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Open Access 01-12-2016 | Review

Human longevity: Genetics or Lifestyle? It takes two to tango

Authors: Giuseppe Passarino, Francesco De Rango, Alberto Montesanto

Published in: Immunity & Ageing | Issue 1/2016

Abstract

Healthy aging and longevity in humans are modulated by a lucky combination of genetic and non-genetic factors. Family studies demonstrated that about 25 % of the variation in human longevity is due to genetic factors. The search for genetic and molecular basis of aging has led to the identification of genes correlated with the maintenance of the cell and of its basic metabolism as the main genetic factors affecting the individual variation of the aging phenotype. In addition, studies on calorie restriction and on the variability of genes associated with nutrient-sensing signaling, have shown that ipocaloric diet and/or a genetically efficient metabolism of nutrients, can modulate lifespan by promoting an efficient maintenance of the cell and of the organism. Recently, epigenetic studies have shown that epigenetic modifications, modulated by both genetic background and lifestyle, are very sensitive to the aging process and can either be a biomarker of the quality of aging or influence the rate and the quality of aging.

On the whole, current studies are showing that interventions modulating the interaction between genetic background and environment is essential to determine the individual chance to attain longevity.

Johnson TE. A personal retrospective on the genetics of aging. Biogerontology. 2002;3(1–2):7–12.CrossRefPubMed

Johnson TE, Wood WB. Genetic analysis of life-span in Caenorhabditis elegans. Proc Natl Acad Sci USA. 1982;79(21):6603–7.CrossRefPubMedPubMedCentral

Johnson TE. Aging can be genetically dissected into component processes using long-lived lines of Caenorhabditis elegans. Proc Natl Acad Sci USA. 1987;84(11):3777–81.CrossRefPubMedPubMedCentral

Friedman DB, Johnson TE. Three mutants that extend both mean and maximum life span of the nematode, Caenorhabditis elegans, define the age-1 gene. J Gerontol. 1988;43(4):B102–9.CrossRefPubMed

Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R. A C. elegans mutant that lives twice as long as wild type. Nature. 1993;366(6454):461–4. doi:10.1038/366461a0.CrossRefPubMed

Gottlieb S, Ruvkun G. daf-2, daf-16 and daf-23: genetically interacting genes controlling Dauer formation in Caenorhabditis elegans. Genetics. 1994;137(1):107–20.PubMedPubMedCentral

Taguchi A, Wartschow LM, White MF. Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science. 2007;317(5836):369–72. doi:10.1126/science.1142179.CrossRefPubMed

Lin K, Dorman JB, Rodan A, Kenyon C. daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science. 1997;278(5341):1319–22.CrossRefPubMed

Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature. 1997;389(6654):994–9. doi:10.1038/40194.CrossRefPubMed

10.

Kenyon C. The plasticity of aging: insights from long-lived mutants. Cell. 2005;120(4):449–60. doi:10.1016/j.cell.2005.02.002.CrossRefPubMed

11.

Kenyon CJ. The genetics of ageing. Nature. 2010;464(7288):504–12. doi:10.1038/nature08980.CrossRefPubMed

12.

Rose G, Passarino G, Franceschi C, De Benedictis G. The variability of the mitochondrial genome in human aging: a key for life and death? Int J Biochem Cell Biol. 2002;34(11):1449–60.CrossRefPubMed

13.

Skulachev VP. The programmed death phenomena, aging, and the Samurai law of biology. Exp Gerontol. 2001;36(7):995–1024.CrossRefPubMed

14.

Schoenmaker M, de Craen AJ, de Meijer PH, Beekman M, Blauw GJ, Slagboom PE, et al. Evidence of genetic enrichment for exceptional survival using a family approach: the Leiden Longevity Study. Eur J Human Genet EJHG. 2006;14(1):79–84. doi:10.1038/sj.ejhg.5201508.PubMed

15.

Montesanto A, Latorre V, Giordano M, Martino C, Domma F, Passarino G. The genetic component of human longevity: analysis of the survival advantage of parents and siblings of Italian nonagenarians. Eur J Human Genet EJHG. 2011;19(8):882–6. doi:10.1038/ejhg.2011.40.CrossRefPubMed

16.

vB Hjelmborg J, Iachine I, Skytthe A, Vaupel JW, McGue M, Koskenvuo M, Kaprio J, Pedersen NL, Christensen K. Genetic influence on human lifespan and longevity. Hum Genet. 2006;119(3):312–21.

17.

Herskind AM, McGue M, Holm NV, Sorensen TI, Harvald B, Vaupel JW. The heritability of human longevity: a population-based study of 2872 Danish twin pairs born 1870–1900. Hum Genet. 1996;97(3):319–23.CrossRefPubMed

18.

Skytthe A, Pedersen NL, Kaprio J, Stazi MA, Hjelmborg JV, Iachine I, et al. Longevity studies in GenomEUtwin. Twin Res Off J Int Soc Twin Studies. 2003;6(5):448–54. doi:10.1375/136905203770326457.CrossRef

19.

Capri M, Salvioli S, Sevini F, Valensin S, Celani L, Monti D, et al. The genetics of human longevity. Ann N Y Acad Sci. 2006;1067:252–63. doi:10.1196/annals.1354.033.CrossRefPubMed

20.

Passarino G, Montesanto A, Dato S, Giordano S, Domma F, Mari V, et al. Sex and age specificity of susceptibility genes modulating survival at old age. Hum Hered. 2006;62(4):213–20. doi:10.1159/000097305.CrossRefPubMed

21.

Perls TT, Wilmoth J, Levenson R, Drinkwater M, Cohen M, Bogan H, et al. Life-long sustained mortality advantage of siblings of centenarians. Proc Natl Acad Sci U S A. 2002;99(12):8442–7. doi:10.1073/pnas.122587599.CrossRefPubMedPubMedCentral

22.

Pawlikowska L, Hu D, Huntsman S, Sung A, Chu C, Chen J, et al. Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging Cell. 2009;8(4):460–72. doi:10.1111/j.1474-9726.2009.00493.x.CrossRefPubMedPubMedCentral

23.

Ziv E, Hu D. Genetic variation in insulin/IGF-1 signaling pathways and longevity. Ageing Res Rev. 2011;10(2):201–4. doi:10.1016/j.arr.2010.09.002.CrossRefPubMed

24.

Morris BJ, Willcox DC, Donlon TA, Willcox BJ. FOXO3: A Major Gene for Human Longevity - A Mini-Review. Gerontology. 2015. doi:10.1159/000375235.PubMed

25.

Bellizzi D, Rose G, Cavalcante P, Covello G, Dato S, De Rango F, et al. A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages. Genomics. 2005;85(2):258–63. doi:10.1016/j.ygeno.2004.11.003.CrossRefPubMed

26.

Sebastiani P, Solovieff N, Dewan AT, Walsh KM, Puca A, Hartley SW, et al. Genetic signatures of exceptional longevity in humans. PLoS One. 2012;7(1):e29848. doi:10.1371/journal.pone.0029848.CrossRefPubMedPubMedCentral

27.

Beekman M, Blanche H, Perola M, Hervonen A, Bezrukov V, Sikora E, et al. Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study. Aging Cell. 2013;12(2):184–93. doi:10.1111/acel.12039.CrossRefPubMedPubMedCentral

28.

Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA. 2009;106(23):9362–7. doi:10.1073/pnas.0903103106.CrossRefPubMedPubMedCentral

29.

Deelen J, Beekman M, Uh HW, Broer L, Ayers KL, Tan Q, et al. Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age. Hum Mol Genet. 2014;23(16):4420–32. doi:10.1093/hmg/ddu139.CrossRefPubMedPubMedCentral

30.

Novelli V, Viviani Anselmi C, Roncarati R, Guffanti G, Malovini A, Piluso G, et al. Lack of replication of genetic associations with human longevity. Biogerontology. 2008;9(2):85–92. doi:10.1007/s10522-007-9116-4.CrossRefPubMed

31.

Ferrario A, Villa F, Malovini A, Araniti F, Puca AA. The application of genetics approaches to the study of exceptional longevity in humans: potential and limitations. Immun Ageing. 2012;9(1):7. doi:10.1186/1742-4933-9-7.CrossRefPubMedPubMedCentral

32.

Villa F, Carrizzo A, Spinelli CC, Ferrario A, Malovini A, Maciąg A, et al. Genetic Analysis Reveals a Longevity-Associated Protein Modulating Endothelial Function and Angiogenesis. Circ Res. 2015;117(4):333–45. doi:10.1161/CIRCRESAHA.117.305875.CrossRefPubMed

33.

Raule N, Sevini F, Li S, Barbieri A, Tallaro F, Lomartire L, et al. The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific. Aging Cell. 2014;13(3):401–7. doi:10.1111/acel.12186.CrossRefPubMedPubMedCentral

34.

Debrabant B, Soerensen M, Flachsbart F, Dato S, Mengel-From J, Stevnsner T, et al. Human longevity and variation in DNA damage response and repair: study of the contribution of sub-processes using competitive gene-set analysis. Eur J Human Genet EJHG. 2014;22(9):1131–6. doi:10.1038/ejhg.2013.299.CrossRefPubMed

35.

Soerensen M, Thinggaard M, Nygaard M, Dato S, Tan Q, Hjelmborg J, et al. Genetic variation in TERT and TERC and human leukocyte telomere length and longevity: a cross-sectional and longitudinal analysis. Aging Cell. 2012;11(2):223–7. doi:10.1111/j.1474-9726.2011.00775.x.CrossRefPubMedPubMedCentral

36.

Crocco P, Barale R, Rose G, Rizzato C, Santoro A, De Rango F, et al. Population-specific association of genes for telomere-associated proteins with longevity in an Italian population. Biogerontology. 2015;16(3):353–64. doi:10.1007/s10522-015-9551-6.CrossRefPubMed

37.

Atzmon G, Cho M, Cawthon RM, Budagov T, Katz M, Yang X, et al. Evolution in health and medicine Sackler colloquium: Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians. Proc Natl Acad Sci U S A. 2010;107 Suppl 1:1710–7. doi:10.1073/pnas.0906191106.CrossRefPubMedPubMedCentral

38.

Altomare K, Greco V, Bellizzi D, Berardelli M, Dato S, DeRango F, et al. The allele (A)(−110) in the promoter region of the HSP70-1 gene is unfavorable to longevity in women. Biogerontology. 2003;4(4):215–20.CrossRefPubMed

39.

Ross OA, Curran MD, Crum KA, Rea IM, Barnett YA, Middleton D. Increased frequency of the 2437 T allele of the heat shock protein 70-Hom gene in an aged Irish population. Exp Gerontol. 2003;38(5):561–5.CrossRefPubMed

40.

Rose G, Crocco P, De Rango F, Montesanto A, Passarino G. Further support to the uncoupling-to-survive theory: the genetic variation of human UCP genes is associated with longevity. PLoS One. 2011;6(12):e29650. doi:10.1371/journal.pone.0029650.CrossRefPubMedPubMedCentral

41.

Junnila RK, List EO, Berryman DE, Murrey JW, Kopchick JJ. The GH/IGF-1 axis in ageing and longevity. Nat Rev Endocrinol. 2013;9(6):366–76. doi:10.1038/nrendo.2013.67.CrossRefPubMedPubMedCentral

42.

Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013;493(7432):338–45. doi:10.1038/nature11861.CrossRefPubMedPubMedCentral

43.

Schachter F, Faure-Delanef L, Guenot F, Rouger H, Froguel P, Lesueur-Ginot L, et al. Genetic associations with human longevity at the APOE and ACE loci. Nat Genet. 1994;6(1):29–32. doi:10.1038/ng0194-29.CrossRefPubMed

44.

Garasto S, Berardelli M, DeRango F, Mari V, Feraco E, De Benedictis G. A study of the average effect of the 3’APOB-VNTR polymorphism on lipidemic parameters could explain why the short alleles (<35 repeats) are rare in centenarians. BMC Med Genet. 2004;5:3. doi:10.1186/1471-2350-5-3.CrossRefPubMedPubMedCentral

45.

Cardelli M, Cavallone L, Marchegiani F, Oliveri F, Dato S, Montesanto A, et al. A genetic-demographic approach reveals male-specific association between survival and tumor necrosis factor (A/G)-308 polymorphism. J Gerontol A Biol Sci Med Sci. 2008;63(5):454–60.CrossRefPubMed

46.

