Advertisement

Genetic Signatures of Centenarians

Chapter

Abstract

Exceptional long-living people, i.e., individuals who belong to the fifth percentile of the survival curve, are genetically predisposed to reach extreme ages. The challenge, since the beginning of the 1990s, was the identification of the genetic variants that predispose these individuals to avoid diseases of ageing and live long and healthy lives. Genetic approaches (study design) were adopted based on the available platforms. Indeed, entrepreneurs started with a candidate gene approach under case–control study design, followed by sibling pair linkage analysis, a first comprehensive unbiased study and back to the case–control study with SNPs array, imputation and whole genome sequencing. Results were analysed either independently or by combining different cohorts through meta-analysis. Furthermore, genetic signatures were identified that predict the phenotypic outcome of exceptional long-living individuals.

Keywords

Ageing Longevity Genomic SNP Linkage Imputation Meta-analysis Sequencing 

References

  1. 1.
    Puca AA, Spinelli C, Accardi G, Villa F, Caruso C. Centenarians as a model to discover genetic and epigenetic signatures of healthy ageing. Mech Ageing Dev. 2018;174:95–102.  https://doi.org/10.1016/j.mad.2017.10.004.CrossRefPubMedGoogle Scholar
  2. 2.
    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.  https://doi.org/10.1186/1742-4933-9-7.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    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.  https://doi.org/10.1073/pnas.122587599.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Lescai F, Marchegiani F, Franceschi C. PON1 is a longevity gene: results of a meta-analysis. Ageing Res Rev. 2009;8(4):277–84.  https://doi.org/10.1016/j.arr.2009.04.001.CrossRefPubMedGoogle Scholar
  5. 5.
    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.  https://doi.org/10.1038/ng0194-29.CrossRefPubMedGoogle Scholar
  6. 6.
    Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, et al. FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci U S A. 2008;105(37):13987–92.  https://doi.org/10.1073/pnas.0801030105.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Mohler PJ, Healy JA, Xue H, Puca AA, Kline CF, Allingham RR, et al. Ankyrin-B syndrome: enhanced cardiac function balanced by risk of cardiac death and premature senescence. PLoS One. 2007;2(10):e1051.  https://doi.org/10.1371/journal.pone.0001051.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Malovini A, Illario M, Iaccarino G, Villa F, Ferrario A, Roncarati R, et al. Association study on long-living individuals from southern Italy identifies rs10491334 in the CAMKIV gene that regulates survival proteins. Rejuvenation Res. 2011;14(3):283–91.  https://doi.org/10.1089/rej.2010.1114.CrossRefPubMedGoogle Scholar
  9. 9.
    Anselmi CV, Malovini A, Roncarati R, Novelli V, Villa F, Condorelli G, et al. Association of the FOXO3A locus with extreme longevity in a southern Italian centenarian study. Rejuvenation Res. 2009;12(2):95–104.  https://doi.org/10.1089/rej.2008.0827.CrossRefPubMedGoogle Scholar
  10. 10.
    Garatachea N, Marin PJ, Santos-Lozano A, Sanchis-Gomar F, Emanuele E, Lucia A. The ApoE gene is related with exceptional longevity: a systematic review and meta-analysis. Rejuvenation Res. 2015;18(1):3–13.  https://doi.org/10.1089/rej.2014.1605.CrossRefPubMedGoogle Scholar
  11. 11.
    Di Bona D, Accardi G, Virruso C, Candore G, Caruso C. Association between genetic variations in the insulin/insulin-like growth factor (Igf-1) signaling pathway and longevity: a systematic review and meta-analysis. Curr Vasc Pharmacol. 2014;12(5):674–81.CrossRefGoogle Scholar
  12. 12.
    Kops GJ, Dansen TB, Polderman PE, Saarloos I, Wirtz KW, Coffer PJ, et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature. 2002;419(6904):316–21.  https://doi.org/10.1038/nature01036.CrossRefPubMedGoogle Scholar
  13. 13.
