Cell divisions and mammalian aging: integrative biology insights from genes that regulate longevity

Despite recent progress in the identification of genes that regulate longevity, aging remains a mysterious process. One influential hypothesis is the idea that the potential for cell division and replacement are important factors in aging. In this work, we review and discuss this perspective in the context of interventions in mammals that appear to accelerate or retard aging. Rather than focus on molecular mechanisms, we interpret results from an integrative biology perspective of how gene products affect cellular functions, which in turn impact on tissues and organisms. We review evidence suggesting that mutations that give rise to features resembling premature aging tend to be associated with cellular phenotypes such as increased apoptosis or premature replicative senescence. In contrast, many interventions in mice that extend lifespan and might delay aging, including caloric restriction, tend to either hinder apoptosis or result in smaller animals and thus may be the product of fewer cell divisions. Therefore, it appears plausible that changes in the number of times that cells, and particularly stem cells, divide during an organism's lifespan influence longevity and aging. We discuss possible mechanisms related to this hypothesis and propose experimental paradigms. BioEssays 30:567–578, 2008. © 2008 Wiley Periodicals, Inc.

[1]  J. Sedivy,et al.  Cellular Senescence in Aging Primates , 2006, Science.

[2]  C. Deng,et al.  Senescence, aging, and malignant transformation mediated by p53 in mice lacking the Brca1 full-length isoform. , 2003, Genes & development.

[3]  Siegfried Hekimi,et al.  Evolutionary conservation of the clk-1-dependent mechanism of longevity: loss of mclk1 increases cellular fitness and lifespan in mice. , 2005, Genes & development.

[4]  G. van Zant,et al.  The role of stem cells in aging. , 2003, Experimental hematology.

[5]  R. Faragher,et al.  The gene responsible for Werner syndrome may be a cell division "counting" gene. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[6]  David W. Lee,et al.  Growth retardation and premature aging phenotypes in mice with disruption of the SNF2-like gene, PASG. , 2004, Genes & development.

[7]  Lin Yan,et al.  Type 5 Adenylyl Cyclase Disruption Increases Longevity and Protects Against Stress , 2007, Cell.

[8]  C. Leeuwenburgh,et al.  Life‐long calorie restriction (CR) increases expression of apoptosis repressor with a caspase recruitment domain (ARC) in the brain , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[9]  A. Zeiher,et al.  Redox regulatory and anti-apoptotic functions of thioredoxin depend on S-nitrosylation at cysteine 69 , 2002, Nature Cell Biology.

[10]  N. Sharpless,et al.  Ink4a/Arf expression is a biomarker of aging. , 2004, The Journal of clinical investigation.

[11]  Robert M. Bachoo,et al.  Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing , 2003, Nature.

[12]  A. Brooks-Wilson,et al.  Progeria of stem cells: stem cell exhaustion in Hutchinson-Gilford progeria syndrome. , 2007, The journals of gerontology. Series A, Biological sciences and medical sciences.

[13]  R. Faragher,et al.  What Can Progeroid Syndromes Tell Us About Human Aging? , 2004, Science.

[14]  R. G. Allen,et al.  Relationship between donor age and the replicative lifespan of human cells in culture: a reevaluation. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Sander van den Heuvel,et al.  Cell-cycle control in Caenorhabditis elegans: how the worm moves from G1 to S , 2005, Oncogene.

[16]  D. Bartel MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[17]  B. J. Jennings,et al.  Early growth determines longevity in male rats and may be related to telomere shortening in the kidney , 1999, FEBS letters.

[18]  J. Hoeijmakers,et al.  A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis , 2006, Nature.

[19]  J. Hoeijmakers,et al.  Premature Aging in Mice Deficient in DNA Repair and Transcription , 2002, Science.

[20]  L. Storms,et al.  Is height related to longevity? , 2003, Life sciences.

[21]  N. Wolf,et al.  Cellular proliferative capacity and life span in small and large dogs. , 1996, The journals of gerontology. Series A, Biological sciences and medical sciences.

