Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The quest for genetic determinants of human longevity: challenges and insights

Nature Reviews Genetics volume 7, pages 436–448 (2006)Cite this article

Key Points

  • Twin studies indicate that approximately 25% of the variation in adult lifespan is caused by genetic differences between individuals, and that genetic influences on lifespan are minimal before the age of 60 but increase after this age.

  • Animal models have made fundamental contributions to lifespan research. In addition, genetic insights into disease (in particular for cardiovascular diseases and premature ageing syndromes), the DNA repair and maintenance system and the immune system have suggested a large number of genes as candidates for involvement in the control of human lifespan.

  • Only for one gene, APOE, have findings of common polymorphisms that have a modest effect on lifespan been replicated in several association studies.

  • No rare genetic variants with substantial beneficial effects on lifespan have been identified.

  • Linkage analyses of longevity are hampered by a lack of multi-generational DNA and the aetiological heterogeneity of longevity, but large international collaborations that aim to ascertain exceptionally long-lived families are underway.

  • The lack of replication in genetic association studies of variants that are candidates for influencing lifespan is probably the result of a combination of factors. These include the predicted small effects of the genetic variants, the small sample sizes that are used, a lack of appropriate control groups and publication bias. Large longitudinal studies are less prone to these problems.

  • Large longitudinal association studies and large linkage studies of long-lived families are useful in the difficult task of finding longevity genes. The resulting data should be combined with demographical data and survival analyses. This combined approach should be used to simultaneously analyse all genetic and non-genetic covariates for which data are available, and to control for the effect of unobserved risk factors.

  • Understanding the genetic basis of longevity is a difficult task, but has the potential to provide insights into central ageing and disease mechanisms that could be targets for the prevention and treatment of late-life disabilities and diseases.

Abstract

Twin studies show that genetic differences account for about a quarter of the variance in adult human lifespan. Common polymorphisms that have a modest effect on lifespan have been identified in one gene, APOE, providing hope that other genetic determinants can be uncovered. However, although variants with substantial beneficial effects have been proposed to exist and several candidates have been put forward, their effects have yet to be confirmed. Human studies of longevity face numerous theoretical and logistical challenges, as the determinants of lifespan are extraordinarily complex. However, large-scale linkage studies of long-lived families, longitudinal candidate-gene association studies and the development of analytical methods provide the potential for future progress.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Large variation in lifespan within a birth cohort.
Figure 2: Some of the molecular pathways that lengthen lifespan in Caenorhabditis elegans and the corresponding components in humans.
Figure 3: Epidemiological evidence for a genetic component to variation in human lifespan.
Figure 4: The frequencies of apolipoprotein E alleles vary with age.

Similar content being viewed by others

References

  1. Vaupel J. W. et al. Biodemographic trajectories of longevity. Science 280, 855–860 (1998). Biodemography is a combination of biology and demography; this paper provides important biodemographical insights into the enigma of increasing longevity.

    CAS  PubMed  Google Scholar 

  2. Corder, E. H. et al. Apolipoprotein E genotype determines survival in the oldest old (85 years or older) who have good cognition. Arch. Neurol. 53, 418–422 (1996).

    CAS  PubMed  Google Scholar 

  3. Henderson, S. T., Rea, S. L. & Johnson, T. E. in Handbook of the Biology of Aging 6th edn (eds Austad, S. N. & Masoro, E. J.) 352–391 (Academic Press, New York, 2005).

    Google Scholar 

  4. Kenyon C. The plasticity of aging: insights from long-lived mutants. Cell 120, 449–460 (2005).

    CAS  PubMed  Google Scholar 

  5. Finch, C. E. & Tanzi, R. E. Genetics of aging. Science 278, 407–411 (1997).

    CAS  PubMed  Google Scholar 

  6. Johnson, T. E. Increased lifespan of age-1 mutants in Caenorhabditis elegans and lower Gompertz rate of aging. Science 249, 908–912 (1990).

