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Genetic determinants of exceptional human longevity: insights from the Okinawa Centenarian Study

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Abstract

Centenarians represent a rare phenotype appearing in roughly 10–20 per 100,000 persons in most industrialized countries but as high as 40–50 per 100,000 persons in Okinawa, Japan. Siblings of centenarians in Okinawa have been found to have cumulative survival advantages such that female centenarian siblings have a 2.58-fold likelihood and male siblings a 5.43-fold likelihood (versus their birth cohorts) of reaching the age of 90 years. This is indicative of a strong familial component to longevity. Centenarians may live such extraordinarily long lives in large part due to genetic variations that either affect the rate of aging and/or have genes that result in decreased susceptibility to age-associated diseases. Some of the most promising candidate genes appear to be those involved in regulatory pathways such as insulin signaling, immunoinflammatory response, stress resistance or cardiovascular function. Although gene variants with large beneficial effects have been suggested to exist, only APOE, an important regulator of lipoproteins has been consistently associated with a longer human lifespan across numerous populations. As longevity is a very complex trait, several issues challenge our ability to identify its genetic influences, such as control for environmental confounders across time, the lack of precise phenotypes of aging and longevity, statistical power, study design and availability of appropriate study populations. Genetic studies on the Okinawan population suggest that Okinawans are a genetically distinct group that has several characteristics of a founder population, including less genetic diversity, and clustering of specific gene variants, some of which may be related to longevity. Further work on this population and other genetic isolates would be of significant interest to the genetics of human longevity.

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References

  • Akisaka M, Suzuki M (1996) The bone density and activities of daily living in Okinawa centenarians. Hong Kong J Gerontol 10:453–457

    Google Scholar 

  • Akisaka M, Suzuki M (1998) Okinawa longevity study. Molecular genetic analysis of HLA genes in the very old. Nippon Ronen Igakkai Zasshi 35:294–298

    PubMed  CAS  Google Scholar 

  • Akisaka M, Asato L, Chan YC, Suzuki M, Uezato T, Yamamoto S (1996) Energy and nutrient intakes of Okinawan centenarians. J Nutr Sci Vitaminol 42:241–248

    PubMed  CAS  Google Scholar 

  • Akisaka M, Suzuki M, Inoko H (1997) Molecular genetic studies on DNA polymorphism of the HLA class II genes associated with human longevity. Tissue Antigens 50:489–493

    Article  PubMed  CAS  Google Scholar 

  • Allen M (2002) Identity and resistance in Okinawa. Rowman and Littlefield, Boston

    Google Scholar 

  • Altomare K, Greco V, Bellizzi D, Berardelli M, Dato S, DeRango F et al (2003) The allele (A)(-110) in the promoter region of the HSP70-1 gene is unfavorable to longevity in women. Biogerontology 4:215–220

    PubMed  CAS  Google Scholar 

  • Ambrosone CB, Freudenheim JL, Thompson PA, Bowman E, Vena JE, Marshall JR et al (1999) Manganese superoxide dismutase (MnSOD) genetic polymorphisms, dietary antioxidants, and risk of breast cancer. Cancer Res 59:602–606

    PubMed  CAS  Google Scholar 

  • Arai Y, Hirose N, Yamamura K, Nakazawa S, Shimizu K, Takayama M et al (2003) Deficiency of cholesteryl ester transfer protein and gene polymorphisms of lipoprotein lipase and hepatic lipase are not associated with longevity. J Mol Med 81:102–109

    PubMed  CAS  Google Scholar 

  • Arantes-Oliveira N, Berman JR, Kenyon C (2003) Healthy animals with extreme longevity. Science 302:611

    PubMed  CAS  Google Scholar 

  • Arking DE, Krebsova A, Macek M Sr, Macek M Jr, Arking A, Mian IS et al (2002) Association of human aging with a functional variant of klotho. Proc Natl Acad Sci USA 99:856–861

    PubMed  CAS  Google Scholar 

  • Atzmon G, Schechter C, Greiner W, Davidson D, Rennert G, Barzilai N (2004) Clinical phenotype of families with longevity. J Am Geriatr Soc 52:274–277

    PubMed  Google Scholar 

  • Aviv A (2004) Telomeres and human aging: facts and fibs. Sci Aging Knowledge Environ 51:pe43

    Google Scholar 

  • Aviv A, Valdes AM, Spector TD (2006) Human telomere biology: pitfalls of moving from the laboratory to epidemiology. Int J Epidemiol [Epub ahead of print on 22 Sept]

  • Barbieri M, Bonafe M, Franceschi C, Paolisso G (2003) Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans. Am J Physiol Endocrinol Metab 285:E1064–E1071

    PubMed  CAS  Google Scholar 

  • Bartke A (2005) Minireview: role of the growth hormone/insulin-like growth factor system in mammalian aging. Endocrinology 146:3718–3723

    PubMed  CAS  Google Scholar 

  • Bartke A, Chandrashekar V, Dominici F, Turyn D, Kinney B, Steger R (2003) Insulin-like growth factor 1 (IGF-1) and aging: controversies and new insights. Biogerontology 4:1–8

    PubMed  CAS  Google Scholar 

  • Barzilai N, Atzmon G, Schechter C, Schaefer EJ, Cupples AL, Lipton R et al (2003) Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA 290:2030–2040

    PubMed  CAS  Google Scholar 

  • Beekman M, Blauw GJ, Houwing-Duistermaat JJ, Brandt BW, Westendorp RG, Slagboom PE (2006) Chromosome 4q25, microsomal transfer protein gene, and human longevity: novel data and a meta-analysis of association studies. J Gerontol Ser A Biol Sci Med Sci 61:355–362

    Google Scholar 

  • Bekaert S, Van Pottelbergh I, De Meyer T, Zmierczak H, Kaufman JM, Van Oostveldt P et al (2005) Telomere length versus hormonal and bone mineral status in healthy elderly men. Mech Ageing Dev 126:1115–1122

    PubMed  CAS  Google Scholar 

  • Bekaert S, De Meyer T, Van Oostveldt P (2005) Telomere attrition as ageing biomarker. Anticancer Res 25:3011–3021

    PubMed  CAS  Google Scholar 

  • Bernstein AM, Willcox BJ, Tamaki H, Kunishima N, Suzuki M, Willcox DC et al (2004) First autopsy study of an Okinawan centenarian: absence of many age-related diseases. J Gerontol Ser A Biol Sci Med Sci 59:1195–1199

    Google Scholar 

  • Bischoff C, Graakjaer J, Petersen HC, Jeune B, Bohr VA, Koelvraa S et al (2006) No association between telomere length and survival among the elderly and oldest old. Epidemiology 17:190–194

    PubMed  Google Scholar 

  • Bisoffi M, Heaphy CM, Griffith JK (2006) Telomeres: prognostic markers for solid tumors. Int J Cancer 119(10):2255–2260

    Google Scholar 

  • Bladbjerg EM, Andersen-Ranberg K, de Maat MP, Kristensen SR, Jeune B, Gram J et al (1999) Longevity is independent of common variations in genes associated with cardiovascular risk. Thromb Haemost 82:1100–1105

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Bluher M, Kahn BB, Kahn CR (2003) Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299:572–574

    PubMed  Google Scholar 

  • Bonafe M, Barbieri M, Marchegiani F, Olivieri F, Ragno E et al (2003) Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity: cues for an evolutionarily conserved mechanism of life span control. J Clin Endocrinol Metab 88:3299–3304

    PubMed  CAS  Google Scholar 

  • Bonnen PE, Pe’er I, Plenge RM, Salit J, Lowe JK, Shapero MH et al (2006) Evaluating potential for whole-genome studies in Kosrae, an isolated population in Micronesia. Nat Genet 38:214–217

    PubMed  CAS  Google Scholar 

  • Braeckman BP, Vanfleteren JR (2006) Genetic control of longevity in C. elegans. Exp Gerontol [Epub ahead of print]

  • Broers JL, Ramaekers FC, Bonne G, Yaou RB, Hutchison CJ (2006) Nuclear lamins: laminopathies and their role in premature ageing. Physiol Rev 86:967–1008

    PubMed  CAS  Google Scholar 

  • Campisi J (2003) Cancer and ageing: rival demons? Nature Rev 3:339–349

    CAS  Google Scholar 

  • Candore G, Aquino A, Balistreri CR, Bulati M, Di Carlo D, Grimaldi MP et al (2006) Inflammation, longevity, and cardiovascular diseases: role of polymorphisms of TLR4. Ann NY Acad Sci 1067:282–287

    PubMed  CAS  Google Scholar 

  • Capri M, Salvioli S, Sevini F, Valensin S, Celani L, Monti D et al (2006) The genetics of human longevity. Ann NY Acad Sci 1067:252–263

    PubMed  CAS  Google Scholar 

  • Caruso C, Candore G, Colonna Romano G, Lio D, Bonafe M, Valensin S et al (2000) HLA, aging, and longevity: a critical reappraisal. Hum Immunol 61:942–949

    PubMed  CAS  Google Scholar 

  • Castro E, Ogburn CE, Hunt KE, Tilvis R, Louhija J, Penttinen R et al (1999) Polymorphisms at the Werner locus: I. Newly identified polymorphisms, ethnic variability of 1367Cys/Arg, and its stability in a population of Finnish centenarians. Am J Med Genet 82:399–403

    PubMed  CAS  Google Scholar 

  • Castro E, Edland SD, Lee L, Ogburn CE, Deeb SS, Brown G, et al. (2000) Polymorphisms at the Werner locus: II. 1074Leu/Phe, 1367Cys/Arg, longevity, and atherosclerosis. Am J Med Genet 95:374–380

    PubMed  CAS  Google Scholar 

  • Chan YC, Suzuki M, Yamamoto S (1997a) Dietary, anthropometric, hematological and biochemical assessment of the nutritional status of centenarians and elderly people in Okinawa, Japan. J Am Coll Nutr 16:229–235

    PubMed  CAS  Google Scholar 

  • Chan YC, Suzuki M, Yamamoto S (1997b) Nutritional status of centenarians assessed by activity and anthropometric, hematological and biochemical characteristics. J Nutr Sci Vitaminol 43:73–81