[22]  R. Kumar,et al.  BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice , 2004, Nature Genetics.

[23]  Hong Jiang,et al.  Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation , 2006, Nature Genetics.

[24]  A. Terzic,et al.  Early aging–associated phenotypes in Bub3/Rae1 haploinsufficient mice , 2006, The Journal of cell biology.

[25]  Joel S Greenberger,et al.  Age‐related intrinsic changes in human bone‐marrow‐derived mesenchymal stem cells and their differentiation to osteoblasts , 2008, Aging cell.

[26]  Richard Weindruch,et al.  The Retardation of Aging and Disease by Dietary Restriction , 1988 .

[27]  Ronald A. DePinho,et al.  How stem cells age and why this makes us grow old , 2007, Nature Reviews Molecular Cell Biology.

[28]  J. Campisi,et al.  Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation , 2004, Journal of Cell Science.

[29]  S. Austad,et al.  Does caloric restriction extend life in wild mice? , 2006, Aging cell.

[30]  M. Lane,et al.  Effects of reduced energy intake on the biology of aging: the primate model , 2000, European journal of clinical nutrition.

[31]  R. Wanke,et al.  Effects of long-term elevated serum levels of growth hormone on life expectancy of mice: Lessons from transgenic animal models , 1993, Mechanisms of Ageing and Development.

[32]  H. Vogel,et al.  Analysis of ku80-Mutant Mice and Cells with Deficient Levels of p53 , 2000, Molecular and Cellular Biology.

[33]  D. Clemmons,et al.  Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. , 2000, Endocrinology.

[34]  R. Holliday,et al.  Genetic effects on the longevity of cultured human fibroblasts. II. DNA repair deficient syndromes. , 1983, Gerontology.

[35]  N. Wolf,et al.  The relationships of animal age and caloric intake to cellular replication in vivo and in vitro: a review. , 1999, The journals of gerontology. Series A, Biological sciences and medical sciences.

[36]  H. Warner Developing a research agenda in biogerontology: basic mechanisms. , 2005, Science of aging knowledge environment : SAGE KE.

[37]  T. Roderick,et al.  Maximum Life Spans in Mice are Extended by Wild Strain Alleles , 2001, Experimental biology and medicine.

[38]  F. Slack,et al.  A Developmental Timing MicroRNA and Its Target Regulate Life Span in C. elegans , 2005, Science.

[39]  S. Elledge,et al.  ATM–Chk2–p53 activation prevents tumorigenesis at an expense of organ homeostasis upon Brca1 deficiency , 2006, The EMBO journal.

[40]  E. Hafen,et al.  An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control , 2001, Current Biology.

[41]  J. Hoeijmakers,et al.  Aging and Genome Maintenance: Lessons from the Mouse? , 2003, Science.

[42]  Richa Saxena,et al.  A common variant of HMGA2 is associated with adult and childhood height in the general population , 2007, Nature Genetics.

[43]  S. Austad,et al.  Growth and Aging: Why Do Big Dogs Die Young? , 2005 .

[44]  J. Shay,et al.  Historical claims and current interpretations of replicative aging , 2002, Nature Biotechnology.

[45]  G. Bray,et al.  Neuroendocrine and pharmacological manipulations to assess how caloric restriction increases life span. , 2001, The journals of gerontology. Series A, Biological sciences and medical sciences.

[46]  J. P. D. Magalhães From cells to ageing: a review of models and mechanisms of cellular senescence and their impact on human ageing. , 2004 .

[47]  Andrzej Bartke,et al.  Dwarf mice and the ageing process , 1996, Nature.

[48]  J. Bridger,et al.  Aging of Hutchinson–Gilford progeria syndrome fibroblasts is characterised by hyperproliferation and increased apoptosis , 2004, Experimental Gerontology.

[49]  K. Chien,et al.  Longevity and Lineages: Toward the Integrative Biology of Degenerative Diseases in Heart, Muscle, and Bone , 2005, Cell.

