Genetics and Genomics of Human Longevity


Longevity is a complex trait which gene–gene, gene–environment, and environment–environment interactions all play important roles in regulating. Candidate gene‐based case‐control studies, longitudinal studies with a long‐term follow‐up, genome/epigenome‐wide association studies, and genome/epigenome‐wide linkage studies all contribute to accumulate current understandings toward human longevity. Up to now, near 300 (3‐fold increase within 4 years) potential genes are involved in human longevity. Based on their functions, these genes are approximately categorised into lipid–lipoprotein metabolism, insulin/IGF1 signalling pathway, genome integrity, and inflammation. Epigenetic regulation in gene expression without changing the primary deoxyribonucleic acid sequence is becoming important in aging and longevity. Increasing evidence from genome‐wide methylation pattern (methylome) and small noncoding ribonucleic acids implies a higher level of regulating mechanism to control the longevity genes. Yet lacking replicated result besides APOE and FOXO3A among the overwhelming explosion of data still remains as a potential concern. Nevertheless, advancing knowledge to human longevity gives the potential to prevent age‐related diseases, and hopefully extend the lifespan.

Key Concepts:

  • Healthy aging or longevity people are often defined as a population with a very late age at death or survival to the extreme age with high physical and cognitive functioning in the absence of the major chronic diseases.

  • Several genes involved in the fundamental cellular processes as lipid–lipoprotein metabolism, insulin/IGF1 signalling pathway, genome integrity and inflammations are closely associated with longevity.

  • Hypothesis‐driven (candidate gene‐based association studies) and hypothesis‐free (genome‐wide association/linkage studies) approaches are used to study human longevity.

  • APOE and FOXO3A are the most extensively studied longevity‐related genes, however, only variants of APOE are consistently replicated throughout studies using different approaches recruiting various ethnic populations.

  • The rise of the epigenetic regulation toward longevity genes suggests a higher level of controlling mechanism besides the genetic impact.

  • The presence of the beneficial gene alleles contributes to the complex phenotype of longevity rather than the absence of the diseases‐associated alleles.

Keywords: aging; genetics; epigenetics; human; longevity; polymorphisms

Figure 1.

A schematic representation showing longevity is a complex trait resulted from many genetic variants. Genes of lipid–lipoprotein metabolism, cell growth‐differentiation, genome integrity maintenance and immunoregulation are involved in the regulation of human longevity. The sophisticated interplays ranging from intracellular (e.g. molecules in the nucleus, or molecules between nucleus and cytosol), intercellular (e.g. cells respond to extracellular stimuli), to large‐scale systematic interplay between circulation, digestive and endocrine systems all work coordinately and eventually affect the human lifespan. Environmental factors as infection and diet may act through immune homoeostasis and metabolic pathways to influence human longevity as well.



Abdelmohsen K, Panda A, Kang MJ et al. (2013) Senescence‐associated lncRNAs: senescence‐associated long noncoding RNAs. Aging Cell 12: 890–900.

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

Atzmon G, Cho M, Cawthon RM et al. (2010) Evolution in health and medicine Sackler colloquium: genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians. Proceedings of the National Academy of Sciences of the USA 107 (Suppl 1): 1710–1717.

Barzilai N, Atzmon G, Schechter C et al. (2003) Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA: The Journal of the American Medical Association 290: 2030–2040.

Beekman M, Blanche H, Perola M et al. (2013) Genome‐wide linkage analysis for human longevity: genetics of Healthy Aging Study. Aging Cell 12: 184–193.

Beekman M, Nederstigt C, Suchiman HE et al. (2010) Genome‐wide association study (GWAS)‐identified disease risk alleles do not compromise human longevity. Proceedings of the National Academy of Sciences of the USA 107: 18046–18049.

Bell JT, Tsai PC, Yang TP et al. (2012) Epigenome‐wide scans identify differentially methylated regions for age and age‐related phenotypes in a healthy ageing population. PLoS Genetics 8: e1002629.

Bonafe M, Barbieri M, Marchegiani F et al. (2003) 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 life span control. Journal of Clinical Endocrinology and Metabolism 88: 3299–3304.

Bonafe M, Marchegiani F, Cardelli M et al. (2002) Genetic analysis of Paraoxonase (PON1) locus reveals an increased frequency of Arg192 allele in centenarians. European Journal of Human Genetics: EJHG 10: 292–296.

Boyden SE and Kunkel LM (2010) High‐density genomewide linkage analysis of exceptional human longevity identifies multiple novel loci. PLoS One 5: e12432.

Campo S, Sardo MA, Trimarchi G et al. (2004) Association between serum paraoxonase (PON1) gene promoter T(‐107)C polymorphism, PON1 activity and HDL levels in healthy Sicilian octogenarians. Experimental Gerontology 39: 1089–1094.

