Human Genetics

, Volume 91, Issue 6, pp 519–526 | Cite as

Prospects for the genetics of human longevity

  • François Schächter
  • Daniel Cohen
  • Tom Kirkwood
Review Article


Longevity varies between and within species. The existence of species-specific limit to human life-span and its partial heritability indicate the existence of genetic factors that influence the ageing process. Insight into the nature of these genetic factors is provided by evolutionary studies, notably the disposable soma theory, which suggests a central role of energy metabolism in determining life-span. Energy is important in two ways. First, the disposable soma theory indicates that the optimum energy investment in cell maintenance and repair processes will be tuned through natural selection to provide adequate, but not excessive, protection against random molecular damages (e.g. to DNA, proteins). All that is required is that the organism remains in a sound condition through its natural expectation of life in the wild environment, where accidents are the predominant cause of mortality. Secondly, energy is implicated because of the intrinsic vulnerability of mitochondria to damage that may interfere with the normal supply of energy to the cell via the oxidative phosphorylation pathways. Oxidative phosphorylation produces ATP, and as a by-product also produces highly reactive oxygen radicals that can damage many cell structures, including the mitochondria themselves. Several lines of evidence link, on the one hand, oxidative damage to cell ageing, and on the other hand, energy-dependent antioxidant defences to the preservation of cellular homeostasis, and hence, longevity. Models of cellular ageing in vitro allow direct investigation of mechanisms, such as oxidative damage, that contribute to limiting human life-span. The genetic substratum of inter-individual differences in longevity may be unraveled by a two-pronged reverse genetics approach: sibling pair analysis applied to nonagenarian and centenarian siblings, combined with association studies of centenarians, may lead to the identification of genetic influences upon human longevity. These studies have become practicable thanks to recent progress in human genome mapping, especially to the development of microsatellite markers and the integration of genetic and physical maps.


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  1. Abbott MH, Murphy EA, Bolling DR, Abbey H (1974) The familial component in longevity, a study of the offspring of nonagenarians II. Preliminary analysis of the completed study. Johns Hopkins Med J 134:1–16Google Scholar
  2. Adelman R, Saul RL, Ames BN (1988) Oxidation damage to DNA: relation to species metabolic rate and life span. Proc Natl Acad Sci USA 85:2706–2708Google Scholar
  3. Allard M (1991) Á la recherché du secret des centenaires. Le cherche midi éditeur, ParisGoogle Scholar
  4. Anderson S, Bankier AT, Barrell BG, De Bruijn MHL, Coulson AR et al, (1981) Sequence and organization of the human mitochondrial genome. Nature 290:457–465Google Scholar
  5. Attardi G, Schatz G (1988) Biogenesis of mitochondria. Annu Rev Cell Biol 4:249–333Google Scholar
  6. Baker KP, Schatz G (1991) Mitochondrial proteins essential for viability mediate protein import into yeast mitochondria. Nature 349:205–208Google Scholar
  7. Belcour L, Begel O, Mosse MO, Vierny C (1981) Mitochondrial DNA amplification in senescent cultures of Podospora anserina. Curr Genet 3:13–21Google Scholar