    PubMed  CAS  Google Scholar 

  • Chinnery PF, Samuels DC, Elson J, Turnbull DM (2002) Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial disease: is there a common mechanism? Lancet 360:1323–1325

    PubMed  CAS  Google Scholar 

  • Christensen K, McGue M, Yashin A, Iachine I, Holm NV, Vaupel JW (2000) Genetic and environmental influences on functional abilities in Danish twins aged 75 years and older. J Gerontol Ser A Biol Sci Med Sci 55:M446–M452

    CAS  Google Scholar 

  • Christensen K, Gaist D, Vaupel JW, McGue M (2002) Genetic contribution to rate of change in functional abilities among Danish twins aged 75 years or more. Am J Epidemiol 155: 132–139

    PubMed  Google Scholar 

  • Christensen K, Johnson TE, Vaupel JW (2006) The quest for genetic determinants of human longevity: challenges and insights. Nat Rev Genet 7:436–448

    PubMed  CAS  Google Scholar 

  • Clancy DJ, Gems D, Harshman LG, Oldham S, Stocker H, Hafen E et al (2001) Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 292:104–106

    PubMed  CAS  Google Scholar 

  • Cockerham WC, Hattori H, Yamori Y (2000) The social gradient in life expectancy: the contrary case of Okinawa in Japan. Soc Sci Med 51:115–122

    PubMed  CAS  Google Scholar 

  • Curb JD, Abbott RD, Rodriguez BL, Masaki K, Chen R, Sharp DS et al (2004) A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coronary heart disease in the elderly. J Lipid Res 45:948–953

    PubMed  CAS  Google Scholar 

  • Cutler RG (1975) Evolution of human longevity and the genetic complexity governing aging rate. Proc Natl Acad Sci 72:4664–4668

    PubMed  CAS  Google Scholar 

  • Dato S, Passarino G, Rose G, Altomare K, Bellizzi D, Mari V et al (2004) Association of the mitochondrial DNA haplogroup J with longevity is population specific. Eur J Hum Genet 12:1080–1082

    PubMed  CAS  Google Scholar 

  • Davis T, Kipling D (2006) Werner syndrome as an example of inflamm-aging: possible therapeutic opportunities for a progeroid syndrome? Rejuvenation Res 9:402–407

    PubMed  CAS  Google Scholar 

  • De Benedictis G, Franceschi C (2006) The unusual genetics of human longevity. Sci Aging Knowledge Environ 2006:pe20

  • De Benedictis G, Carotenuto L, Carrieri G, De Luca M, Falcone E, Rose G et al (1998) Gene/longevity association studies at four autosomal loci (REN, THO, PARP, SOD2). Eur J Hum Genet 6:534–541

    PubMed  Google Scholar 

  • De Benedictis G, Rose G, Carrieri G, De Luca M, Falcone E, Passarino G et al (1999) Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans. FASEB J 13:1532–1536

    PubMed  Google Scholar 

  • De Martinis M, Franceschi C, Monti D, Ginaldi L (2005) Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett 579:2035–2039

    PubMed  Google Scholar 

  • DeMichele A, Martin AM, Mick R, Gor P, Wray L, Klein-Cabral M et al (2003) Interleukin-6 -174G–>C polymorphism is associated with improved outcome in high-risk breast cancer. Cancer Res 63:8051–8056

    PubMed  CAS  Google Scholar 

  • Edo MD, Andres V (2005) Aging, telomeres, and atherosclerosis. Cardiovasc Res 66:213–221

    PubMed  CAS  Google Scholar 

  • Egan KM, Thompson PA, Titus-Ernstoff L, Moore JH, Ambrosone CB (2003) MnSOD polymorphism and breast cancer in a population-based case-control study. Cancer Lett 199:27–33

    PubMed  CAS  Google Scholar 

  • Evert J, Lawler E, Bogan H, Perls T (2003) Morbidity profiles of centenarians: survivors, delayers, and escapers. J Gerontol Ser A Biol Sci Med Sci 58:232–237

    Google Scholar 

  • Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E et al (2000) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann NY Acad Sci 908:244–254

    Article  PubMed  CAS  Google Scholar 

  • Frederiksen H, Christensen K (2003) The influence of genetic factors on physical functioning and exercise in second half of life. Scand J Med Sci Sports 13:9–18

    PubMed  CAS  Google Scholar 

  • Frederiksen H, McGue M, Jeune B, Gaist D, Nybo H, Skytthe A et al (2002) Do children of long-lived parents age more successfully? Epidemiology 13:334–339

    PubMed  Google Scholar 

  • Frederiksen H, Gaist D, Bathum L, Andersen K, McGue M, Vaupel JW et al (2003) Angiotensin I-converting enzyme (ACE) gene polymorphism in relation to physical performance, cognition and survival-a follow-up study of elderly Danish twins. Ann Epidemiol 13:57–65

    PubMed  Google Scholar 

  • Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S et al (2006) Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 63:168–174

    PubMed  Google Scholar 

  • Gavrilov LA, Gavrilova NS (2002) Evolutionary theories of aging and longevity. Scientific World Journal 2:339–356