Carrieri G, Marzi E, Olivieri F et al. (2004) The G/C915 polymorphism of transforming growth factor beta1 is associated with human longevity: a study in Italian centenarians. Aging Cell 3: 443–448.

Deelen J, Beekman M, Uh HW et al. (2011) Genome‐wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited. Aging Cell 10: 686–698.

Deelen J, Beekman M, Uh HW et al. (2014) Genome‐wide association meta‐analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age. Human Molecular Genetics 23: 4420–4432.

Deelen J, Uh HW, Monajemi R et al. (2013) Gene set analysis of GWAS data for human longevity highlights the relevance of the insulin/IGF‐1 signaling and telomere maintenance pathways. Age 35: 235–249.

Eggertsen G, Tegelman R, Ericsson S, Angelin B and Berglund L (1993) Apolipoprotein E polymorphism in a healthy Swedish population: variation of allele frequency with age and relation to serum lipid concentrations. Clinical Chemistry 39: 2125–2129.

Flachsbart F, Caliebe A, Kleindorp R et al. (2009) Association of FOXO3A variation with human longevity confirmed in German centenarians. Proceedings of the National Academy of Sciences of the USA 106: 2700–2705.

Garatachea N, Emanuele E, Calero M et al. (2014) ApoE gene and exceptional longevity: insights from three independent cohorts. Experimental Gerontology 53: 16–23.

Gaspari L, Pedotti P, Bonafe M et al. (2003) Metabolic gene polymorphisms and p53 mutations in healthy centenarians and younger controls. Biomarkers: Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals 8: 522–528.

Gombar S, Jung HJ, Dong F et al. (2012) Comprehensive microRNA profiling in B‐cells of human centenarians by massively parallel sequencing. BMC Genomics 13: 353–364.

Groß S, Uta‐Dorothee I, Klintschar M and Bartel F (2014) Germline genetics of the p53 pathway affect longevity in a gender specific manner. Current Aging Science. doi:10.2174/1874609807666140321150751 (Epub ahead of print).

Halaschek‐Wiener J, Vulto I, Fornika D et al. (2008) Reduced telomere length variation in healthy oldest old. Mechanisms of Ageing and Development 129: 638–641.

Hannum G, Guinney J, Zhao L et al. (2013) Genome‐wide methylation profiles reveal quantitative views of human aging rates. Molecular Cell 49: 359–367.

van Heemst D, Beekman M, Mooijaart SP et al. (2005a) Reduced insulin/IGF‐1 signalling and human longevity. Aging Cell 4: 79–85.

van Heemst D, Mooijaart SP, Beekman M et al. and Long Life study g (2005b) Variation in the human TP53 gene affects old age survival and cancer mortality. Experimental Gerontology 40: 11–15.

vB Hjelmborg J, Iachine I, Skytthe A et al. (2006) Genetic influence on human lifespan and longevity. Human Genetics 119: 312–321.

Hurme M, Lehtimaki T, Jylha M, Karhunen PJ and Hervonen A (2005) Interleukin‐6 ‐174G/C polymorphism and longevity: a follow‐up study. Mechanisms of Ageing and Development 126: 417–418.

Kerber RA, O'Brien E, Boucher KM, Smith KR and Cawthon RM (2012) A genome‐wide study replicates linkage of 3p22‐24 to extreme longevity in humans and identifies possible additional loci. PLoS One 7: e34746.

Kojima T, Kamei H, Aizu T et al. (2004) Association analysis between longevity in the Japanese population and polymorphic variants of genes involved in insulin and insulin‐like growth factor 1 signaling pathways. Experimental Gerontology 39: 1595–1598.

Lee JH, Cheng R, Honig LS et al. (2014) Genome wide association and linkage analyses identified three loci‐4q25, 17q23.2, and 10q11.21‐associated with variation in leukocyte telomere length: the Long Life Family Study. Frontiers in Genetics 4: 310.

Li Y, Wang WJ, Cao H et al. (2009) Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Human Molecular Genetics 18: 4897–4904.

Lio D, Scola L, Crivello A et al. (2002) Gender‐specific association between −1082 IL‐10 promoter polymorphism and longevity. Genes and Immunity 3: 30–33.

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 Medical Genetics 8 (Suppl 1): S13.

Moskalev AA, Aliper AM, Smit‐McBride Z, Buzdin A and Zhavoronkov A (2014) Genetics and epigenetics of aging and longevity. Cell Cycle 13: 1063–1077.