Di Bona D, Vasto S, Capurso C, Christiansen L, Deiana L, Franceschi C, et al. Effect of interleukin-6 polymorphisms on human longevity: a systematic review and meta-analysis. Ageing Res Rev. 2009;8(1):36–42. doi:10.1016/j.arr.2008.09.001.CrossRefPubMed

47.

Longo VD, Antebi A, Bartke A, Barzilai N, Brown-Borg HM, Caruso C, et al. Interventions to Slow Aging in Humans: Are We Ready? Aging Cell. 2015;14(4):497–510. doi:10.1111/acel.12338.CrossRefPubMedPubMedCentral

48.

Prolla TA, Mattson MP. Molecular mechanisms of brain aging and neurodegenerative disorders: lessons from dietary restriction. Trends Neurosci. 2001;24(11 Suppl):S21–31.CrossRefPubMed

49.

Ghosh S, Wanders D, Stone KP, Van NT, Cortez CC, Gettys TW. A systems biology analysis of the unique and overlapping transcriptional responses to caloric restriction and dietary methionine restriction in rats. FASEB J Off Publication Federation Am Soc Exp Biol. 2014;28(6):2577–90. doi:10.1096/fj.14-249458.CrossRef

50.

Willcox DC, Willcox BJ, Todoriki H, Suzuki M. The Okinawan diet: health implications of a low-calorie, nutrient-dense, antioxidant-rich dietary pattern low in glycemic load. J Am Coll Nutr. 2009;28(Suppl):500S–16S.CrossRefPubMed

51.

Poulain M, Pes GM, Grasland C, Carru C, Ferrucci L, Baggio G, et al. Identification of a geographic area characterized by extreme longevity in the Sardinia island: the AKEA study. Exp Gerontol. 2004;39(9):1423–9. doi:10.1016/j.exger.2004.06.016.CrossRefPubMed

52.

Pes GM, Tolu F, Dore MP, Sechi GP, Errigo A, Canelada A, et al. Male longevity in Sardinia, a review of historical sources supporting a causal link with dietary factors. Eur J Clin Nutr. 2015;69(4):411–8. doi:10.1038/ejcn.2014.230.CrossRefPubMed

53.

Montesanto A, Passarino G, Senatore A, Carotenuto L, De Benedictis G. Spatial analysis and surname analysis: complementary tools for shedding light on human longevity patterns. Ann Hum Genet. 2008;72(Pt 2):253–60. doi:10.1111/j.1469-1809.2007.00405.x.CrossRefPubMed

54.

Bellizzi D, D’Aquila P, Montesanto A, Corsonello A, Mari V, Mazzei B, et al. Global DNA methylation in old subjects is correlated with frailty. Age. 2012;34(1):169–79. doi:10.1007/s11357-011-9216-6.CrossRefPubMedPubMedCentral

55.

Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14(10):R115. doi:10.1186/gb-2013-14-10-r115.CrossRefPubMedPubMedCentral

56.

Horvath S, Garagnani P, Bacalini MG, Pirazzini C, Salvioli S, Gentilini D, et al. Accelerated epigenetic aging in Down syndrome. Aging Cell. 2015;14(3):491–5. doi:10.1111/acel.12325.CrossRefPubMedPubMedCentral

57.

Marioni RE, Shah S, McRae AF, Chen BH, Colicino E, Harris SE, et al. DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol. 2015;16:25. doi:10.1186/s13059-015-0584-6.CrossRefPubMedPubMedCentral

58.

Horvath S, Mah V, Lu AT, Woo JS, Choi OW, Jasinska AJ, et al. The cerebellum ages slowly according to the epigenetic clock. Aging. 2015;7(5):294–306.CrossRefPubMedPubMedCentral

Title: Human longevity: Genetics or Lifestyle? It takes two to tango
Authors: Giuseppe Passarino
Francesco De Rango
Alberto Montesanto
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Immunity & Ageing / Issue 1/2016
Electronic ISSN: 1742-4933
DOI: https://doi.org/10.1186/s12979-016-0066-z

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