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Effect of longevity genetic variants on the molecular aging rate

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A Correction to this article was published on 18 June 2021

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Abstract

We conducted a genome-wide association study of 1320 centenarians from the New England Centenarian Study (median age = 104 years) and 2899 unrelated controls using >9 M genetic variants imputed to the HRC panel of ~65,000 haplotypes. The genetic variants with the most significant associations were correlated to 4131 proteins that were profiled in the serum of a subset of 224 study participants using a SOMAscan array. The genetic associations were replicated in a genome-wide association study of 480 centenarians and ~800 controls of Ashkenazi Jewish descent. The proteomic associations were replicated in a proteomic scan of approximately 1000 Ashkenazi Jewish participants from a third cohort. The analysis replicated a protein signature associated with APOE genotypes and confirmed strong overexpression of BIRC2 (p < 5E−16) and under-expression of APOB in carriers of the APOE2 allele (p < 0.05). The analysis also discovered and replicated associations between longevity variants and slower changes of protein biomarkers of aging, including a novel protein signature of rs2184061 (CDKN2A/CDKN2B in chromosome 9) that suggests a genetic regulation of GDF15. The analyses showed that longevity variants correlate with proteome signatures that could be manipulated to discover healthy-aging targets.

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References

  1. Hitt R, Young-Xu Y, Silver M, Perls T. Centenarians: the older you get, the healthier you have been. Lancet. 1999;354(9179):652.

    Article  CAS  PubMed  Google Scholar 

  2. Terry DF, Sebastiani P, Andersen SL, Perls TT. Disentangling the roles of disability and morbidity in survival to exceptional old age. Arch Intern Med. 2008;168(3):277–83.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Andersen SL, et al. Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. J Gerontol A Biol Sci Med Sci. 2012;67(4):395–405.

    Article  PubMed  Google Scholar 

  4. Pignolo RJ. Exceptional human longevity. Mayo Clin Proc. 2019;94(1):110–24.

    Article  PubMed  Google Scholar 

  5. Melzer D, Pilling LC, Ferrucci L. The genetics of human ageing. Nat Rev Genet. 2020;21(2):88–101.

    Article  CAS  PubMed  Google Scholar 

  6. Perls T, Shea-Drinkwater M, Bowen-Flynn J, Ridge SB, Kang S, Joyce E, et al. Exceptional familial clustering for extreme longevity in humans. J Am Geriatr Soc. 2000;48(11):1483–5.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sebastiani P, Nussbaum L, Andersen SL, Black MJ, Perls TT. Increasing sibling relative risk of survival to older and older ages and the importance of precise definitions of “aging,” “life span,” and “longevity”. J Gerontol A Biol Sci Med Sci. 2016;71(3):340–6.

    Article  PubMed  Google Scholar 

  9. Deelen J, Beekman M, Uh HW, Helmer Q, Kuningas M, Christiansen L, et al. Genome-wide association study identifies a single major locus contributing to survival into old age: the APOE locus revisited. Aging Cell. 2011;10(4):686–98.

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Broer L, Buchman AS, Deelen J, Evans DS, Faul JD, Lunetta KL, et al. GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. J Gerontol A Biol Sci Med Sci. 2015;70(1):110–8.

    Article  CAS  PubMed  Google Scholar 

  12. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Deelen J, Evans DS, Arking DE, Tesi N, Nygaard M, Liu X, et al. A meta-analysis of genome-wide association studies identifies multiple longevity genes. Nat Commun. 2019;10(1):3669.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 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. 2019;74(1):44–51.

    Article  CAS  PubMed  Google Scholar 

  15. Bae H et al. Associations of FOXO3A polymorphisms with extreme human longevity in four longevity studies. J Gerontol A Biol Sci Med Sci. 2017; p. E-pub ahead of print Jul 18, 2017.

  16. Pilling LC, Atkins JL, Bowman K, Jones SE, Tyrrell J, Beaumont RN, et al. Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants. Aging (Albany NY). 2016;8(3):547–60.

    Article  CAS  Google Scholar 

  17. McCorrison J, et al. Genetic support for longevity-enhancing drug targets: issues, preliminary data, and future directions. J Gerontol. 2019;74(Supplement_1):S61–71.

    Article  Google Scholar 

  18. King EA, Davis JW, Degner JF. Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval. PLoS Genet. 2019;15(12):e1008489.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Davies DR, Gelinas AD, Zhang C, Rohloff JC, Carter JD, O'Connell D, et al. Unique motifs and hydrophobic interactions shape the binding of modified DNA ligands to protein targets. Proc Natl Acad Sci U S A. 2012;109(49):19971–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tanaka T, Biancotto A, Moaddel R, Moore AZ, Gonzalez-Freire M, Aon MA, et al. Plasma proteomic signature of age in healthy humans. Aging Cell. 2018;17:e12799.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Suhre K, Arnold M, Bhagwat AM, Cotton RJ, Engelke R, Raffler J, et al. Connecting genetic risk to disease end points through the human blood plasma proteome. Nat Commun. 2017;8:14357.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Emilsson V, et al. Co-regulatory networks of human serum proteins link genetics to disease: Science; 2018.

  23. Sebastiani P et al. A serum protein signature of APOE genotypes in centenarians. Aging Cell. 2019; p. e13023.

  24. Sebastiani P, Perls TT. The genetics of extreme longevity: lessons from the New England Centenarian Study. Front Genet. 2012;3:277.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Das S, Forer L, Schönherr S, Sidore C, Locke AE, Kwong A, et al. Next-generation genotype imputation service and methods. Nature Genetics. 2016;48(10):1284–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Loh P-R, Danecek P, Palamara PF, Fuchsberger C, A Reshef Y, K Finucane H, et al. Reference-based phasing using the haplotype reference consortium panel. Nature Genetics. 2016;48(11):1443–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Suh Y, Atzmon G, Cho M-O, Hwang D, Bingrong L, Leahy DJ, et al. Functionally significant insulin-like growth factor 1 receptor mutations in centenarians. Proc Natl Acad Sci U S A. 2008;105:3438–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang WB et al. Insulin-like growth factor-1 and IGF binding proteins predict all-cause mortality and morbidity in older adults. Cells. 2020; 9(6).

  29. Bell F, Miller M. Life tables for the United States Social Security Area 1900-2100. Actuarial Study No. 116; 2005.

  30. Conomos MP, Reiner AP, Weir BS, Thornton TA. Model-free estimation of recent genetic relatedness. Am J Hum Genet. 2016;98(1):127–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gogarten SM, Sofer T, Chen H, Yu C, Brody JA, Thornton TA, et al. Genetic association testing using the GENESIS R/Bioconductor package. Bioinformatics. 2019;35(24):5346–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Candia J, Cheung F, Kotliarov Y, Fantoni G, Sellers B, Griesman T, et al. Assessment of variability in the SOMAscan assay. Scientific Reports. 2017;7(1):14248.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Lehallier B, Gate D, Schaum N, Nanasi T, Lee SE, Yousef H, et al. Undulating changes in human plasma proteome profiles across the lifespan. Nat Med. 2019;25(12):1843–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Federico A, Monti S. hypeR: an R package for geneset enrichment workflows. Bioinformatics. 2020;36(4):1307–8.

    Article  CAS  PubMed  Google Scholar 

  35. Melville SA, Buros J, Parrado AR, Vardarajan B, Logue MW, Shen L, et al. Multiple loci influencing hippocampal degeneration identified by genome scan. Annals of Neurology. 2012;72(1):65–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Perry JRB, et al. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature. 2014;514(7520):92–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Timmers PRHJ, Mounier N, Lall K, Fischer K, Ning Z, Feng X, et al. Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances. eLife. 2019;8:e39856.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Sebastiani P et al. Protein signatures of centenarians and their offspring suggest centenarians age slower than other humans. Aging Cell. 2021; p. e13290.

  39. Hwang SJ, et al. A genome-wide association for kidney function and endocrine-related traits in the NHLBI’s Framingham Heart Study. BMC Med Genet. 2007;8(Suppl 1):S10.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Hao Y, Chai KH, McLoughlin DM, Chan HYE, Lau KF. Promoter characterization and genomic organization of the human X11β gene APBA2. NeuroReport. 2012;23(3):146–51.

    Article  CAS  PubMed  Google Scholar 

  41. Quesada V, Freitas-Rodríguez S, Miller J, Pérez-Silva JG, Jiang ZF, Tapia W, et al. Giant tortoise genomes provide insights into longevity and age-related disease. Nat Ecol Evol. 2019;3(1):87–95.

    Article  PubMed  Google Scholar 

  42. Ehnholm C, Lukka M, Kuusi T, Nikkilä E, Utermann G. Apolipoprotein E polymorphism in the Finnish population: gene frequencies and relation to lipoprotein concentrations. J Lipid Res. 1986;27(3):227–35.

    Article  CAS  PubMed  Google Scholar 

  43. Haddy N, Bacquer DD, Chemaly MM, Maurice M, Ehnholm C, Evans A, et al. The importance of plasma apolipoprotein E concentration in addition to its common polymorphism on inter-individual variation in lipid levels: results from Apo Europe. Eur J Hum Genet. 2002;10(12):841–50.

    Article  CAS  PubMed  Google Scholar 

  44. Cao J, Nomura SO, Steffen BT, Guan W, Remaley AT, Karger AB, et al. Apolipoprotein B discordance with low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol in relation to coronary artery calcification in the Multi-Ethnic Study of Atherosclerosis (MESA). J Clin Lipidol. 2020;14(1):109–121 e5.

    Article  PubMed  Google Scholar 

  45. Marivin A, Berthelet J, Plenchette S, Dubrez L. The inhibitor of apoptosis (IAPs) in adaptive response to cellular stress. Cells. 2012;1(4):711–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N, Garg P, et al. IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell. 2007;131(4):669–81.

    Article  CAS  PubMed  Google Scholar 

  47. Mak PY, Mak DH, Ruvolo V, Jacamo R, Kornblau SM, Kantarjian H, et al. Apoptosis repressor with caspase recruitment domain modulates second mitochondrial-derived activator of caspases mimetic-induced cell death through BIRC2/MAP3K14 signalling in acute myeloid leukaemia. Br J Haematol. 2014;167(3):376–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hinz M, Stilmann M, Arslan SÇ, Khanna KK, Dittmar G, Scheidereit C. A cytoplasmic ATM-TRAF6-cIAP1 module links nuclear DNA damage signaling to ubiquitin-mediated NF-kappaB activation. Mol Cell. 2010;40(1):63–74.

    Article  CAS  PubMed  Google Scholar 

  49. Moutaoufik MT, et al. Rewiring of the human mitochondrial interactome during neuronal reprogramming reveals regulators of the respirasome and neurogenesis. iScience. 2019;19:1114–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Basisty N, Kale A, Jeon OH, Kuehnemann C, Payne T, Rao C, et al. A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol. 2020;18(1):e3000599.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Wiklund FE, Bennet AM, Magnusson PKE, Eriksson UK, Lindmark F, Wu L, et al. Macrophage inhibitory cytokine-1 (MIC-1/GDF15): a new marker of all-cause mortality. Aging Cell. 2010;9(6):1057–64.

    Article  CAS  PubMed  Google Scholar 

  53. Johnen H, Lin S, Kuffner T, Brown DA, Tsai VWW, Bauskin AR, et al. Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1. Nat Med. 2007;13(11):1333–40.

    Article  CAS  PubMed  Google Scholar 

  54. Salminen M, Viljanen A, Eloranta S, Viikari P, Wuorela M, Vahlberg T, et al. Frailty and mortality: an 18-year follow-up study among Finnish community-dwelling older people. Aging Clin Exp Res. 2020;32(10):2013–9.

    Article  PubMed  Google Scholar 

  55. Croze F, et al. Expression of insulin-like growth factor-I and insulin-like growth factor-binding protein-1 in the rat uterus during decidualization. Endocrinology. 1990;127(4):1995–2000.

    Article  CAS  PubMed  Google Scholar 

  56. Martinez-Aguilar E, Gomez-Rodriguez V, Orbe J, Rodriguez JA, Fernández-Alonso L, Roncal C, et al. Matrix metalloproteinase 10 is associated with disease severity and mortality in patients with peripheral arterial disease. Journal of Vascular Surgery. 2015;61(2):428–35.

    Article  PubMed  Google Scholar 

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Funding

This work was supported by the National Institute on Aging (NIA cooperative agreements U19-AG023122 and UH2AG064704, and grant R01 AG061844), the Nathan Shock Center of Excellence for the basic Biology of Aging (P30AG038072) (N. B.), the Einstein-Paul Glenn Foundation for Medical Research Center for the Biology of Human Aging (N. B.), NIH/NIA 1 R01AG044829 (PIs-Veghese/Barzilai), NIH/NIA1 NIH-1 R01AG 046949-R01 AG057909-01 (PIs Barzilai & Zhang), U19 AG056278 (Vjig), K23AG051148 (SM), R01AG061155 (SM), the National Institute of General Medical Sciences (grant R24 GM134210), and the NIH Office of the Director (grant S10 OD021728).

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Authors and Affiliations

  1. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

    Anastasia Gurinovich & Zeyuan Song

  2. Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, USA

    William Zhang, Nir Barzilai & Sofiya Millman

  3. Bioinformatics Program, Boston University, Boston, MA, USA

    Anthony Federico & Stefano Monti

  4. Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA

    Stefano Monti

  5. Department of Medicine, Geriatrics Section, Boston University School of Medicine, Boston, MA, USA

    Stacy L. Andersen & Thomas T. Perls

  6. Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA, 02139, USA

    Lori L. Jennings

  7. Regeneron Pharmaceuticals, 777 Old Saw Mill River Rd, Tarrytown, NY, 10591, USA

    David J. Glass

  8. Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA, USA

    Paola Sebastiani

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  1. Anastasia Gurinovich
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Correspondence to Paola Sebastiani.

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L.L.J. is an employee and stock-holder of Novartis. D.J.G is an employee and stock-holder of Regeneron Pharmaceuticals.

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Gurinovich, A., Song, Z., Zhang, W. et al. Effect of longevity genetic variants on the molecular aging rate. GeroScience 43, 1237–1251 (2021). https://doi.org/10.1007/s11357-021-00376-4

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