Murabito JM, Yuan R and Lunetta KL (2012) The search for longevity and healthy aging genes: insights from epidemiological studies and samples of long‐lived individuals. Journals of Gerontology Series A, Biological Sciences and Medical Sciences 67: 470–479.

Nebel A, Kleindorp R, Caliebe A et al. (2011) A genome‐wide association study confirms APOE as the major gene influencing survival in long‐lived individuals. Mechanisms of Ageing and Development 132: 324–330.

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 3: 63–76.

Noren Hooten N, Fitzpatrick M, Wood WH III et al. (2013) Age‐related changes in microRNA levels in serum. Aging 5: 725–740.

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: 460–472.

Schachter F, Faure‐Delanef L, Guenot F et al. (1994) Genetic associations with human longevity at the APOE and ACE loci. Nature Genetics 6: 29–32.

Sebastiani P, Bae H, Sun FX et al. (2013) Meta‐analysis of genetic variants associated with human exceptional longevity. Aging 5: 653–661.

Sebastiani P, Riva A, Montano M et al. (2011) Whole genome sequences of a male and female supercentenarian, ages greater than 114 years. Frontiers in Genetics 2: 90.

Sebastiani P, Solovieff N, Dewan AT et al. (2012) Genetic signatures of exceptional longevity in humans. PLoS One 7: e29848.

Soerensen M, Dato S, Tan Q et al. (2012a) Human longevity and variation in GH/IGF‐1/insulin signaling, DNA damage signaling and repair and pro/antioxidant pathway genes: cross sectional and longitudinal studies. Experimental Gerontology 47: 379–387.

Soerensen M, Dato S, Tan Q et al. (2013) Evidence from case‐control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity. Age 35: 487–500.

Soerensen M, Thinggaard M, Nygaard M et al. (2012b) Genetic variation in TERT and TERC and human leukocyte telomere length and longevity: a cross‐sectional and longitudinal analysis. Aging Cell 11: 223–227.

Stessman J, Maaravi Y, Hammerman‐Rozenberg R et al. (2005) Candidate genes associated with ageing and life expectancy in the Jerusalem longitudinal study. Mechanisms of Ageing and Development 126: 333–339.

Willcox BJ, Donlon TA, He Q et al. (2008) FOXO3A genotype is strongly associated with human longevity. Proceedings of the National Academy of Sciences of the USA 105: 13987–13992.

Willcox BJ, He Q, Chen R et al. (2006) Midlife risk factors and healthy survival in men. JAMA: the Journal of the American Medical Association 296: 2343–2350.

Xia Y, Gueguen R, Vincent‐Viry M, Siest G and Visvikis S (2003) Effect of six candidate genes on early aging in a French population. Aging Clinical and Experimental Research 15: 111–116.

Further Reading

Andersen SL, Sebastiani P, Dworkis DA, Feldman L and Perls TT (2012) Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. Journals of Gerontology Series A, Biological Sciences and Medical Sciences 67: 395–405.

Chang AL, Bitter PH Jr., Qu K et al. (2013) Rejuvenation of gene expression pattern of aged human skin by broadband light treatment: a pilot study. Journal of Investigative Dermatology 133: 394–402.

Chung WH, Dao RL, Chen LK and Hung SI (2010) The role of genetic variants in human longevity. Ageing Research Reviews 9 (Suppl 1): S67–S78.

Kahn AJ (2014) FOXO3 and related transcription factors in development, aging, and exceptional longevity. Journals of Gerontology Series A, Biological Sciences and Medical Sciences. doi: 10.1093/gerona/glu044 (Epub ahead of print).

Labat‐Robert J and Robert L (2014) Longevity and aging. Role of free radicals and xanthine oxidase. A review. Pathologie‐Biologie 62: 61–66.

Raichlen DA and Alexander GE (2014) Exercise, APOE genotype, and the evolution of the human lifespan. Trends in Neurosciences 37: 247–255.

Rajpathak SN, Liu Y, Ben‐David O et al. (2011) Lifestyle factors of people with exceptional longevity. Journal of the American Geriatrics Society 59: 1509–1512.

Seripa D, D'Onofrio G, Panza F et al. (2011) The genetics of the human APOE polymorphism. Rejuvenation Research 14: 491–500.

Sevini F, Giuliani C, Vianello D et al. (2014) mtDNA mutations in human aging and longevity: controversies and new perspectives opened by high‐throughput technologies. Experimental Gerontology 56: 234–244.

Zhu H, Belcher M and van der Harst P (2011) Healthy aging and disease: role for telomere biology? Clinical Science 120: 427–440.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Wu, Yi‐Chih, Chung, Wen‐Hung, and Hung, Shuen‐Iu(Sep 2014) Genetics and Genomics of Human Longevity. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024643]