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AGE

, Volume 35, Issue 2, pp 455–469 | Cite as

Genomics of human health and aging

  • Alexander M. KulminskiEmail author
  • Irina Culminskaya
Article

Abstract

Despite notable progress of the candidate-gene and genome-wide association studies (GWAS), understanding the role of genes contributing to human health and lifespan is still very limited. We use the Framingham Heart Study to elucidate if recognizing the role of evolution and systemic processes in an aging organism could advance such studies. We combine throughput methods of GWAS with more detail methods typical for candidate-gene analyses and show that both lifespan and ages at onset of CVD and cancer can be controlled by the same allelic variants. The risk allele carriers are at highly significant risk of premature death (e.g., RR = 2.9, p = 5.0 × 10−66), onset of CVD (e.g., RR = 1.6, p = 4.6 × 10−17), and onset of cancer (e.g., RR = 1.6, p = 1.5 × 10−6). The mechanism mediating the revealed genetic associations is likely associated with biological aging. These aging-related phenotypes are associated with a complex network which includes, in this study, 62 correlated SNPs even so these SNPs can be on non-homologous chromosomes. A striking result is three-fold, highly significant (p = 3.6 × 10−10) enrichment of non-synonymous SNPs (N = 27) in this network compared to the entire qualified set of the studied SNPs. Functional significance of this network is strengthened by involvement of genes for these SNPs in fundamental biological processes related to aging (e.g., response to stimuli, protein degradation, apoptosis) and by connections of these genes with neurological (20 genes) and cardio-vascular (nine genes) processes and tumorigenesis (10 genes). These results document challenging role of gene networks in regulating human health and aging and call for broadening focus on genomics of such phenotypes.

Keywords

Aging Lifespan Survival Healthy aging Gene networks 

Notes

Acknowledgments

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Aging or the National Institutes of Health. The Framingham Heart Study and the Framingham SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University. The Framingham SHARe data used for the analyses described in this manuscript were obtained through dbGaP (accession numbers phs000007.v7.p4 and phs000007.v14.p5). This manuscript was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or the NHLBI. We thank our colleagues, A. Yashin, S. Ukraitseva, and K. Arbeev, for fruitful discussion of the results. A.M.K. contributed to the study conception, design, statistical and biological analyses, interpretation of the results, and writing the manuscript. I.C. contributed to the study design, biological analyses, interpretation of the results, and writing the manuscript.

Supplementary material

11357_2011_9362_MOESM1_ESM.pdf (25 kb)
Online Resource 1 Statistics for 63 SNPs pre-selected at the first stage of the analyses according to tentative association with at least one of the four endophenotypes at genome-wide level p <10−6 (PDF 25 kb)
11357_2011_9362_MOESM2_ESM.pdf (95 kb)
Online Resource 2 Conditional and unconditional minus-log-transformed p values for the 63 pre-selected SNPs. Blue color denotes original unconditional estimates. Red color shows the estimates conditional on three proxy SNPs, i.e., rs9330200, rs2292664, and rs5491. CVD denotes cardiovascular diseases, SBP denotes systolic blood pressure, and TC denotes total cholesterol (PDF 95 kb)
11357_2011_9362_MOESM3_ESM.pdf (12 kb)
Online Resource 3 Associations of each of the three proxy SNPs with each of the four endophenotypes (PDF 11 kb)
11357_2011_9362_MOESM4_ESM.pdf (184 kb)
Online Resource 4 Empirical Kaplan–Meier age patterns of probability of staying free of CVD or cancer. Curves show the age at onset of ac CVD and df cancer through 2007 for the minor-allele carriers and major-allele homozygotes of a, d rs9330200, b, e rs2292664, and c, f rs5491. Crosses show censored individuals. HLE denotes “healthy life expectancy” defined as life without (ac) CVD or (df) cancer. Letter “n” denotes the number of total/diseased individuals. CI confidence interval (PDF 184 kb)
11357_2011_9362_MOESM5_ESM.pdf (61 kb)
Online Resource 5 Annotation of genes identified for 62 SNPs showing linkage disequilibrium and associations with phenotypes (PDF 61 kb)
11357_2011_9362_MOESM6_ESM.pdf (15 kb)
Online Resource 6 Analysis of 50 genes for the revealed SNPs on enrichment in Gene Ontology (GO) biological processes (PDF 14 kb)
11357_2011_9362_MOESM7_ESM.pdf (16 kb)
Online Resource 7 Analysis of 57 genes for the revealed SNPs on enrichment in Gene Ontology (GO) molecular function (PDF 15 kb)

References

  1. Alexander DM, Williams LM, Gatt JM, Dobson-Stone C, Kuan SA, Todd EG, Schofield PR, Cooper NJ, Gordon E (2007) The contribution of apolipoprotein E alleles on cognitive performance and dynamic neural activity over six decades. Biol Psychol 75(3):229–238. doi: 10.1016/j.biopsycho.2007.03.001 PubMedCrossRefGoogle Scholar
  2. Arking DE, Chakravarti A (2009) Understanding cardiovascular disease through the lens of genome-wide association studies. Trends Genet 25(9):387–394. doi: 10.1016/j.tig.2009.07.007 PubMedCrossRefGoogle Scholar
  3. Barzilai N, Gabriely I (2010) Genetic studies reveal the role of the endocrine and metabolic systems in aging. J Clin Endocrinol Metab 95(10):4493–4500. doi: 10.1210/jc.2010-0859 PubMedCrossRefGoogle Scholar
  4. Barzilai N, Atzmon G, Schechter C, Schaefer EJ, Cupples AL, Lipton R, Cheng S, Shuldiner AR (2003) Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA 290(15):2030–2040PubMedCrossRefGoogle Scholar
  5. Beekman M, Nederstigt C, Suchiman HE, Kremer D, van der Breggen R, Lakenberg N, Alemayehu WG, de Craen AJ, Westendorp RG, Boomsma DI, de Geus EJ, Houwing-Duistermaat JJ, Heijmans BT, Slagboom PE (2010) Genome-wide association study (GWAS)-identified disease risk alleles do not compromise human longevity. Proc Natl Acad Sci USA 107(42):18046–18049. doi: 10.1073/pnas.1003540107 PubMedCrossRefGoogle Scholar
  6. Bergman A, Atzmon G, Ye K, MacCarthy T, Barzilai N (2007) Buffering mechanisms in aging: a systems approach toward uncovering the genetic component of aging. PLoS Comput Biol 3(8):e170PubMedCrossRefGoogle Scholar
  7. Bishop NA, Lu T, Yankner BA (2010) Neural mechanisms of ageing and cognitive decline. Nature 464(7288):529–535. doi: 10.1038/nature08983 PubMedCrossRefGoogle Scholar
