Skip to main content

Genetics of Human Longevity and Healthy Aging

  • Chapter
  • First Online:
The Epidemiology of Aging

Abstract

Genetic factors contribute to human aging and longevity through the modulation of biologic pathways, but few longevity-gene associations have been replicated to date. Participants in prospective epidemiologic studies provide an opportunity to investigate the genetics of many age-related phenotypes, but large discovery and replication samples are needed for genetic discovery. Today’s genome-wide genotyping of centenarians and participants in longitudinal cohort-based and family-based studies provide the opportunity to assemble these large samples, as does today’s unprecedented collaboration among investigators in the United States, Europe and around the world. This collaboration will make it necessary to standardize the definitions of aging phenotypes, and to assess potential sources of bias and confounding when planning a study and interpreting results. To date, the vast majority of genetic association studies have used populations of European descent. It is essential that in the future, such studies examine other worldwide populations to determine whether gene and allelic effects are heterogeneous across various genetic and environmental backgrounds. The collaboration of international scientists may aid in the translation of genetic associations, and thus uncover the functions of gene variants in the biologic mechanisms that lead to human aging.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 229.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 299.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 299.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Kenyon CJ (2010) The genetics of ageing. Nature 464(7288):504–512

    Article  PubMed  CAS  Google Scholar 

  2. Liu T, Johnson JA, Casella G et al (2004) Sequencing complex diseases with HapMap. Genetics 168(1):503–511

    Article  PubMed  CAS  Google Scholar 

  3. National Institute on Aging (2009) NIA panel on the characterization of participants in studies of exceptional survival in humans. US National Institutes of Health: National Institute of Aging. Web site http://www.nia.nih.gov/about/events/2011/nia-panel-characterization-participants-studies-exceptional-survival-humans. Accessed 30 Mar 2012

  4. Newman AB, Glynn NW, Taylor CA et al (2011) Health and function of participants in the Long Life Family Study: a comparison with other cohorts. Aging (Albany NY) 3(1):63–76

    Google Scholar 

  5. Fried LP, Borhani NO, Enright P et al (1991) The Cardiovascular Health Study: design and rationale. Ann Epidemiol 1(3):263–276

    Article  PubMed  CAS  Google Scholar 

  6. Schoenmaker M, de Craen AJ, de Meijer PH et al (2006) Evidence of genetic enrichment for exceptional survival using a family approach: the Leiden Longevity Study. Eur J Hum Genet 14(1):79–84

    PubMed  Google Scholar 

  7. Westendorp RG, van Heemst D, Rozing MP et al (2009) Nonagenarian siblings and their offspring display lower risk of mortality and morbidity than sporadic nonagenarians: the Leiden Longevity Study. J Am Geriatr Soc 57(9):1634–1637

    Article  PubMed  Google Scholar 

  8. Rozing MP, Houwing-Duistermaat JJ, Slagboom PE et al (2010) Familial longevity is associated with decreased thyroid function. J Clin Endocrinol Metab 95(11):4979–4984

    Article  PubMed  CAS  Google Scholar 

  9. Rozing MP, Westendorp RG, de Craen AJ et al (2010) Favorable glucose tolerance and lower prevalence of metabolic syndrome in offspring without diabetes mellitus of nonagenarian siblings: the Leiden longevity study. J Am Geriatr Soc 58(3):564–569

    Article  PubMed  Google Scholar 

  10. Stover PJ, Harlan WR, Hammond JA et al (2010) A toolkit for interdisciplinary genetics research. Curr Opin Lipidol 21(2):136–140

    Article  PubMed  CAS  Google Scholar 

  11. Federal Interagency Forum on Aging-Related Statistics (2008) Older Americans 2008: key indicators of well-being. U.S. Government Printing Office, Washington, DC

    Google Scholar 

  12. Xu J, Kochanek KD, Tejada-Vera B (2009) Deaths: preliminary data for 2007. National vital statistics reports, vol 58, no 1. National Center for Health Statistics, Hyattsville

    Google Scholar 

  13. Kestenbaum B, Ferguson BR (2005) Number of centenarians in the United States Jan 1, 1990, Jan 1 2000, and Jan 1 2010 based on improved medical data. Society of Actuaries. Web site http://www.soa.org/library/monographs/retirement-systems/living-to-100-and-beyond/2005/january/m-li05-1-xxvi.pdf. Accessed 8 Mar 2011

