrine signaling in flies, worms and mice increase longevity. Another effective strategy for prolonging the lifespan is caloric restriction: in data presented here, the persistence of estrogen-sensitive cells in the hypothalamus of caloric restricted 22-month-old female mice, may explain the persistence of reproductive function at an age, when reproductive function has long ceased in ad libitum fed controls. Still another strategy utilizes the effects of epidermal growth factor (EGF) to promote in vitro proliferation of neuroglia, astrocytes and oligodendrocytes. Their subsequent de-differentiation generates immature precursor cells potentially capable of differentiating into neuroblasts and neurons. These and other examples suggest that, in terms of functional outcomes, "the genome proposes but the phenome disposes".

  12. Calendar aging of a graphite/LiFePO4 cell

    Science.gov (United States)

    Kassem, M.; Bernard, J.; Revel, R.; Pélissier, S.; Duclaud, F.; Delacourt, C.

    2012-06-01

    Graphite/LFP commercial cells are stored under 3 different conditions of temperature (30 °C, 45 °C, and 60 °C) and SOC (30%, 65%, and 100%) during up to 8 months. Several non-destructive electrochemical tests are performed at different storage times in order to understand calendar aging phenomena. After storage, all the cells except those stored at 30 °C exhibited capacity fade. The extent of capacity fade strongly increases with storage temperature and to a lesser extent with the state of charge. From in-depth data analysis, cyclable lithium loss was identified as the main source of capacity fade. This loss arises from side reactions taking place at the anode, e.g. solvent decomposition leading to the growth of the solid electrolyte interphase. However, the existence of reversible capacity loss also suggests the presence of side reactions occurring at the cathode, which are less prominent than those at the anode. The analyses do not show any evidence about active-material loss in the electrodes. The cells do not suffer substantial change in internal resistance. According to EIS analysis, the overall impedance increase is 70% or less.

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

    Science.gov (United States)

    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.

  14. 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".

  15. c-Kit-positive cardiac stem cells nested in hypoxic niches are activated by stem cell factor reversing the aging myopathy.

    Science.gov (United States)

    Sanada, Fumihiro; Kim, Junghyun; Czarna, Anna; Chan, Noel Yan-Ki; Signore, Sergio; Ogórek, Barbara; Isobe, Kazuya; Wybieralska, Ewa; Borghetti, Giulia; Pesapane, Ada; Sorrentino, Andrea; Mangano, Emily; Cappetta, Donato; Mangiaracina, Chiara; Ricciardi, Mario; Cimini, Maria; Ifedigbo, Emeka; Perrella, Mark A; Goichberg, Polina; Choi, Augustine M; Kajstura, Jan; Hosoda, Toru; Rota, Marcello; Anversa, Piero; Leri, Annarosa

    2014-01-03

    Hypoxia favors stem cell quiescence, whereas normoxia is required for stem cell activation, but whether cardiac stem cell (CSC) function is regulated by the hypoxic/normoxic state of the cell is currently unknown. A balance between hypoxic and normoxic CSCs may be present in the young heart, although this homeostatic control may be disrupted with aging. Defects in tissue oxygenation occur in the old myocardium, and this phenomenon may expand the pool of hypoxic CSCs, which are no longer involved in myocyte renewal. Here, we show that the senescent heart is characterized by an increased number of quiescent CSCs with intact telomeres that cannot re-enter the cell cycle and form a differentiated progeny. Conversely, myocyte replacement is controlled only by frequently dividing CSCs with shortened telomeres; these CSCs generate a myocyte population that is chronologically young but phenotypically old. Telomere dysfunction dictates their actual age and mechanical behavior. However, the residual subset of quiescent young CSCs can be stimulated in situ by stem cell factor reversing the aging myopathy. Our findings support the notion that strategies targeting CSC activation and growth interfere with the manifestations of myocardial aging in an animal model. Although caution has to be exercised in the translation of animal studies to human beings, our data strongly suggest that a pool of functionally competent CSCs persists in the senescent heart and that this stem cell compartment can promote myocyte regeneration effectively, partly correcting the aging myopathy.

  16. Temperature and humidity effect on aging of silicone rubbers as sealing materials for proton exchange membrane fuel cell applications

    International Nuclear Information System (INIS)

    Chang, Huawei; Wan, Zhongmin; Chen, Xi; Wan, Junhua; Luo, Liang; Zhang, Haining; Shu, Shuiming; Tu, Zhengkai

    2016-01-01

    Highlights: • Aging of silicone rubbers with different hardness was investigated. • Existed water molecules from humidified gases can accelerate the aging process. • Silicone rubber with hardness of 40 is more suitable as sealing materials. • Silicone rubbers can be used as sealing materials below 80 °C but not above 100 °C. - Abstract: Durability and reliability of seals around perimeter of each unit are critical to the lifetime of proton exchange membrane fuel cells. In this study, we investigate the aging of silicone rubbers with different hardness, often used as sealing materials for fuel cells, subjected to dry and humidified air at different temperatures. The aging properties are characterized by variation of permanent compression set value under compression, mechanical properties, and surface morphology as well. The results show that aging of silicone rubbers becomes more severe with the increase in subjected temperature. At temperature above 100 °C, silicone rubbers are not suitable for fuel cell applications. The existed water molecules from humidified gases can accelerate the aging of silicone rubbers. Among the tested samples, silicone rubber with hardness of 40 is more durable than that with hardness of 30 and 50 for fuel cells. The change of chemical structure after aging suggests that the aging of silicone rubbers mainly results from the chemical decomposition of cross-linker units for connection of polysiloxane backbones and of methyl groups attached to silicon atoms.

  17. Alloreactive cytotoxic T lymphocytes from aged mice express increased lysis of autologous and third-party target cells

    NARCIS (Netherlands)

    Kruisbeek, A.M.; Steinmeier, F.A.

    1980-01-01

    Much data support the notion that with increasing age a decline in T cell effector function occurs. In the present study, qualitative rather than quantitative age-related changes in vitro alloreactive cytotoxic T lymphocyte (CTL) responses were observed. The level of specific alloreactive CTL

  18. 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

  19. 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.

  20. Impact of the Hayflick Limit on T cell responses to infection: lessons from aging and HIV disease.

    Science.gov (United States)

    Effros, Rita B

    2004-02-01

    Aging and HIV disease show certain immunological similarities. In both situations, control over viral infection is diminished, and there is an increase in certain types of cancer. The immune cell type responsible for controlling viral infections and cancer is the so-called CD8 or cytotoxic T cell. In elderly persons and individuals chronically infected with HIV, there are high proportions of CD8 T cells that resemble cells that reach the end stage of replicative senescence in cell culture after repeated rounds of antigen-driven proliferation. Senescent cultures are characterized by irreversible cell cycle arrest, shortened telomeres, inability to upregulate telomerase, loss of CD28 expression, and apoptosis resistance. Strategies that retard replicative senescence may, therefore, provide novel approaches to enhancing immune function during aging and HIV disease.

  1. Effects of chronic malnourishment and aging on the ultrastructure of pyramidal cells of the dorsal hippocampus.

    Science.gov (United States)

    Castro-Chavira, Susana Angelica; Aguilar-Vázquez, Azucena Ruth; Martínez-Chávez, Yvonne; Palma, Lourdes; Padilla-Gómez, Euridice; Diaz-Cintra, Sofia

    2016-10-01

    Malnourishment (M) produces permanent alterations during the development of the CNS and might modify the aging process. In pyramidal neurons (PN) of the hippocampus, which are associated with learning and memory performance, few studies have focused on changes at the subcellular level under chronic malnutrition (ChM) in young (Y, 2 months old) and aged (A, 22 months old) rats. The present work evaluated the extent to which ChM disrupts organelles in PN of the dorsal hippocampus CA1 as compared to controls (C). Ultrastructural analysis was performed at 8000×  and 20 000×  magnification: Nucleus eccentricity and somatic, cytoplasmic, and nuclear areas were measured; and in the PN perikaryon, density indices (number of organelles/cytoplasmic area) of Golgi membrane systems (GMS, normal, and swollen), mitochondria (normal and abnormal), and vacuolated organelles (lysosomes, lipofuscin granules, and multivesicular bodies (MVB)) were determined. The density of abnormal mitochondria, swollen GMS, and MVB increased significantly in the AChM group compared to the other groups. The amount of lipofuscin was significantly greater in the AChM than in the YChM groups - a sign of oxidative stress due to malnutrition and aging; however, in Y animals, ChM showed no effect on organelle density or the cytoplasmic area. An increased density of lysosomes as well as nucleus eccentricity was observed in the AC group, which also showed an increase in the cytoplasmic area. Malnutrition produces subcellular alterations in vulnerable hippocampal pyramidal cells, and these alterations may provide an explanation for the previously reported deficient performance of malnourished animals in a spatial memory task in which aging and malnutrition were shown to impede the maintenance of long-term memory.

  2. Aging and photo-aging DNA repair phenotype of skin cells-Evidence toward an effect of chronic sun-exposure

    Energy Technology Data Exchange (ETDEWEB)

    Prunier, Chloe; Masson-Genteuil, Gwenaeelle [Laboratoire Lesions des Acides Nucleiques, CEA, DSM, INAC, SCIB, UMR-E CEA/UJF-Grenoble 1, 17 Rue des Martyrs, F-38054 Grenoble Cedex 9 (France); Ugolin, Nicolas [Laboratoire de Cancerologie Experimentale, CEA, DSV, IRCM, SREIT, BP6, Fontenay-aux-Roses Cedex F-92265 (France); Sarrazy, Fanny [Laboratoire Lesions des Acides Nucleiques, CEA, DSM, INAC, SCIB, UMR-E CEA/UJF-Grenoble 1, 17 Rue des Martyrs, F-38054 Grenoble Cedex 9 (France); Sauvaigo, Sylvie, E-mail: sylvie.sauvaigo@cea.fr [Laboratoire Lesions des Acides Nucleiques, CEA, DSM, INAC, SCIB, UMR-E CEA/UJF-Grenoble 1, 17 Rue des Martyrs, F-38054 Grenoble Cedex 9 (France)

    2012-08-01

    Several studies have demonstrated the deleterious effect of aging on the capacity of cells to repair their DNA. However, current existing assays aimed at measuring DNA repair address only a specific repair step dedicated to the correction of a specific DNA lesion type. Consequently they provide no information regarding the repair pathways that handle other types of lesions. In addition to aging, consequences of photo-exposure on these repair processes remain elusive. In this study we evaluated the consequence of aging and of chronic and/or acute photo-exposure on DNA repair in human skin fibroblasts using a multiplexed approach, which provided detailed information on several repair pathways at the same time. The resulting data were analyzed with adapted statistics/bioinformatics tools. We showed that, irrespective of the repair pathway considered, excision/synthesis was less efficient in non-exposed cells from elderly compared to cells from young adults and that photo-exposure disrupted this very clear pattern. Moreover, it was evidenced that chronic sun-exposure induced changes in DNA repair properties. Finally, the identification of a specific signature at the level of the NER pathway in cells repeatedly exposed to sun revealed a cumulative effect of UVB exposure and chronic sun irradiation. The uses of bioinformatics tools in this study was essential to fully take advantage of the large sum of data obtained with our multiplexed DNA repair assay and unravel the effects of environmental exposure on DNA repair pathways.

  3. Overexpression of Insulin-Like Growth Factor 1 Enhanced the Osteogenic Capability of Aging Bone Marrow Mesenchymal Stem Cells.

    Science.gov (United States)

    Chen, Ching-Yun; Tseng, Kuo-Yun; Lai, Yen-Liang; Chen, Yo-Shen; Lin, Feng-Huei; Lin, Shankung

    2017-01-01

    Many studies have indicated that loss of the osteoblastogenic potential in bone marrow mesenchymal stem cells (bmMSCs) is the major component in the etiology of the aging-related bone deficit. But how the bmMSCs lose osteogenic capability in aging is unclear. Using 2-dimentional cultures, we examined the dose response of human bmMSCs, isolated from adult and aged donors, to exogenous insulin-like growth factor 1 (IGF-1), a growth factor regulating bone formation. The data showed that the mitogenic activity and the osteoblastogenic potential of bmMSCs in response to IGF-1 were impaired with aging, whereas higher doses of IGF-1 increased the proliferation rate and osteogenic potential of aging bmMSCs. Subsequently, we seeded IGF-1-overexpressing aging bmMSCs into calcium-alginate scaffolds and incubated in a bioreactor with constant perfusion for varying time periods to examine the effect of IGF-1 overexpression to the bone-forming capability of aging bmMSCs. We found that IGF-1 overexpression in aging bmMSCs facilitated the formation of cell clusters in scaffolds, increased the cell survival inside the cell clusters, induced the expression of osteoblast markers, and enhanced the biomineralization of cell clusters. These results indicated that IGF-1 overexpression enhanced cells' osteogenic capability. Thus, our data suggest that the aging-related loss of osteogenic potential in bmMSCs can be attributed in part to the impairment in bmMSCs' IGF-1 signaling, and support possible application of IGF-1-overexpressing autologous bmMSCs in repairing bone defect of the elderly and in producing bone graft materials for repairing large scale bone injury in the elderly.

  4. Mechanical strain modulates age-related changes in the proliferation and differentiation of mouse adipose-derived stromal cells

    Directory of Open Access Journals (Sweden)

    Chiang Wen-Sheng

    2010-03-01

    Full Text Available Abstract Background Previous studies on the effects of aging in human and mouse mesenchymal stem cells suggest that a decline in the number and differentiation potential of stem cells may contribute to aging and aging-related diseases. In this report, we used stromal cells isolated from adipose tissue (ADSCs of young (8-10 weeks, adult (5 months, and old (21 months mice to test the hypothesis that mechanical loading modifies aging-related changes in the self-renewal and osteogenic and adipogenic differentiation potential of these cells. Results We show that aging significantly reduced the proliferation and increased the adipogenesis of ADSCs, while the osteogenic potential is not significantly reduced by aging. Mechanical loading (10% cyclic stretching, 0.5 Hz, 48 h increased the subsequent proliferation of ADSCs from mice of all ages. Although the number of osteogenic colonies with calcium deposition was increased in ADSCs subjected to pre-strain, it resulted from an increase in colony number rather than from an increase in osteogenic potential after strain. Pre-strain significantly reduced the number of oil droplets and the expression of adipogenic marker genes in adult and old ADSCs. Simultaneously subjecting ADSCs to mechanical loading and adipogenic induction resulted in a stronger inhibition of adipogenesis than that caused by pre-strain. The reduction of adipogenesis by mechanical strain was loading-magnitude dependent: loading with 2% strain only resulted in a partial inhibition, and loading with 0.5% strain could not inhibit adipogenesis in ADSCs. Conclusions We demonstrate that mechanical stretching counteracts the loss of self-renewal in aging ADSCs by enhancing their proliferation and, at the same time, reduces the heightened adipogenesis of old cells. These findings are important for the further study of stem cell control and treatment for a variety of aging related diseases.

  5. Immunochemical expression of proliferative cell nuclear antigen in aging cultured astrocytes

    Directory of Open Access Journals (Sweden)

    M. C. Vanzani

    2003-08-01

    Full Text Available Cell differentiation degree and mitotic activity were sequentially assessed by immunoperoxidase labeling of glial fibrillary acidic protein (GFAP and proliferative cell nuclear antigen (PCNA, respectively, in rat brain cultured astrocytes maintained up to 60 days in vitro (DIV of first subculture, or weekly passaged until their 12th subculture. Cell count was performed through a 0.01 mm2 section reticule and morphometric analysis with a stereological grid. The number of double immunoreactive cells peaked by 2 DIV to achieve its lowest value at 60 DIV. At 24 hs of cell seeding of successive passages, such values peaked by the 6th subculture to gradually decrease thereafter. Increasing cell hypertrophy was found during the long-term first subculture but not after passaging. At the end of the observation period, doubly immunolabeled astrocytes were still recorded, thus evidencing retention of proliferative potential despite aging.El grado de diferenciación celular y la actividad mitótica fueron secuencialmente determinados mediante marcación por inmunoperoxidasa de la proteína gliofibrilar ácida (GFAP y del antígeno nuclear de proliferación celular (PCNA, respectivamente, en cultivos astrocitarios obtenidos de encéfalo de rata y mantenidos hasta 60 días in vitro (DIV de su primer subcultivo, o mediante pasajes semanales hasta el 12do subcultivo. El conteo celular se realizó mediante una retícula de 0.01-mm2 de sección y el análisis morfométrico con una grilla estereológica. El número de células doblemente inmunorreactivas alcanzó valores máximos a los 2 DIV para descender a los menores a los 60 DIV. A las 24 hs de sembrado celular de los sucesivos pasajes, esos valores ascendieron hacia el 6to subcultivo para luego declinar. En cuanto a la hipertrofia celular, se observó en todo el curso del primer subcultivo, pero no durante los posteriores pasajes. Al final del período de observación, todavía se continuaban detectando