    Puca AA, Ferrario A, Maciag A, Accardi G, Aiello A, Gambino CM, et al. Association of immunoglobulin GM allotypes with longevity in long-living individuals from southern Italy. Immun Ageing. 2018;15:26.  https://doi.org/10.1186/s12979-018-0134-7.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Geesaman BJ, Benson E, Brewster SJ, Kunkel LM, Blanche H, Thomas G, et al. Haplotype-based identification of a microsomal transfer protein marker associated with the human lifespan. Proc Natl Acad Sci U S A. 2003;100(24):14115–20.  https://doi.org/10.1073/pnas.1936249100.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Puca AA, Daly MJ, Brewster SJ, Matise TC, Barrett J, Shea-Drinkwater M, et al. A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4. Proc Natl Acad Sci U S A. 2001;98(18):10505–8.  https://doi.org/10.1073/pnas.181337598.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Huffman DM, Deelen J, Ye K, Bergman A, Slagboom EP, Barzilai N, et al. Distinguishing between longevity and buffered-deleterious genotypes for exceptional human longevity: the case of the MTP gene. J Gerontol A Biol Sci Med Sci. 2012;67(11):1153–60.  https://doi.org/10.1093/gerona/gls103.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Greenwood TA, Rana BK, Schork NJ. Human haplotype block sizes are negatively correlated with recombination rates. Genome Res. 2004;14(7):1358–61.  https://doi.org/10.1101/gr.1540404.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, et al. The structure of haplotype blocks in the human genome. Science. 2002;296(5576):2225–9.  https://doi.org/10.1126/science.1069424.CrossRefPubMedGoogle Scholar
  19. 19.
    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.  https://doi.org/10.1371/journal.pone.0029848.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Conneely KN, Capell BC, Erdos MR, Sebastiani P, Solovieff N, Swift AJ, et al. Human longevity and common variations in the LMNA gene: a meta-analysis. Aging Cell. 2012;11(3):475–81.  https://doi.org/10.1111/j.1474-9726.2012.00808.x.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Castro E, Edland SD, Lee L, Ogburn CE, Deeb SS, Brown G, et al. Polymorphisms at the Werner locus: II. 1074Leu/Phe, 1367Cys/Arg, longevity, and atherosclerosis. Am J Med Genet. 2000;95(4):374–80.CrossRefGoogle Scholar
  22. 22.
    Gentschew L, Flachsbart F, Kleindorp R, Badarinarayan N, Schreiber S, Nebel A. Polymorphisms in the superoxidase dismutase genes reveal no association with human longevity in Germans: a case-control association study. Biogerontology. 2013;14(6):719–27.  https://doi.org/10.1007/s10522-013-9470-3.CrossRefPubMedGoogle Scholar
  23. 23.
    Hitt R, Young-Xu Y, Silver M, Perls T. Centenarians: the older you get, the healthier you have been. Lancet. 1999;354(9179):652.  https://doi.org/10.1016/S0140-6736(99)01987-X.CrossRefPubMedGoogle Scholar
  24. 24.
    Villa F, Carrizzo A, Spinelli CC, Ferrario A, Malovini A, Maciag A, et al. Genetic analysis reveals a longevity-associated protein modulating endothelial function and angiogenesis. Circ Res. 2015;117(4):333–45.  https://doi.org/10.1161/CIRCRESAHA.117.305875.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Villa F, Carrizzo A, Ferrario A, Maciag A, Cattaneo M, Spinelli CC, et al. A model of evolutionary selection: the cardiovascular protective function of the longevity associated variant of BPIFB4. Int J Mol Sci. 2018;19(10)  https://doi.org/10.3390/ijms19103229.CrossRefGoogle Scholar
  26. 26.
    Spinelli CC, Carrizzo A, Ferrario A, Villa F, Damato A, Ambrosio M, et al. LAV-BPIFB4 isoform modulates eNOS signalling through Ca2+/PKC-alpha-dependent mechanism. Cardiovasc Res. 2017;113(7):795–804.  https://doi.org/10.1093/cvr/cvx072.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Puca AA, Carrizzo A, Villa F, Ferrario A, Casaburo M, Maciag A, et al. Vascular ageing: the role of oxidative stress. Int J Biochem Cell Biol. 2013;45(3):556–9.  https://doi.org/10.1016/j.biocel.2012.12.024.CrossRefPubMedGoogle Scholar
  28. 28.