  14. Krach CA, Velkoff VA (1999) Centenarians in the United States. U.S. Bureau of the census, Current population reports, series P23-199RV. U.S. Government Printing Office, Washington, DC

    Google Scholar 

  15. Evert J, Lawler E, Bogan H et al (2003) Morbidity profiles of centenarians: survivors, delayers, and escapers. J Gerontol A Biol Sci Med Sci 58(3):232–237

    Article  PubMed  Google Scholar 

  16. Terry DF, Wilcox M, McCormick MA et al (2003) Cardiovascular advantages among the offspring of centenarians. J Gerontol A Biol Sci Med Sci 58(5):M425–M431

    Article  PubMed  Google Scholar 

  17. Atzmon G, Schechter C, Greiner W et al (2004) Clinical phenotype of families with longevity. J Am Geriatr Soc 52(2):274–277

    Article  PubMed  Google Scholar 

  18. Willcox BJ, He Q, Chen R et al (2006) Midlife risk factors and healthy survival in men. JAMA 296(19):2343–2350

    Article  PubMed  CAS  Google Scholar 

  19. Reed DM, Foley DJ, White LR et al (1998) Predictors of healthy aging in men with high life expectancies. Am J Public Health 88(10):1463–1468

    Article  PubMed  CAS  Google Scholar 

  20. Fried LP, Tangen CM, Walston J et al (2001) Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 56(3):M146–M156

    Article  PubMed  CAS  Google Scholar 

  21. Bandeen-Roche K, Xue QL, Ferrucci L et al (2006) Phenotype of frailty: characterization in the women’s health and aging studies. J Gerontol A Biol Sci Med Sci 61(3):262–266

    Article  PubMed  Google Scholar 

  22. Carmelli D, Kelly-Hayes M, Wolf PA et al (2000) The contribution of genetic influences to measures of lower-extremity function in older male twins. J Gerontol A Biol Sci Med Sci 55(1):B49–B53

    Article  PubMed  CAS  Google Scholar 

  23. Frederiksen H, Gaist D, Petersen HC et al (2002) Hand grip strength: a phenotype suitable for identifying genetic variants affecting mid- and late-life physical functioning. Genet Epidemiol 23(2):110–122

    Article  PubMed  Google Scholar 

  24. Karasik D, Hannan MT, Cupples LA et al (2004) Genetic contribution to biological aging: the Framingham Study. J Gerontol A Biol Sci Med Sci 59(3):218–226

    Article  PubMed  Google Scholar 

  25. Cauley JA, Lui LY, Barnes D et al (2009) Successful skeletal aging: a marker of low fracture risk and longevity. The Study of Osteoporotic Fractures (SOF). J Bone Miner Res 24(1):134–143

    Article  PubMed  Google Scholar 

  26. Yaffe K, Lindquist K, Vittinghoff E et al (2010) The effect of maintaining cognition on risk of disability and death. J Am Geriatr Soc 58(5):889–894

    Article  PubMed  Google Scholar 

  27. Newman AB, Boudreau RM, Naydeck BL et al (2008) A physiologic index of comorbidity: relationship to mortality and disability. J Gerontol A Biol Sci Med Sci 63(6):603–609

    Article  PubMed  Google Scholar 

  28. Matteini AM, Fallin MD, Kammerer CM et al (2010) Heritability estimates of endophenotypes of long and health life: the Long Life Family Study. J Gerontol A Biol Sci Med Sci 65(12):1375–1379

    Article  PubMed  Google Scholar 

  29. Kerber RA, O’Brien E, Smith KR et al (2001) Familial excess longevity in Utah genealogies. J Gerontol A Biol Sci Med Sci 56(3):B130–B139

    Article  PubMed  CAS  Google Scholar 

  30. Barzilai N, Gabriely I (2010) Genetic studies reveal the role of the endocrine and metabolic systems in aging. J Clin Endocrinol Metab 95(10):4493–4500

    Article  PubMed  CAS  Google Scholar 

  31. Christensen K, Frederiksen H, Vaupel JW et al (2003) Age trajectories of genetic variance in physical functioning: a longitudinal study of Danish twins aged 70 years and older. Behav Genet 33(2):125–136

    Article  PubMed  Google Scholar 

  32. Penrose LS (1953) The genetical background of common diseases. Acta Genet Stat Med 4(2–3):257–265

    PubMed  CAS  Google Scholar 

  33. Guo SW (1998) Inflation of sibling recurrence-risk ratio, due to ascertainment bias and/or overreporting. Am J Hum Genet 63(1):252–258