  6. The Effects of Age and Latent Cytomegalovirus Infection on NK-Cell Phenotype and Exercise Responsiveness in Man

    Directory of Open Access Journals (Sweden)

    Austin B. Bigley

    2015-01-01

    Full Text Available The redeployment of NK-cells in response to an acute bout of exercise is thought to be an integral component of the “fight-or-flight” response, preparing the body for potential injury or infection. We showed previously that CMV seropositivity impairs the redeployment of NK-cells with exercise in the young. In the current study, we examined the effect of aging on the redeployment of NK-cells with exercise in the context of CMV. We show here that CMV blunts the exercise-induced redeployment of NK-cells in both younger (23–39 yrs and older (50–64 yrs subjects with older CMVneg subjects showing the largest postexercise mobilization and 1 h postexercise egress of NK-cells. The blunted exercise response in CMVpos individuals was associated with a decreased relative redeployment of the CD158a+ and CD57+ NK-cell subsets in younger and older individuals. In addition, we show that aging is associated with a CMV-independent increase in the proportion of NK-cells expressing the terminal differentiation marker CD57, while CMV is associated with an age-dependent decrease in the proportion of NK-cells expressing the inhibitory receptors KLRG1 (in the younger group and CD158a (in the older group. Collectively, these data suggest that CMV may decrease NK-cell mediated immunosurveillance after exercise in both younger and older individuals.

  7. Effect of miR-138 on the antioxidant function of lens epithelial cells affected by age-related cataracts

    Directory of Open Access Journals (Sweden)

    Bo Lu

    2018-03-01

    Full Text Available AIM: To investigate the effects and mechanism of miR-138 in mediating the antioxidant function of lens epithelial cells affected by age-related cataracts. METHODS: Real-time quantitative PCR(RT-qPCRwas used to detect miR-138 expression in the anterior lens capsules of healthy people, the anterior lens capsules of patients with age-related cataracts, and human epithelial cell line(SRA01/04cells exposed to oxidative stress. A 2', 7'-dichloro-fluorescein diacetate(DCFH-DAprobe was used to measure the levels of endogenous reactive oxygen species(ROSin human lens epithelial cells(hLECsexposed to 400μmol/L H2O2 for 1h. SRA01/04 cells were transfected with either miR-138 mimics, mimic controls, miR-138 inhibitors or inhibitor controls. After 72h, these cells were exposed to 400μmol/L H2O2 for 1h, then p53 and Bax mRNA expression were measured using RT-qPCR. Expression of p53 and Bax protein were also measured by western blotting analysis. Finally, cell viability was assessed using an MTS assay. RESULTS: Compared to the control group, expression of miR-138 in the anterior lens capsules of age-related cataract patients and in SRA01/04 cells exposed to oxidative stress significantly increased(PPPPCONCLUSION: The expression of miR-138 is upregulated in the anterior lens capsules of age-related cataract patients. MiR-138 decreases the anti-oxidative stress capacity of lens epithelial cells by upregulating p53 and Bax, while inhibiting cell proliferation and repair. This finding suggests that miR-138 may play a key role in the development of age-related cataracts.

  8. 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

  9. Age-specific bone tumour incidence rates are governed by stem cell exhaustion influencing the supply and demand of progenitor cells.

    Science.gov (United States)

    Richardson, Richard B

    2014-07-01

    Knudson's carcinogenic model, which simulates incidence rates for retinoblastoma, provides compelling evidence for a two-stage mutational process. However, for more complex cancers, existing multistage models are less convincing. To fill this gap, I hypothesize that neoplasms preferentially arise when stem cell exhaustion creates a short supply of progenitor cells at ages of high proliferative demand. To test this hypothesis, published datasets were employed to model the age distribution of osteochondroma, a benign lesion, and osteosarcoma, a malignant one. The supply of chondrogenic stem-like cells in femur growth plates of children and adolescents was evaluated and compared with the progenitor cell demand of longitudinal bone growth. Similarly, the supply of osteoprogenitor cells from birth to old age was compared with the demands of bone formation. Results show that progenitor cell demand-to-supply ratios are a good risk indicator, exhibiting similar trends to the unimodal and bimodal age distributions of osteochondroma and osteosarcoma, respectively. The hypothesis also helps explain Peto's paradox and the finding that taller individuals are more prone to cancers and have shorter lifespans. The hypothesis was tested, in the manner of Knudson, by its ability to convincingly explain and demonstrate, for the first time, a bone tumour's bimodal age-incidence curve. Crown Copyright © 2014. Published by Elsevier Ireland Ltd. All rights reserved.

  10. Effect of aging on GHRF-induced growth hormone release from anterior pituitary cells in primary culture

    International Nuclear Information System (INIS)

    Spik, K.W.; Boyd, R.L.; Sonntag, W.E.

    1991-01-01

    Five criteria were developed to validate the primary cell culture model for comparison of GRF-induced release of growth hormone in pituitary tissue from aging animals. Pituitaries from young (5-mo), middle-aged (14-mo), and old (24-mo) male Fischer 344 rats were dispersed using either trypsin/trypsin inhibitor or dispase and compared with respect to the number of pituitary cells recovered, cell viability, 3H-leucine incorporation into total protein, time course for recovery of optimal response to GRF, and the dose-relationship for GRF-induced release of growth hormone 2, 4, and 6 days after dispersal. Results indicated that direct comparison of cellular responses between tissues from young, middle-aged, and old rats in primary cell culture is confounded by variations in time for recovery of optimal responses, the effects of the enzymes used for dispersal, and the methods used to express the data

  11. Metformin inhibits age-related centrosome amplification in Drosophila midgut stem cells through AKT/TOR pathway.

    Science.gov (United States)

    Na, Hyun-Jin; Park, Joung-Sun; Pyo, Jung-Hoon; Jeon, Ho-Jun; Kim, Young-Shin; Arking, Robert; Yoo, Mi-Ae

    2015-07-01

    We delineated the mechanism regulating the inhibition of centrosome amplification by metformin in Drosophila intestinal stem cells (ISCs). Age-related changes in tissue-resident stem cells may be closely associated with tissue aging and age-related diseases, such as cancer. Centrosome amplification is a hallmark of cancers. Our recent work showed that Drosophila ISCs are an excellent model for stem cell studies evaluating age-related increase in centrosome amplification. Here, we showed that metformin, a recognized anti-cancer drug, inhibits age- and oxidative stress-induced centrosome amplification in ISCs. Furthermore, we revealed that this effect is mediated via down-regulation of AKT/target of rapamycin (TOR) activity, suggesting that metformin prevents centrosome amplification by inhibiting the TOR signaling pathway. Additionally, AKT/TOR signaling hyperactivation and metformin treatment indicated a strong correlation between DNA damage accumulation and centrosome amplification in ISCs, suggesting that DNA damage might mediate centrosome amplification. Our study reveals the beneficial and protective effects of metformin on centrosome amplification via AKT/TOR signaling modulation. We identified a new target for the inhibition of age- and oxidative stress-induced centrosome amplification. We propose that the Drosophila ISCs may be an excellent model system for in vivo studies evaluating the effects of anti-cancer drugs on tissue-resident stem cell aging. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  12. 'It means everyone should know their status': exploring lay conceptions of sickle cell trait and sickle cell trait screening among African Americans within middle reproductive age.

    Science.gov (United States)

    Mayo-Gamble, Tilicia L; Barnes, Priscilla A; Cunningham Erves, Jennifer; Middlestadt, Susan E; Lin, Hsien-Chang

    2017-02-21

    This study examined the meaning of sickle cell trait and sickle cell trait screening from the lay perspective of African Americans. African Americans (N = 300), ages 18-35 and unaware of their sickle cell trait status, completed two open-ended questions from a larger survey. One question asked for their understanding of sickle cell trait; the other asked for their understanding of sickle cell trait screening. Content analysis occurred in two phases: (1) In vivo and holistic coding; and (2) focused coding. Four categories emerged illustrating lay conceptions of sickle cell trait; (1) Perceived as an illness; (2) Perceived recognition of the inheritance pattern of sickle cell trait; (3) Perceived lack of knowledge of sickle cell trait; and (4) Perceived importance of sickle cell trait. Five categories emerged illustrating lay conceptions for sickle cell trait screening: (1) Perceived recognition that screening means getting tested for sickle cell trait; (2) Perceived lack of knowledge of sickle cell trait screening; (3) Perceived health benefit of sickle cell trait screening; (4) Perceived importance of sickle cell trait screening; and (5) Perceived barriers to sickle cell trait screening. Sickle cell trait and sickle cell trait screening are concepts that are both regarded as important among this high-risk population. However, there is still misunderstanding concerning the hereditary nature and reproductive implications of sickle cell trait. Interventions seeking to improve communication on the need for sickle cell trait screening should begin by identifying what the population at large understands, knows and/or believes to improve their ability to make informed health decisions.