  8. Bloss CS, Pawlikowska L, Schork NJ (2011) Contemporary human genetic strategies in aging research. Ageing Res Rev 10(2):191–200. doi: 10.1016/j.arr.2010.07.005 PubMedCrossRefGoogle Scholar
  9. Charlesworth B (1996) Evolution of senescence: Alzheimer’s disease and evolution. Curr Biol 6(1):20–22PubMedCrossRefGoogle Scholar
  10. Christensen K, Johnson TE, Vaupel JW (2006) The quest for genetic determinants of human longevity: challenges and insights. Nat Rev Genet 7(6):436–448PubMedCrossRefGoogle Scholar
  11. Cupples LA, Heard-Costa N, Lee M, Atwood LD (2009) Genetics Analysis Workshop 16 Problem 2: the Framingham Heart Study data. BMC Proc 3(Suppl 7):S3PubMedCrossRefGoogle Scholar
  12. Cutler RG, Mattson MP (2006) The adversities of aging. Ageing Res Rev 5(3):221–238. doi: 10.1016/j.arr.2006.05.002 PubMedCrossRefGoogle Scholar
  13. De Benedictis G, Tan Q, Jeune B, Christensen K, Ukraintseva SV, Bonafe M, Franceschi C, Vaupel JW, Yashin AI (2001) Recent advances in human gene-longevity association studies. Mech Ageing Dev 122(9):909–920PubMedCrossRefGoogle Scholar
  14. Deelen J, Beekman M, Uh HW, Helmer Q, Kuningas M, Christiansen L, Kremer D, van de Breggen R, Suchiman HE, Lakenberg N, van den Akker EB, Passtoors WM, Tiemeier H, van Heemst D, de Craen AJ, Rivadeneira F, de Geus EJ, Perola M, van der Ouderaa FJ, Gunn DA, Boomsma DI, Uitterlinden AG, Christensen K, van Duijn CM, Heijmans BT, Houwing-Duistermaat JJ, Westendorp RG, Slagboom PE (2011) Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited. Aging Cell. doi: 10.1111/j.1474-9726.2011.00705.x
  15. Depp CA, Glatt SJ, Jeste DV (2007) Recent advances in research on successful or healthy aging. Curr Psychiatry Rep 9(1):7–13PubMedCrossRefGoogle Scholar
  16. Di Rienzo A, Hudson RR (2005) An evolutionary framework for common diseases: the ancestral-susceptibility model. Trends Genet 21(11):596–601. doi: 10.1016/j.tig.2005.08.007 PubMedCrossRefGoogle Scholar
  17. Drenos F, Kirkwood TB (2010) Selection on alleles affecting human longevity and late-life disease: the example of apolipoprotein E. PLoS One 5(4):e10022. doi: 10.1371/journal.pone.0010022 PubMedCrossRefGoogle Scholar
  18. Evert J, Lawler E, Bogan H, Perls T (2003) Morbidity profiles of centenarians: survivors, delayers, and escapers. J Gerontol A Biol Sci Med Sci 58(3):232–237PubMedCrossRefGoogle Scholar
  19. Finch CE (2005) Developmental origins of aging in brain and blood vessels: an overview. Neurobiol Aging 26(3):281–291. doi: 10.1016/j.neurobiolaging.2004.03.015 PubMedCrossRefGoogle Scholar
  20. Finch CE (2010) Evolution in health and medicine Sackler colloquium: evolution of the human lifespan and diseases of aging: roles of infection, inflammation, and nutrition. Proc Natl Acad Sci USA 107(Suppl 1):1718–1724. doi: 10.1073/pnas.0909606106 PubMedCrossRefGoogle Scholar
  21. Finch CE, Tanzi RE (1997) Genetics of aging. Science 278(5337):407–411PubMedCrossRefGoogle Scholar
  22. Flachsbart F, Caliebe A, Kleindorp R, Blanche H, von Eller-Eberstein H, Nikolaus S, Schreiber S, Nebel A (2009) Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc Natl Acad Sci USA 106(8):2700–2705. doi: 10.1073/pnas.0809594106 PubMedCrossRefGoogle Scholar
  23. Franceschi C, Valensin S, Bonafe M, Paolisso G, Yashin AI, Monti D, De Benedictis G (2000) The network and the remodeling theories of aging: historical background and new perspectives. Exp Gerontol 35(6–7):879–896PubMedCrossRefGoogle Scholar