    PubMed  Google Scholar 

  • Geesaman BJ, Benson E, Brewster SJ, Kunkel LM, Blanche H, Thomas G et al (2003) Haplotype-based identification of a microsomal transfer protein marker associated with the human lifespan. Proc Natl Acad Sci 100:14115–14120

    PubMed  CAS  Google Scholar 

  • Gems D, Partridge L (2001) Insulin/IGF signaling and ageing: seeing the bigger picture. Curr Opin Genet Dev 11:287–292

    PubMed  CAS  Google Scholar 

  • Gerdes LU, Jeune B, Ranberg KA, Nybo H, Vaupel JW (2000) Estimation of apolipoprotein E genotype-specific relative mortality risks from the distribution of genotypes in centenarians and middle-aged men: apolipoprotein E gene is a “frailty gene,” not a “longevity gene”. Genet Epidemiol 19:202–210

    PubMed  CAS  Google Scholar 

  • Greaves LC, Taylor RW (2006) Mitochondrial DNA mutations in human disease. IUBMB Life 58:143–151

    Article  PubMed  CAS  Google Scholar 

  • Guarente L, Kenyon C (2000) Genetic pathways that regulate ageing in model organisms. Nature 408:255–262

    PubMed  CAS  Google Scholar 

  • Gudmundsson H, Gudbjartsson DF, Frigge M, Gulcher JR, Stefansson K (2000) Inheritance of human longevity in Iceland. Eur J Hum Genet 8:743–749

    PubMed  CAS  Google Scholar 

  • Gupta S, Agrawal A, Agrawal S, Su H, Gollapudi S (2006) A paradox of immunodeficiency and inflammation in human aging: lessons learned from apoptosis. Immun Ageing 19:3–5

    Google Scholar 

  • Haan MN, Shemanski L, Jagust WJ, Manolio TA, Kuller L (1999) The role of APOE epsilon 4 in modulating effects of other risk factors for cognitive decline in elderly persons. JAMA 282:40–46

    PubMed  CAS  Google Scholar 

  • Hadley EC, Rossi WK (2005) Exceptional survival in human populations: National Institute on Aging perspectives and programs. Mech Ageing Dev 126:231–234

    PubMed  Google Scholar 

  • Hasty P (2005) The impact of DNA damage, genetic mutation and cellular responses on cancer prevention, longevity and aging: observations in humans and mice. Mech Ageing Dev 126:71–77

    PubMed  CAS  Google Scholar 

  • Heijmans B, Westendorp R, Slagboom P (2000) Common gene variants, mortality and extreme longevity in humans. Exp Gerontol 35:865–877

    PubMed  CAS  Google Scholar 

  • Hennekam RC (2006) Hutchinson-Gilford progeria syndrome: review of the phenotype. Am J Med Genet A [Epub ahead of print]

  • Hirai M, Suzuki S, Hinokio Y, Yamada T, Yoshizumi S, Suzuki C et al (2005) WRN gene 1367 Arg allele protects against development of type 2 diabetes mellitus. Diabetes Res Clin Pract 69:287–292

    PubMed  CAS  Google Scholar 

  • Hirose N, Arai Y, Yamamura K, Suzuki M, Akisaka M (1999) Genetics of aging and longevity in Japanese centenarians. In: Tauchi H, Sato T, Watanabe T (eds) Medical research for the final stages of human aging. Institute for Medical Science of Aging: Aichi Medical University Press, Aichi, Japan, pp 124–131

    Google Scholar 

  • Hirschhorn JN, Daly MJ (2005) Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 6:95–108

    PubMed  CAS  Google Scholar 

  • Hjelmborg JV, Iachine I, Skytthe A, Vaupel JW, McGue M, Koskenvuo M et al (2006) Genetic influence on human lifespan and longevity. Hum Genet 119:312–321

    PubMed  Google Scholar 

  • Honig LS, Schupf N, Lee JH, Tang MX, Mayeux R (2006) Shorter telomeres are associated with mortality in those with APOE epsilon4 and dementia. Ann Neurol 60:181–187

    PubMed  Google Scholar 

  • Hung RJ, Boffetta P, Brennan P, Malaveille C, Gelatti U, Placidi D et al (2004) Genetic polymorphisms of MPO, COMT, MnSOD, NQO1, interactions with environmental exposures and bladder cancer risk. Carcinogenesis 25:973–978

    PubMed  CAS  Google Scholar 

  • Hurme M, Lehtimaki T, Jylha M, Karhunen PJ, Hervonen A (2005) Interleukin-6 -174G/C polymorphism and longevity: a follow-up study. Mech Ageing Dev 126:417–418

    PubMed  CAS  Google Scholar 

  • Ishii N, Ishii T, Hartman PS (2006) The role of the electron transport gene SDHS on lifespan and cancer. Exp Gerontol 2006 [Epub ahead of print]

  • Japan Health and Welfare Bureau for the Elderly (2003) Japan annual centenarian report. Japan Health and Welfare Bureau for the Elderly, Tokyo, Japan