  8. Beverton RJ (1987) Longevity in fish: some ecological and evolutionary considerations. In: Woodhead AD, Thompson KH (eds) Evolution of senescence. A comparative approach. Plenum, New York, pp 145–160Google Scholar
  9. Bishop DT, Williamson JA (1990) The power of identity-by-state methods for linkage analysis. Am J Hum Genet 46:254–265Google Scholar
  10. Blackwelder WC, Elston RC (1985) A comparison of sib-pair linkage tests for disease susceptibility loci. Genet Epidemiol 2:85–97Google Scholar
  11. Boehnke M (1990) Sample-size guidelines for linkage analysis of a dominant locus for a quantitative trait by the method of lod scores. Am J Hum Genet 47:218–227Google Scholar
  12. Calder WA (1984) Size, function and life history. Harvard University Press, Cambridge, MassGoogle Scholar
  13. Calder WA (1985) The comparative biology of longevity and lifetime energetics. Exp Gerontol 20:161–170Google Scholar
  14. Chumakov I, Rigault P, Guillou S, Ougen P, Billault A, Guasconi G, Gervy P, Le Gall I, Soularue P, Grinas P, Bougueleret L, Bellanée-Chantelot C, Lacroix B, Barillot E, Gesnouin P, Pook S, Vayssex G, Frelat G, Schmitz A, Sambucy JL, Bosch A, Estivill X, Weissenbach J, Vignal A, Riethman H, Cox D, Patterson D, Gardiner K, Masahira H, Sakaki Y, Ichikawa H, Ohsi M, Le Paslier D, Heilig R, Antonarakis S, Cohen D (1992) Continuum of overlapping clones spanning the entire human chromosome 21q. Nature 359:380–386Google Scholar
  15. Clayton DA (1984) Transcription of the mammalian mitochondrial genome. Annu Rev Biochem 53:573–594Google Scholar
  16. Clayton DA, Doda JN, Friedberg EC (1974) The absence of a pyrimidine dimer repair mechanism in mammalian mitochondria. Proc Natl Acad Sci USA 71:2777–2781Google Scholar
  17. Clerget-Darpoux F, Bonaiti-Pellié C (1992) Strategies based on marker information for the study of human diseases. Ann Hum Genet 56:147–155Google Scholar
  18. Corbisier P, Remacle J (1990) Involvement of mitochondria in cell degeneration. Eur J Cell Biol 51:173–182Google Scholar
  19. Corral-Debrinski M, Shoffner JM, Lott MT, Wallace DC (1992) Association of mitochondrial DNA damage with aging and coronary atherosclerotic heart disease. Mutat Res 275:169–180Google Scholar
  20. Cortopassi GA, Arnheim N (1990) Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res 18:6927–6933Google Scholar
  21. Cortopassi GA, Shibata D, Soong NW, Arnheim N (1992) A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc Natl Acad Sci USA 89:7370–7374Google Scholar
  22. Cox NJ, Bell GI (1989) Disease associations, chance, artifact or susceptibility genes? Diabetes 38:947–950Google Scholar
  23. Cristofalo VJ, Doggett DL, Brooks-Frederich KM, Phillips PD (1989) Growth factors as probes of cell aging. Exp Gerontol 24:367–374Google Scholar
  24. Demenais F, Lathrop GM (1993) Use of the regressive models in linkage analysis of quantitative traits. Genet Epidemio (in press)Google Scholar
  25. Else PL, Hulbert AJ (1981) Comparison of the “mammal machine” and the “reptile machine”: energy production. Am J Physiol 204:R3-R9Google Scholar
  26. Evans MJ, Scarpulla RC (1990) NRF-1: a trans-activator of nuclear-encoded respiratory genes in animal cells. Genes Dev 4:1023–1034Google Scholar
  27. Feingold N (1972) Phénomènes d'association dans une population. Nouv Rev Fr Hematol 12:471–475Google Scholar
  28. Finch CE (1990) Longevity, senescence and the genome. University of Chicago Press, ChicagoGoogle Scholar
  29. Fleming JE, Miquel J, Cottrell SF, Yengoyan LS, Economos AC (1982) Is cell ageing caused by respiratory-dependent injury to the mitochondrial genome? Gerontology 28:44–53Google Scholar
  30. Francis AA, Lee WH, Francis AA, Lee WH, Regan JD (1981) The relationship of DNA excision repair of ultraviolet-induced lesions to the maximum life-span of mammals. Mech Ageing Dev 16:181–189Google Scholar
  31. Fridovitch I (1975) Superoxide dismutases. Annu Rev Biochem 44:147–159Google Scholar
  32. Glueck CG, Gartside P, Fallat W, Sielski J, Steiner PM (1976) Longevity syndromes: familial hypobeta and familial hyperalpha lipoproteinemia. J Lab Clin Med 88:941–956Google Scholar
  33. Goldstein S (1990) Replicative senescence: the human fibroblast comes of age. Science 249:1129–1133Google Scholar
  34. Greenberg DA (1993) Linkage analysis of “necessary” disease loci versus “susceptibility” loci. Am J Hum Genet 52:135–143Google Scholar
  35. Grube K, Bürkle A (1992) Poly(ADP-ribose) polymerase activity in mononuclear leukocytes of 13 mammalian species correlates with species-specific life span. Proc Natl Acad Sci USA 89:11759–11763Google Scholar
  36. Hara E, Tsurui H, Shinozaki A, Nakada S, Oda K (1991) Cooperative effet of antisense-Rb and antisense-p53 oligomers on the extension of life-span in human diploid fibroblasts. Biochem Biophys Res Commun 179:528–534Google Scholar
  37. Harding AE (1991) Neurological disease and mitochondrial genes. Trends Neurosci 14:132–138Google Scholar
  38. Harley CB, Fuchter AB, Greider CW (1990) Telomeres shorten during aging of human fibroblasts. Nature 345:458–460Google Scholar
  39. Harman D (1972) The biological clock: the mitochondria? J Am Geriatr Soc 20:145–147Google Scholar
  40. Harman D (1991) The aging process: major risk factor for disease and death. Proc Natl Acad Sci USA 88:5360–5363Google Scholar
  41. Hart R, Setlow RB (1974) Correlation between deoxyribonucleic acid excision-repair and life-span in a number of mammalian species. Proc Natl Acad Sci USA 71:2169–2173Google Scholar
  42. Harvey PH, Pagel MD (1991) The comparative method in evolutionary biology. Oxford University Press, OxfordGoogle Scholar
  43. Hayakawa M, Torii K, Sugyiama S, Tanaka M, Ozawa T (1991) Age-associated accumulation of 8-hydroxydeoxyguanosine in mitochondrial DNA of human diaphragm. Biochem Biophys Res Commun 179:1023–1029Google Scholar
  44. Hayflick L (1965) The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 37:614–636Google Scholar
  45. Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid strains. Exp Cell Res 25:585–621Google Scholar
  46. Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ (1990) Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348:334–336Google Scholar
  47. Holliday R (1990) The limited proliferation of cultured human diploid cells: regulation or senescence? J Gerontol 45:B36–41Google Scholar
  48. Holt IJ, Harding JA, Morgan-Hughes JA (1988) Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331:717–719Google Scholar
  49. Hulbert AJ, Else PL (1981) Comparison of the “mammal machine” and the “reptile machine”: energy use and thyroid activity. Am J Physiol 241:R350-R356Google Scholar
  50. Ikebe S, Tanaka M, Ohno K, Sato W, Hattori K, Kondo T, Mizuno Y, Ozawa T (1990) Increase of deleted mitochondrial DNA in the striatum in Parkinson's disease and senescence. Biochem Biophys Res Commun 170:1044–1048Google Scholar
  51. Jarvik LF, Falek A, Kallman FJ, Lorge I (1960) Survival trends in a senescent twin population. Am J Hum Genet 12:170–179Google Scholar
  52. Jeunemaître X, Soubrier F, Kotelevtsev YV, Lifton RP, Willimas CS, Charru A, Hint SC, Hopkins PN, Williams RR, Lalouel JM, Corvol P (1992) Molecular basis of human hypertension: role of angiotensinogen. Cell 71:169–180Google Scholar
  53. Johns DR, Drachman DB, Hurko O (1989) Identical mitochondrial DNA deletion in blood and muscle. Lancet 1:393–394Google Scholar
  54. Johnson TE (1990) Increased lifespan of Age-1 mutants in Caenorhabditis elegans and lower Gompertz rate of aging. Science 249:908–912Google Scholar
  55. Julier C, Hyer NR, Davies J, Merlin F, Soularue P, Briant L, Cathelineau G, Deschamps I, Rotter JI, Froguel P, Boutard C, Bell JI, Lathrop GM (1991) Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. Nature 354:155–159Google Scholar
  56. Kadenbach B, Müller-Höcker J (1990) Mutations of mitochondrial DNA and human death. Natur Wissch 77:221–225Google Scholar
  57. Kirkwood TBL (1981) Repair and its evolution: survival versus reproduction. In: Townsend CR, Calow P (eds) Physiological ecology: an evolutionary approach to resource use. Blackwell Scientific Publications, Oxford, pp 165–189Google Scholar
  58. Kirkwood TBL (1991) Genetic basis of limited cell proliferation. Mutat Res 256:323–328Google Scholar
  59. Kirkwood TBL (1992) Comparative life-spans of species: why do species have the life-spans they do? Am J Clin Nutr 55:1191–1195Google Scholar
  60. Kirkwood TBL, Franceschi C (1992) Is aging as complex as it would appear? New perspectives in aging research. Ann NY Acad Sci 663:412–417Google Scholar
  61. Kirkwood TBL, Rose MR (1991) Evolution of senescence: late survival sacrificed for reproduction. Philos Trans R Soc Lond [Biol] 332:15–24Google Scholar
  62. Lange K (1986) The affected sib pair method using identity by state relations. Am J Hum Genet 39:148–150Google Scholar
  63. Lestienne P (1992) Mitochondrial DNA mutations in human diseases: a review. Biochimie 74:123–130Google Scholar
  64. Linnane AW, Baumer A, Maxwell RJ, Preston H, Zhank C, Marzuki S (1990) Mitochondrial gene mutation: the ageing process and degenerative diseases. Biochem Int 22:1067–1076Google Scholar
  65. Lusis AJ (1988) Genetic factors affecting blood lipoproteins: the candidate gene approach. J Lipid Res 29:397–429Google Scholar
  66. Macieira-Coelho A, Nordenksjöld B (1990) Cancer and aging. CRC Press, Boca Raton, FlaGoogle Scholar
  67. Maier JAM, Voulalas P, Roeder D, Maciag T (1990) Extension of the life-span of human endothelial cells by interleukin-1α antisense oligomer. Science 249:1570–1574Google Scholar
  68. Martin GM, Sprague C, Epstein C (1970) Replicative life-span of cultivated human cells: effects of donor's age, tissue and genotype. Lab Invest 23:86–91Google Scholar
  69. Medvedev ZA (1990) An attempt at a rational classification of theories of ageing. Biol Rev 65:375–398Google Scholar
  70. Mignotte B, Larcher JC, Zheng DQ, Esnault C, Coulaud D, Feunteun J (1990) SV40 induced cellular immortalization: phenotypic changes associated with the loss of proliferative capacity in a conditionally immortalized cell line. Oncogene 5:1529–1533Google Scholar
  71. Murphy BJ, Robin ED, Tapper DP, Wong RJ, Clayton DA (1984) Hypoxic coordinate regulation of mitochondrial enzymes in mammalian cells. Science 223:707–709Google Scholar
  72. NIH/CEPH Collaborative Mapping Group (1992) A comprehensive genetic linkage map of the human genome. Science 258:67–86Google Scholar
  73. Niwa Y, Ishimoto K, Kanoh T (1990) Induction of superoxide dismutase in leukocytes by paraquat: correlation with age and possible predictor of longevity. Blood 76:835–841Google Scholar
  74. Nuell MJ, Stewart DA, Walker L, Friedman V, Wood CM, Owens FA, Smith JR, Schneider EL, Dell'Orco RT, Lumpkin CD, Danner DB, McClung JK (1991) Prohibitin, an evolutionarily conserved intracellular protein that blocks DNA synthesis in normal fibroblasts and HeLa cells. Mol Cell Biol 11:1372–1381Google Scholar
