Each animal species displays a specific life span, rate of aging and pattern of development of age-dependent diseases. The genetic bases of these related features are being studied experimentally in invertebrate and vertebrate model systems as well as in humans through medical records. Three types of mutants are being analyzed: (i) short-lived mutants that are prone to age-dependent diseases and might be models of accelerated aging; (ii) mutants that show overt molecular defects but that do not live shorter lives than controls, and can be used to test specific theories about the molecular causes of aging and age-dependent diseases; and (iii) long-lived mutants that might advance the understanding of the molecular physiology of slow-aging animals and aid the discovery of molecular targets that could be used to manipulate rates of aging to benefit human health. Here, I analyze some of what we know today and discuss what we should try to find out in the future to understand the aging phenomenon.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Friedman, D.B. & Johnson, T.E. A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 118, 75–86 (1988).
Kenyon, C., Chang, J., Gensch, E., Rudner, A. & Tabtiang, R.A. C. elegans mutant that lives twice as long as wild type. Nature 366, 461–464 (1993).
Wong, A., Boutis, P. & Hekimi, S. Mutations in the clk-1 gene of Caenorhabditis elegans affect developmental and behavioral timing. Genetics 139, 1247–1259 (1995).
Lakowski, B. & Hekimi, S. Determination of life-span in Caenorhabditis elegans by four clock genes. Science 272, 1010–1013 (1996).
Lin, Y.J., Seroude, L. & Benzer, S. Extended life-span and stress resistance in the Drosophila mutant methuselah. Science 282, 943–946 (1998).
Rogina, B., Reenan, R.A., Nilsen, S.P. & Helfand, S.L. Extended life-span conferred by cotransporter gene mutations in Drosophila. Science 290, 2137–2140 (2000).
Holzenberger, M. et al. IGF-1 receptor regulates life span and resistance to oxidative stress in mice. Nature 421, 182–187 (2003).
Liu, X. et al. Evolutionary conservation of the clk-1-dependent mechanism of longevity: loss of mclk1 increases cellular fitness and life span in mice. Genes Dev. 19, 2424–2434 (2005).
Perls, T.T. et al. Life-long sustained mortality advantage of siblings of centenarians. Proc. Natl. Acad. Sci. USA 99, 8442–8447 (2002).
Terry, D.F. et al. Lower all-cause, cardiovascular, and cancer mortality in centenarians' offspring. J. Am. Geriatr. Soc. 52, 2074–2076 (2004).
Perls, T. et al. Exceptional familial clustering for extreme longevity in humans. J. Am. Geriatr. Soc. 48, 1483–1485 (2000).
Barger, J.L., Walford, R.L. & Weindruch, R. The retardation of aging by caloric restriction: its significance in the transgenic era. Exp. Gerontol. 38, 1343–1351 (2003).
Liang, H. et al. Genetic mouse models of extended life span. Exp. Gerontol. 38, 1353–1364 (2003).
Smith, G.S., Walford, R.L. & Mickey, M.R. Life span and incidence of cancer and other diseases in selected long-lived inbred mice and their F 1 hybrids. J. Natl. Cancer Inst. 50, 1195–1213 (1973).
Blackwell, B.N., Bucci, T.J., Hart, R.W. & Turturro, A. Longevity, body weight, and neoplasia in ad libitum-fed and diet-restricted C57BL6 mice fed NIH-31 open formula diet. Toxicol. Pathol. 23, 570–582 (1995).
Cosgrove, G.E., Satterfield, L.C., Bowles, N.D. & Klima, W.C. Diseases of aging untreated virgin female RFM and BALB/c mice. J. Gerontol. 33, 178–183 (1978).
Ferri, C.P. et al. Global prevalence of dementia: a Delphi consensus study. Lancet 366, 2112–2117 (2005).
Parkin, D.M., Bray, F., Ferlay, J. & Pisani, P. Global cancer statistics, 2002. CA Cancer J. Clin. 55, 74–108 (2005).
Patil, C.K., Mian, I.S. & Campisi, J. The thorny path linking cellular senescence to organismal aging. Mech. Ageing Dev. 126, 1040–1045 (2005).
Mortimer, R.K. & Johnston, J.R. Life span of individual yeast cells. Nature 183, 1751–1752 (1959).
Kennedy, B.K. & Guarente, L. Genetic analysis of aging in Saccharomyces cerevisiae. Trends Genet. 12, 355–359 (1996).
Kenney, W.L. & Munce, T.A. Invited review: aging and human temperature regulation. J. Appl. Physiol. 95, 2598–2603 (2003).
Strigini, L. & Ryan, T. Wound healing in elderly human skin. Clin. Dermatol. 14, 197–206 (1996).
Holliday, R. The close relationship between biological aging and age-associated pathologies in humans. J. Gerontol. A Biol. Sci. Med. Sci. 59, B543–B546 (2004).
Hayflick, L. The not-so-close relationship between biological aging and age-associated pathologies in humans. J. Gerontol. A Biol. Sci. Med. Sci. 59, B547–B550 (2004).
Masoro, E.J. Overview of caloric restriction and ageing. Mech. Ageing Dev. 126, 913–922 (2005).
Martin, G.M. The Werner mutation: does it lead to a “public” or “private” mechanism of aging? Mol. Med. 3, 356–358 (1997).
Hekimi, S., Burgess, J., Bussiere, F., Meng, Y. & Benard, C. Genetics of life span in C. elegans: molecular diversity, physiological complexity, mechanistic simplicity. Trends Genet. 17, 712–718 (2001).
Martin, G.M. Genetic modulation of senescent phenotypes in Homo sapiens. Cell 120, 523–532 (2005).
Hasty, P., Campisi, J., Hoeijmakers, J., van Steeg, H. & Vijg, J. Aging and genome maintenance: lessons from the mouse? Science 299, 1355–1359 (2003).
Epstein, C.J., Martin, G.M. & Motulsky, A.G. Werner's syndrome; caricature of aging. A genetic model for the study of degenerative diseases. Trans. Assoc. Am. Physicians 78, 73–81 (1965).
Epstein, C.J., Martin, G.M., Schultz, A.L. & Motulsky, A.G. Werner's syndrome a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process. Medicine (Baltimore) 45, 177–221 (1966).
Bartke, A. Minireview: role of the growth hormone/insulin-like growth factor system in mammalian aging. Endocrinology 146, 3718–3723 (2005).
Rollo, C.D. Growth negatively impacts the life span of mammals. Evol. Dev. 4, 55–61 (2002).
Miller, R.A., Harper, J.M., Galecki, A. & Burke, D.T. Big mice die young: early life body weight predicts longevity in genetically heterogeneous mice. Aging Cell 1, 22–29 (2002).
Samaras, T.T., Elrick, H. & Storms, L.H. Is height related to longevity? Life Sci. 72, 1781–1802 (2003).
Trifunovic, A. et al. Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. Proc. Natl. Acad. Sci. USA 102, 17993–17998 (2005).
Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004).
Harding, A.E. Growing old: the most common mitochondrial disease of all? Nat. Genet. 2, 251–252 (1992).
Wallace, D.C. A mitochondrial paradigm for degenerative diseases and ageing. Novartis Found. Symp. 235, 247–263 (2001).
Wallace, D.C. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu. Rev. Genet. 39, 359–407 (2005).
Van Remmen, H. et al. Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol. Genomics 16, 29–37 (2003).
Keaney, M., Matthijssens, F., Sharpe, M., Vanfleteren, J. & Gems, D. Superoxide dismutase mimetics elevate superoxide dismutase activity in vivo but do not retard aging in the nematode Caenorhabditis elegans. Free Radic. Biol. Med. 37, 239–250 (2004).
Magwere, T. et al. The effects of exogenous antioxidants on life span and oxidative stress resistance in Drosophila melanogaster. Mech. Ageing Dev. 127, 356–370 (2006).
Sohal, R.S. & Allen, R.G. Oxidative stress as a causal factor in differentiation and aging: a unifying hypothesis. Exp. Gerontol. 25, 499–522 (1990).