    Villa F, Malovini A, Carrizzo A, Spinelli CC, Ferrario A, Maciag A, et al. Serum BPIFB4 levels classify health status in long-living individuals. Immun Ageing. 2015;12:27.  https://doi.org/10.1186/s12979-015-0054-8.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Spinetti G, Sangalli E, Specchia C, Villa F, Spinelli C, Pipolo R, et al. The expression of the BPIFB4 and CXCR4 associates with sustained health in long-living individuals from Cilento-Italy. Aging. 2017;9(2):370–80.  https://doi.org/10.18632/aging.101159.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Vecchione C, Villa F, Carrizzo A, Spinelli CC, Damato A, Ambrosio M, et al. A rare genetic variant of BPIFB4 predisposes to high blood pressure via impairment of nitric oxide signaling. Sci Rep. 2017;7(1):9706.  https://doi.org/10.1038/s41598-017-10341-x.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Sebastiani P, Gurinovich A, Bae H, Andersen S, Malovini A, Atzmon G, et al. Four genome-wide association studies identify new extreme longevity variants. J Gerontol A Biol Sci Med Sci. 2017;72(11):1453–64.  https://doi.org/10.1093/gerona/glx027.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Puca AA, Andrew P, Novelli V, Anselmi CV, Somalvico F, Cirillo NA, et al. Fatty acid profile of erythrocyte membranes as possible biomarker of longevity. Rejuvenation Res. 2008;11(1):63–72.  https://doi.org/10.1089/rej.2007.0566.CrossRefPubMedGoogle Scholar
  33. 33.
    Frigolet ME, Gutierrez-Aguilar R. The role of the novel lipokine palmitoleic acid in health and disease. Adv Nutr. 2017;8(1):173S–81S.  https://doi.org/10.3945/an.115.011130.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Sebastiani P, Gurinovich A, Nygaard M, Sasaki T, Sweigart B, Bae H, et al. APOE alleles and extreme human longevity. J Gerontol A Biol Sci Med Sci. 2018;74:44.  https://doi.org/10.1093/gerona/gly174.CrossRefPubMedCentralGoogle Scholar
  35. 35.
    Gorbunova V, Seluanov A, Mao Z, Hine C. Changes in DNA repair during aging. Nucleic Acids Res. 2007;35(22):7466–74.  https://doi.org/10.1093/nar/gkm756.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Seluanov A, Mittelman D, Pereira-Smith OM, Wilson JH, Gorbunova V. DNA end joining becomes less efficient and more error-prone during cellular senescence. Proc Natl Acad Sci U S A. 2004;101(20):7624–9.  https://doi.org/10.1073/pnas.0400726101.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Pilia G, Chen WM, Scuteri A, Orru M, Albai G, Dei M, et al. Heritability of cardiovascular and personality traits in 6,148 Sardinians. PLoS Genet. 2006;2(8):e132.  https://doi.org/10.1371/journal.pgen.0020132.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J, et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 2007;3(7):e115.  https://doi.org/10.1371/journal.pgen.0030115.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Chen WM, Abecasis GR. Family-based association tests for genomewide association scans. Am J Hum Genet. 2007;81(5):913–26.  https://doi.org/10.1086/521580.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Erikson GA, Bodian DL, Rueda M, Molparia B, Scott ER, Scott-Van Zeeland AA, et al. Whole-genome sequencing of a healthy aging cohort. Cell. 2016;165(4):1002–11.  https://doi.org/10.1016/j.cell.2016.03.022.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Sebastiani P, Riva A, Montano M, Pham P, Torkamani A, Scherba E, et al. Whole genome sequences of a male and female supercentenarian, ages greater than 114 years. Front Genet. 2011;2:90.  https://doi.org/10.3389/fgene.2011.00090.CrossRefPubMedGoogle Scholar
  42. 42.
    Ye K, Beekman M, Lameijer EW, Zhang Y, Moed MH, van den Akker EB, et al. Aging as accelerated accumulation of somatic variants: whole-genome sequencing of centenarian and middle-aged monozygotic twin pairs. Twin Res Hum Genet. 2013;16(6):1026–32.  https://doi.org/10.1017/thg.2013.73.CrossRefPubMedGoogle Scholar
  43. 43.
    Gierman HJ, Fortney K, Roach JC, Coles NS, Li H, Glusman G, et al. Whole-genome sequencing of the world’s oldest people. PLoS One. 2014;9(11):e112430.  https://doi.org/10.1371/journal.pone.0112430.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Kajiwara Y, Akram A, Katsel P, Haroutunian V, Schmeidler J, Beecham G, et al. FE65 binds Teashirt, inhibiting expression of the primate-specific caspase-4. PLoS One. 2009;4(4):e5071.  https://doi.org/10.1371/journal.pone.0005071.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Kakuyama H, Soderberg L, Horigome K, Winblad B, Dahlqvist C, Naslund J, et al. CLAC binds to aggregated Abeta and Abeta fragments, and attenuates fibril elongation. Biochemistry. 2005;44(47):15602–9.  https://doi.org/10.1021/bi051263e.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Cardiovascular Research Unit, IRCCS MultiMedicaMilanItaly
  2. 2.Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”University of SalernoBaronissiItaly

Personalised recommendations