  13. Donor age and C1orf132/MIR29B2C determine age-related methylation signature of blood after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Spólnicka, Magdalena; Piekarska, Renata Zbieć; Jaskuła, Emilia; Basak, Grzegorz W; Jacewicz, Renata; Pięta, Agnieszka; Makowska, Żanetta; Jedrzejczyk, Maciej; Wierzbowska, Agnieszka; Pluta, Agnieszka; Robak, Tadeusz; Berent, Jarosław; Branicki, Wojciech; Jędrzejczak, Wiesław; Lange, Andrzej; Płoski, Rafał

    2016-01-01

    Our recent study demonstrated that DNA methylation status in a set of CpGs located in ELOVL2, C1orf132, TRIM59, KLF14, and FHL2 can accurately predict calendar age in blood. In the present work, we used these markers to evaluate the effect of allogeneic hematopoietic stem cell transplantation (HSCT) on the age-related methylation signature of human blood. DNA methylation in 32 CpGs was investigated in 16 donor-recipient pairs using pyrosequencing. DNA was isolated from the whole blood collected from recipients 27-360 days (mean 126) after HSCT and from the donors shortly before the HSCT. It was found that in the recipients, the predicted age did not correlate with their calendar age but was correlated with the calendar age (r = 0.94, p = 4 × 10(-8)) and predicted age (r = 0.97, p = 5 × 10(-10)) of a respective donor. Despite this strong correlation, the predicted age of a recipient was consistently lower than the predicted age of a donor by 3.7 years (p = 7.8 × 10(-4)). This shift was caused by hypermethylation of the C1orf132 CpGs, for C1orf132 CpG_1. Intriguingly, the recipient-donor methylation difference correlated with calendar age of the donor (r = 0.76, p = 6 × 10(-4)). This finding could not trivially be explained by shifts of the major cellular factions of blood. We confirm the single previous report that after HSCT, the age of the donor is the major determinant of age-specific methylation signature in recipient's blood. A novel finding is the unique methylation dynamics of C1orf132 which encodes MIR29B2C implicated in the self-renewing of hematopoietic stem cells. This observation suggests that C1orf132 could influence graft function after HSCT.

  14. Fluvastatin inhibits AGE-induced cell proliferation and migration via an ERK5-dependent Nrf2 pathway in vascular smooth muscle cells.

    Directory of Open Access Journals (Sweden)

    Ae-Rang Hwang

    Full Text Available Advanced glycation endproduct (AGE-induced vascular smooth muscle cell (VSMC proliferation and reactive oxygen species (ROS production are emerging as important mechanisms of diabetic vasculopathy, but little is known about the molecular mechanism responsible for the antioxidative effects of statins on AGEs. It has been reported that statins exert pleiotropic effects on the cardiovascular system due to decreases in AGE-induced cell proliferation, migration, and vascular inflammation. Thus, in the present study, the authors investigated the molecular mechanism by which statins decrease AGE-induced cell proliferation and VSMC migration. In cultured VSMCs, statins upregulated Nrf2-related antioxidant gene, NQO1 and HO-1, via an ERK5-dependent Nrf2 pathway. Inhibition of ERK5 by siRNA or BIX02189 (a specific ERK5 inhibitor reduced the statin-induced upregulations of Nrf2, NQO1, and HO-1. Furthermore, fluvastatin was found to significantly increase ARE promoter activity through ERK5 signaling, and to inhibit AGE-induced VSMC proliferation and migration as determined by MTT assay, cell counting, FACS analysis, a wound scratch assay, and a migration chamber assay. In addition, AGE-induced proliferation was diminished in the presence of Ad-CA-MEK5α encoding a constitutively active mutant form of MEK5α (an upstream kinase of ERK5, whereas depletion of Nrf2 restored statin-mediated reduction of AGE-induced cell proliferation. Moreover, fluvastatin suppressed the protein expressions of cyclin D1 and Cdk4, but induced p27, and blocked VSMC proliferation by regulating cell cycle. These results suggest statin-induced activation of an ERK5-dependent Nrf2 pathway reduces VSMC proliferation and migration induced by AGEs, and that the ERK5-Nrf2 signal module be viewed as a potential therapeutic target of vasculopathy in patients with diabetes and complications of the disease.

  15. Pulmonary hypertension in sickle cell disease children under 10 years of age.

    Science.gov (United States)

    Colombatti, Raffaella; Maschietto, Nicola; Varotto, Elena; Grison, Alessandra; Grazzina, Nicoletta; Meneghello, Linda; Teso, Simone; Carli, Modesto; Milanesi, Ornella; Sainati, Laura

    2010-09-01

    Despite the finding of elevated Tricuspid Regurgitant Velocity (TRV) in children below 5 years of age, the prevalence and evolution of Pulmonary Hypertension (PH) in young children with sickle cell disease (SCD) are unclear. In order to identify predictive factors of precocious PH development, SCD children > or =3 years old, at steady state, underwent annual echocardiography and Tissue Doppler Imaging (TDI). Patients receiving chronic transfusion were excluded. Thirty-seven of seventy-five patients were > or =3 years, with measurable TRV. In our young population (mean age 6.2 years) of mainly African, HbS/HbS patients, 8/37 (21.6%) had TRV > or =2.5 m/s, 8% being only 3 years old. Significant correlation was found between precocious TRV elevation and high platelet and reticulocyte counts and frequent acute chest syndromes (ACS). In multivariate analysis, ACS was the only variable predicting TRV > or =2.5 m/s. TDI of the 37 patients showed signs of diastolic dysfunction of the left ventricle. At follow-up all eight patients with high TRV displayed further increase and seven more developed TRV > or =2.5 m/s. PH seems to begin in children earlier than expected. Factors involved in its early onset might be different from the ones causing its development in older children or adults. African children might benefit from early screening and re-assessment once a year.

  16. Immunosenescence and immunecheckpoint inhibitors in non-small cell lung cancer patients: Does age really matter?

    Science.gov (United States)

    Ferrara, Roberto; Mezquita, Laura; Auclin, Edouard; Chaput, Nathalie; Besse, Benjamin

    2017-11-01

    Immunotherapy has dramatically changed the therapeutic scenario in non-small cell lung cancer (NSCLC), extending overall survival, with a favorable safety profile. However, there is still a gap of knowledge about the efficacy of immune checkpoint inhibitors (ICIs) in elderly patients. Data from randomized clinical trials testing ICIs are conflicting and often lack adequate statistical power. Although two large meta-analyses suggested an absence of a significant survival benefit in patients older than 75years, expanded access programs and retrospective cohort studies of ICIs in the real-life setting, showed comparable survival outcomes and safety profiles between older and younger patients. In this complex scenario, a further unresolved issue is the potential correlation between older age and immunotherapy primary resistance, a phenomenon probably linked to the continuous and progressive remodeling of immune functions with ageing, known as immunosenescence. Defining the role of ICIs in elderly NSCLC patients and exploring the molecular mechanisms underlying a possible lack of benefit or even accelerated tumor growth during immunotherapy are two major challenges for future research in this field of cancer treatment. In this review, we describe the major hallmarks of immunosenescence and we summarize the existing clinical data of ICIs in elderly NSCLC patients. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  17. Uncovering the cellular and molecular changes in tendon stem/progenitor cells attributed to tendon aging and degeneration.