    Article  PubMed  CAS  Google Scholar 

  34. Perls TT, Bubrick E, Wager CG et al (1998) Siblings of centenarians live longer. Lancet 351(9115):1560

    Article  PubMed  CAS  Google Scholar 

  35. Perls TT, Wilmoth J, Levenson R et al (2002) Life-long sustained mortality advantage of siblings of centenarians. Proc Natl Acad Sci U S A 99(12):8442–8447

    Article  PubMed  CAS  Google Scholar 

  36. Willcox BJ, Willcox DC, He Q et al (2006) Siblings of okinawan centenarians share lifelong mortality advantages. J Gerontol A Biol Sci Med Sci 61(4):345–354

    Article  PubMed  Google Scholar 

  37. Hjelmborg JV, Iachine I, Skytthe A et al (2006) Genetic influence on human lifespan and longevity. Hum Genet 119(3):312–321

    Article  Google Scholar 

  38. McGue M, Vaupel JW, Holm N et al (1993) Longevity is moderately heritable in a sample of Danish twins born 1870–1880. J Gerontol 48(6):B237–B244

    Article  PubMed  CAS  Google Scholar 

  39. Herskind AM, McGue M, Holm NV et al (1996) The heritability of human longevity: a population-based study of 2872 Danish twin pairs born 1870–1900. Hum Genet 97(3):319–323

    Article  PubMed  CAS  Google Scholar 

  40. Iachine IA, Holm NV, Harris JR et al (1998) How heritable is individual susceptibility to death? the results of an analysis of survival data on Danish, Swedish and Finnish twins. Twin Res 1(4):196–205

    PubMed  CAS  Google Scholar 

  41. Mitchell BD, Hsueh WC, King TM et al (2001) Heritability of life span in the Old Order Amish. Am J Med Genet 102(4):346–352

    Article  PubMed  CAS  Google Scholar 

  42. Reed T, Dick DM (2003) Heritability and validity of healthy physical aging (wellness) in elderly male twins. Twin Res 6(3):227–234

    PubMed  Google Scholar 

  43. Almasy L, Blangero J (1998) Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 62(5):1198–1211

    Article  PubMed  CAS  Google Scholar 

  44. Franceschi C, Motta L, Valensin S et al (2000) Do men and women follow different trajectories to reach extreme longevity? Italian Multicenter Study on Centenarians (IMUSCE). Aging (Milano) 12(2):77–84

    CAS  Google Scholar 

  45. Lee JH, Flaquer A, Costa R et al (2004) Genetic influences on life span and survival among elderly African-Americans, Caribbean Hispanics, and Caucasians. Am J Med Genet A 128(2):159–164

    Article  Google Scholar 

  46. Murabito JM, Yang Q, Fox C et al (2005) Heritability of age at natural menopause in the Framingham Heart Study. J Clin Endocrinol Metab 90(6):3427–3430

    Article  PubMed  CAS  Google Scholar 

  47. Towne B, Czerwinski SA, Demerath EW et al (2005) Heritability of age at menarche in girls from the Fels Longitudinal Study. Am J Phys Anthropol 128(1):210–219

    Article  PubMed  Google Scholar 

  48. Karasik D, Cupples LA, Hannan MT et al (2003) Age, gender, and body mass effects on quantitative trait loci for bone mineral density: the Framingham Study. Bone 33(3):308–316

    Article  PubMed  CAS  Google Scholar 

  49. Gatz M, Reynolds CA, Fratiglioni L et al (2006) Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 63(2):168–174

    Article  PubMed  Google Scholar 

  50. Eriksson M, Brown WT, Gordon LB et al (2003) Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423(6937):293–298

    Article  PubMed  CAS  Google Scholar 

  51. Merideth MA, Gordon LB, Clauss S et al (2008) Phenotype and course of Hutchinson-Gilford progeria syndrome. N Engl J Med 358(6):592–604

    Article  PubMed  CAS  Google Scholar 

  52. Olive M, Harten I, Mitchell R et al (2010) Cardiovascular pathology in Hutchinson-Gilford Progeria: correlation with the vascular pathology of aging. Arterioscler Thromb Vasc Biol 30(11):2301–2309

    Article  PubMed  CAS  Google Scholar 

  53. Burtner CR, Kennedy BK (2010) Progeria syndromes and ageing: what is the connection? Nat Rev Mol Cell Biol 11(8):567–578