[50]  Alessandro Minelli,et al.  The Development of Animal Form: Ontogeny, Morphology, and Evolution , 2003 .

[51]  R. G. Allen,et al.  Replicative senescence: a critical review , 2004, Mechanisms of Ageing and Development.

[52]  N. Wolf,et al.  Long-term caloric restriction delays age-related decline in proliferation capacity of murine lens epithelial cells in vitro and in vivo. , 1997, Investigative ophthalmology & visual science.

[53]  S. Austad,et al.  Genetic modulation of hormone levels and life span in hybrids between laboratory and wild-derived mice. , 2006, The journals of gerontology. Series A, Biological sciences and medical sciences.

[54]  A. Bartke Can Growth Hormone (GH) Accelerate Aging? Evidence from GH-Transgenic Mice , 2003, Neuroendocrinology.

[55]  Irving L. Weissman,et al.  Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age , 2007, Nature.

[56]  R. DePinho,et al.  Essential role of limiting telomeres in the pathogenesis of Werner syndrome , 2004, Nature Genetics.

[57]  R. S. Sohal,et al.  Genotype and age influence the effect of caloric intake on mortality in mice , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[58]  Linda Yang,et al.  Cdc42 GTPase-activating protein deficiency promotes genomic instability and premature aging-like phenotypes , 2007, Proceedings of the National Academy of Sciences.

[59]  María A Blasco,et al.  Telomere Shortening and Tumor Formation by Mouse Cells Lacking Telomerase RNA , 1997, Cell.

[60]  A. Bhandoola,et al.  Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss. , 2007, Cell stem cell.

[61]  George M. Martin,et al.  Lessons from human progeroid syndromes , 2000, Nature.

[62]  Andrzej Bartke,et al.  Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[63]  Howard T. Jacobs,et al.  Premature ageing in mice expressing defective mitochondrial DNA polymerase , 2004, Nature.

[64]  J. Kaprio,et al.  The association between body height and coronary heart disease among Finnish twins and singletons. , 2003, International Journal of Epidemiology.

[65]  J. Campisi,et al.  Bloom syndrome cells undergo p53-dependent apoptosis and delayed assembly of BRCA1 and NBS1 repair complexes at stalled replication forks , 2003, The Journal of cell biology.

[66]  Tadashi Hirakawa,et al.  Overexpression of human thioredoxin in transgenic mice controls oxidative stress and life span. , 2002, Antioxidants & redox signaling.

[67]  K. Manova-Todorova,et al.  Enhanced Growth of Mice Lacking the Cyclin-Dependent Kinase Inhibitor Function of p27 Kip1 , 1996, Cell.

[68]  S. Tavaré,et al.  Counting human somatic cell replications: methylation mirrors endometrial stem cell divisions. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[69]  G. Martin The genetics and epigenetics of altered proliferative homeostasis in ageing and cancer , 2007, Mechanisms of Ageing and Development.

[70]  V. Rangnekar,et al.  Cancer resistance in transgenic mice expressing the SAC module of Par-4. , 2007, Cancer research.

[71]  F. Sierra,et al.  Models of accelerated ageing can be informative about the molecular mechanisms of ageing and/or age-related pathology , 2003, Mechanisms of Ageing and Development.

[72]  C. Atwood,et al.  Living and Dying for Sex , 2004, Gerontology.

[73]  C. Rollo Growth negatively impacts the life span of mammals , 2002, Evolution & development.

[74]  Laura Scott,et al.  Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome , 2003, Nature.

[75]  Stephen N. Jones,et al.  p53 mutant mice that display early ageing-associated phenotypes , 2002, Nature.

[76]  L. Cox,et al.  From old organisms to new molecules: integrative biology and therapeutic targets in accelerated human ageing , 2007, Cellular and Molecular Life Sciences.

[77]  S. Bennett,et al.  Pleiotropic effects of growth hormone and insulin-like growth factor (IGF)-1 on biological aging: inferences from moderate caloric-restricted animals. , 1999, The journals of gerontology. Series A, Biological sciences and medical sciences.

[78]  B. Thiers Genomic Instability and Aging-like Phenotype in the Absence of Mammalian SIRT6 , 2007 .

[79]  J. Hoeijmakers,et al.  Divide and conquer: nucleotide excision repair battles cancer and ageing. , 2003, Current opinion in cell biology.

[80]  J. Campisi,et al.  Ageing: Balancing regeneration and cancer , 2006, Nature.

[81]  Revisiting the role of fat mass in the life extension induced by caloric restriction. , 1999, The journals of gerontology. Series A, Biological sciences and medical sciences.

[82]  E. Kahn,et al.  [ON AGING]. , 1964, Psychiatria et neurologia.

[83]  João Pedro de Magalhães,et al.  The Influence of Genes on the Aging Process of Mice , 2005, Genetics.

[84]  I. Weissman,et al.  Rejuvenation of aged progenitor cells by exposure to a young systemic environment , 2005, Nature.

[85]  I. Mian,et al.  The thorny path linking cellular senescence to organismal aging , 2005, Mechanisms of Ageing and Development.

[86]  G. Schellenberg,et al.  Positional Cloning of the Werner's Syndrome Gene , 1996, Science.

[87]  Xianjin Zhou,et al.  Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor HMGI-C , 1995, Nature.

[88]  J. de Magalhães Open-minded scepticism: inferring the causal mechanisms of human ageing from genetic perturbations. , 2005, Ageing research reviews.

[89]  E. Nera,et al.  Calorie restriction and cellular proliferation in various tissues of the female Swiss Webster mouse. , 1990, Cancer letters.

[90]  M. Tatar,et al.  The Endocrine Regulation of Aging by Insulin-like Signals , 2003, Science.

[91]  J. P. D. Magalhães Open-minded scepticism: inferring the causal mechanisms of human ageing from genetic perturbations , 2005, Ageing Research Reviews.

[92]  J. de Magalhães,et al.  Telomeres and telomerase: a modern fountain of youth? , 2004, Rejuvenation research.

[93]  J. Campisi,et al.  Replicative Senescence: An Old Lives' Tale? , 1996, Cell.

[94]  Keisuke Kuida,et al.  Reduced Apoptosis and Cytochrome c–Mediated Caspase Activation in Mice Lacking Caspase 9 , 1998, Cell.

[95]  E. Friedberg,et al.  The Cockayne syndrome group A gene encodes a WD repeat protein that interacts with CSB protein and a subunit of RNA polymerase II TFIIH , 1995, Cell.

[96]  P. Leder,et al.  A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[97]  L. Hayflick How and why we age , 1994, Experimental Gerontology.

[98]  Pascal J. Goldschmidt-Clermont,et al.  Aging, Progenitor Cell Exhaustion, and Atherosclerosis , 2003, Circulation.

[99]  B. Zwaan,et al.  Reduced insulin/IGF‐1 signalling and human longevity , 2005, Aging cell.

[100]  Pier Paolo Pandolfi,et al.  The p66shc adaptor protein controls oxidative stress response and life span in mammals , 1999, Nature.

[101]  Gayle M. Smythe,et al.  Notch-Mediated Restoration of Regenerative Potential to Aged Muscle , 2003, Science.

[102]  D. Gaylor,et al.  Upregulation of apoptosis with dietary restriction: implications for carcinogenesis and aging. , 1998, Environmental health perspectives.

[103]  S. Benzer,et al.  Regulation of Lifespan in Drosophila by Modulation of Genes in the TOR Signaling Pathway , 2004, Current Biology.

[104]  Richard A. Miller,et al.  Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[105]  A. Bartke,et al.  Genes that prolong life: relationships of growth hormone and growth to aging and life span. , 2001, The journals of gerontology. Series A, Biological sciences and medical sciences.

[106]  J. Hoeijmakers,et al.  Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice. , 2006, Mutation research.