  24. Franco OH, Karnik K, Osborne G, Ordovas JM, Catt M, van der Ouderaa F (2009) Changing course in ageing research: the healthy ageing phenotype. Maturitas 63(1):13–19. doi: 10.1016/j.maturitas.2009.02.006 PubMedCrossRefGoogle Scholar
  25. Frazer KA, Murray SS, Schork NJ, Topol EJ (2009) Human genetic variation and its contribution to complex traits. Nat Rev Genet 10(4):241–251. doi: 10.1038/nrg2554 PubMedCrossRefGoogle Scholar
  26. Gibson G (2009) Decanalization and the origin of complex disease. Nat Rev Genet 10(2):134–140. doi: 10.1038/nrg2502 PubMedCrossRefGoogle Scholar
  27. Goh KI, Cusick ME, Valle D, Childs B, Vidal M, Barabasi AL (2007) The human disease network. Proc Natl Acad Sci USA 104(21):8685–8690. doi: 10.1073/pnas.0701361104 PubMedCrossRefGoogle Scholar
  28. Goldstein DB (2009) Common genetic variation and human traits. N Engl J Med 360(17):1696–1698. doi: 10.1056/NEJMp0806284 PubMedCrossRefGoogle Scholar
  29. Gorlov IP, Gorlova OY, Sunyaev SR, Spitz MR, Amos CI (2008) Shifting paradigm of association studies: value of rare single-nucleotide polymorphisms. Am J Hum Genet 82(1):100–112. doi: 10.1016/j.ajhg.2007.09.006 PubMedCrossRefGoogle Scholar
  30. Govindaraju DR, Cupples LA, Kannel WB, O’Donnell CJ, Atwood LD, D’Agostino RB Sr, Fox CS, Larson M, Levy D, Murabito J, Vasan RS, Splansky GL, Wolf PA, Benjamin EJ (2008) Genetics of the Framingham Heart Study population. Adv Genet 62:33–65. doi: 10.1016/S0065-2660(08)00602-0 PubMedCrossRefGoogle Scholar
  31. Graber JH, Churchill GA, Dipetrillo KJ, King BL, Petkov PM, Paigen K (2006) Patterns and mechanisms of genome organization in the mouse. J Exp Zool A Comp Exp Biol 305(9):683–688. doi: 10.1002/jez.a.322 PubMedGoogle Scholar
  32. Greer EL, Brunet A (2008) Signaling networks in aging. J Cell Sci 121(Pt 4):407–412. doi: 10.1242/jcs.021519 PubMedCrossRefGoogle Scholar
  33. Hawkes K, O’Connell JF, Jones NG, Alvarez H, Charnov EL (1998) Grandmothering, menopause, and the evolution of human life histories. Proc Natl Acad Sci USA 95(3):1336–1339PubMedCrossRefGoogle Scholar
  34. Iachine IA, Holm NV, Harris JR, Begun AZ, Iachina MK, Laitinen M, Kaprio J, Yashin AI (1998) How heritable is individual susceptibility to death? The results of an analysis of survival data on Danish, Swedish and Finnish twins. Twin Res 1(4):196–205PubMedGoogle Scholar
  35. Johnson TE (2006) For the special issue: the nematode Caenorhabditis elegans in aging research. Exp Gerontol 41(10):887–889. doi: 10.1016/j.exger.2006.08.002 PubMedCrossRefGoogle Scholar
  36. Kathiresan S, Willer CJ, Peloso GM, Demissie S, Musunuru K, Schadt EE, Kaplan L, Bennett D, Li Y, Tanaka T, Voight BF, Bonnycastle LL, Jackson AU, Crawford G, Surti A, Guiducci C, Burtt NP, Parish S, Clarke R, Zelenika D, Kubalanza KA, Morken MA, Scott LJ, Stringham HM, Galan P, Swift AJ, Kuusisto J, Bergman RN, Sundvall J, Laakso M, Ferrucci L, Scheet P, Sanna S, Uda M, Yang Q, Lunetta KL, Dupuis J, de Bakker PI, O’Donnell CJ, Chambers JC, Kooner JS, Hercberg S, Meneton P, Lakatta EG, Scuteri A, Schlessinger D, Tuomilehto J, Collins FS, Groop L, Altshuler D, Collins R, Lathrop GM, Melander O, Salomaa V, Peltonen L, Orho-Melander M, Ordovas JM, Boehnke M, Abecasis GR, Mohlke KL, Cupples LA (2009) Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 41(1):56–65. doi: 10.1038/ng.291 PubMedCrossRefGoogle Scholar