    CAS  PubMed  Google Scholar 

  7. Johnson, T. E. et al. Relationship between increased longevity and stress resistance as assessed through gerontogene mutations in Caenorhabditis elegans. Exp. Gerontol. 36, 1609–1617 (2001).

    CAS  PubMed  Google Scholar 

  8. Houthoofd, K., Braeckman, B. P., Johnson, T. E. & Vanfleteren, J. R. Extending life-span in C. elegans. Science 305, 1238–1239 (2004). Describes how combining genetic and environmental interventions was used to extend adult C. elegans lifespan almost eightfold: the greatest extension to have been achieved in any organism.

    CAS  PubMed  Google Scholar 

  9. Walker, D. W., McColl, G., Jenkins, N. L., Harris, J. & Lithgow, G. J. Natural selection: evolution of lifespan in C. elegans. Nature 405, 296–297 (2000).

    CAS  PubMed  Google Scholar 

  10. Henderson, S. T. & Johnson, T. E. daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr. Biol. 11, 1975–1980 (2001); erratum in Curr. Biol. 15, 690 (2005).

    CAS  PubMed  Google Scholar 

  11. Herndon, L. A. et al. Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans. Nature 419, 808–814 (2002).

    CAS  PubMed  Google Scholar 

  12. Rea, S., Wu, D., Cypser, J. R., Vaupel, J. W. & Johnson, T. E. A stress-sensitive reporter predicts longevity in isogenic populations of Caenorhabditis elegans. Nature Genet. 37, 894–898 (2005).

    CAS  PubMed  Google Scholar 

  13. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Ogg, S. et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signal in C. elegans. Nature Genet. 389, 994–999 (1997).

    CAS  Google Scholar 

  15. McElwee, J., Bubb, K. & Thomas, J. H. Transcriptional outputs of the Caenorhabditis elegans forkhead protein DAF-16. Aging Cell 2, 111–121 (2003).

    CAS  PubMed  Google Scholar 

  16. Murphy, C. T. et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424, 277–283 (2003).

    CAS  PubMed  Google Scholar 

  17. Tatar, M., Bartke, A. & Antebi, A. The endocrine regulation of aging by insulin-like signals. Science 299, 1346–1351 (2003). Provides an extensive review of the endocrine regulation of ageing by insulin-like signals in mammals and invertebrates.

    CAS  PubMed  Google Scholar 

  18. Rea, S. & Johnson, T. E. A metabolic model for determination of longevity in the nematode Caenorhabditis elegans. Dev. Cell 2, 197–203 (2003).

    Google Scholar 

  19. Ventura, N. et al. Reduced expression of frataxin extends the lifespan of Caenorhabditis elegans. Aging Cell, 4, 109–112 (2005).

    CAS  PubMed  Google Scholar 

  20. Perls, T. T. et al. Siblings of centenarians live longer. Lancet 351, 1560 (1998).

    CAS  PubMed  Google Scholar 

  21. Gudmundsson, G. et al. Inheritance of human longevity in Iceland. Eur. J. Hum. Genet. 8, 743–749 (2000).

    CAS  PubMed  Google Scholar 

  22. Harris, J. R. et al. Age differences in genetic and environmental influences for health from the Swedish adoption/twin study of aging. J. Gerontol. 47, P213–P220 (1992).

    CAS  PubMed  Google Scholar 

  23. Charlesworth, B. Optimization models, quantitative genetics, and mutation. Evolution 44, 520–538 (1990).

    PubMed  Google Scholar 

  24. Partridge, L. & Gems, D. Mechanisms of ageing: public or private? Nature Rev. Genet. 3, 165–175 (2002). This paper updates the evolutionary theory of ageing, explaining why certain previous predictions from evolutionary studies (for example, lack of single-gene longevity mutants) are not contradictory to evolutionary theory.

    CAS  PubMed  Google Scholar 

  25. Iachine, I. A. et al. How heritable is individual susceptibility to death? The results of an analysis of survival data on Danish, Swedish and Finnish twins. Twin Res. 1, 196–205 (1998).