    Article  PubMed  CAS  Google Scholar 

  54. Puca AA, Daly MJ, Brewster SJ et al (2001) A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4. Proc Natl Acad Sci U S A 98(18):10505–10508

    Article  PubMed  CAS  Google Scholar 

  55. Reed T, Dick DM, Uniacke SK et al (2004) Genome-wide scan for a healthy aging phenotype provides support for a locus near D4S1564 promoting healthy aging. J Gerontol A Biol Sci Med Sci 59(3):227–232

    Article  PubMed  Google Scholar 

  56. Geesaman BJ, Benson E, Brewster SJ et al (2003) Haplotype-based identification of a microsomal transfer protein marker associated with the human lifespan. Proc Natl Acad Sci U S A 100(24):14115–14120

    Article  PubMed  CAS  Google Scholar 

  57. Nebel A, Croucher PJ, Stiegeler R et al (2005) No association between microsomal triglyceride transfer protein (MTP) haplotype and longevity in humans. Proc Natl Acad Sci U S A 102(22):7906–7909

    Article  PubMed  CAS  Google Scholar 

  58. Beekman M, Blauw GJ, Houwing-Duistermaat JJ et al (2006) Chromosome 4q25, microsomal transfer protein gene, and human longevity: novel data and a meta-analysis of association studies. J Gerontol A Biol Sci Med Sci 61(4):355–362

    Article  PubMed  Google Scholar 

  59. Bathum L, Christiansen L, Tan Q et al (2005) 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(10):1154–1158

    Article  PubMed  CAS  Google Scholar 

  60. Franceschi C, Bezrukov V, Blanche H et al (2007) Genetics of healthy aging in Europe: the EU-integrated project GEHA (GEnetics of Healthy Aging). Ann N Y Acad Sci 1100:21–45

    Article  PubMed  CAS  Google Scholar 

  61. de Magalhaes JP, Budovsky A, Lehmann G et al (2009) The Human Ageing Genomic Resources: online databases and tools for biogerontologists. Aging Cell 8(1):65–72

    Article  PubMed  Google Scholar 

  62. Human Aging Genomic Resources (2010) Human Aging Genomic Resources. Web site http://genomics.senescence.info. Accessed 27 Sept 2010

  63. Christensen K, Johnson TE (2006) The quest for genetic determinants of human longevity: challenges and insights. Nat Rev Genet 7(6):436–448

    Article  PubMed  CAS  Google Scholar 

  64. Willcox BJ, Donlon TA, He Q et al (2008) FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci U S A 105(37):13987–13992

    Article  PubMed  CAS  Google Scholar 

  65. Schachter F, Faure-Delanef L, Guenot F et al (1994) Genetic associations with human longevity at the APOE and ACE loci. Nat Genet 6(1):29–32

    Article  PubMed  CAS  Google Scholar 

  66. Anselmi CV, Malovini A, Roncarati R et al (2009) Association of the FOXO3A locus with extreme longevity in a southern italian centenarian study. Rejuvenation Res 12(2):95–104

    Article  PubMed  CAS  Google Scholar 

  67. Flachsbart F, Caliebe A, Kleindorp R et al (2009) Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc Natl Acad Sci U S A 106(8):2700–2705

    Article  PubMed  CAS  Google Scholar 

  68. Li Y, Wang WJ, Cao H et al (2009) Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Hum Mol Genet 18(24):4897–4904

    Article  PubMed  CAS  Google Scholar 

  69. Lunetta KL, D’Agostino RB Sr, Karasik D et al (2007) Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study. BMC Med Genet 8(Suppl 1):S13

    Article  PubMed  Google Scholar 

  70. dbGaP Genotypes and Phenotypes (2010) Framingham SNP Health Association Resources (SHARe). http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000007.v1.p1. Accessed 7 Sept 2010

  71. Cupples LA, Arruda HT, Benjamin EJ et al (2007) The Framingham heart study 100K SNP genome-wide association study resource: overview of 17 phenotype working group reports. BMC Med Genet 8(Suppl 1):S1

    Article  PubMed  Google Scholar 

  72. Psaty BM, O’Donnell CJ, Gudnason V et al (2009) Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium: design of prospective ­meta-analyses of genome-wide association studies from 5 cohorts. Circ Cardiovasc Genet 2(1):73–80