  37. Kenyon C (2005) The plasticity of aging: insights from long-lived mutants. Cell 120(4):449–460PubMedCrossRefGoogle Scholar
  38. Kirkwood TB (2011) Systems biology of ageing and longevity. Philos Trans R Soc Lond B Biol Sci 366(1561):64–70. doi: 10.1098/rstb.2010.0275 PubMedCrossRefGoogle Scholar
  39. Kirkwood TB, Austad SN (2000) Why do we age? Nature 408(6809):233–238PubMedCrossRefGoogle Scholar
  40. Koga H, Kaushik S, Cuervo AM (2011) Protein homeostasis and aging: the importance of exquisite quality control. Ageing Res Rev 10(2):205–215. doi: 10.1016/j.arr.2010.02.001 PubMedCrossRefGoogle Scholar
  41. Koropatnick TA, Kimbell J, Chen R, Grove JS, Donlon TA, Masaki KH, Rodriguez BL, Willcox BJ, Yano K, Curb JD (2008) A prospective study of high-density lipoprotein cholesterol, cholesteryl ester transfer protein gene variants, and healthy aging in very old Japanese-American men. J Gerontol A Biol Sci Med Sci 63(11):1235–1240PubMedCrossRefGoogle Scholar
  42. Kraja AT, Hunt SC, Rao DC, Davila-Roman VG, Arnett DK, Province MA (2011) Genetics of hypertension and cardiovascular disease and their interconnected pathways: lessons from large studies. Curr Hypertens Rep 13(1):46–54. doi: 10.1007/s11906-010-0174-7 PubMedCrossRefGoogle Scholar
  43. Ku CS, Loy EY, Pawitan Y, Chia KS (2010) The pursuit of genome-wide association studies: where are we now? J Hum Genet 55(4):195–206. doi: 10.1038/jhg.2010.19 PubMedCrossRefGoogle Scholar
  44. Kulminski AM (2011) Complex phenotypes and phenomenon of genome-wide inter-chromosomal linkage disequilibrium in the human genome. Exp Gerontol 46:979–986PubMedCrossRefGoogle Scholar
  45. Kulminski AM, Culminskaya I, Ukraintseva SV, Arbeev KG, Land KC, Yashin AI (2010) Beta2-adrenergic receptor gene polymorphisms as systemic determinants of healthy aging in an evolutionary context. Mech Ageing Dev 131(5):338–345. doi: 10.1016/j.mad.2010.04.001 PubMedCrossRefGoogle Scholar
  46. Kulminski AM, Culminskaya I, Ukraintseva SV, Arbeev KG, Arbeeva L, Wu D, Akushevich I, Land KC, Yashin AI (2011) Trade-off in the effects of the apolipoprotein E polymorphism on the ages at onset of CVD and cancer influences human lifespan. Aging Cell. doi: 10.1111/j.1474-9726.2011.00689.x
  47. Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A, Glazer NL, Morrison AC, Johnson AD, Aspelund T, Aulchenko Y, Lumley T, Kottgen A, Vasan RS, Rivadeneira F, Eiriksdottir G, Guo X, Arking DE, Mitchell GF, Mattace-Raso FU, Smith AV, Taylor K, Scharpf RB, Hwang SJ, Sijbrands EJ, Bis J, Harris TB, Ganesh SK, O’Donnell CJ, Hofman A, Rotter JI, Coresh J, Benjamin EJ, Uitterlinden AG, Heiss G, Fox CS, Witteman JC, Boerwinkle E, Wang TJ, Gudnason V, Larson MG, Chakravarti A, Psaty BM, van Duijn CM (2009) Genome-wide association study of blood pressure and hypertension. Nat Genet 41(6):677–687. doi: 10.1038/ng.384 PubMedCrossRefGoogle Scholar
  48. Lunetta KL, D’Agostino RB Sr, Karasik D, Benjamin EJ, Guo CY, Govindaraju R, Kiel DP, Kelly-Hayes M, Massaro JM, Pencina MJ, Seshadri S, Murabito JM (2007) Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study. BMC Med Genet 8(Suppl 1):S13PubMedCrossRefGoogle Scholar
  49. Ly DH, Lockhart DJ, Lerner RA, Schultz PG (2000) Mitotic misregulation and human aging. Science 287(5462):2486–2492PubMedCrossRefGoogle Scholar
  50. Manev H (2009) Hypotheses on mechanisms linking cardiovascular and psychiatric/neurological disorders. Cardiovasc Psychiatry Neurol 2009:197132. doi: 10.1155/2009/197132 PubMedGoogle Scholar
  51. Manolio TA, Brooks LD, Collins FS (2008) A HapMap harvest of insights into the genetics of common disease. J Clin Invest 118(5):1590–1605. doi: 10.1172/JCI34772 PubMedCrossRefGoogle Scholar
  52. Martin GM (1999) APOE alleles and lipophylic pathogens. Neurobiol Aging 20(4):441–443PubMedCrossRefGoogle Scholar
  53. Martin GM (2007) Modalities of gene action predicted by the classical evolutionary biological theory of aging. Ann N Y Acad Sci 1100:14–20. doi: 10.1196/annals.1395.002 PubMedCrossRefGoogle Scholar
  54. Martin GM, Bergman A, Barzilai N (2007) Genetic determinants of human health span and life span: progress and new opportunities. PLoS Genet 3(7):e125PubMedCrossRefGoogle Scholar
  55. McClellan J, King MC (2010) Genetic heterogeneity in human disease. Cell 141(2):210–217. doi: 10.1016/j.cell.2010.03.032 PubMedCrossRefGoogle Scholar
  56. Melzer D, Hurst AJ, Frayling T (2007) Genetic variation and human aging: progress and prospects. J Gerontol A Biol Sci Med Sci 62(3):301–307PubMedCrossRefGoogle Scholar
  57. Newman AB, Walter S, Lunetta KL, Garcia ME, Slagboom PE, Christensen K, Arnold AM, Aspelund T, Aulchenko YS, Benjamin EJ, Christiansen L, D’Agostino RB Sr, Fitzpatrick AL, Franceschini N, Glazer NL, Gudnason V, Hofman A, Kaplan R, Karasik D, Kelly-Hayes M, Kiel DP, Launer LJ, Marciante KD, Massaro JM, Miljkovic I, Nalls MA, Hernandez D, Psaty BM, Rivadeneira F, Rotter J, Seshadri S, Smith AV, Taylor KD, Tiemeier H, Uh HW, Uitterlinden AG, Vaupel JW, Walston J, Westendorp RG, Harris TB, Lumley T, van Duijn CM, Murabito JM (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 A Biol Sci Med Sci 65(5):478–487. doi: 10.1093/gerona/glq028 PubMedCrossRefGoogle Scholar
  58. Newton-Cheh C, Johnson T, Gateva V, Tobin MD, Bochud M, Coin L, Najjar SS, Zhao JH, Heath SC, Eyheramendy S, Papadakis K, Voight BF, Scott LJ, Zhang F, Farrall M, Tanaka T, Wallace C, Chambers JC, Khaw KT, Nilsson P, van der Harst P, Polidoro S, Grobbee DE, Onland-Moret NC, Bots ML, Wain LV, Elliott KS, Teumer A, Luan J, Lucas G, Kuusisto J, Burton PR, Hadley D, McArdle WL, Brown M, Dominiczak A, Newhouse SJ, Samani NJ, Webster J, Zeggini E, Beckmann JS, Bergmann S, Lim N, Song K, Vollenweider P, Waeber G, Waterworth DM, Yuan X, Groop L, Orho-Melander M, Allione A, Di Gregorio A, Guarrera S, Panico S, Ricceri F, Romanazzi V, Sacerdote C, Vineis P, Barroso I, Sandhu MS, Luben RN, Crawford GJ, Jousilahti P, Perola M, Boehnke M, Bonnycastle LL, Collins FS, Jackson AU, Mohlke KL, Stringham HM, Valle TT, Willer CJ, Bergman RN, Morken MA, Doring A, Gieger C, Illig T, Meitinger T, Org E, Pfeufer A, Wichmann HE, Kathiresan S, Marrugat J, O’Donnell CJ, Schwartz SM, Siscovick DS, Subirana I, Freimer NB, Hartikainen AL, McCarthy MI, O’Reilly PF, Peltonen L, Pouta A, de Jong PE, Snieder H, van Gilst WH, Clarke R, Goel A, Hamsten A, Peden JF, Seedorf U, Syvanen AC, Tognoni G, Lakatta EG, Sanna S, Scheet P, Schlessinger D, Scuteri A, Dorr M, Ernst F, Felix SB, Homuth G, Lorbeer R, Reffelmann T, Rettig R, Volker U, Galan P, Gut IG, Hercberg S, Lathrop GM, Zelenika D, Deloukas P, Soranzo N, Williams FM, Zhai G, Salomaa V, Laakso M, Elosua R, Forouhi NG, Volzke H, Uiterwaal CS, van der Schouw YT, Numans ME, Matullo G, Navis G, Berglund G, Bingham SA, Kooner JS, Connell JM, Bandinelli S, Ferrucci L, Watkins H, Spector TD, Tuomilehto J, Altshuler D, Strachan DP, Laan M, Meneton P, Wareham NJ, Uda M, Jarvelin MR, Mooser V, Melander O, Loos RJ, Elliott P, Abecasis GR, Caulfield M, Munroe PB (2009) Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet 41(6):666–676. doi: 10.1038/ng.361 PubMedCrossRefGoogle Scholar
  59. Olshansky SJ, Perry D, Miller RA, Butler RN (2007) Pursuing the longevity dividend: scientific goals for an aging world. Ann N Y Acad Sci 1114:11–13. doi: 10.1196/annals.1396.050 PubMedCrossRefGoogle Scholar
  60. Petkov PM, Graber JH, Churchill GA, DiPetrillo K, King BL, Paigen K (2005) Evidence of a large-scale functional organization of mammalian chromosomes. PLoS Genet 1(3):e33. doi: 10.1371/journal.pgen.0010033 PubMedCrossRefGoogle Scholar
  61. Petkov PM, Graber JH, Churchill GA, DiPetrillo K, King BL, Paigen K (2007) Evidence of a large-scale functional organization of mammalian chromosomes. PLoS Biol 5(5):e127. doi: 10.1371/journal.pbio.0050127, author reply e128PubMedCrossRefGoogle Scholar
  62. Plomin R, Haworth CM, Davis OS (2009) Common disorders are quantitative traits. Nat Rev Genet 10(12):872–878. doi: 10.1038/nrg2670 PubMedCrossRefGoogle Scholar
  63. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575. doi: 10.1086/519795 PubMedCrossRefGoogle Scholar
  64. Reed SI (2003) Ratchets and clocks: the cell cycle, ubiquitylation and protein turnover. Nat Rev Mol Cell Biol 4(11):855–864. doi: 10.1038/nrm1246nrm1246 PubMedCrossRefGoogle Scholar
  65. Roy AK, Oh T, Rivera O, Mubiru J, Song CS, Chatterjee B (2002) Impacts of transcriptional regulation on aging and senescence. Ageing Res Rev 1(3):367–380PubMedCrossRefGoogle Scholar
  66. Salvioli S, Olivieri F, Marchegiani F, Cardelli M, Santoro A, Bellavista E, Mishto M, Invidia L, Capri M, Valensin S, Sevini F, Cevenini E, Celani L, Lescai F, Gonos E, Caruso C, Paolisso G, De Benedictis G, Monti D, Franceschi C (2006) Genes, ageing and longevity in humans: problems, advantages and perspectives. Free Radic Res 40(12):1303–1323. doi: 10.1080/10715760600917136 PubMedCrossRefGoogle Scholar
  67. Salvioli S, Capri M, Tieri P, Loroni J, Barbi C, Invidia L, Altilia S, Santoro A, Pirazzini C, Pierini M, Bellavista E, Alberghina L, Franceschi C (2008) Different types of cell death in organismal aging and longevity: state of the art and possible systems biology approach. Curr Pharm Des 14(3):226–236PubMedCrossRefGoogle Scholar
  68. Samuels MA (2007) The brain–heart connection. Circulation 116(1):77–84. doi: 10.1161/CIRCULATIONAHA.106.678995 PubMedCrossRefGoogle Scholar
  69. Sebastiani P, Solovieff N, Puca A, Hartley SW, Melista E, Andersen S, Dworkis DA, Wilk JB, Myers RH, Steinberg MH, Montano M, Baldwin CT, Perls TT (2010) Genetic signatures of exceptional longevity in humans. Science. doi: 10.1126/science.1190532