    CAS  PubMed  Google Scholar 

  26. Vaupel, J. W., Manton, K. G. & Stallard, E. The impact of heterogeneity in individual frailty on the dynamics of mortality. Demography 16, 439–454 (1979).

    CAS  PubMed  Google Scholar 

  27. 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).

    CAS  PubMed  Google Scholar 

  28. Skytthe, A. et al. Longevity studies in GenomEUtwin. Twin Res. 6, 448–454 (2003).

    PubMed  Google Scholar 

  29. Hjelmborg, J. V. et al. Genetic influence on human lifespan and longevity. Human Genet. 119, 312–321 (2006). An international twin study showing that genetic influences on lifespan are minimal before the age of 60, but then increase after this age.

    Google Scholar 

  30. Sorensen, T. I. et al. Genetic and environmental influences on premature death in adult adoptees. N. Engl. J. Med. 318, 727–732 (1988).

    CAS  PubMed  Google Scholar 

  31. Petersen, L., Andersen, P. K. & Sorensen, T. I. Premature death of adult adoptees: analyses of a case–cohort sample. Genet. Epidemiol. 28, 376–382 (2005).

    PubMed  Google Scholar 

  32. Perls, T. T. et al. Life-long sustained mortality advantage of siblings of centenarians. Proc. Natl Acad. Sci. USA 99, 8442–8447 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Kerber, R. A. et al. Familial excess longevity in Utah genealogies. J. Gerontol. A 56, B130–B139 (2001).

  34. Schoenmaker, M. et al. Evidence of genetic enrichment for exceptional survival using a family approach: the Leiden Longevity Study. Eur. J. Hum. Genet. 14, 79–84 (2005).

    Google Scholar 

  35. Yu, C. E. et al. Positional cloning of the Werner's syndrome gene. Science 272, 258–262 (1996).

    CAS  PubMed  Google Scholar 

  36. Kipling, D. et al. What can progeroid syndromes tell us about human aging? Science. 305, 1426–1431 (2004). The authors summarize the strengths and weaknesses of the premature ageing syndromes as models for human ageing.

    CAS  PubMed  Google Scholar 

  37. Eriksson, M. et al. Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome. Nature 423, 293–298 (2003).

    CAS  PubMed  Google Scholar 

  38. Andersen-Ranberg, K. et al. Healthy centenarians do not exist, but autonomous centenarians do: a population-based study of morbidity among Danish Centenarians. J. Am. Geriatr. Soc. 49, 900–908 (2001). Demonstrates that centenarians are generally not free of diseases, as non-population-based studies have suggested.

    CAS  PubMed  Google Scholar 

  39. Hitt, R. et al. Centenarians: the older you get, the healthier you have been. Lancet 354, 652 (1999).

    CAS  PubMed  Google Scholar 

  40. Berzlanovich, A. M. et al. Do centenarians die healthy? An autopsy study. J. Gerontol. A 60, 862–865 (2005).

    Google Scholar 

  41. Risch, N. & Merikangas, K. The future of genetic studies of complex human diseases. Science 273, 1516–1517 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Tan, Q. et al. Power of non-parametric linkage analysis in mapping genes contributing to human longevity in long-lived sib-pairs. Genet. Epidemiol. 26, 245–253 (2004).

    PubMed  Google Scholar 

  43. Tan, Q., Kruse, T. A. & Christensen, K. Design and analysis in genetic studies of human ageing and longevity. Ageing Res. Rev. 5 Dec 2005 [Epub ahead of print].

  44. Puca, A. A. et al. A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4. Proc. Natl Acad. Sci. USA 98, 10505–10508 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Geesaman, B. J. et al. Haplotype-based identification of a microsomal transfer protein marker associated with the human lifespan. Proc. Natl Acad. Sci. USA 100, 14115–14120 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Lewis, S. J. & Brunner, E. J. Methodological problems in genetic association studies of longevity — the apolipoprotein E gene as an example. Int. J. Epidemiol. 33, 962–970 (2004). Covers the caveats and potential biases in genetic association studies of longevity.