  75. Olshansky SJ, Carnes BA, Cassel C (1990) In search of Methuselah: estimating the upper limits to human longevity. Science 250:634–640Google Scholar
  76. Ozawa T, Yoneda M, Tanaka M, Ohno K, Sato W, Suzuki H, Nashikimi M et al (1988) Maternal inheritance of mitochondrial DNA in a family with mitochondrial myopathy. Biochem Biophys Res Commun 154:1240–1247Google Scholar
  77. Oziewacz HD (1990) Molecular analysis of ageing processes in fungi. Mutat Res 237:1–8Google Scholar
  78. Pearl R, Pearl de W (1934) The ancestry of the long-lived. Johns Hopkins University Press, BaltimoreGoogle Scholar
  79. Pereira-Smith OM, Smith JR (1983) Evidence for the recessive nature of cellular immortality. Science 221:962–966Google Scholar
  80. Pereira-Smith OM, Smith JR (1988) Genetic analysis of indefinite division in human cells: identification of four complementation groups. Proc Natl Acad Sci USA 85:6042–6046Google Scholar
  81. Proust J, Moulias R, Fumeron F, Bekkhoucha F, Busson M, Schmidt M, Hors J (1982) HLA and longevity. Tissue Antigens 19:168–173Google Scholar
  82. Richter C, Kass GEN (1991) Oxidative stress in mitochondria: its relationship to cellular Ca++ homeostasis, cell death, proliferation, and differentiation. Chem Biol Interact 77:1–23Google Scholar
  83. Richter CH (1988) Do mitochondrial DNA fragments promote cancer and aging? FEBS Lett 241:1–5Google Scholar
  84. Richter CH, Park JW, Ames BN (1988) Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci USA 85:6465–6467Google Scholar
  85. Risch N (1990) Linkage strategies for genetically complex traits. III. The effect of marker polymorphism on analysis of affected relative pairs. Am J Hum Genet 46:242–253Google Scholar
  86. Röhme D (1981) Evidence for a relationship between longevity of mammalian species and life-spans of normal fibroblasts in vitro and erythrocytes in vivo. Proc Natl Acad Sci USA 78:5009–5013Google Scholar
  87. Rose MR (1984) Laboratory evolution of postponed senescence in Drosophila melanogaster. Evolution 38:1004–1010Google Scholar
  88. Sacher GA (1977) Life table modification and life prolongation. In: Finch CE, Hayflick L (eds) Handbook of the biology of aging. Van Nostrand, New York, pp 582–638Google Scholar
  89. Scholte HR (1988) The biochemical basis of mitochondrial diseases. J Bioenerg Biomembr 20:161–191Google Scholar
  90. Schraufstatter I, Hinshaw D, Hyslop P, Spragg R, Cochrane C (1986) Oxidant injury of cells: DNA strand breaks activate polyadenosine diphosphate-ribose polymerase and lead to depletion of nicotinamide adenine dinucleotide. J Clin Invest 77:1312–1320Google Scholar
  91. Seboun E, Robinson MA, Doolittle TH, Ciulla TA, Kindt TJ, Hauser SL (1989) A susceptibility locus for multiple sclerosis is linked to the T cell receptor β chain complex. Cell 57:1095–1100Google Scholar
  92. Seshadri T, Campisi J (1990) Repression of c-fos transcription and an altered genetic program in senescent human fibroblasts. Science 247:205–209Google Scholar
  93. Shay JW, Pereira-Smith OM, Wright WE (1991) A role for both Rb and p53 in the regulation of human cellular senescence. Exp Cell Res 196:33–39Google Scholar
  94. Söllner T, Rassow J, Wiedmann M, Schlossmann J, Keil P, Neupert W, Pfanner N (1992) Mapping of the protein import machinery in the mitochondrial outer membrane by crosslinking of translocation intermediates. Nature 355:84–87Google Scholar
  95. Soong NW, Hinton DR, Cortopassi GA, Arnheim N (1992) Mosaicism for a specific somatic mitochondrial DNA mutation in adult human brain. Nature Genet 2:318–323Google Scholar
  96. Stein GH, Beeson M, Gordon I (1990) Failure to phosphorylate the retinoblastoma gene product in senescent human fibroblasts. Science 249:666–669Google Scholar
  97. Strehler BL (1977) Time, cells and aging, 2nd edn. Academic Press, New YorkGoogle Scholar
  98. Suarez BK, Rice JP, Reich T (1978) The generalized sib pair IBD distribution: its use in the detection of linkage. Ann Hum Genet 42:87–94Google Scholar
  99. Takata H, Ishii T, Suzuki M, Sekiguchi S, Iri H (1987) Influence of major histocompatibility complex region genes on human longevity among Okinawan-Japanese centenarians and nonagenarians. Lancet II:824–826Google Scholar
  100. Thomson G (1986) Determining the mode of inheritance of RFLP-associated diseases using the affected sib-pair method. Am J Hum Genet 39:207–221Google Scholar
  101. Tzagoloff A, Myers AM (1986) Genetics of mitochondrial biogenesis. Annu Rev Biochem 55:249–285Google Scholar
  102. Uitterlinden AG, Slagboom PE, Knook DL, Vijg J (1989) Two-dimensional DNA fingerprinting of human individuals. Proc Natl Acad Sci USA 86:2742–2746Google Scholar
  103. Vaziri H, Schächter F, Uchida I, Wei L, Zhu X, Effros R, Cohen D, Harley CB (1993) Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. Am J Hum Genet (in press)Google Scholar
  104. Wallace DC (1992) Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science 256:628–632Google Scholar
  105. Wang E (1989) Stalin, a nonproliferation-specific protein, is associated with the nuclear envelope and is heterogeneously distributed in cells leaving quiescent state. J Cell Physiol 140:418–426Google Scholar
  106. Wange E, Tomaszewski G (1991) Granular presence of terminin is the marker to distinguish between the senescent and quiescent states. J Cell Physiol 147:514–522Google Scholar
  107. Weeks DE, Lange K (1988) The affected-pedigree-member method of linkage analysis. Am J Hum Genet 42:315–326Google Scholar
  108. Weissenbach J, Gyapay G, Dib C, Vignal A, Morisette J, Millaseau P, Vayssex G, Lathrop GM (1992) A second generation linkage map of the human genome. Nature 359:794–801Google Scholar
  109. Wicking C, Williamson B (1991) From linked marker to gene. Trends Genet 7:288–293Google Scholar
  110. Wright RM, Horrum MA, Cummings DJ (1982) Are mitochondrial structural genes selectively amplified during senescence in Podospora anserina? Cell 29:505–515Google Scholar
  111. Wright WE, Pereira-Smith OM, Shay JW (1989) Reversible cellular senescence: implications for immortalization of normal human diploid fibroblasts. Mol Cell Biol 9:3088–3092Google Scholar
  112. Yen Tch, Su JH, King KL, Wei YH (1991) Ageing associated 5 kb deletion in human liver mitochondrial DNA. Biochem Biophys Res Commun 178:124–131Google Scholar
  113. Yuzaki M, Ohkoshi N, Kanazawa L, Kagawa Y, Ohta S (1989) Multiple deletions in mitochondrial DNA at direct repeats of non-D-loop regions in cases of familial mitochondrial myopathy. Biochem Biophys Res Commun 164:1352–1357Google Scholar
  114. Zeviani M, Servidei S, Gellera C, Bertini E, DiMauro S, DiDonato S (1989) An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region. Nature 339:309–311Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • François Schächter
    • 1
  • Daniel Cohen
    • 1
  • Tom Kirkwood
    • 2
  1. 1.Centre d'Etude du Polymorphisme HumainParisFrance
  2. 2.National Institute for Medical ResearchLondonUK

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