    Article  PubMed  Google Scholar 

  73. Newman AB, Walter S, Lunetta KL et al (2010) A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the cohorts for heart and aging research in genomic epidemiology consortium. J Gerontol A Biol Sci Med Sci 65(5):478–487

    Article  PubMed  Google Scholar 

  74. Conover CA, Bale LK (2007) Loss of pregnancy-associated plasma protein A extends lifespan in mice. Aging Cell 6(5):727–729

    Article  PubMed  CAS  Google Scholar 

  75. Sebastiani P, Solovieff N, Puca A et al (2011) Science 333(6041):404. doi: 10.1126/science.1190532. Epub 1 Jul 2010. Retraction in /pubmed/21778381

  76. Chatterton C (2010) Longevity gene study results ‘flawed’, say experts. Bionews 566. http://www.bionews.org.uk/page_65903.asp. Accessed 30 Mar 2012

  77. MacAuthur D (2010) Serious flaws in “longevity genes” study. Scienceblogs.com. http://scienceblogs.com/geneticfuture/2010/07/serious_potential_flaws_in_lon.php. Accessed 12 Oct 2010. (The link given is no longer active. The article can be accessed on www.wired.com at: http://www.wired.com/wiredscience/2010/07/Serious-flaws-revealed-in-longevity-genes-study)

  78. Sebastiani P, Solovieff N, Puca A, Hartley SW, Melista E, Andersen S, Dworkis DA, Wilk JB, Myers RH, Steinberg MH, Montano M, Baldwin CT, Perls TT (2011) Retraction. Science 333(6041):404

    Article  PubMed  CAS  Google Scholar 

  79. O’Brien E, Kerber R, Smith K et al (2007) Familial mortality in the Utah population database: characterizing a human aging phenotype. J Gerontol A Biol Sci Med Sci 62(8):803–812

    Article  PubMed  Google Scholar 

  80. Terry DF, Wilcox MA, McCormick MA et al (2004) Lower all-cause, cardiovascular, and cancer mortality in centenarians’ offspring. J Am Geriatr Soc 52(12):2074–2076

    Article  PubMed  Google Scholar 

  81. Beekman M, Nederstigt C, Suchiman HE et al (2010) Genome-wide association study (GWAS)-identified disease risk alleles do not compromise human longevity. Proc Natl Acad Sci U S A 107(42):18046–18049

    Article  PubMed  CAS  Google Scholar 

  82. Pulit SL, Voight BF, de Bakker PI (2010) Multiethnic genetic association studies improve power for locus discovery. PLoS One 5(9):e12600

    Article  PubMed  Google Scholar 

  83. Pawlikowska L, Hu D, Huntsman S et al (2009) Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging Cell 8(4):460–472

    Article  PubMed  CAS  Google Scholar 

  84. Nebel A, Schreiber S (2005) Allelic variation and human longevity. Sci Aging Knowledge Environ 2005(29):e23

    Article  Google Scholar 

  85. Zeng Y, Cheng L, Chen H et al (2010) Effects of FOXO genotypes on longevity: a biodemographic analysis. J Gerontol A Biol Sci Med Sci 65(12):1285–1299

    Article  PubMed  Google Scholar 

  86. Ng SB, Buckingham KJ, Lee C et al (2010) Exome sequencing identifies the cause of a mendelian disorder. Nat Genet 42(1):30–35

    Article  PubMed  CAS  Google Scholar 

  87. Bookshelf: U.S. National Library of Medicine, National Institutes of Health (2011) Epigenomics scientific background. National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/books/NBK45788/#epi_sci_bkgrd.About_Epigenetics. Accessed 27 July 2011

  88. Bjornsson HT, Sigurdsson MI, Fallin MD et al (2008) Intra-individual change over time in DNA methylation with familial clustering. JAMA 299(24):2877–2883

    Article  PubMed  CAS  Google Scholar 

  89. Gravina S, Vijg J (2010) Epigenetic factors in aging and longevity. Pflugers Arch 459(2):247–258

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

The writing of this chapter and heritability analyses conducted by Dr. Lunetta and Dr. Murabito were funded by a grant from the National Institute of Aging R01 AG29451.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joanne M. Murabito M.D. ScM .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Murabito, J.M., Lunetta, K.L. (2012). Genetics of Human Longevity and Healthy Aging. In: Newman, A., Cauley, J. (eds) The Epidemiology of Aging. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5061-6_13

Download citation

Publish with us

Policies and ethics