  • Japan Health and Welfare Bureau for the Elderly (2006) Japan annual centenarian report. Japan Health and Welfare Bureau for the Elderly, Tokyo, Japan

  • Jordan BD, Relkin NR, Ravdin LD, Jacobs AR, Bennett A, Gandy S (1997) Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing. JAMA 278:136–140

    PubMed  CAS  Google Scholar 

  • Julien JP, Kriz J (2006) Transgenic mouse models of amyotrophic lateral sclerosis. Biochim Biophys Acta [Epub ahead of print]

  • Kagawa Y (1978) Impact of Westernization on the nutrition of Japanese: changes in physique, cancer, longevity and centenarians. Prev Med 7:205–217

    PubMed  CAS  Google Scholar 

  • Kerber RA, O’Brien E, Smith KR, Cawthon RM (2001) Familial excess longevity in Utah genealogies. J Gerontol Ser A Biol Sci Med Sci 56:B130–B139

    CAS  Google Scholar 

  • Kerr G (2000) Okinawa: the history of an island people. Tuttle, Boston

    Google Scholar 

  • Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, Atkinson C, Malarkey WB, Glaser R (2003) Chronic stress and age-related increases in the proinflammatory cytokine IL-6. Proc Natl Acad Sci 100:9090–9095

    PubMed  CAS  Google Scholar 

  • Kojima T, Kamei H, Aizu T, Arai Y, Takayama M, Nakazawa S et al (2004) Association analysis between longevity in the Japanese population and polymorphic variants of genes involved in insulin and insulin-like growth factor 1 signaling pathways. Exp Gerontol 39:1595–1598

    Google Scholar 

  • Lebra WP (1986) Okinawan religion: belief, ritual and social structure. University of Hawaii Press, Honolulu

    Google Scholar 

  • Lee IM, Blair SN, Allison DB, Folsom AR, Harris TB, Manson JE et al (2001) Epidemiologic data on the relationships of caloric intake, energy balance, and weight gain over the life span with longevity and morbidity. J Gerontol Ser A Biol Sci Med Sci 56:7–19

    Google Scholar 

  • Lin K, Hsin H, Libina N, Kenyon C (2001) Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet 28:139–145

    PubMed  CAS  Google Scholar 

  • Lin P, Hsueh YM, Ko JL, Liang YF, Tsai KJ, Chen CY (2003) Analysis of NQO1, GSTP1, and MnSOD genetic polymorphisms on lung cancer risk in Taiwan. Lung Cancer 40:123-129

    Google Scholar 

  • Lin YJ, Seroude L, Benzer S (1998) Extended life span and stress resistance in the Drosophila mutant Methuselah. Science 282:943–946

    PubMed  CAS  Google Scholar 

  • Lio D, Scola L, Crivello A, Colonna-Romano G, Candore G, Bonafe M et al (2002) Gender-specific association between -1082 IL-10 promoter polymorphism and longevity. Genes Immun 3:30–33

    PubMed  CAS  Google Scholar 

  • Lithgow GJ, Walker GA (2002) Stress resistance as a determinate of C. elegans lifespan. Mech Ageing Dev 123:765–771

    PubMed  Google Scholar 

  • Longo VD, Fabrizio P (2002) Regulation of longevity and stress resistance: a molecular strategy conserved from yeast to humans? Cell Mol Life Sci 59:903–908

    PubMed  CAS  Google Scholar 

  • Longo VD, Finch CE (2003) Evolutionary medicine: from dwarf model systems to healthy centenarians? Science 299:1342–1345

    PubMed  Google Scholar 

  • Luft FC (1999) Bad genes, good people, association, linkage, longevity and the prevention of cardiovascular disease. Clin Exp Pharmacol Physiol 26:576–579

    PubMed  CAS  Google Scholar 

  • Martin GM, Oshima J, Gray MD, Poot M (1999) What geriatricians should know about the Werner syndrome. J Am Geriatr Soc 47: 1136–1144

    PubMed  CAS  Google Scholar 

  • Martin-Ruiz CM, Gussekloo J, van Heemst D, von Zglinicki T, Westendorp RG (2005) Telomere length in white blood cells is not associated with morbidity or mortality in the oldest old: a population-based study. Aging Cell 4:287–290

    PubMed  CAS  Google Scholar 

  • Masoro EJ (2006) Dietary restriction-induced life extension: a broadly based biological phenomenon. Biogerontology [Epub ahead of print]

  • McClearn GE, Johansson B, Berg S, Pedersen NL, Ahern F, Petrill SA et al (1997) Substantial genetic influence on cognitive abilities in twins 80 or more years old. Science 276:1560–1563

    PubMed  CAS  Google Scholar 

  • Merriwether DA, Clark AG, Ballinger SW, Schurr TG, Soodyall H, Jenkins T et al (1991) The structure of human mitochondrial DNA variation. J Mol Evol 33:543–555

    PubMed  CAS  Google Scholar 

  • Mitchell JR, Hoeijmakers JH, Niedernhofer LJ (2003) Divide and conquer: nucleotide excision repair battles cancer and ageing. Curr Opin Cell Biol 15:232–240