    PubMed  Google Scholar 

  47. Ioannidis, J. P. Genetic associations: false or true? Trends Mol. Med. 9, 135–138 (2003).

    PubMed  Google Scholar 

  48. Nybo, H. et al. Predictors of mortality in 2,249 nonagenarians — the Danish 1905-cohort survey. J. Am. Geriatr. Soc. 51, 1365–1373 (2003).

    PubMed  Google Scholar 

  49. Finch, C. E. & Crimmins, E. M. Inflammatory exposure and historical changes in human life-spans. Science 305, 1736–1739 (2004).

    CAS  PubMed  Google Scholar 

  50. Francheschi, C. et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. NY Acad. Sci. 908, 244–254 (2000).

    Google Scholar 

  51. Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921–923 (1993).

    CAS  PubMed  Google Scholar 

  52. Panza, F. et al. Vascular genetic factors and human longevity. Mech. Ageing Dev. 125, 169–178 (2004).

    CAS  PubMed  Google Scholar 

  53. Jordan, B. D. et al. Apolipoprotein E ɛ4 associated with chronic traumatic brain injury in boxing. JAMA 278, 136–140 (1997).

    CAS  PubMed  Google Scholar 

  54. Haan, M. N., Shemanski, L., Jagust, W. J., Manolio, T. A. & Kuller, L. The role of APOE ε4 in modulating effects of other risk factors for cognitive decline in elderly persons. JAMA 282, 40–46 (1999).

    CAS  PubMed  Google Scholar 

  55. Gerdes, L. U. et al. Estimation of apolipoprotein E genotype-specific relative mortality risks from the distribution of genotypes in centenarians and middle-aged men: apolipoprotein E gene is a 'frailty gene,' not a 'longevity gene'. Genet. Epidemiol. 19, 202–210 (2000).

    CAS  PubMed  Google Scholar 

  56. Bathum, L. et al. Apolipoprotein E genotypes: relationship to cognitive functioning, cognitive decline, and survival in nonagenarians. J. Am. Geriatr. Soc. 54, 654–658 (2006).

    PubMed  Google Scholar 

  57. Atzmon, G. et al. Lipoprotein genotype and conserved pathway for exceptional longevity in humans. PLoS Biol. 4, e113 (2006).

    PubMed  PubMed Central  Google Scholar 

  58. Nebel, A. et al. No association between microsomal triglyceride transfer protein (MTP) haplotype and longevity in humans. Proc. Natl Acad. Sci. USA 102, 7906–7909 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Bathum, L. et al. No evidence for an association between extreme longevity and microsomal transfer protein polymorphisms in a longitudinal study of 1651 nonagenarians. Eur. J. Hum. Genet. 13, 1154–1158 (2005).

    CAS  PubMed  Google Scholar 

  60. Kritchevsky, S. B. et al. Angiotensin-converting enzyme insertion/deletion genotype, exercise, and physical decline. JAMA 294, 691–698 (2005).

    CAS  PubMed  Google Scholar 

  61. Luft, F. C. Bad genes, good people, association, linkage, longevity and the prevention of cardiovascular disease. Clin. Exp. Pharmacol. Physiol 26, 576–579 (1999).

    CAS  PubMed  Google Scholar 

  62. Frederiksen, H. et al. Angiotensin I-converting enzyme (ACE) gene polymorphism in relation to physical performance, cognition and survival-a follow-up study of elderly Danish twins. Ann. Epidemiol. 13, 57–65 (2003).

    PubMed  Google Scholar 

  63. Bladbjerg, E. M. et al. Longevity is independent of common variations in genes associated with cardiovascular risk. Thromb. Haemost. 82, 1100–1105 (1999).

