Skip to main content
SpringerLink
Log in

Genetic Signatures of Centenarians

  • Chapter
  • First Online:
Centenarians

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.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 54.99
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. 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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cardiovascular Research Unit, IRCCS MultiMedica, Milan, Italy

    Francesco Villa, Anna Ferrario & Annibale Alessandro Puca

  2. Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, SA, Italy

    Annibale Alessandro Puca

Authors
  1. Francesco Villa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anna Ferrario
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Annibale Alessandro Puca
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Annibale Alessandro Puca .

Editor information

Editors and Affiliations

  1. Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy

    Calogero Caruso

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Villa, F., Ferrario, A., Puca, A.A. (2019). Genetic Signatures of Centenarians. In: Caruso, C. (eds) Centenarians. Springer, Cham. https://doi.org/10.1007/978-3-030-20762-5_6

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-20762-5_6

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-20761-8

  • Online ISBN: 978-3-030-20762-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation