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16 - Lessons from Exceptionally Long-Lived Individuals and Long-Living Families

Implications for Medical Research on Ageing and Age-Related Diseases

Published online by Cambridge University Press:  14 November 2024

By
Larissa Smulders  and
Joris Deelen
Edited by
Jean-François Lemaître  and
Samuel Pavard
Jean-François Lemaître
Affiliation:
Centre National de la Recherche Scientifique (CNRS)
Samuel Pavard
Affiliation:
National Museum of Natural History, Paris
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Summary

This chapter presents how scientists currently use the increasing number of individuals who live to an age above 90 years (i.e. long-lived individuals) to investigate biological determinants of longevity. It will provide an overview of the most extensive studies of exceptionally long-lived individuals and long-living families that have been established since the early 1970s. The focus of the chapter will be on the metabolic phenotypes and the genetic determinants that characterize them. It will discuss the delayed occurrence of age-related disease in long-lived individuals and their offspring as well as their favourable immune-metabolic profile, that is, improved glycaemic control, lipid and thyroid metabolism and immunity. Moreover, it will provide an overview of studies focused on unravelling the genetic component of longevity, which is assumed to be partly responsible for the observed immune-metabolic profile. The findings from these studies indicate that longevity is most likely determined by many different rare protective genetic variants that still need to be identified, for example using whole genome/exome sequencing approaches. Last, but not least, the chapter will discuss some of the implications of the presented findings for medical research on ageing and age-related diseases.

Keywords

long-living familiesmetabolic phenotypesglycaemic controllipid metabolismthyroid metabolismimmunitygenetics
Type
Chapter
Information
The Biodemography of Ageing and Longevity , pp. 311 - 330
Publisher: Cambridge University Press
Print publication year: 2024

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References

Oeppen, J., Vaupel, J.W. 2002. Demography: broken limits to life expectancy. Science 296, 1029–1031.CrossRefGoogle ScholarPubMed
Woolf, S.H., Schoomaker, H. 2019. Life expectancy and mortality rates in the United States, 1959–2017. JAMA 322, 1996–2016.CrossRefGoogle ScholarPubMed
Crimmins, E.M. 2015. Lifespan and healthspan: past, present, and promise. Gerontologist 55, 901–911.CrossRefGoogle ScholarPubMed
Fries, J.F. 2005. The compression of morbidity. Milbank Q. 83, 801–823.CrossRefGoogle ScholarPubMed
Van den Berg, N., Rodriguez-Girondo, M., Dijk, I.K., Mourits, R.J., Mandemakers, K., Janssens, A. 2019. Longevity defined as top 10% survivors and beyond is transmitted as a quantitative genetic trait. Nat. Commun. 10, 35.CrossRefGoogle ScholarPubMed
Andersen, S.L., Sebastiani, P., Dworkis, D.A., Feldman, L., Perls, T.T. 2012. Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. J. Gerontol. Biol. Sci. Med. Sci. 67, 395–405.CrossRefGoogle ScholarPubMed
Sanabe, E., Ashitomi, I., Suzuki, M. 1977. Social and medical survey of centenarians. Okinawa J. Pub. Health 9, 98–106.Google Scholar
Perls, T.T., Bochen, K., Freeman, M., Alpert, L., Silver, M.H. 1999. Validity of reported age and centenarian prevalence in New England. Age Ageing 28, 193–197.CrossRefGoogle ScholarPubMed
Schoenmaker, M., Craen, A.J., Meijer, P.H., Beekman, M., Blauw, G.J., Slagboom, P.E. 2006. Evidence of genetic enrichment for exceptional survival using a family approach: the Leiden Longevity Study. Eur. J. Hum. Genet. 14, 79–84.CrossRefGoogle ScholarPubMed
Newman, A.B., Glynn, N.W., Taylor, C.A., Sebastiani, P., Perls, T.T., Mayeux, R. 2011. Health and function of participants in the Long Life Family Study: a comparison with other cohorts. Aging 3, 63–76.CrossRefGoogle Scholar
Ismail, K., Nussbaum, L., Sebastiani, P., Andersen, S., Perls, T., Barzilai, N. 2016. Compression of morbidity is observed across cohorts with exceptional longevity. J. Am. Geriatr. Soc. 64, 1583–1591.CrossRefGoogle ScholarPubMed
Sebastiani, P., Sun, F.X., Andersen, S.L., Lee, J.H., Wojczynski, M.K., Sanders, J.L. 2013. Families enriched for exceptional longevity also have increased health-span: Findings from the long life family study. Front Public Health 1, 38.CrossRefGoogle ScholarPubMed
Westendorp, R.G., Heemst, D., Rozing, M.P., Frolich, M., Mooijaart, S.P., Blauw, G.J. 2009. Nonagenarian siblings and their offspring display lower risk of mortality and morbidity than sporadic nonagenarians: The Leiden Longevity Study. J. Am. Geriatr. Soc. 57, 1634–1637.CrossRefGoogle ScholarPubMed
Evert, J., Lawler, E., Bogan, H., Perls, T. 2003. Morbidity profiles of centenarians: survivors, delayers, and escapers. J. Gerontol. Biol. Sci. Med. Sci. 58, 232–237.CrossRefGoogle ScholarPubMed
Bucci, L., Ostan, R., Cevenini, E., Pini, E., Scurti, M., Vitale, G. 2016. Centenarians’ offspring as a model of healthy aging: a reappraisal of the data on Italian subjects and a comprehensive overview. Aging 8, 510–519.CrossRefGoogle Scholar
Terry, D.F., Wilcox, M.A., McCormick, M.A., Pennington, J.Y., Schoenhofen, E.A., Andersen, S.L. 2004. Lower all-cause, cardiovascular, and cancer mortality in centenarians’ offspring. J. Am. Geriatr. Soc. 52, 2074–2076.CrossRefGoogle ScholarPubMed
Andersen, S.L., Sweigart, B., Sebastiani, P., Drury, J., Sidlowski, S., Perls, T.T. 2019. Reduced prevalence and incidence of cognitive impairment among centenarian offspring. J. Gerontol. Biol. Sci. Med. Sci. 74, 108–113.CrossRefGoogle ScholarPubMed
Sato, Y., Atarashi, K., Plichta, D.R., Arai, Y., Sasajima, S., Kearney, S.M. 2021. Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians. Nature 599, 458–464.CrossRefGoogle ScholarPubMed
Rozing, M.P., Westendorp, R.G., Frolich, M., Craen, A.J., Beekman, M., Heijmans, B.T. 2009. Human insulin/IGF-1 and familial longevity at middle age. Aging 1, 714–722.CrossRefGoogle ScholarPubMed
Suh, Y., Atzmon, G., Cho, M.O., Hwang, D., Liu, B., Leahy, D.J. 2008. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc. Natl. Acad. Sci. U. A 105, 3438–3442.CrossRefGoogle ScholarPubMed
Vitale, G., Brugts, M.P., Ogliari, G., Castaldi, D., Fatti, L.M., Varewijck, A.J. 2012. Low circulating IGF-I bioactivity is associated with human longevity: findings in centenarians’ offspring. Aging 4, 580–589.CrossRefGoogle ScholarPubMed
Deelen, J., Kettunen, J., Fischer, K., Spek, A., Trompet, S., Kastenmuller, G. 2019. A metabolic profile of all-cause mortality risk identified in an observational study of 44,168 individuals. Nat. Commun. 10, 3346.CrossRefGoogle Scholar
Li, X., Ploner, A., Wang, Y., Zhan, Y., Pedersen, N.L., Magnusson, P.K. 2021. Clinical biomarkers and associations with healthspan and lifespan: Evidence from observational and genetic data. EBioMedicine 66, 103318.CrossRefGoogle ScholarPubMed
Barbe-Tuana, F., Funchal, G., Schmitz, C.R.R., Maurmann, R.M., Bauer, M.E. 2020. The interplay between immunosenescence and age-related diseases. Semin. Immunopathol. 42, 545–557.CrossRefGoogle ScholarPubMed
Fulop, T., Larbi, A., Dupuis, G., Le Page, A., Frost, E.H., Cohen, A.A. 2017. Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes? Front Immunol. 8, 1960.CrossRefGoogle ScholarPubMed
Rea, I.M., Gibson, D.S., McGilligan, V., McNerlan, S.E., Alexander, H.D., Ross, O.A. 2018. Age and age-related diseases: role of inflammation triggers and cytokines. Front Immunol. 9, 586.CrossRefGoogle Scholar
Deelen, J., Akker, E.B., Trompet, S., Heemst, D., Mooijaart, S.P., Slagboom, P.E. 2016. Employing biomarkers of healthy ageing for leveraging genetic studies into human longevity. Exp. Gerontol. 82, 166–174.CrossRefGoogle ScholarPubMed
Ruhaak, L.R., Uh, H.W., Beekman, M., Hokke, C.H., Westendorp, R.G., Houwing-Duistermaat, J. 2011. Plasma protein N-glycan profiles are associated with calendar age, familial longevity and health. J. Proteome Res. 10, 1667–1674.CrossRefGoogle ScholarPubMed
Ruhaak, L.R., Uh, H.W., Beekman, M., Koeleman, C.A., Hokke, C.H., Westendorp, R.G. 2010. Decreased levels of bisecting GlcNAc glycoforms of IgG are associated with human longevity. PLoS ONE 5, 12566.CrossRefGoogle ScholarPubMed
Passtoors, W.M., Boer, J.M., Goeman, J.J., Akker, E.B., Deelen, J., Zwaan, B.J. 2012. Transcriptional profiling of human familial longevity indicates a role for ASF1A and IL7R. PLoS ONE 7, 27759.CrossRefGoogle ScholarPubMed
Xiao, F.H., Chen, X.Q., Yu, Q., Ye, Y., Liu, Y.W., Yan, D. 2018. Transcriptome evidence reveals enhanced autophagy-lysosomal function in centenarians. Genome Res. 28, 1601–1610.CrossRefGoogle ScholarPubMed
Sebastiani, P., Federico, A., Morris, M., Gurinovich, A., Tanaka, T., Chandler, K.B. 2021. Protein signatures of centenarians and their offspring suggest centenarians age slower than other humans. Aging Cell 20, 13290.CrossRefGoogle ScholarPubMed
Collino, S., Montoliu, I., Martin, F.P., Scherer, M., Mari, D., Salvioli, S. 2013. Metabolic signatures of extreme longevity in northern Italian centenarians reveal a complex remodeling of lipids, amino acids, and gut microbiota metabolism. PLoS ONE 8, 56564.CrossRefGoogle ScholarPubMed
Gonzalez-Covarrubias, V., Beekman, M., Uh, H.W., Dane, A., Troost, J., Paliukhovich, I. 2013. Lipidomics of familial longevity. Aging Cell 12, 426–434.CrossRefGoogle ScholarPubMed
Gentilini, D., Mari, D., Castaldi, D., Remondini, D., Ogliari, G., Ostan, R. 2013. Role of epigenetics in human aging and longevity: genome-wide DNA methylation profile in centenarians and centenarians’ offspring. Age 35, 1961–1973.CrossRefGoogle ScholarPubMed
Gutman, D., Rivkin, E., Fadida, A., Sharvit, L., Hermush, V., Rubin, E. 2020. Exceptionally long-lived individuals (ELLI) demonstrate slower aging calculated by DNA methylation clocks as possible modulators for healthy longevity. Int. J. Mol. Sci. 21, 615.CrossRefGoogle ScholarPubMed
Horvath, S., Pirazzini, C., Bacalini, M.G., Gentilini, D., Blasio, A.M., Delledonne, M. 2015. Aging. 7, 1159–1170.CrossRefGoogle Scholar
Marioni, R.E., Shah, S., McRae, A.F., Chen, B.H., Colicino, E., Harris, S.E. 2015. DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol. 16, 25.CrossRefGoogle ScholarPubMed
Van den Berg, D., Rodriguez-Girondo, M., Craen, A.J.M., Houwing-Duistermaat, J.J., Beekman, M., Slagboom, P.E. 2018. Longevity around the turn of the 20th century: Life-long sustained survival advantage for parents of Today’s Nonagenarians. J. Gerontol. Biol. Sci. Med. Sci. 73, 1295–1302.CrossRefGoogle Scholar
Pedersen, J.K., Elo, I.T., Schupf, N., Perls, T.T., Stallard, E., Yashin, A.I. 2017. The survival of spouses marrying into longevity-enriched families. J. Gerontol. Biol. Sci. Med. Sci. 72, 109–114.CrossRefGoogle ScholarPubMed
Perls, T.T., Wilmoth, J., Levenson, R., Drinkwater, M., Cohen, M., Bogan, H. 2002. Life-long sustained mortality advantage of siblings of centenarians. Proc. Natl. Acad. Sci. U. A 99, 8442–8447.CrossRefGoogle ScholarPubMed
Schoenmaker, M., Craen, A.J., Meijer, P.H., Beekman, M., Blauw, G.J., Slagboom, P.E. 2006. Evidence of genetic enrichment for exceptional survival using a family approach: the Leiden Longevity Study. Eur. J. Hum. Genet. 14, 79–84.CrossRefGoogle ScholarPubMed
Rajpathak, S.N., Liu, Y., Ben-David, O., Reddy, S., Atzmon, G., Crandall, J. 2011. Lifestyle factors of people with exceptional longevity. J. Am. Geriatr. Soc. 59, 1509–1512.CrossRefGoogle ScholarPubMed
Van den Berg, N., Beekman, M., Smith, K.R., Janssens, A., Slagboom, P.E. 2017. Historical demography and longevity genetics: Back to the future. Ageing Res. Rev. 38, 28–39.CrossRefGoogle ScholarPubMed
Beekman, M., Nederstigt, C., Suchiman, H.E., Kremer, D., Breggen, R., Lakenberg, N. 2010. Genome-wide association study (GWAS)-identified disease risk alleles do not compromise human longevity. Proc. Natl. Acad. Sci. U. A 107, 18046–18049.CrossRefGoogle Scholar
Gutman, D., Lidzbarsky, G., Milman, S., Gao, T., Sin-Chan, P., Gonzaga-Jauregui, C. 2020. Similar burden of pathogenic coding variants in exceptionally long-lived individuals and individuals without exceptional longevity. Aging Cell 19, 13216.CrossRefGoogle ScholarPubMed
Stevenson, M., Bae, H., Schupf, N., Andersen, S., Zhang, Q., Perls, T. 2015. Burden of disease variants in participants of the Long Life Family Study. Aging 7, 123–132.CrossRefGoogle ScholarPubMed
Bonafe, M., Olivieri, F., Mari, D., Baggio, G., Mattace, R., Sansoni, P. 1999. p53 variants predisposing to cancer are present in healthy centenarians. Am. J. Hum. Genet. 64, 292–295.CrossRefGoogle ScholarPubMed
Garagnani, P., Marquis, J., Delledonne, M., Pirazzini, C., Marasco, E., Kwiatkowska, K.M. 2021. Whole-genome sequencing analysis of semi-supercentenarians. eLife 10, e57849.CrossRefGoogle ScholarPubMed
Lin, J.-R., Sin-Chan, P., Napolioni, V., Torres, G.G., Mitra, J., Zhang, Q. 2021. Rare genetic coding variants associated with human longevity and protection against age-related diseases. Nat. Aging 1, 783–794.CrossRefGoogle ScholarPubMed
Mahley, R.W., Rall, S.C.J. 2000. Apolipoprotein E: far more than a lipid transport protein. Annu. Rev. Genomics Hum. Genet. 1, 507–537.CrossRefGoogle ScholarPubMed
Broer, L., Buchman, A.S., Deelen, J., Evans, D.S., Faul, J.D., Lunetta, K.L. 2015. GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. J. Gerontol. Biol. Sci. Med. Sci. 70, 110–118.CrossRefGoogle ScholarPubMed
Flachsbart, F., Caliebe, A., Kleindorp, R., Blanche, H., Eller-Eberstein, H., Nikolaus, S. 2009. Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc. Natl. Acad. Sci. U. A 106, 2700–2705.CrossRefGoogle ScholarPubMed
Willcox, B.J., Donlon, T.A., He, Q., Chen, R., Grove, J.S., Yano, K. 2008. FOXO3A genotype is strongly associated with human longevity. Proc. Natl. Acad. Sci. U. A 105, 13987–13982.CrossRefGoogle ScholarPubMed
Grossi, V., Forte, G., Sanese, P., Peserico, A., Tezil, T., Lepore Signorile, M. 2018. The longevity SNP rs2802292 uncovered: HSF1 activates stress-dependent expression of FOXO3 through an intronic enhancer. Nucleic Acids Res. 46, 5587–5600.CrossRefGoogle ScholarPubMed
Budovsky, A., Craig, T., Wang, J., Tacutu, R., Csordas, A., Lourenco, J. 2013. LongevityMap: a database of human genetic variants associated with longevity. Trends Genet. 29, 559–560.CrossRefGoogle ScholarPubMed
Dato, S., Soerensen, M., Rango, F., Rose, G., Christensen, K., Christiansen, L. 2018. The genetic component of human longevity: New insights from the analysis of pathway-based SNP-SNP interactions. Aging Cell 17, 12755.CrossRefGoogle ScholarPubMed
Debrabant, B., Soerensen, M., Flachsbart, F., Dato, S., Mengel-From, J., Stevnsner, T. 2014. Human longevity and variation in DNA damage response and repair: study of the contribution of sub-processes using competitive gene-set analysis. Eur. J. Hum. Genet. 22, 1131–1136.CrossRefGoogle ScholarPubMed
Deelen, J., Uh, H.W., Monajemi, R., Heemst, D., Thijssen, P.E., Bohringer, S. 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.CrossRefGoogle ScholarPubMed
Passtoors, W.M., Beekman, M., Deelen, J., Breggen, R., Maier, A.B., Guigas, B. 2013. Gene expression analysis of mTOR pathway: association with human longevity. Aging Cell 12, 24–31.CrossRefGoogle ScholarPubMed
Boyden, S.E., Kunkel, L.M. 2010. High-density genomewide linkage analysis of exceptional human longevity identifies multiple novel loci. PLoS ONE 5, 12432.CrossRefGoogle ScholarPubMed
Beekman, M., Blauw, G.J., Houwing-Duistermaat, J.J., Brandt, B.W., Westendorp, R.G., Slagboom, P.E. 2006. Chromosome 4q25, microsomal transfer protein gene, and human longevity: novel data and a meta-analysis of association studies. J. Gerontol. Biol. Sci. Med. Sci. 61, 355–362.CrossRefGoogle Scholar
Geesaman, B.J., Benson, E., Brewster, S.J., Kunkel, L.M., Blanche, H., Thomas, G. 2003. Haplotype-based identification of a microsomal transfer protein marker associated with the human lifespan. Proc. Natl. Acad. Sci. U. A 100, 14115–14120.CrossRefGoogle ScholarPubMed
Kerber, R.A., O’Brien, E., Boucher, K.M., Smith, K.R., Cawthon, R.M. 2012. A genome-wide study replicates linkage of 3p22-24 to extreme longevity in humans and identifies possible additional loci. PLoS ONE 7, 34746.CrossRefGoogle ScholarPubMed
Puca, A.A., Daly, M.J., Brewster, S.J., Matise, T.C., Barrett, J., Shea-Drinkwater, M. 2001. A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4. Proc. Natl. Acad. Sci. U. A 98, 10505–10508.CrossRefGoogle ScholarPubMed
Beekman, M., Blanche, H., Perola, M., Hervonen, A., Bezrukov, V., Sikora, E. 2013. Genome-wide linkage analysis for human longevity: genetics of Healthy Aging Study. Aging Cell 12, 184–193.CrossRefGoogle ScholarPubMed
Deelen, J., Beekman, M., Uh, H.W., Helmer, Q., Kuningas, M., Christiansen, L. 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.CrossRefGoogle ScholarPubMed
Flachsbart, F., Ellinghaus, D., Gentschew, L., Heinsen, F.A., Caliebe, A., Christiansen, L. 2016. Immunochip analysis identifies association of the RAD50/IL13 region with human longevity. Aging Cell 15, 585–588.CrossRefGoogle ScholarPubMed
Nebel, A., Kleindorp, R., Caliebe, A., Nothnagel, M., Blanche, H., Junge, O. 2011. A genome-wide association study confirms APOE as the major gene influencing survival in long-lived individuals. Mech. Ageing Dev. 132, 324–330.CrossRefGoogle ScholarPubMed
Newman, A.B., Walter, S., Lunetta, K.L., Garcia, M.E., Slagboom, P.E., Christensen, K. 2010. A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. J. Gerontol. Biol. Sci. Med. Sci. 65, 478–487.CrossRefGoogle ScholarPubMed
Sebastiani, P., Solovieff, N., Dewan, A.T., Walsh, K.M., Puca, A., Hartley, S.W. 2012. Genetic signatures of exceptional longevity in humans. PLoS ONE 7, 29848.CrossRefGoogle ScholarPubMed
Torres, G.G., Nygaard, M., Caliebe, A., Blanche, H., Chantalat, S., Galan, P. 2021. Exome-wide association study identifies FN3KRP and PGP as new candidate longevity genes. J. Gerontol. Biol. Sci. Med. Sci. 76, 786-795.CrossRefGoogle ScholarPubMed
Deelen, J., Beekman, M., Uh, H.W., Broer, L., Ayers, K.L., Tan, Q. 2014. Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age. Hum. Mol. Genet. 23, 4420–4432.CrossRefGoogle ScholarPubMed
Deelen, J., Evans, D.S., Arking, D.E., Tesi, N., Nygaard, M., Liu, X. 2019. A meta-analysis of genome-wide association studies identifies multiple longevity genes. Nat. Commun. 10, 3669.CrossRefGoogle ScholarPubMed
Gurinovich, A., Song, Z., Zhang, W., Federico, A., Monti, S., Andersen, S.L. 2021. Effect of longevity genetic variants on the molecular aging rate. Geroscience 43, 1237–1251.Google Scholar
Liu, X., Song, Z., Li, Y., Yao, Y., Fang, M., Bai, C. 2021. Integrated genetic analyses revealed novel human longevity loci and reduced risks of multiple diseases in a cohort study of 15,651 Chinese individuals. Aging Cell 20, 13323.CrossRefGoogle Scholar
Sebastiani, P., Gurinovich, A., Bae, H., Andersen, S., Malovini, A., Atzmon, G. 2017. Four genome-wide association studies identify new extreme longevity variants. J. Gerontol. Biol. Sci. Med. Sci. 72, 1453–1464.CrossRefGoogle ScholarPubMed
Zeng, Y., Nie, C., Min, J., Liu, X., Li, M., Chen, H. 2016. Novel loci and pathways significantly associated with longevity. Sci. Rep. 6, 21243.CrossRefGoogle ScholarPubMed
Rodriguez-Girondo, M., Berg, N., Hof, M.H., Beekman, M., Slagboom, E. 2021. Improved selection of participants in genetic longevity studies: family scores revisited. BMC Med. Res. Methodol. 21, 7.CrossRefGoogle ScholarPubMed
Sebastiani, P., Hadley, E.C., Province, M., Christensen, K., Rossi, W., Perls, T.T. 2009. A family longevity selection score: ranking sibships by their longevity, size, and availability for study. Am. J. Epidemiol. 170, 1555–1562.CrossRefGoogle ScholarPubMed
Yashin, A.I., Benedictis, G., Vaupel, J.W., Tan, Q., Andreev, K.F., Iachine, I.A. 1999. Genes, demography, and life span: the contribution of demographic data in genetic studies on aging and longevity. Am. J. Hum. Genet. 65, 1178–1193.CrossRefGoogle ScholarPubMed
Lee, S., Abecasis, G.R., Boehnke, M., Lin, X. 2014. Rare-variant association analysis: study designs and statistical tests. Am. J. Hum. Genet. 95, 5–23.CrossRefGoogle ScholarPubMed
Flachsbart, F., Dose, J., Gentschew, L., Geismann, C., Caliebe, A., Knecht, C. 2017 Identification and characterization of two functional variants in the human longevity gene FOXO3. Nat Commun 8.CrossRefGoogle ScholarPubMed
Tazearslan, C., Huang, J., Barzilai, N., Suh, Y. 2011. Impaired IGF1R signaling in cells expressing longevity-associated human IGF1R alleles. Aging Cell 10, 551–554.CrossRefGoogle ScholarPubMed
Ryu, S., Han, J., Norden-Krichmar, T.M., Zhang, Q., Lee, S., Zhang, Z. 2021. Genetic signature of human longevity in PKC and NF-kappaB signaling. Aging Cell 20, 13362.CrossRefGoogle ScholarPubMed
Lin, J.-R., Sin-Chan, P., Napolioni, V., Torres, G.G., Mitra, J., Zhang, Q. 2021. Rare genetic coding variants associated with human longevity and protection against age-related diseases. Nat. Aging 1, 783–794.CrossRefGoogle ScholarPubMed
Garagnani, P., Marquis, J., Delledonne, M., Pirazzini, C., Marasco, E., Kwiatkowska, K.M. 2021. Whole-genome sequencing analysis of semi-supercentenarians. eLife 10.CrossRefGoogle ScholarPubMed
Gierman, H.J., Fortney, K., Roach, J.C., Coles, N.S., Li, H., Glusman, G. 2014. Whole-genome sequencing of the world’s oldest people. PLoS ONE 9, 112430.CrossRefGoogle ScholarPubMed
Gutman, D., Lidzbarsky, G., Milman, S., Gao, T., Sin-Chan, P., Gonzaga-Jauregui, C. 2020. Similar burden of pathogenic coding variants in exceptionally long-lived individuals and individuals without exceptional longevity. Aging Cell 19, 13216.CrossRefGoogle ScholarPubMed
Holstege, H., Pfeiffer, W., Sie, D., Hulsman, M., Nicholas, T.J., Lee, C.C. 2014. Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis. Genome Res. 24, 733–742.CrossRefGoogle ScholarPubMed
Nygaard, H.B., Erson-Omay, E.Z., Wu, X., Kent, B.A., Bernales, C.Q., Evans, D.M. 2019. Whole-exome sequencing of an exceptional longevity cohort. J. Gerontol. Biol. Sci. Med. Sci. 74, 1386–1390.CrossRefGoogle ScholarPubMed
Sebastiani, P., Riva, A., Montano, M., Pham, P., Torkamani, A., Scherba, E. 2011. Whole genome sequences of a male and female supercentenarian, ages greater than 114 years. Front Genet. 2, 90.Google ScholarPubMed
Shen, S., Li, C., Xiao, L., Wang, X., Lv, H., Shi, Y. 2020. Whole-genome sequencing of Chinese centenarians reveals important genetic variants in aging WGS of centenarian for genetic analysis of aging. Hum. Genomics 14, 23.CrossRefGoogle ScholarPubMed
Van den Akker, E.B., Pitts, S.J., Deelen, J., Moed, M.H., Potluri, S., Rooij, J. 2016. Uncompromised 10-year survival of oldest old carrying somatic mutations in DNMT3A and TET2. Blood 127, 1512–1515.CrossRefGoogle ScholarPubMed
Ahadi, S., Zhou, W., Schussler-Fiorenza Rose, S.M., Sailani, M.R., Contrepois, K., Avina, M. 2020. Personal aging markers and ageotypes revealed by deep longitudinal profiling. Nat. Med. 26, 83–90.CrossRefGoogle ScholarPubMed
Kudryashova, K.S., Burka, K., Kulaga, A.Y., Vorobyeva, N.S., Kennedy, B.K. 2020. Aging biomarkers: From functional tests to multi-omics approaches. Proteomics 20, 1900408.CrossRefGoogle ScholarPubMed
Lara, J., Cooper, R., Nissan, J., Ginty, A.T., Khaw, K.T., Deary, I.J. 2015. A proposed panel of biomarkers of healthy ageing. BMC Med. 13, 222.CrossRefGoogle ScholarPubMed
Fabbri, E., Zoli, M., Gonzalez-Freire, M., Salive, M.E., Studenski, S.A., Ferrucci, L. 2015. Aging and multimorbidity: New tasks, priorities, and frontiers for integrated gerontological and clinical research. J. Am. Med. Dir. Assoc. 16, 640–647.CrossRefGoogle ScholarPubMed
Heilbronn, L.K., Jonge, L., Frisard, M.I., DeLany, J.P., Larson-Meyer, D.E., Rood, J. 2006. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA 295, 1539–1548.CrossRefGoogle ScholarPubMed
Van de Rest, O., Schutte, B.A., Deelen, J., Stassen, S.A., Akker, E.B., Heemst, D. 2016. Metabolic effects of a 13-weeks lifestyle intervention in older adults: the Growing Old Together Study. Aging 8, 111–126.CrossRefGoogle ScholarPubMed
Pavard, S., Coste, C.F.D. 2021. Evolutionary demographic models reveal the strength of purifying selection on susceptibility alleles to late-onset diseases. Nat. Ecol. Evol. 5, 392–400 (doi:10.1038/s41559-020-01355-2).CrossRefGoogle ScholarPubMed
Fontana, L., Partridge, L., Longo, V.D. 2010. Extending healthy life span: from yeast to humans. Science 328, 321–326.CrossRefGoogle ScholarPubMed
Fontana, L., Partridge, L. 2015. Promoting health and longevity through diet: from model organisms to humans. Cell 161, 106–118.CrossRefGoogle ScholarPubMed
Johnson, S.C., Kaeberlein, M. 2016. Rapamycin in aging and disease: maximizing efficacy while minimizing side effects. Oncotarget 7, 44876–44878.CrossRefGoogle ScholarPubMed
Mannick, J.B., Del Giudice, G., Lattanzi, M., Valiante, N.M., Praestgaard, J., Huang, B. 2014. mTOR inhibition improves immune function in the elderly. Sci. Transl. Med. 6, 268179.CrossRefGoogle ScholarPubMed
Mannick, J.B., Morris, M., Hockey, H.P., Roma, G., Beibel, M., Kulmatycki, K. 2018. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci. Transl. Med. 10, eaaq1564.CrossRefGoogle ScholarPubMed
Most, J., Tosti, V., Redman, L.M., Fontana, L. 2017. Calorie restriction in humans: an update. Ageing Res. Rev. 39, 36–45.CrossRefGoogle ScholarPubMed
Holstege, H., Beker, N., Dijkstra, T., Pieterse, K., Wemmenhove, E., Schouten, K. 2018. The 100-plus Study of cognitively healthy centenarians: rationale, design and cohort description. Eur. J. Epidemiol. 33, 1229–1249.CrossRefGoogle ScholarPubMed
Rasmussen, S.H., Andersen-Ranberg, K., Thinggaard, M., Jeune, B., Skytthe, A., Christiansen, L. 2017. Cohort profile: the 1895, 1905, 1910 and 1915 Danish Birth Cohort Studies – secular trends in the health and functioning of the very old. Int. J. Epidemiol. 46, 1746–1746.CrossRefGoogle ScholarPubMed
Frisoni, G.B., Louhija, J., Geroldi, C., Trabucchi, M. 2001. Longevity and the epsilon2 allele of apolipoprotein E: the Finnish Centenarians Study. J. Gerontol. Biol. Sci. Med. Sci. 56, 75–78.CrossRefGoogle ScholarPubMed
Robine, J.M., Cheung, S.L., Saito, Y., Jeune, B., Parker, M.G., Herrmann, F.R. 2010. Centenarians today: new insights on selection from the 5-COOP Study. Curr. Gerontol. Geriatr. Res., 2010, 120354.CrossRefGoogle ScholarPubMed
Blanche, H., Cabanne, L., Sahbatou, M., Thomas, G. 2001. A study of French centenarians: are ACE and APOE associated with longevity? C. R. Acad. Sci. III 324, 129–135.CrossRefGoogle ScholarPubMed
Nebel, A., Croucher, P.J., Stiegeler, R., Nikolaus, S., Krawczak, M., Schreiber, S. 2005. No association between microsomal triglyceride transfer protein (MTP) haplotype and longevity in humans. Proc. Natl. Acad. Sci. U. A 102, 7906–7909.CrossRefGoogle ScholarPubMed
Arai, Y., Inagaki, H., Takayama, M., Abe, Y., Saito, Y., Takebayashi, T. 2014. Physical independence and mortality at the extreme limit of life span: supercentenarians study in Japan. J. Gerontol. Biol. Sci. Med. Sci. 69, 486–494.CrossRefGoogle ScholarPubMed
Barzilai, N., Gabriely, I., Gabriely, M., Iankowitz, N., Sorkin, J.D. 2001. Offspring of centenarians have a favorable lipid profile. J. Am. Geriatr. Soc. 49, 76–79.CrossRefGoogle ScholarPubMed
Anselmi, C.V., Malovini, A., Roncarati, R., Novelli, V., Villa, F., Condorelli, G. 2009. Association of the FOXO3A locus with extreme longevity in a southern Italian centenarian study. Rejuvenation Res. 12, 95–104.CrossRefGoogle Scholar
Samuelsson, S.M., Alfredson, B.B., Hagberg, B., Samuelsson, G., Nordbeck, B., Brun, A. 1997. The Swedish Centenarian Study: a multidisciplinary study of five consecutive cohorts at the age of 100. Int. J. Aging Hum. Dev. 45, 223–253.CrossRefGoogle ScholarPubMed
Gondo, Y., Hirose, N., Arai, Y., Inagaki, H., Masui, Y., Yamamura, K. 2006. Functional status of centenarians in Tokyo, Japan: developing better phenotypes of exceptional longevity. J. Gerontol. Biol. Sci. Med. Sci. 61, 305–310.CrossRefGoogle ScholarPubMed
De Rango, F., Dato, S., Bellizzi, D., Rose, G., Marzi, E., Cavallone, L. 2008. A novel sampling design to explore gene-longevity associations: the ECHA Study. Eur. J. Hum. Genet. 16, 236–242.CrossRefGoogle ScholarPubMed
Skytthe, A., Valensin, S., Jeune, B., Cevenini, E., Balard, F., Beekman, M. 2011. Design, recruitment, logistics, and data management of the GEHA (Genetics of Healthy Ageing) project. Exp. Gerontol. 46, 934–945.CrossRefGoogle ScholarPubMed
Atzmon, G., Pollin, T.I., Crandall, J., Tanner, K., Schechter, C.B., Scherer, P.E. 2008. Adiponectin levels and genotype: a potential regulator of life span in humans. J. Gerontol. Biol. Sci. Med. Sci. 63, 447–453.CrossRefGoogle ScholarPubMed
Wijsman, C.A., Rozing, M.P., Streefland, T.C., Cessie, S., Mooijaart, S.P., Slagboom, P.E. 2011. Familial longevity is marked by enhanced insulin sensitivity. Aging Cell 10, 114–121.CrossRefGoogle ScholarPubMed
Barzilai, N., Atzmon, G., Schechter, C., Schaefer, E.J., Cupples, A.L., Lipton, R. 2003. Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA 290, 2030–2040.CrossRefGoogle ScholarPubMed
Vaarhorst, A.A., Beekman, M., Suchiman, E.H., Heemst, D., Houwing-Duistermaat, J.J., Westendorp, R.G. 2011. Lipid metabolism in long-lived families: the Leiden Longevity Study. Age 33, 219–227.CrossRefGoogle ScholarPubMed
Atzmon, G., Barzilai, N., Surks, M.I., Gabriely, I. 2009. Genetic predisposition to elevated serum thyrotropin is associated with exceptional longevity. J. Clin. Endocrinol. Metab. 94, 4768–4775.CrossRefGoogle ScholarPubMed
Jansen, S.W., Akintola, A.A., Roelfsema, F., Spoel, E., Cobbaert, C.M., Ballieux, B.E. 2015. Human longevity is characterised by high thyroid stimulating hormone secretion without altered energy metabolism. Sci. Rep. 5, 11525.CrossRefGoogle ScholarPubMed
Rozing, M.P., Westendorp, R.G., Craen, A.J., Frolich, M., Heijmans, B.T., Beekman, M. 2010. Low serum free triiodothyronine levels mark familial longevity: the Leiden Longevity Study. J. Gerontol. Biol. Sci. Med. Sci. 65, 365–368.CrossRefGoogle Scholar
Pellicano, M., Buffa, S., Goldeck, D., Bulati, M., Martorana, A., Caruso, C. 2014. Evidence for less marked potential signs of T-cell immunosenescence in centenarian offspring than in the general age-matched population. J. Gerontol. Biol. Sci. Med. Sci. 69, 495–504.CrossRefGoogle ScholarPubMed
Buffa, S., Pellicano, M., Bulati, M., Martorana, A., Goldeck, D., Caruso, C. 2013. A novel B cell population revealed by a CD38/CD24 gating strategy: CD38(-)CD24 (-) B cells in centenarian offspring and elderly people. Age 35, 2009–2024.CrossRefGoogle Scholar
Colonna-Romano, G., Buffa, S., Bulati, M., Candore, G., Lio, D., Pellicano, M. 2010. B cells compartment in centenarian offspring and old people. Curr. Pharm. Des. 16, 604–608.CrossRefGoogle ScholarPubMed
Derhovanessian, E., Maier, A.B., Beck, R., Jahn, G., Hahnel, K., Slagboom, P.E. 2010. Hallmark features of immunosenescence are absent in familial longevity. J. Immunol. 185, 4618–4624.CrossRefGoogle ScholarPubMed
Raz, Y., Guerrero-Ros, I., Maier, A., Slagboom, P.E., Atzmon, G., Barzilai, N. 2017. Activation-induced autophagy is preserved in CD4+ T-cells in familial longevity. J. Gerontol. Biol. Sci. Med. Sci. 72, 1201–1206.CrossRefGoogle ScholarPubMed

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