    CAS  PubMed  Google Scholar 

  64. Blanche, H., Cabanne, L., Sahbatou, M. & Thomas, G. A study of French centenarians: are ACE and APOE associated with longevity? C. R. Acad. Sci. III 324, 129–135 (2001).

    CAS  PubMed  Google Scholar 

  65. Bonafe, M. et al. Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity: cues for an evolutionarily conserved mechanism of lifespan control. J. Clin. Endocrinol. Metab. 88, 3299–3304 (2003).

    CAS  PubMed  Google Scholar 

  66. van Heemst, D. et al. Reduced insulin/IGF-1 signalling and human longevity. Aging Cell 4, 79–85 (2005).

    CAS  PubMed  Google Scholar 

  67. Bathum, L. et al. Association of mutations in the hemochromatosis gene with shorter life expectancy. Arch. Intern. Med. 16, 2441–2444 (2001).

    Google Scholar 

  68. Beutler, E. et al. Penetrance of 845G>A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 359, 211–218 (2002).

    PubMed  Google Scholar 

  69. Coppin, H. et al. Longevity and carrying the C282Y mutation for haemochromatosis on the HFE gene: case control study of 492 French centenarians. BMJ 327, 132–133 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Delatycki, M. B. et al. Use of community genetic screening to prevent HFE-associated hereditary haemochromatosis. Lancet 366, 314–316 (2005).

    CAS  PubMed  Google Scholar 

  71. Bruunsgaard, H., Pedersen, M. & Pedersen, B. K. Aging and proinflammatory cytokines. Curr. Opin. Hematol. 8, 131–136 (2001).

    CAS  PubMed  Google Scholar 

  72. Harris, T. B. et al. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am. J. Med. 106, 506–512 (1999).

    CAS  PubMed  Google Scholar 

  73. Ershler, W. B. & Keller, E. T. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu. Rev. Med. 51, 245–270 (2000).

    CAS  PubMed  Google Scholar 

  74. Cohen, H. J., Pieper, C. F., Harris, T., Rao, K. M. & Currie, M. S. The association of plasma IL-6 levels with functional disability in community-dwelling elderly. J. Gerontol. A 52, M201–M208 (1997).

    CAS  Google Scholar 

  75. De Maat, M. P. et al. Genetic influence on inflammation variables in the elderly. Arterioscler. Thromb. Vasc. Biol. 24, 2168–2173 (2004).

    CAS  PubMed  Google Scholar 

  76. De Craen, A. J. et al. Heritability estimates of innate immunity: an extended twin study. Genes Immun. 6, 167–170 (2005).

    CAS  PubMed  Google Scholar 

  77. Nauck, M. et al. The interleukin-6 G(–174)C promoter polymorphism in the LURIC cohort: no association with plasma interleukin-6, coronary artery disease, and myocardial infarction. J. Mol. Med. 80, 507–513 (2002).

    CAS  PubMed  Google Scholar 

  78. Humphries, S. E., Luong, L. A., Ogg, M. S., Hawe, E. & Miller, G. J. The interleukin-6 –174 G/C promoter polymorphism is associated with risk of coronary heart disease and systolic blood pressure in healthy men. Eur. Heart J. 22, 2243–2252 (2001).

    CAS  PubMed  Google Scholar 

  79. Christiansen, L. et al. Modest implication of interleukin-6 promoter polymorphisms in longevity. Mech. Ageing Dev. 125, 391–395 (2004).

    CAS  PubMed  Google Scholar 

  80. Hurme, M., Lehtimaki, T., Jylha, M., Karhunen, P. J. & Hervonen, A. Interleukin-6 –174G/C polymorphism and longevity: a follow-up study. Mech. Ageing Dev. 26, 417–418 (2005).

    Google Scholar 

  81. Tanaka, M., Gong, J. S., Zhang, J., Yoneda, M. & Yagi, K. Mitochondrial genotype associated with longevity. Lancet 351, 185–186 (1998).

    CAS  PubMed  Google Scholar 

  82. Zhang, J. et al. Striking higher frequency in centenarians and twins of mtDNA mutation causing remodeling of replication origin in leukocytes. Proc. Natl Acad. Sci. USA 100, 1116–1121 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. De Benedictis, G. et al. Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans. FASEB J. 13, 1532–1536 (1999).

    CAS  PubMed  Google Scholar 

  84. Dato, S. et al. Association of the mitochondrial DNA haplogroup J with longevity is population specific. Eur. J. Hum. Genet. 12, 1080–1082 (2004).

    CAS  PubMed  Google Scholar 

  85. Opresko P. L. et al. The Werner syndrome helicase and exonuclease cooperate to resolve telomeric D loops in a manner regulated by TRF1 and TRF2. Mol. Cell 14, 763–774 (2004).

    CAS  PubMed  Google Scholar 

  86. Castro, E. et al. Polymorphisms at the Werner locus: I. Newly identified polymorphisms, ethnic variability of 1367Cys/Arg, and its stability in a population of Finnish centenarians. Am. J. Med. Genet. 82, 399–403 (1999).

    CAS  PubMed  Google Scholar 

  87. Bohr, V. A. et al. Werner syndrome protein 1367 variants and disposition towards coronary artery disease in Caucasian patients. Mech. Ageing Dev. 125, 491–496 (2004).

    CAS  PubMed  Google Scholar 

  88. Morita, H. et al. A polymorphic variant C1367R of the Werner helicase gene and atherosclerotic diseases in the Japanase population. Thromb. Haemost. 82, 160–161 (1999).

    CAS  PubMed  Google Scholar 

  89. Castro, E. et al. Polymorphisms at the Werner locus: II. 1074Leu/Phe, 1367Cys/Arg, longevity, and atherosclerosis. Am. J. Med. Genet. 95, 374–380 (2000).

    CAS  PubMed  Google Scholar 

  90. Kuningas, M. et al. Impact of genetic variations in the WRN gene on age related pathologies and mortality. Mech. Ageing Dev. 127, 307–313 (2006).

    CAS  PubMed  Google Scholar 

  91. Cherif, H., Tarry, J. L., Ozanne, S. E. & Hales, C. N. Ageing and telomeres: a study into organ- and gender-specific telomere shortening. Nucleic Acids Res. 31, 1576–1583 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Joeng, K. S. et al. Long lifespan in worms with long telomeric DNA. Nature Genet. 36, 607–611 (2004).

    CAS  PubMed  Google Scholar 

  93. Blasco, M. A. et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997).

    CAS  PubMed  Google Scholar 

  94. Cawthon, R. M., Smith, K. R., O'Brien, E., Sivatchenko, A. & Kerber, R. A. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 361, 393–395 (2003).

    CAS  PubMed  Google Scholar 

  95. Martin-Ruiz, C. M. et al. Telomere length in white blood cells is not associated with morbidity or mortality in the oldest old: a population-based study. Aging Cell 4, 287–290 (2005).

    CAS  PubMed  Google Scholar 

  96. Bischoff, C. et al. No association between telomere length and survival among the elderly and oldest old. Epidemiology 17, 190–194 (2006).

    PubMed  Google Scholar 

  97. Jeune, B. & Vaupel, J. W. (eds) Validation of Exceptional Longevity. Odense Monographs on Population Aging No. 6 (Odense Univ. Press, 1999).

    Google Scholar 

  98. Yashin, A. I. et al. Genes, demography, and lifespan: the contribution of demographic data in genetic studies on aging and longevity. Am. J. Hum. Genet. 65, 1178–1193 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Yashin, A. I. et al. Genes and longevity: lessons from studies of centenarians. J. Gerontol. A 55, B319–B328 (2000).