Sohal, R.S. Oxidative stress hypothesis of aging. Free Radic. Biol. Med. 33, 573–574 (2002).
Lakowski, B. & Hekimi, S. The genetics of caloric restriction in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 95, 13091–13096 (1998).
Rudolph, K.L. et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96, 701–712 (1999).
Blasco, M.A. et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997).
Sharpless, N.E. & DePinho, R.A. Telomeres, stem cells, senescence, and cancer. J. Clin. Invest. 113, 160–168 (2004).
Li, Y. et al. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat. Genet. 11, 376–381 (1995).
Van Remmen, H. et al. Multiple deficiencies in antioxidant enzymes in mice result in a compound increase in sensitivity to oxidative stress. Free Radic. Biol. Med. 36, 1625–1634 (2004).
Kirkwood, T.B. Evolution of ageing. Nature 270, 301–304 (1977).
Feng, J., Bussiere, F. & Hekimi, S. Mitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans. Dev. Cell 1, 633–644 (2001).
Matheu, A. et al. Increased gene dosage of Ink4a/Arf results in cancer resistance and normal aging. Genes Dev. 18, 2736–2746 (2004).
Miller, R.A. Genetic approaches to the study of aging. J. Am. Geriatr. Soc. 53, 284–286 (2005).
Kurosu, H. et al. Suppression of aging in mice by the hormone Klotho. Science 309, 1829–1833 (2005).
Schriner, S.E. et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308, 1909–1911 (2005).
Chiu, C.H., Lin, W.D., Huang, S.Y. & Lee, Y.H. Effect of a C/EBP gene replacement on mitochondrial biogenesis in fat cells. Genes Dev. 18, 1970–1975 (2004).
Carrière, A., Liu, X. & Hekimi, S. The age of heterozygosity. Age (Omaha) 28, 201–208 (2006).
Kenyon, C. The plasticity of aging: insights from long-lived mutants. Cell 120, 449–460 (2005).
Tatar, M., Bartke, A. & Antebi, A. The endocrine regulation of aging by insulin-like signals. Science 299, 1346–1351 (2003).
Clancy, D.J. et al. Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 292, 104–106 (2001).
Tatar, M. et al. A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292, 107–110 (2001).
Felkai, S. et al. CLK-1 controls respiration, behavior and aging in the nematode Caenorhabditis elegans. EMBO J. 18, 1783–1792 (1999).
Dillin, A. et al. Rates of behavior and aging specified by mitochondrial function during development. Science 298, 2398–2401 (2002).
Lee, S.S. et al. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat. Genet. 33, 40–48 (2003).
Balaban, R.S., Nemoto, S. & Finkel, T. Mitochondria, oxidants, and aging. Cell 120, 483–495 (2005).
Kaeberlein, M., McVey, M. & Guarente, L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 13, 2570–2580 (1999).
Howitz, K.T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae life span. Nature 425, 191–196 (2003).
Tissenbaum, H.A. & Guarente, L. Increased dosage of a sir-2 gene extends life span in Caenorhabditis elegans. Nature 410, 227–230 (2001).
Rogina, B. & Helfand, S.L. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc. Natl. Acad. Sci. USA 101, 15998–16003 (2004).
Bordone, L. et al. Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol. 4, e31 (2006).
Mostoslavsky, R. et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315–329 (2006).
Picard, F. et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 429, 771–776 (2004).
Herskind, A.M. et al. The heritability of human longevity: a population-based study of 2872 Danish twin pairs born 1870–1900. Hum. Genet. 97, 319–323 (1996).
Perls, T. & Terry, D. Genetics of exceptional longevity. Exp. Gerontol. 38, 725–730 (2003).
Atzmon, G. et al. Lipoprotein genotype and conserved pathway for exceptional longevity in humans. PLoS Biol. 4, e113 (2006).
Evert, J., Lawler, E., Bogan, H. & Perls, T. Morbidity profiles of centenarians: survivors, delayers, and escapers. J. Gerontol. A Biol. Sci. Med. Sci. 58, 232–237 (2003).
Andersen, S.L. et al. Cancer in the oldest old. Mech. Ageing Dev. 126, 263–267 (2005).
Kohn, R.R. Cause of death in very old people. J. Am. Med. Assoc. 247, 2793–2797 (1982).
Branicky, R., Benard, C. & Hekimi, S. clk-1, mitochondria, and physiological rates. Bioessays 22, 48–56 (2000).
Hodgkin, J. & Barnes, T.M. More is not better: brood size and population growth in a self-fertilizing nematode. Proc. Biol. Sci. 246, 19–24 (1991).
Marden, J.H., Rogina, B., Montooth, K.L. & Helfand, S.L. Conditional tradeoffs between aging and organismal performance of Indy long-lived mutant flies. Proc. Natl. Acad. Sci. USA 100, 3369–3373 (2003).
Walker, D.W., McColl, G., Jenkins, N.L., Harris, J. & Lithgow, G.J. Evolution of life span in C. elegans. Nature 405, 296–297 (2000).
Rubner, M. Das Problem der Lebensdaur und Seiner Beziehunger zum Wachstum und Ernarnhung (Oldenberg, Munich, 1908).
Lombard, D.B. et al. Mutations in the WRN gene in mice accelerate mortality in a p53-null background. Mol. Cell. Biol. 20, 3286–3291 (2000).
Berman, J.R. & Kenyon, C. Germ-cell loss extends C. elegans life span through regulation of DAF-16 by kri-1 and lipophilic-hormone signaling. Cell 124, 1055–1068 (2006).
Jia, K., Chen, D. & Riddle, D.L. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131, 3897–3906 (2004).
Ludewig, A.H. et al. A novel nuclear receptor/coregulator complex controls C. elegans lipid metabolism, larval development, and aging. Genes Dev. 18, 2120–2133 (2004).
Rottiers, V. et al. Hormonal control of C. elegans dauer formation and life span by a Rieske-like oxygenase. Dev. Cell 10, 473–482 (2006).
Narbonne, P. & Roy, R. Inhibition of germline proliferation during C. elegans dauer development requires PTEN, LKB1 and AMPK signalling. Development 133, 611–619 (2006).
Hansen, M., Hsu, A.L., Dillin, A. & Kenyon, C. New genes tied to endocrine, metabolic, and dietary regulation of life span from a Caenorhabditis elegans genomic RNAi screen. PLoS Genet 1, 119–128 (2005).
Boehm, M. & Slack, F. A developmental timing microRNA and its target regulate life span in C. elegans. Science 310, 1954–1957 (2005).
Oh, S.W. et al. JNK regulates life span in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16. Proc. Natl. Acad. Sci. USA 102, 4494–4499 (2005).
Murphy, C.T. et al. Genes that act downstream of DAF-16 to influence the life span of Caenorhabditis elegans. Nature 424, 277–283 (2003).
McElwee, J.J., Schuster, E., Blanc, E., Thomas, J.H. & Gems, D. Shared transcriptional signature in Caenorhabditis elegans Dauer larvae and long-lived daf-2 mutants implicates detoxification system in longevity assurance. J. Biol. Chem. 279, 44533–44543 (2004).
Lund, J. et al. Transcriptional profile of aging in C. elegans. Curr. Biol. 12, 1566–1573 (2002).
Oh, S.W. et al. Identification of direct DAF-16 targets controlling longevity, metabolism and diapause by chromatin immunoprecipitation. Nat. Genet. 38, 251–257 (2006).
For discussions and insightful work, I thank the past and present members of my laboratory and my colleagues in the field. My laboratory is funded by McGill University, the National Science and Research Council of Canada (NSERC) and a research contract from Chronogen, Inc. I hold the Strathcona Chair of Zoology.
S.H. is the founder of, a shareholder of, and a consultant for Chronogen, a biotechnology company interested in aging research.
About this article
Middle age enhances expression of innate immunity genes in a female mouse model of pulmonary fibrosis
Different Mechanisms of Longevity in Long-Lived Mouse andCaenorhabditis elegansMutants Revealed by Statistical Analysis of Mortality Rates
Mechanisms of Ageing and Development (2015)