    PubMed  CAS  Google Scholar 

  • Mitrunen K, Sillanpaa P, Kataja V, Eskelinen M, Kosma VM, Benhamou S et al (2001) Association between manganese superoxide dismutase (MnSOD) gene polymorphism and breast cancer risk. Carcinogenesis 22:827–829

    PubMed  CAS  Google Scholar 

  • Nebel A, Schreiber S (2005) Allelic variation and human longevity. Sci Aging Knowledge Environ 2005:pe23

  • Nebel A, Croucher PJP, 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 102:7906–7909

    PubMed  CAS  Google Scholar 

  • Niemi AK, Hervonen A, Hurme M, Karhunen PJ, Jylha M, Majamaa K (2003) Mitochondrial DNA polymorphisms associated with longevity in a Finnish population. Hum Genet 112:29–33

    PubMed  CAS  Google Scholar 

  • Niemi AK, Moilanen JS, Tanaka M, Hervonen A, Hurme M, Lehtimaki T et al (2005) A combination of three common inherited mitochondrial DNA polymorphisms promotes longevity in Finnish and Japanese subjects. Eur J Hum Genet 13:166–170

    PubMed  CAS  Google Scholar 

  • Ogura C, Nakamoto H, Uema T, Yamamoto K, Yonemori T, Yoshimura T (1995) Prevalence of senile dementia in Okinawa, Japan. Int J Epidemiol 24:373–380

    PubMed  CAS  Google Scholar 

  • Panossian LA, Porter VR, Valenzuela HF, Zhu X, Reback E, Masterman D et al (2003) Telomere shortening in T cells correlates with Alzheimer’s disease status. Neurobiol Aging 24:77–84

    PubMed  CAS  Google Scholar 

  • Peila R, Launer LJ (2006) Inflammation and dementia: epidemiologic evidence. Acta Neurol Scand 185:102–106

    CAS  Google Scholar 

  • Perls T, Terry D (2003) Genetics of exceptional longevity. Exp Gerontol 38:725–730

    PubMed  Google Scholar 

  • Perls TT, Bubrick E, Wager CG, Vijg J, Kruglyak L (1998) Siblings of centenarians live longer. Lancet 351:1560

    PubMed  CAS  Google Scholar 

  • Perls T, Kunkel LM, Puca AA (2002) The genetics of exceptional human longevity. JAGS 50:339–368

    Google Scholar 

  • Pes GM, Lio D, Carru C, Deiana L, Baggio G, Franceschi C et al (2004) Association between longevity and cytokine gene polymorphisms. A study in Sardinian centenarians. Aging Clin Exp Res 16:244–248

    PubMed  CAS  Google Scholar 

  • Pollex RL, Hegele RA (2004) Hutchinson-Gilford progeria syndrome. Clin Genet 66: 375–381

    PubMed  CAS  Google Scholar 

  • Poulain M, Pes GM, Grasland C, Carru C, Ferrucci L, Baggio G et al (2004) Identification of a geographic area characterized by extreme longevity in the Sardinia Island: the AKEA study. Exp Gerontol 39:1423–1429

    PubMed  Google Scholar 

  • Pritchard JK, Donnelly P (2001) Case-control studies of association in structured or admixed populations. Theor Popul Biol 60:227–237

    PubMed  CAS  Google Scholar 

  • Puca AA, Daly MJ, Brewster SJ, Matise TC, Barrett J, Shea-Drinkwater M et al (2001) A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4. Proc Natl Acad Sci 98:10505–10508

    PubMed  CAS  Google Scholar 

  • Rea IM, Ross OA, Armstrong M, McNerlan S, Alexander DH, Curran MD et al (2003) Interleukin-6-gene C/G 174 polymorphism in nonagenarian and octogenarian subjects in the BELFAST study. Reciprocal effects on IL-6, soluble IL-6 receptor and for IL-10 in serum and monocyte supernatants. Mech Ageing Dev 124:555–561

    PubMed  CAS  Google Scholar 

  • Rea IM, McKeown PP, McMaster D, Young IS, Patterson C, Savage MJ et al (2004) Paraoxonase polymorphisms PON1 192 and 55 and longevity in Italian centenarians and Irish nonagenarians. A pooled analysis. Exp Gerontol 39:629–635

    PubMed  CAS  Google Scholar 

  • Rivadeneira F, Houwing-Duistermaat JJ, Vaessen N, Vergeer-Drop JM, Hofman A, Pols HA et al (2003) Association between an insulin-like growth factor I gene promoter polymorphism and bone mineral density in the elderly: the Rotterdam Study. J Clin Endocrinol Metab 88:3878–3884

    PubMed  CAS  Google Scholar 

  • Rodriguez BL, Lau N, Burchfiel CM, Abbott RD, Sharp DS, Yano K et al (1999) Glucose intolerance and 23-year risk of coronary heart disease and total mortality: the Honolulu Heart Program. Diabetes Care 22:1262–1265

    PubMed  CAS  Google Scholar 

  • Rogina B, Reenan RA, Nilsen SP, Helfand SL (2000) Extended life-span conferred by co transporter gene mutations in Drosophila. Science 290:2137–2140