  100. Vaupel, J. W. & Yashin, A. I. in Demography: Analysis and Synthesis; a Treatise in Population Studies Vol. 1 (eds Caselli, G., Vallin, J. & Wunsch, G.) 271–277 (Academic Press, London, 2006). This is a concise, accessible review of approaches for dealing with unobserved heterogeneity.

    Google Scholar 

  101. Vaupel, J. W. & Yashin, A. I. Heterogeneity's ruses: some surprising effects of selection on population dynamics. Am. Stat. 39, 176–185 (1985). This is the best elementary introduction to the problems of unobserved heterogeneity.

    CAS  PubMed  Google Scholar 

  102. Johnson, T. E. et al. Longevity genes in the nematode Caenorhabditis elegans also mediate increased resistance to stress and prevent disease. J. Inherit. Metab. Dis. 25, 197–206 (2002).

    CAS  PubMed  Google Scholar 

  103. Johnson, T. E. & Wood, W. B. Genetic analysis of life-span in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 79, 6603–6607 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Reed, T. et al. Genome-wide scan for a healthy aging phenotype provides support for a locus near D4S1564 promoting healthy aging. J. Gerontol. A 59, 227–232 (2004).

    Google Scholar 

  105. Barzilai, N. et al. Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA 290, 2030–2040 (2003).

    CAS  PubMed  Google Scholar 

  106. Cellini, E. et al. Cholesteryl ester transfer protein (CETP) I405V polymorphism and longevity in Italian centenarians. Mech. Ageing Dev. 126, 826–828 (2005).

    CAS  PubMed  Google Scholar 

  107. Christiansen, L. et al. The catalase –262C/T promoter polymorphism and aging phenotypes. J. Gerontol A 59, B886–B889 (2004).

    Google Scholar 

  108. Altomare, K. et al. The allele (A)−110 in the promoter region of the HSP70-1 gene is unfavorable to longevity in women. Biogerontology 4, 215–220 (2003).

    CAS  PubMed  Google Scholar 

  109. Ross, O. A. et al. Increased frequency of the 2437T allele of the heat shock protein 70-Hom gene in an aged Irish population. Exp. Gerontol. 38, 561–565 (2003).

    CAS  PubMed  Google Scholar 

  110. Christiansen, L., Bathum, L., Frederiksen, H. & Christensen, K. Paraoxonase 1 polymorphisms and survival. Eur. J. Hum. Genet 12, 843–847 (2004).

    CAS  PubMed  Google Scholar 

  111. Rea, I. M. et al. Paraoxonase polymorphisms PON1 192 and 55 and longevity in Italian centenarians and Irish nonagenarians. A pooled analysis. Exp. Gerontol. 39, 629–635 (2004).

    CAS  PubMed  Google Scholar 

  112. Carru, C. et al. Association between the HFE mutations and longevity: a study in Sardinian population. Mech. Ageing. Dev. 124, 529–532 (2003).

    CAS  PubMed  Google Scholar 

  113. Todesco, L. et al. Methylenetetrahydrofolate reductase polymorphism, plasma homocysteine and age. Eur. J. Clin. Invest 29, 1003–1009 (1999).

    CAS  PubMed  Google Scholar 

  114. Kluijtmans, L. A. & Whitehead, A. S. Reduced frequency of the thermolabile methylenetetrahydrofolate reductase genotype in the elderly. Atherosclerosis 146, 395–397 (1999).

    CAS  PubMed  Google Scholar 

  115. Stessman, J. et al. Candidate genes associated with ageing and life expectancy in the Jerusalem longitudinal study. Mech. Ageing. Dev. 26, 333–339 (2005).

    Google Scholar 

  116. Bellizzi, D. et al. A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages. Genomics 85, 258–263 (2005).

    CAS  PubMed  Google Scholar 

  117. Rose, G. et al. Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly. Exp. Gerontol. 38, 1065–1070 (2003).

    CAS  PubMed  Google Scholar 

  118. Bonafe, M. et al. P53 codon 72 polymorphism and longevity: additional data on centenarians from continental Italy and Sardinia. Am. J. Hum. Genet. 65, 1782–1785 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Carrieri, G. et al. The G/C915 polymorphism of transforming growth factor β1 is associated with human longevity: a study in Italian centenarians. Aging Cell 3, 443–448 (2004).