    Science.gov (United States)

    Kohler, Julia; Popov, Cvetan; Klotz, Barbara; Alberton, Paolo; Prall, Wolf Christian; Haasters, Florian; Müller-Deubert, Sigrid; Ebert, Regina; Klein-Hitpass, Ludger; Jakob, Franz; Schieker, Matthias; Docheva, Denitsa

    2013-12-01

    Although the link between altered stem cell properties and tissue aging has been recognized, the molecular and cellular processes of tendon aging have not been elucidated. As tendons contain stem/progenitor cells (TSPC), we investigated whether the molecular and cellular attributes of TSPC alter during tendon aging and degeneration. Comparing TSPC derived from young/healthy (Y-TSPC) and aged/degenerated human Achilles tendon biopsies (A-TSPC), we observed that A-TSPC exhibit a profound self-renewal and clonogenic deficits, while their multipotency was still retained. Senescence analysis showed a premature entry into senescence of the A-TSPC, a finding accompanied by an upregulation of p16(INK4A). To identify age-related molecular factors, we performed microarray and gene ontology analyses. These analyses revealed an intriguing transcriptomal shift in A-TSPC, where the most differentially expressed probesets encode for genes regulating cell adhesion, migration, and actin cytoskeleton. Time-lapse analysis showed that A-TSPC exhibit decelerated motion and delayed wound closure concomitant to a higher actin stress fiber content and a slower turnover of actin filaments. Lastly, based on the expression analyses of microarray candidates, we suggest that dysregulated cell-matrix interactions and the ROCK kinase pathway might be key players in TSPC aging. Taken together, we propose that during tendon aging and degeneration, the TSPC pool is becoming exhausted in terms of size and functional fitness. Thus, our study provides the first fundamental basis for further exploration into the molecular mechanisms behind tendon aging and degeneration as well as for the selection of novel tendon-specific therapeutical targets. © 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  18. [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.

  19. Cell cycle age dependence for radiation-induced G2 arrest: evidence for time-dependent repair

    International Nuclear Information System (INIS)

    Rowley, R.

    1985-01-01

    Exponentially growing eucaryotic cells, irradiated in interphase, are delayed in progression to mitosis chiefly by arrest in G 2 . The sensitivity of Chinese hamster ovary cells to G 2 arrest induction by X rays increases through the cell cycle, up to the X-ray transition point (TP) in G 2 . This age response can be explained by cell cycle age-dependent changes in susceptibility of the target(s) for G 2 arrest and/or by changes in capability for postirradiation recovery from G 2 arrest damage. Discrimination between sensitivity changes and repair phenomena is possible only if the level of G 2 arrest-causing damage sustained by a cell at the time of irradiation and the level ultimately expressed as arrest can be determined. The ability of caffeine to ameliorate radiation-induced G 2 arrest, while inhibiting repair of G 2 arrest-causing damage makes such an analysis possible. In the presence of caffeine, progression of irradiated cells was relatively unperturbed, but on caffeine removal, G 2 arrest was expressed. The duration of G 2 arrest was independent of the length of the prior caffeine exposure. This finding indicates that the target for G 2 arrest induction is present throughout the cell cycle and that the level of G 2 arrest damage incurred is initially constant for all cell cycle phases. The data are consistent with the existence of a time-dependent recovery mechanism to explain the age dependence for radiation induction of G 2 arrest

  20. Influence of aging on the heat and gas emissions from commercial lithium ion cells in case of thermal failure

    Directory of Open Access Journals (Sweden)

    Michael Lammer

    2018-03-01

    Full Text Available A method for thermal ramp experiments on cylindrical 18650 Li-ion cells has been established. The method was applied on pristine cells as well as on devices aged by cyclisation or by storage at elevated temperature respectively. The tested cells comprise three types of LiNi0.8Co0.15Al0.05O2 cells for either high power or high energy applications. The heat flux to and from the cell was investigated. Degradation and exothermic breakdown released large amounts of heat and gas. The total gas and heat emission from cycled cells was significantly larger than emission from cells aged by storage. After aging, the low energy cell ICR18650HE4 did not transgress into thermal runaway. Gas composition changed mainly in the early stage of the experiment. The composition of the initial gas release changed from predominantly CO2 towards hydrocarbons. The thermal runaway emitted for all tests a comparable mixture of H2, CO and CO2.

  1. Endothelial progenitor cells (EPCs) in ageing and age-related diseases: How currently available treatment modalities affect EPC biology, atherosclerosis, and cardiovascular outcomes.

    Science.gov (United States)

    Altabas, Velimir; Altabas, Karmela; Kirigin, Lora

    2016-10-01

    Endothelial progenitor cells (EPCs) are mononuclear cells that circulate in the blood and are derived from different tissues, expressing cell surface markers that are similar to mature endothelial cells. The discovery of EPCs has lead to new insights in vascular repair and atherosclerosis and also a new theory for ageing. EPCs from the bone marrow and some other organs aid in vascular repair by migrating to distant vessels where they differentiate into mature endothelial cells and replace old and injured endothelial cells. The ability of EPCs to repair vascular damage depends on their number and functionality. Currently marketed drugs used in a variety of diseases can modulate these characteristics. In this review, the effect of currently available treatment options for cardiovascular and metabolic disorders on EPC biology will be discussed. The various EPC-based therapies that will be discussed include lipid-lowering agents, antihypertensive agents, antidiabetic drugs, phosphodiesteraze inhibitors, hormones, as well as EPC capturing stents. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  2. 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.

  3. Regionally distinct responses of microglia and glial progenitor cells to whole brain irradiation in adult and aging rats.

    Science.gov (United States)

    Hua, Kun; Schindler, Matthew K; McQuail, Joseph A; Forbes, M Elizabeth; Riddle, David R

    2012-01-01

    Radiation therapy has proven efficacy for treating brain tumors and metastases. Higher doses and larger treatment fields increase the probability of eliminating neoplasms and preventing reoccurrence, but dose and field are limited by damage to normal tissues. Normal tissue injury is greatest during development and in populations of proliferating cells but also occurs in adults and older individuals and in non-proliferative cell populations. To better understand radiation-induced normal tissue injury and how it may be affected by aging, we exposed young adult, middle-aged, and old rats to 10 Gy of whole brain irradiation and assessed in gray- and white matter the responses of microglia, the primary cellular mediators of radiation-induced neuroinflammation, and oligodendrocyte precursor cells, the largest population of proliferating cells in the adult brain. We found that aging and/or irradiation caused only a few microglia to transition to the classically "activated" phenotype, e.g., enlarged cell body, few processes, and markers of phagocytosis, that is seen following more damaging neural insults. Microglial changes in response to aging and irradiation were relatively modest and three markers of reactivity - morphology, proliferation, and expression of the lysosomal marker CD68- were regulated largely independently within individual cells. Proliferation of oligodendrocyte precursors did not appear to be altered during normal aging but increased following irradiation. The impacts of irradiation and aging on both microglia and oligodendrocyte precursors were heterogeneous between white- and gray matter and among regions of gray matter, indicating that there are regional regulators of the neural response to brain irradiation. By several measures, the CA3 region of the hippocampus appeared to be differentially sensitive to effects of aging and irradiation. The changes assessed here likely contribute to injury following inflammatory challenges like brain irradiation and

  4. Regionally distinct responses of microglia and glial progenitor cells to whole brain irradiation in adult and aging rats.

    Directory of Open Access Journals (Sweden)

    Kun Hua

    Full Text Available Radiation therapy has proven efficacy for treating brain tumors and metastases. Higher doses and larger treatment fields increase the probability of eliminating neoplasms and preventing reoccurrence, but dose and field are limited by damage to normal tissues. Normal tissue injury is greatest during development and in populations of proliferating cells but also occurs in adults and older individuals and in non-proliferative cell populations. To better understand radiation-induced normal tissue injury and how it may be affected by aging, we exposed young adult, middle-aged, and old rats to 10 Gy of whole brain irradiation and assessed in gray- and white matter the responses of microglia, the primary cellular mediators of radiation-induced neuroinflammation, and oligodendrocyte precursor cells, the largest population of proliferating cells in the adult brain. We found that aging and/or irradiation caused only a few microglia to transition to the classically "activated" phenotype, e.g., enlarged cell body, few processes, and markers of phagocytosis, that is seen following more damaging neural insults. Microglial changes in response to aging and irradiation were relatively modest and three markers of reactivity - morphology, proliferation, and expression of the lysosomal marker CD68- were regulated largely independently within individual cells. Proliferation of oligodendrocyte precursors did not appear to be altered during normal aging but increased following irradiation. The impacts of irradiation and aging on both microglia and oligodendrocyte precursors were heterogeneous between white- and gray matter and among regions of gray matter, indicating that there are regional regulators of the neural response to brain irradiation. By several measures, the CA3 region of the hippocampus appeared to be differentially sensitive to effects of aging and irradiation. The changes assessed here likely contribute to injury following inflammatory challenges like

  5. Nuclear protein accumulation in cellular senescence and organismal aging revealed with a novel single-cell resolution fluorescence microscopy assay.

    Science.gov (United States)

    De Cecco, Marco; Jeyapalan, Jessie; Zhao, Xiaoai; Tamamori-Adachi, Mimi; Sedivy, John M

    2011-10-01

    Replicative cellular senescence was discovered some 50 years ago. The phenotypes of senescent cells have been investigated extensively in cell culture, and found to affect essentially all aspects of cellular physiology. The relevance of cellular senescence in the context of age-associated pathologies as well as normal aging is a topic of active and ongoing interest. Considerable effort has been devoted to biomarker discovery to enable the microscopic detection of single senescent cells in tissues. One characteristic of senescent cells documented very early in cell culture studies was an increase in cell size and total protein content, but whether this occurs in vivo is not known. A limiting factor for studies of protein content and localization has been the lack of suitable fluorescence microscopy tools. We have developed an easy and flexible method, based on the merocyanine dye known as NanoOrange, to visualize and quantitatively measure total protein levels by high resolution fluorescence microscopy. NanoOrange staining can be combined with antibody-based immunofluorescence, thus providing both specific target and total protein information in the same specimen. These methods are optimally combined with automated image analysis platforms for high throughput analysis. We document here increasing protein content and density in nuclei of senescent human and mouse fibroblasts in vitro, and in liver nuclei of aged mice in vivo. Additionally, in aged liver nuclei NanoOrange revealed protein-dense foci that colocalize with centromeric heterochromatin.

  6. Relationship between sensitivity to ultraviolet light and budding in yeast cells of different culture ages

    International Nuclear Information System (INIS)

    Atsuta, J.; Okajima, S.

    1976-01-01

    Subpopulations of yeast cells, consisting of cells of different sizes and different percentages of budding cells, were prepared by centrifugation through sucrose solutions with linear density gradients of cultures at different phases of the growth cycle. Ultraviolet survival of these cells was determined by colony counting, and the survival rate was compared with the cells' respiratory rates. Individual budding cells and interdivisional cells, and also mother cells and daughter cells derived from irradiated budding cells, were isolated by the micromanipulation technique. The number of divisions in each cell was measured during a 21-hr incubation period immediately after irradiation. In the population in the logarithmic phase consisting of homogeneous cells of middle size, no difference in uv sensitivity was observed between mother cells and daughter cells, irrespective of mutual adhesion. Budding cell resistance was observed in the population in the transitional phase; this was due to the lesser uv sensitivity of daughter cells in the fresh medium. In the stationary phase, daughter cells were rather more sensitive than mother cells or interdivisional cells, so there was little difference in uv sensitivity between budding cells and interdivisional cells

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

    Science.gov (United States)

    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.

  8. Age-Associated Methylation Suppresses SPRY1, Leading to a Failure of Re-quiescence and Loss of the Reserve Stem Cell Pool in Elderly Muscle

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    Anne Bigot

    2015-11-01

    Full Text Available The molecular mechanisms by which aging affects stem cell number and function are poorly understood. Murine data have implicated cellular senescence in the loss of muscle stem cells with aging. Here, using human cells and by carrying out experiments within a strictly pre-senescent division count, we demonstrate an impaired capacity for stem cell self-renewal in elderly muscle. We link aging to an increased methylation of the SPRY1 gene, a known regulator of muscle stem cell quiescence. Replenishment of the reserve cell pool was modulated experimentally by demethylation or siRNA knockdown of SPRY1. We propose that suppression of SPRY1 by age-associated methylation in humans inhibits the replenishment of the muscle stem cell pool, contributing to a decreased regenerative response in old age. We further show that aging does not affect muscle stem cell senescence in humans.

  9. FSH-FSHR3-stem cells in ovary surface epithelium: basis for adult ovarian biology, failure, aging, and cancer.

    Science.gov (United States)

    Bhartiya, Deepa; Singh, Jarnail

    2015-01-01

    Despite extensive research, genetic basis of premature ovarian failure (POF) and ovarian cancer still remains elusive. It is indeed paradoxical that scientists searched for mutations in FSH receptor (FSHR) expressed on granulosa cells, whereas more than 90% of cancers arise in ovary surface epithelium (OSE). Two distinct populations of stem cells including very small embryonic-like stem cells (VSELs) and ovarian stem cells (OSCs) exist in OSE, are responsible for neo-oogenesis and primordial follicle assembly in adult life, and are modulated by FSH via its alternatively spliced receptor variant FSHR3 (growth factor type 1 receptor acting via calcium signaling and the ERK/MAPK pathway). Any defect in FSH-FSHR3-stem cell interaction in OSE may affect folliculogenesis and thus result in POF. Ovarian aging is associated with a compromised microenvironment that does not support stem cell differentiation into oocytes and further folliculogenesis. FSH exerts a mitogenic effect on OSE and elevated FSH levels associated with advanced age may provide a continuous trigger for stem cells to proliferate resulting in cancer, thus supporting gonadotropin theory for ovarian cancer. Present review is an attempt to put adult ovarian biology, POF, aging, and cancer in the perspective of FSH-FSHR3-stem cell network that functions in OSE. This hypothesis is further supported by the recent understanding that: i) cancer is a stem cell disease and OSE is the niche for ovarian cancer stem cells; ii) ovarian OCT4-positive stem cells are regulated by FSH; and iii) OCT4 along with LIN28 and BMP4 are highly expressed in ovarian cancers. © 2015 Society for Reproduction and Fertility.

  10. Transplanted Adipose-Derived Stem Cells Ameliorate Testicular Dysfunction In A D-Galactose-Induced Aging Rat Model.

    Science.gov (United States)

    Yang, Chun; Du, Yi-Kuan; Wang, Jun; Luan, Ping; Yang, Qin-Lao; Huang, Wen-Hua; Yuan, Lin

    2015-10-01

    Glycation product accumulation during aging of slowly renewing tissues may be an important mechanism underlying aging of the testis. Adipose-derived stem cells (ADSCs) have shown promise in a novel tissue regenerative technique and may have utility in treating sexual dysfunction. ADSCs have also been found to be effective in antiaging therapy, although the mechanism underlying their effects remains unknown. This study was designed to investigate the anti-aging effect of ADSCs in a D-galactose (D-gal)-induced aging animal model and to clarify the underlying mechanism. Randomly selected 6-week-old male Sprague-Dawley rats were subcutaneously injected with D-gal daily for 8 weeks. Two weeks after completion of treatment, D-gal-induced aging rats were randomized to receive caudal vein injections of 3 × 10(6) 5-bromo 2'deoxy-uridine-labeled ADSCs or an equal volume of phosphate-buffered saline. Serum testosterone level, steroidogenic enzymes (3-β-hydroxysteroid dehydrogenase), and superoxide dismutase (SOD) activity decreased significantly in aging rats compared with the control group; serum lipid peroxidation, spermatogenic cell apoptosis, and methane dicarboxylic aldehyde (MDA) expression increased significantly. ADSCs increased the SOD level and reduced the MDA level in the aging animal model and restored levels of serum testosterone, steroidogenic enzymes, and spermatogenic cell apoptosis. These results demonstrate that ADSCs can contribute to testicular regeneration during aging. ADSCs also provide functional benefits through glycation suppression and antioxidant effects in a rat model of aging. Although some ADSCs differentiated into Leydig cells, the paracrine pathway seems to play a main role in this process, resulting in the reduction of apoptosis. © 2015 Wiley Periodicals, Inc.

  11. Increase of NK-T cells in aged depressed patients not treated with antidepressive drugs

    NARCIS (Netherlands)

    Flentge, F; van den Berg, MD; Bouhuys, AL; The, HT

    2000-01-01

    Background: A change in number and/or activity of natural killer cells has repeatedly been reported in depressive illness. Much less attention has yet been given to the subgroup of natural killer cells that are positive Sor the T-cell marker CD3 (NK-T cells). These cells possibly have important

  12. Index of CD34+ Cells and Mononuclear Cells in the Bone Marrow of Spinal Cord Injury Patients of Different Age Groups: A Comparative Analysis

    Directory of Open Access Journals (Sweden)

    Vidyasagar Devaprasad Dedeepiya

    2012-01-01

    Full Text Available Introduction. Recent evidence of safety and efficacy of Bone Marrow Mononuclear Cells (BMMNC in spinal cord injury makes the Bone Marrow (BM CD34+ percentage and the BMMNC count gain significance. The indices of BM that change with body mass index and aging in general population have been reported but seldom in Spinal Cord Injury (SCI victims, whose parameters of relevance differ from general population. Herein, we report the indices of BMMNC in SCI victims. Materials and Methods. BMMNCs of 332 SCI patients were isolated under GMP protocols. Cell count by Trypan blue method and CD34+ cells by flow cytometry were documented and analysed across ages and gender. Results. The average BMMNC per ml in the age groups 0–20, 21–40, 41–60, and 61–80 years were 4.71, 4.03, 3.67, and 3.02 million and the CD34+ were 1.05%, 1.04%, 0.94%, and 0.93% respectively. The decline in CD34+ was sharp between 20–40 and 40–60 age groups. Females of reproductive age group had lesser CD34+. Conclusion. The BMMNC and CD34+ percentages decline with aging in SCI victims. Their lower values in females during reproductive age should be analysed for relevance to hormonal influence. This study offers reference values of BMMNC and CD34+ of SCI victims for successful clinical application.

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

    Directory of Open Access Journals (Sweden)

    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.

  14. Phenotypic and gene expression modification with normal brain aging in GFAP-positive astrocytes and neural stem cells.

    Science.gov (United States)

    Bernal, Giovanna M; Peterson, Daniel A

    2011-06-01

    Astrocytes secrete growth factors that are both neuroprotective and supportive for the local environment. Identified by glial fibrillary acidic protein (GFAP) expression, astrocytes exhibit heterogeneity in morphology and in the expression of phenotypic markers and growth factors throughout different adult brain regions. In adult neurogenic niches, astrocytes secrete vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) within the neurogenic niche and are also a source of special GFAP-positive multipotent neural stem cells (NSCs). Normal aging is accompanied by a decline in CNS function and reduced neurogenesis. We asked whether a decreased availability of astrocyte-derived factors may contribute to the age-related decline in neurogenesis. Determining alterations of astrocytic activity in the aging brain is crucial for understanding CNS homeostasis in aging and for assessing appropriate therapeutic targets for an aging population. We found region-specific alterations in the gene expression of GFAP, VEGF, and FGF-2 and their receptors in the aged brain corresponding to changes in astrocytic reactivity, supporting astrocytic heterogeneity and demonstrating a differential aging effect. We found that GFAP-positive NSCs uniquely coexpress both VEGF and its key mitotic receptor Flk-1 in both young and aged hippocampus, indicating a possible autocrine/paracrine signaling mechanism. VEGF expression is lost once NSCs commit to a neuronal fate, but Flk-1-mediated sensitivity to VEGF signaling is maintained. We propose that age-related astrocytic changes result in reduced VEGF and FGF-2 signaling, which in turn limits NSC and progenitor cell maintenance and contributes to decreased neurogenesis. © 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

  15. Elevated levels of interferon-γ production by memory T cells do not promote transplant tolerance resistance in aged recipients.

    Directory of Open Access Journals (Sweden)

    James I Kim

    Full Text Available Immunosenescence predisposes the elderly to infectious and autoimmune diseases and impairs the response to vaccination. We recently demonstrated that ageing also impedes development of transplantation tolerance. Unlike their young counterparts (8-12 weeks of age aged male recipients (greater than 12 months of age transplanted with a full MHC-mismatched heart are resistant to tolerance mediated by anti-CD45RB antibody. Surprisingly, either chemical or surgical castration restored tolerance induction to levels observed using young recipients. Based on the strong impact of endocrine modulation on transplant tolerance, we explored the impact of ageing and castration on the immune system. Here we report a significant increase in the percentage of T cells that produce interferon-γ (IFN-γ in aged male versus young male animals and that the overall increase in IFN-γ production was due to an expansion of IFN-γ-producing memory T cells in aged animals. In contrast to IFN-γ production, we did not observe differences in IL-10 expression in young versus old male mice. We hypothesized that endocrine modulation would diminish the elevated levels of IFN-γ production in aged recipients, however, we observed no significant reduction in the percentage of IFN-γ+ T cells upon castration. Furthermore, we neutralized interferon-γ by antibody and did not observe an effect on graft survival. We conclude that while elevated levels of interferon-γ serves as a marker of tolerance resistance in aged mice, other as yet to be identified factors are responsible for its cause. Defining these factors may be relevant to design of tolerogenic strategies for aged recipients.

  16. Potential of Induced Pluripotent Stem Cells (iPSCs for Treating Age-Related Macular Degeneration (AMD

    Directory of Open Access Journals (Sweden)

    Mark Fields

    2016-12-01

    Full Text Available The field of stem cell biology has rapidly evolved in the last few decades. In the area of regenerative medicine, clinical applications using stem cells hold the potential to be a powerful tool in the treatment of a wide variety of diseases, in particular, disorders of the eye. Embryonic stem cells (ESCs and induced pluripotent stem cells (iPSCs are promising technologies that can potentially provide an unlimited source of cells for cell replacement therapy in the treatment of retinal degenerative disorders such as age-related macular degeneration (AMD, Stargardt disease, and other disorders. ESCs and iPSCs have been used to generate retinal pigment epithelium (RPE cells and their functional behavior has been tested in vitro and in vivo in animal models. Additionally, iPSC-derived RPE cells provide an autologous source of cells for therapeutic use, as well as allow for novel approaches in disease modeling and drug development platforms. Clinical trials are currently testing the safety and efficacy of these cells in patients with AMD. In this review, the current status of iPSC disease modeling of AMD is discussed, as well as the challenges and potential of this technology as a viable option for cell replacement therapy in retinal degeneration.

  17. Potential of Induced Pluripotent Stem Cells (iPSCs) for Treating Age-Related Macular Degeneration (AMD).

    Science.gov (United States)

    Fields, Mark; Cai, Hui; Gong, Jie; Del Priore, Lucian

    2016-12-08

    The field of stem cell biology has rapidly evolved in the last few decades. In the area of regenerative medicine, clinical applications using stem cells hold the potential to be a powerful tool in the treatment of a wide variety of diseases, in particular, disorders of the eye. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are promising technologies that can potentially provide an unlimited source of cells for cell replacement therapy in the treatment of retinal degenerative disorders such as age-related macular degeneration (AMD), Stargardt disease, and other disorders. ESCs and iPSCs have been used to generate retinal pigment epithelium (RPE) cells and their functional behavior has been tested in vitro and in vivo in animal models. Additionally, iPSC-derived RPE cells provide an autologous source of cells for therapeutic use, as well as allow for novel approaches in disease modeling and drug development platforms. Clinical trials are currently testing the safety and efficacy of these cells in patients with AMD. In this review, the current status of iPSC disease modeling of AMD is discussed, as well as the challenges and potential of this technology as a viable option for cell replacement therapy in retinal degeneration.

  18. Transplantation of autologous synovial mesenchymal stem cells promotes meniscus regeneration in aged primates.

    Science.gov (United States)

    Kondo, Shimpei; Muneta, Takeshi; Nakagawa, Yusuke; Koga, Hideyuki; Watanabe, Toshifumi; Tsuji, Kunikazu; Sotome, Shinichi; Okawa, Atsushi; Kiuchi, Shinji; Ono, Hideo; Mizuno, Mitsuru; Sekiya, Ichiro

    2017-06-01

    Transplantation of aggregates of synovial mesenchymal stem cells (MSCs) enhanced meniscus regeneration in rats. Anatomy and biological properties of the meniscus depend on animal species. To apply this technique clinically, it is valuable to investigate the use of animals genetically close to humans. We investigated whether transplantation of aggregates of autologous synovial MSCs promoted meniscal regeneration in aged primates. Chynomolgus primates between 12 and 13 years old were used. After the anterior halves of the medial menisci in both knees were removed, an average of 14 aggregates consisting of 250,000 synovial MSCs were transplanted onto the meniscus defect. No aggregates were transplanted to the opposite knee for the control. Meniscus and articular cartilage were analyzed macroscopically, histologically, and by MRI T1rho mapping at 8 (n = 3) and 16 weeks (n = 4). The medial meniscus was larger and the modified Pauli's histological score for the regenerated meniscus was better in the MSC group than in the control group in each primate at 8 and 16 weeks. Mankin's score for the medial femoral condyle cartilage was better in the MSC group than in the control group in all primates at 16 weeks. T1rho value for both the regenerated meniscus and adjacent articular cartilage in the MSC group was closer to the normal meniscus than in the control group in all primates at 16 weeks. Transplantation of aggregates of autologous synovial MSCs promoted meniscus regeneration and delayed progression of degeneration of articular cartilage in aged primates. This is the first report dealing with meniscus regeneration in primates. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1274-1282, 2017. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  19. Choice of Cell Source in Cell-Based Therapies for Retinal Damage due to Age-Related Macular Degeneration: A Review

    Directory of Open Access Journals (Sweden)

    Sudhakar John

    2013-01-01

    Full Text Available Background. Age-related macular degeneration (AMD is a complex disorder that affects primarily the macula involving the retinal pigment epithelium (RPE but also to a certain extent the photoreceptor layer and the retinal neurons. Cell transplantation is a promising option for AMD and clinical trials are underway using different cell types. Methods. We hypothesize that instead of focusing on a particular cell source for concurrent regeneration of all the retinal layers and also to prevent exhaustive research on an array of cell sources for regeneration of each layer, the choice should depend on, precisely, which layer is damaged. Results. Thus, for a damage limited to the retinal pigment epithelial (RPE layer, the choice we suggest would be RPE cells. When the damage extends to rods and cones, the choice would be bone marrow stem cells and when retinal neurons are involved, relatively immature stem cell populations with an inherent capacity to yield neuronal lineage such as hematopoietic stem cells, embryonic stem cells, or induced pluripotent stem cells can be tried. Conclusion. This short review will prove to be a valuable guideline for those working on cell therapy for AMD to plan their future directions of research and therapy for this condition.

  20. Resveratrol Improves Tube Formation in AGE-Induced Late Endothelial Progenitor Cells by Suppressing Syndecan-4 Shedding

    Directory of Open Access Journals (Sweden)

    Han Wu

    2018-01-01

    Full Text Available Dysfunction of endothelial progenitor cells (EPCs contributes to cardiovascular complications in diabetes, and resveratrol has been shown to improve EPC functions. Syndecan-4 (Synd4, a cell surface heparin sulfate proteoglycan, has been shown to promote neovascularization. Thus, the present study was performed to determine whether resveratrol promoted angiogenesis of EPCs by regulating Synd4. Late EPCs were isolated from human peripheral blood and stimulated with AGEs. Western blot showed that AGEs induced Synd4 shedding in a dose- and time-dependent manner. AGE-induced Synd4 shedding was partly reversed by NAC or resveratrol, along with normalized ROS production. Overexpression of Synd4 or pretreatment of resveratrol reversed AGE-impaired tube formation of EPCs and regulated the Akt/eNOS pathway. Furthermore, resveratrol suppressed Synd4 shedding via the inhibition of oxidative stress and improved tube formation of late EPCs via the regulation of the Synd4/Akt/eNOS pathway.

  1. Test series 1: seismic-fragility tests of naturally-aged Class 1E Gould NCX-2250 battery cells

    International Nuclear Information System (INIS)

    Bonzon, L.L.; Hente, D.B.; Kukreti, B.M.; Schendel, J.S.; Tulk, J.D.; Janis, W.J.; Black, D.A.; Paulsen, G.D.; Aucoin, B.D.

    1984-09-01

    The seismic-fragility response of naturally-aged, nuclear station, safety-related batteries is of interest for two reasons: (1) to determine actual failure modes and thresholds; and (2) to determine the validity of using the electrical capacity of individual cells as an indicator of the end-of-life of a battery, given a seismic event. This report covers the first test series of an extensive program using 12-year old, lead-calcium, Gould NCX-2250 cells, from the James A. Fitzpatrick Nuclear Power Station operated by the New York Power Authority. Seismic tests with three cell configurations were performed using a triaxial shake table: single-cell tests, rigidly mounted; multi-cell (three) tests, mounted in a typical battery rack; and single-cell tests specifically aimed towards examining propagation of pre-existing case cracks. In general the test philosophy was to monitor the electrical properties including discharge capacity of cells through a graduated series of g-level step increases until either the shake-table limits were reached or until electrical failure of the cells occurred. Of nine electrically active cells, six failed during seismic testing over a range of imposed g-level loads in excess of a 1-g ZPA. Post-test examination revealed a common failure mode, the cracking at the abnormally brittle, positive lead bus-bar/post interface; further examination showed that the failure zone was extremely coarse grained and extensively corroded. Presently accepted accelerated-aging methods for qualifying batteries, per IEEE Std. 535-1979, are based on plate growth, but these naturally-aged 12-year old cells showed no significant plate growth

  2. The effects of red blood cell preparation method on in vitro markers of red blood cell aging and inflammatory response.

    Science.gov (United States)

    Radwanski, Katherine; Garraud, Olivier; Cognasse, Fabrice; Hamzeh-Cognasse, Hind; Payrat, Jean-Marc; Min, Kyungyoon

    2013-12-01

    Studies are currently under way examining whether the age of stored red blood cells (RBCs) affects clinical outcome in transfusion recipients. The effects of storage duration on the RBC storage lesion are well documented, while fewer studies are available regarding the effect of RBC production method. In this study, we compared in vitro RBC quality variables and markers of inflammatory response in apheresis and whole blood (WB)-derived RBCs, specifically those prepared after an overnight room temperature hold (RTH) of WB. SAGM RBCs, prepared from WB after overnight RTH (n = 10), were compared to SAGM RBCs prepared using an apheresis device (Alyx, n = 10). As a control, SAGM RBCs were also prepared within 2 hours of WB collection (2-hr WB, n = 10). All RBCs were stored at 4°C for 42 days with weekly assay of in vitro variables, cytokines and/or chemokines, and neutrophil activation after incubation with RBC supernatant. RTH WB RBCs exhibited decreased levels of 2,3-diphosphoglycerate acid (2.3 μmol/g hemoglobin [Hb] ± 2.1 vs. 13.7 ± 1.3 μmol/g Hb) and morphology (160 ± 10 vs. 192 ± 5) on Day 1 and increased hemolysis (0.45 ± 0.21% vs. 0.31 ± 0.09%) and microparticles (6.1 ± 2.8/10(3) RBCs vs. 3.9 ± 1.1/10(3) RBCs) on Day 42 compared to apheresis RBCs. Gro-α and ENA-78 cytokine levels were significantly higher in RTH WB than Alyx RBCs during storage. CD11b expression was highest in neutrophils exposed to supernatant from RTH WB RBCs (p < 0.05). RBC preparation method has a meaningful effect on the RBC storage lesion, which should be taken into account in addition to length of storage. © 2013 American Association of Blood Banks.

  3. Circulating endothelial progenitor cell numbers are not associated with donor organ age or allograft vasculopathy in cardiac transplant recipients.

    Science.gov (United States)

    Thomas, H E; Parry, G; Dark, J H; Arthur, H M; Keavney, B D

    2009-02-01

    Increasing age is associated with reduced numbers of circulating endothelial progenitor cells (EPCs). It is unclear whether this relates to depletion or impairment of bone marrow progenitors, or to deficient mobilization signals from aging tissues. In cardiac transplant patients, one previous study has reported an association between circulating EPCs and the risk of cardiac allograft vasculopathy (CAV). We investigated whether increased donor heart age, a strong risk factor for CAV, was associated with reduced circulating EPC numbers in a group of cardiac transplant recipients matched for factors which influence EPC numbers, but with maximally discordant donor heart ages. We identified 32 patient pairs, matched for factors known to influence EPC numbers, but who had discordant donor heart ages by at least 20 years. EPCs were quantified using flow cytometry for absolute counts of cells expressing all the combinations of CD45, CD34, CD133 and the kinase domain receptor (KDR). There were no significant differences in the numbers of circulating EPCs between patients with old or young donor heart age. There was no association between the presence of CAV and circulating EPC numbers. We suggest that the increased susceptibility to CAV of older donor hearts is not mediated via circulating EPCs. Our results are consistent with the theory that the normal age-related decline in EPC numbers relates to bone marrow aging rather than failure of target tissues to induce EPC mobilization.

  4. Red blood cells open promising avenues for longitudinal studies of ageing in laboratory, non-model and wild animals.

    Science.gov (United States)

    Stier, Antoine; Reichert, Sophie; Criscuolo, Francois; Bize, Pierre

    2015-11-01

    Age