    PubMed  CAS  Google Scholar 

  • Rose G, Dato S, Altomare K, Bellizzi D, Garasto S, Greco V et al (2003) Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly. Exp Gerontol 38:1065–1070

    PubMed  CAS  Google Scholar 

  • Roth GS, Lane MA, Ingram DK, Mattison JA, Elahi D, Tobin JD et al (2002) Biomarkers of caloric restriction may predict longevity in humans. Science 297:811

    PubMed  CAS  Google Scholar 

  • Samani NJ, Boultby R, Butler R, Thompson JR, Goodall AH (2001) Telomere shortening in atherosclerosis. Lancet 358:472–473

    PubMed  CAS  Google Scholar 

  • Sampayo JN, Gill MS, Lithgow GJ (2003) Oxidative stress and aging-the use of superoxide dismutase/catalase mimetics to extend lifespan. Biochem Soc Trans 31:1305–1307

    Article  PubMed  CAS  Google Scholar 

  • Sanabe E, Ashitomi I, Suzuki M (1977) Social and medical survey of centenarians. Okinawa J Public Health 9:98–106

    Google Scholar 

  • Schachter F (1998) Causes, effects, and constraints in the genetics of human longevity. Am J Hum Genet 62:1008–1014

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Scola L, Lio D, Crivello A, Candore G, Forte GI, Colonna-Romano G et al (2006) Analysis of HLA-DQA, HLA-DQB frequencies in a group of Sardinian centenarians. Rejuvenation Res 9:157–160

    PubMed  CAS  Google Scholar 

  • Service S, Molina J, Deyoung J, Jawaheer D, Aldana I, Vu T et al (2006) Magnitude and distribution of linkage disequilibrium in population isolates and implications for genome-wide association studies. Nat Genet 38:556–560

    PubMed  CAS  Google Scholar 

  • Sho H (2001) History and characteristics of Okinawan longevity food. Asia Pac J Clin Nutr 10:159–164

    PubMed  CAS  Google Scholar 

  • Simon NM, Smoller JW, McNamara KL, Maser RS, Zalta AK, Pollack MH et al (2006) Telomere shortening and mood disorders: preliminary support for a chronic stress model of accelerated aging. Biol Psychiatry 60:432–435

    PubMed  CAS  Google Scholar 

  • Singh R, Kolvraa S, Bross P, Gregersen N, Andersen Nexo B et al (2004) Association between low self-rated health and heterozygosity for -110A > C polymorphism in the promoter region of HSP70-1 in aged Danish twins. Biogerontology 5:169–176

    PubMed  CAS  Google Scholar 

  • Stoehlmacher J, Ingles SA, Park DJ, Zhang W, Lenz HJ (2002) The -9Ala/-9Val polymorphism in the mitochondrial targeting sequence of the manganese superoxide dismutase gene (MnSOD) is associated with age among Hispanics with colorectal carcinoma. Oncol Rep 9:235–238

    PubMed  CAS  Google Scholar 

  • Suzuki M, Hirose N (1999) Endocrine function of centenarians. In: Tauchi H, Sato T, Watanabe T (eds) Medical research for the final stages of human aging. Institute for Medical Science of Aging: Aichi Medical University Press, Aichi, Japan, pp 101–110

    Google Scholar 

  • Suzuki M, Mori H, Asato T, Sakugawa H, Ishii T, Hosoda Y (1985) A medical study of centenarians: case control study of genetic factors, family history and longevity. Japan J Geriatr 22:457–467

    CAS  Google Scholar 

  • Suzuki M, Willcox BJ, Willcox DC (2001) Implications from and for food cultures for cardiovascular disease: longevity. Asia Pac J Clin Nutr 10:165–171

    PubMed  CAS  Google Scholar 

  • Takata H, Suzuki M, Ishii T, Sekiguchi S, Iri H (1987) Influence of major histocompatibility complex region genes on human longevity among Okinawan-Japanese centenarians and nonagenarians. Lancet 10:824–826

    Google Scholar 

  • Tanaka M, Gong J, Zhang J, Yamada Y, Borgeld HJ, Yagi K (2000) Mitochondrial genotype associated with longevity and its inhibitory effect on mutagenesis. Mech Ageing Dev 116:65–76

    PubMed  CAS  Google Scholar 

  • Tanaka M, Cabrera VM, Gonzalez AM, Larruga JM, Takeyasu T, Fuku N et al (2004) Mitochondrial genome variation in eastern Asia and the peopling of Japan. Genome Res 14:1832–1850

    PubMed  CAS  Google Scholar 

  • Tatar M, Bartke A, Antebi A (2003) The endocrine regulation of aging by insulin-like signals. Science 299:1346–1351

    PubMed  CAS  Google Scholar 

  • Taufer M, Peres A, de Andrade VM, de Oliveira G, Sa G, do Canto ME et al (2005) Is the Val16Ala manganese superoxide dismutase polymorphism associated with the aging process? J Gerontol Ser A Biol Sci Med Sci 60:432–438

    Google Scholar 

  • Todesco L, Angst C, Litynski P, Loehrer F, Fowler B, Haefeli WE (1999) Methylenetetrahydrofolate reductase polymorphism, plasma homocysteine and age. Eur J Clin Investig 29:1003–1009

    CAS  Google Scholar 

  • Todoriki H, Willcox DC, Willcox BJ (2004) The effects of post-war dietary change on longevity and health in Okinawa. Okinawa J Amer Studies 1:52–61

    Google Scholar 

  • Toupance B, Godelle B, Gouyon PH, Schachter F (1998) A model for antagonistic pleiotropic gene action for mortality and advanced age. Am J Hum Genet 62:1525–1534

    PubMed  CAS  Google Scholar 

  • Turner BJ, Atkin JD, Farg MA, Zang da W, Rembach A, Lopes EC et al (2005) Impaired extracellular secretion of mutant superoxide dismutase 1 associates with neurotoxicity in familial amyotrophic lateral sclerosis. J Neurosci 25:108–117

    PubMed  CAS  Google Scholar 

  • Vaessen N, Heutink P, Janssen JA, Witteman JC, Testers L, Hofman A et al (2001) A polymorphism in the gene for IGF-I: functional properties and risk for type 2 diabetes and myocardial infarction. Diabetes 50:637–642

    PubMed  CAS  Google Scholar 

  • Vaillent GE (1991) The association of ancestral longevity with successful aging. J Gerontol 46:P292–P298

    Google Scholar 

  • van Heemst D, Beekman M, Mooijaart SP, Heijmans BT, Brandt BW, Zwaan BJ et al (2005) Reduced insulin/IGF-1 signalling and human longevity. Aging Cell 4:79–85

    PubMed  Google Scholar 

  • Vaupel JW (1997) The remarkable improvements in survival at older ages. Philos Trans R Soc Lond B Biol Sci 352:1799–1804

    PubMed  CAS  Google Scholar 

  • Vijg J, van Orsouw N (2002) Searching for determinants of human aging and longevity: opportunities and challenges. Mech Ageing Dev 123:195–205

    PubMed  CAS  Google Scholar 

  • Wang XY, Hurme M, Jylha M, Hervonen A (2001) Lack of association between human longevity and polymorphisms of IL-1 cluster, IL-6, IL-10 and TNF-alpha genes in Finnish nonagenarians. Mech Ageing Dev 123:29–38

    PubMed  CAS  Google Scholar 

  • Warner HR (2003) Subfield history: use of model organisms in the search for human aging genes. Sci Aging Knowledge Environ 2003(6):RE1

  • Warner HR (2005) Longevity genes: from primitive organisms to humans. Mech Ageing Dev 126:235–242

    PubMed  CAS  Google Scholar 

  • Willcox DC (2005) Okinawan longevity: where do we go from here? Nutr Dietetics 8:9–17

    Google Scholar 

  • Willcox BJ, Willcox DC, Suzuki M (2004) The Okinawa diet. Random House, New York

    Google Scholar 

  • Willcox BJ, Willcox DC, He Q, Curb JD, Suzuki M (2006) Siblings of Okinawan centenarians share lifelong mortality advantages. J Gerontol Ser A Biol Sci Med Sci 61:345–354

    Google Scholar 

  • Willcox DC, Willcox BJ, Todoriki H, Curb JD, Suzuki M (2006) Caloric restriction and human longevity: what can we learn from the Okinawans? Biogerontology 7:173–177

    PubMed  Google Scholar 

  • Woodson K, Tangrea JA, Lehman TA, Modali R, Taylor KM, Snyder K et al (2003) Manganese superoxide dismutase (MnSOD) polymorphism, alpha-tocopherol supplementation and prostate cancer risk in the alpha-tocopherol, beta-carotene cancer prevention study (Finland). Cancer Causes Control 214:513–518

    Google Scholar 

  • Ye L, Miki T, Nakura J, Oshima J, Kamino K, Rakugi H et al (1997) Association of a polymorphic variant of the Werner helicase gene with myocardial infarction in a Japanese population. Am J Med Genet 68:494–498

    PubMed  CAS  Google Scholar 

  • Zhang H, Risch N (1996) Mapping quantitative-trait loci in humans by use of extreme concordant sib pairs: selected sampling by parental phenotypes. Am J Hum Genet 59:951–957

    PubMed  CAS  Google Scholar 

  • Zhang J, Asin-Cayuela J, Fish J, Michikawa Y, Bonafe M, Olivieri F et al (2003) Strikingly higher frequency in centenarians and twins of mtDNA mutation causing remodeling of replication origin in leukocytes. Proc Natl Acad Sci 100:1116–1121

    PubMed  CAS  Google Scholar 

  • Zubenko GS, Stiffler JS, Hughes HB, III, Fatigati MJ, Zubenko WN (2002) Genome survey for loci that influence successful aging: sample characterization, method validation, and initial results for the Y chromosome. Am J Geriatr Psychiatry 10:619–630

    PubMed  Google Scholar 

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Willcox, D.C., Willcox, B.J., Hsueh, WC. et al. Genetic determinants of exceptional human longevity: insights from the Okinawa Centenarian Study. AGE 28, 313–332 (2006). https://doi.org/10.1007/s11357-006-9020-x

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