    CAS  PubMed  Google Scholar 

  120. Arking, D. E. et al. Association of human aging with a functional variant of klotho. Proc. Natl Acad. Sci. USA 99, 856–861 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Arking, D. E. et al. Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity. Circ. Res. 4, 412–418 (2005).

    Google Scholar 

  122. Castro, E. et al. Polymorphisms at the Werner locus: II. 1074Leu/Phe, 1367Cys/Arg, longevity, and atherosclerosis. Am. J. Med. Genet. 95, 374–380 (2000).

    CAS  PubMed  Google Scholar 

  123. Kim, D. J. et al. Association between the MLH1 gene and longevity. Hum. Genet. 119, 353–354 (2006).

    PubMed  Google Scholar 

Download references

Acknowledgements

We thank L. Bathum, V.A. Bohr, L. Christiansen, M. McGue, and J.C. Murray for valuable suggestions and comments. This work was supported by the US National Institute on Aging, the Long Life Family Study, GenomEUtwin, and Genetics of Healthy Ageing.

Author information

Authors and Affiliations

  1. Epidemiology, Institute of Public Health, University of Southern Denmark, J.B. Winslows Vej 9B, Odense C, 5000, Denmark

    Kaare Christensen

  2. Department of Integrative Physiology, Institute for Behavioral Genetics, University of Colorado, Boulder, 80309-0447, Colorado, USA

    Thomas E. Johnson

  3. Max Planck Institute for Demographic Research, Konrad-Zuse-Strasse, Rostock, 18057, Germany

    James W. Vaupel

Authors
  1. Kaare Christensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas E. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James W. Vaupel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kaare Christensen.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

OMIM

Alzheimer disease

haemochromatosis

Hutchinson–Gilford disease

Werner syndrome

FURTHER INFORMATION

Genetics of Healthy Ageing (GEHA) project web site

GenomEUtwin

Long Life Family Study

Science of Aging Knowledge Environment

The Human Mortality Database

Glossary

Cohort

A designated group of individuals who are studied over a time period.

Pleiotropy

The action of a single gene on two or more distinct phenotypic characters.

Recurrence risk

The likelihood that a given condition that is diagnosed in one or more family members will recur in other family members or in subsequent generations.

Proband

A subject who is ascertained on the basis of their phenotype; probands are often used to identify affected families for genetic studies.

Segmental progeroid syndromes

Syndromes that mimic normal ageing and affect multiple organs and tissues.

Linkage analysis

Mapping genes by typing genetic markers in families to identify chromosome regions that are associated with disease or trait values within pedigrees more often than are expected by chance. Such linked regions are more likely to contain a causal genetic variant than other genomic regions.

Non-parametric analysis

Non-parametric approaches are statistical procedures that are not based on models or assumptions pertaining to the distribution of the quantitative trait.

Association studies

Studies in which a genetic variant is genotyped in a population for which phenotypic information is available (such as disease occurrence, or a range of different trait values). If a correlation is observed between genotype and phenotype, there is said to be an association between the variant and the disease or trait.

Haplotype

An experimentally determined profile of genetic markers that are present on a single chromosome of a given individual.

Phlebotomy

A procedure that involves puncturing a vein to withdraw blood.

Genome-wide association studies

Association studies in which variants across the entire genome are tested for association with a trait of interest. To reduce the amount of genoptying, such studies generally make use of proxy markers (usually SNPs), which, by virtue of falling into blocks of linkage disequilibrium, also provide information about other variants.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Christensen, K., Johnson, T. & Vaupel, J. The quest for genetic determinants of human longevity: challenges and insights. Nat Rev Genet 7, 436–448 (2006). https://doi.org/10.1038/nrg1871

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg1871

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing