The Experts below are selected from a list of 1002 Experts worldwide ranked by ideXlab platform
Rita B. Effros - One of the best experts on this subject based on the ideXlab platform.
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Impact of the Hayflick Limit on T cell responses to infection: lessons from aging and HIV disease.
Mechanisms of ageing and development, 2004Co-Authors: Rita B. EffrosAbstract: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.
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From Hayflick to Walford: the role of T cell replicative senescence in human aging.
Experimental gerontology, 2004Co-Authors: Rita B. EffrosAbstract: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.
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replicative senescence in the immune system impact of the Hayflick Limit on t cell function in the elderly
American Journal of Human Genetics, 1998Co-Authors: Rita B. EffrosAbstract:Gerontologists, lured by the prospect of understandingthe cellular events that underlie the gross features ofhuman aging, are focusing increasingly on replicative(orcellular) senescence. The term “replicative senescence”describes the irreversible state of growth arrest experi-enced by all mitotically competent cells of human originfollowing a fairly predictable number of cell divisions inculture. First identified in human fetal fibroblasts byHayflick, replicative senescence, or the so-called Hay-flick Limit, results from an intrinsic natural barrier tounLimited cell division exhibited by all normal somaticcells.The characteristics of replicative senescencehavebeenexplored in a variety of cell types (reviewed in Smithand Smith 1996; see also Be´rube´ et al. 1998 [in thisissue]), but only recently has this model been applied tothe immune system. Ironically, the Hayflick Limit maybe particularly deleterious for immune cells, since theability to undergo rapid clonal expansion is absolutelyessential to their function. The decline of T-cell immunefunction during aging suggests that T cells might be anideal system in which to explore the potential role ofreplicative senescence during in vivo aging. Well-char-acterized cell surface markers, signal transduction path-ways, and functional traits further enhance the potentialutility of T cells as a model system, both to elucidatethe process of replicative senescence itself and to assessits physiological consequences.This review will summarize the results of research onT-cell replicative senescence in cell culture and will dem-onstrate that cells from elderly people have undergonechanges in vivo that are similar to those observed in thecell culture model. I will argue that T-cell replicativesenescence contributes to increased morbidity and mor-tality during aging and that the proportion of replica-
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Replicative senescence of T cells: Does the Hayflick Limit lead to immune exhaustion?
Immunology Today, 1997Co-Authors: Rita B. Effros, Graham PawelecAbstract:Extensive in vitro research on fibroblasts has defined numerous genetic and phenotypic changes associated with replicative senescence. Identification of T-cell replicative senescence as a feature of human immunodeficiency virus (HIV) disease and ageing suggests this phenomenon merits more careful consideration by immunologists, especially with regard to chronic infection, memory and adoptive immunotherapy.
Florence Chainiaux - One of the best experts on this subject based on the ideXlab platform.
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From the Hayflick mosaic to the mosaics of ageing. Role of stress-induced premature senescence in human ageing.
The international journal of biochemistry & cell biology, 2002Co-Authors: Olivier Toussaint, José Remacle, Jean François Dierick, Thierry Pascal, Christophe Frippiat, Stéphanie Zdanov, João Pedro De Magalhães, Véronique Royer, Florence ChainiauxAbstract:The Hayflick Limit-senescence of proliferative cell types-is a fundamental feature of proliferative cells in vitro. Various human proliferative cell types exposed in vitro to many types of subcytotoxic stresses undergo stress-induced premature senescence (SIPS) (also called stress-induced premature senescence-like phenotype, according to the definition of senescence). The known mechanisms of appearance the main features of SIPS are reviewed: senescent-like morphology, growth arrest, senescence-related changes in gene expression, telomere shortening. Long before telomere-shortening induces senescence, other factors such as culture conditions or lack of 'feeder cells' can trigger either SIPS or prolonged reversible G(0) phase of the cell cycle. In vivo, 'proliferative' cell types of aged individuals are likely to compose a mosaic made of cells irreversibly growth arrested or not. The higher level of stress to which these cells have been exposed throughout their life span, the higher proportion of the cells of this mosaic will be in SIPS rather than in telomere-shortening dependent senescence. All cell types undergoing SIPS in vivo, most notably the ones in stressful conditions, are likely to participate in the tissular changes observed along ageing. For instance, human diploid fibroblasts (HDFs) exposed in vivo and in vitro to pro-inflammatory cytokines display biomarkers of senescence and might participate in the degradation of the extracellular matrix observed in ageing.
Harry Rubin - One of the best experts on this subject based on the ideXlab platform.
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Promise and problems in relating cellular senescence in vitro to aging in vivo
Archives of gerontology and geriatrics, 2002Co-Authors: Harry RubinAbstract:Abstract According to the ‘Hayflick Limit’, human fetal fibroblasts have a uniform, Limited replicative lifespan of about 50 population doublings in cell culture. This concept was extrapolated to diverse cells in the body. It seemed to decrease with the age of the cell donor and, as a form of cell senescence, was thought to underlie the aging process. More discriminating analysis, however, showed that the fibroblasts decayed in a stochastic manner from the time of their explantation, at a rate that increased with the number of population doublings in culture. There was no consistent relation to the age of the donor. Despite the contradictory evidence, the original version of the Hayflick Limit retained its general acceptance. Cell senescence was attributed to the absence of telomerase in the fibroblasts, which resulted in shortening of telomeres at each division until they fell below a critical length needed for further division. However, it is well established that stem cells in renewing tissues undergo many more than 50 divisions in a lifetime, without apparent senescence. Contrary to early findings of no telomerase in most tissues, their stem cells retain telomerase and presumably telomere length despite many divisions in vivo. Massive accumulation of lipofuscin granules occurs under stress in long term crowded cultures, but the granules dissipate on subculture or neoplastic transformation. The overall results indicate a critical disjunction between cell senescence in vitro and aging in vivo. By contrast, cell culture has been useful in showing a need for telomere capping in maintaining cell stability and viability. It may also provide information about the biochemical mechanism of lipofuscin production.
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The disparity between human cell senescence in vitro and lifelong replication in vivo
Nature biotechnology, 2002Co-Authors: Harry RubinAbstract:Cultured human fibroblasts undergo senescence (a loss of replicative capacity) after a uniform, fixed number of ∼50 population doublings, commonly termed the Hayflick Limit. It has been long known from clonal and other quantitative studies, however, that cells decline in replicative capacity from the time of explantation and do so in a stochastic manner, with a half-life of only ∼8 doublings. The apparent 50-cell doubling Limit reflects the expansive propagation of the last surviving clone. The relevance of either figure to survival of cells in the body is questionable, given that stem cells in some renewing tissues undergo >1,000 divisions in a lifetime with no morphological sign of senescence. Oddly enough, these observations have had little if any effect on general acceptance of the Hayflick Limit in its original form. The absence of telomerase in cultured human cells and the shortening of telomeres at each population doubling have suggested that telomere length acts as a mitotic clock that accounts for their Limited lifespan. This concept assumed an iconic character with the report that ectopic expression of telomerase by a vector greatly extended the lifespan of human cells. That something similar might occur in vivo seemed consistent with initial reports that most human somatic tissues lack telomerase activity. More careful study, however, has revealed telomerase activity in stem cells and some dividing transit cells of many renewing tissues and even in dividing myocytes of repairing cardiac muscle. It now seems likely that telomerase is active in vivo where and when it is needed to maintain tissue integrity. Caution is recommended in applying telomerase inhibition to kill telomerase-expressing cancer cells, because it would probably damage stem cells in essential organs and even increase the likelihood of secondary cancers. The risk may be especially high in sun-exposed skin, where there are usually thousands of p53-mutant clones of keratinocytes predisposed to cancer.
Olivier Toussaint - One of the best experts on this subject based on the ideXlab platform.
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From the Hayflick mosaic to the mosaics of ageing. Role of stress-induced premature senescence in human ageing.
The international journal of biochemistry & cell biology, 2002Co-Authors: Olivier Toussaint, José Remacle, Jean François Dierick, Thierry Pascal, Christophe Frippiat, Stéphanie Zdanov, João Pedro De Magalhães, Véronique Royer, Florence ChainiauxAbstract:The Hayflick Limit-senescence of proliferative cell types-is a fundamental feature of proliferative cells in vitro. Various human proliferative cell types exposed in vitro to many types of subcytotoxic stresses undergo stress-induced premature senescence (SIPS) (also called stress-induced premature senescence-like phenotype, according to the definition of senescence). The known mechanisms of appearance the main features of SIPS are reviewed: senescent-like morphology, growth arrest, senescence-related changes in gene expression, telomere shortening. Long before telomere-shortening induces senescence, other factors such as culture conditions or lack of 'feeder cells' can trigger either SIPS or prolonged reversible G(0) phase of the cell cycle. In vivo, 'proliferative' cell types of aged individuals are likely to compose a mosaic made of cells irreversibly growth arrested or not. The higher level of stress to which these cells have been exposed throughout their life span, the higher proportion of the cells of this mosaic will be in SIPS rather than in telomere-shortening dependent senescence. All cell types undergoing SIPS in vivo, most notably the ones in stressful conditions, are likely to participate in the tissular changes observed along ageing. For instance, human diploid fibroblasts (HDFs) exposed in vivo and in vitro to pro-inflammatory cytokines display biomarkers of senescence and might participate in the degradation of the extracellular matrix observed in ageing.
A L Mazin - One of the best experts on this subject based on the ideXlab platform.
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Suicidal function of DNA methylation in age-related genome disintegration.
Ageing research reviews, 2009Co-Authors: A L MazinAbstract:Abstract This article is dedicated to the 60th anniversary of 5-methylcytosine discovery in DNA. Cytosine methylation can affect genetic and epigenetic processes, works as a part of the genome-defense system and has mutagenic activity; however, the biological functions of this enzymatic modification are not well understood. This review will put forward the hypothesis that the host-defense role of DNA methylation in silencing and mutational destroying of retroviruses and other intragenomic parasites was extended during evolution to most host genes that have to be inactivated in differentiated somatic cells, where it acquired a new function in age-related self-destruction of the genome. The proposed model considers DNA methylation as the generator of 5mC > T transitions that induce 40–70% of all spontaneous somatic mutations of the multiple classes at CpG and CpNpG sites and flanking nucleotides in the p53, FIX, hprt, gpt human genes and some transgenes. The accumulation of 5mC-dependent mutations explains: global changes in the structure of the vertebrate genome throughout evolution; the loss of most 5mC from the DNA of various species over their lifespan and the Hayflick Limit of normal cells; the polymorphism of methylation sites, including asymmetric mCpNpN sites; cyclical changes of methylation and demethylation in genes. The suicidal function of methylation may be a special genetic mechanism for increasing DNA damage and the programmed genome disintegration responsible for cell apoptosis and organism aging and death.
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Life span prediction from the rate of age-related DNA demethylation in normal and cancer cell lines.
Experimental gerontology, 1995Co-Authors: A L MazinAbstract:A method has been proposed for the Hayflick Limit prediction by the analysis of the 5-methylcytosine content in DNA at earlier and later cell passages. The following facts were used as the basis of the method: (i) the rate of m5C loss from DNA remains approximately constant during cell divisions and it does not depend on the cell donor age; (ii) this rate is inversely proportional to the Hayflick Limit as well as to the life span of cell donor species; (iii) the period corresponded to loss of all m5C residues from the genome coincides with or somewhat exceeds the Hayflick Limit of normal cells. The prognosis of the Hayflick Limit has usually been found in good agreement with the experimental evidences for various human, hamster, and mouse cell lines. The method proposed may be used for early detection of precrisis and cancer cells. The age-related m5C loss may result from accumulation of the m5C→T + C transitions occurring with DNA methylation in every cell division.
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loss of total 5 methylcytosine from the genome during cell culture aging coincides with the Hayflick Limit
Molecular Biology, 1993Co-Authors: A L MazinAbstract: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.