  70. Sierra F, Hadley E, Suzman R, Hodes R (2008) Prospects for life span extension. Annu Rev Med. doi: 10.1146/annurev.med.60.061607.220533
  71. Slagboom PE, Beekman M, Passtoors WM, Deelen J, Vaarhorst AA, Boer JM, van den Akker EB, van Heemst D, de Craen AJ, Maier AB, Rozing M, Mooijaart SP, Heijmans BT, Westendorp RG (2011) Genomics of human longevity. Philos Trans R Soc Lond B Biol Sci 366(1561):35–42. doi: 10.1098/rstb.2010.0284 PubMedCrossRefGoogle Scholar
  72. Soltow QA, Jones DP, Promislow DE (2010) A network perspective on metabolism and aging. Integr Comp Biol 50(5):844–854. doi: 10.1093/icb/icq094 PubMedCrossRefGoogle Scholar
  73. Splansky GL, Corey D, Yang Q, Atwood LD, Cupples LA, Benjamin EJ, D’Agostino RB Sr, Fox CS, Larson MG, Murabito JM, O’Donnell CJ, Vasan RS, Wolf PA, Levy D (2007) The Third Generation Cohort of the National Heart, Lung, and Blood Institute's Framingham Heart Study: design, recruitment, and initial examination. Am J Epidemiol 165(11):1328–1335. doi: 10.1093/aje/kwm021 PubMedCrossRefGoogle Scholar
  74. Summers K, Crespi BJ (2010) Xmrks the spot: life history tradeoffs, sexual selection and the evolutionary ecology of oncogenesis. Mol Ecol 19(15):3022–3024PubMedCrossRefGoogle Scholar
  75. Sun H, Fang H, Chen T, Perkins R, Tong W (2006) GOFFA: gene ontology for functional analysis—a FDA gene ontology tool for analysis of genomic and proteomic data. BMC Bioinformatics 7(Suppl 2):S23. doi: 10.1186/1471-2105-7-S2-S23 PubMedCrossRefGoogle Scholar
  76. Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Ripatti S, Chasman DI, Willer CJ, Johansen CT, Fouchier SW, Isaacs A, Peloso GM, Barbalic M, Ricketts SL, Bis JC, Aulchenko YS, Thorleifsson G, Feitosa MF, Chambers J, Orho-Melander M, Melander O, Johnson T, Li X, Guo X, Li M, Shin Cho Y, Jin Go M, Jin Kim Y, Lee JY, Park T, Kim K, Sim X, Twee-Hee Ong R, Croteau-Chonka DC, Lange LA, Smith JD, Song K, Hua Zhao J, Yuan X, Luan J, Lamina C, Ziegler A, Zhang W, Zee RY, Wright AF, Witteman JC, Wilson JF, Willemsen G, Wichmann HE, Whitfield JB, Waterworth DM, Wareham NJ, Waeber G, Vollenweider P, Voight BF, Vitart V, Uitterlinden AG, Uda M, Tuomilehto J, Thompson JR, Tanaka T, Surakka I, Stringham HM, Spector TD, Soranzo N, Smit JH, Sinisalo J, Silander K, Sijbrands EJ, Scuteri A, Scott J, Schlessinger D, Sanna S, Salomaa V, Saharinen J, Sabatti C, Ruokonen A, Rudan I, Rose LM, Roberts R, Rieder M, Psaty BM, Pramstaller PP, Pichler I, Perola M, Penninx BW, Pedersen NL, Pattaro C, Parker AN, Pare G, Oostra BA, O’Donnell CJ, Nieminen MS, Nickerson DA, Montgomery GW, Meitinger T, McPherson R, McCarthy MI, McArdle W, Masson D, Martin NG, Marroni F, Mangino M, Magnusson PK, Lucas G, Luben R, Loos RJ, Lokki ML, Lettre G, Langenberg C, Launer LJ, Lakatta EG, Laaksonen R, Kyvik KO, Kronenberg F, Konig IR, Khaw KT, Kaprio J, Kaplan LM, Johansson A, Jarvelin MR, Janssens AC, Ingelsson E, Igl W, Kees Hovingh G, Hottenga JJ, Hofman A, Hicks AA, Hengstenberg C, Heid IM, Hayward C, Havulinna AS, Hastie ND, Harris TB, Haritunians T, Hall AS, Gyllensten U, Guiducci C, Groop LC, Gonzalez E, Gieger C, Freimer NB, Ferrucci L, Erdmann J, Elliott P, Ejebe KG, Doring A, Dominiczak AF, Demissie S, Deloukas P, de Geus EJ, de Faire U, Crawford G, Collins FS, Chen YD, Caulfield MJ, Campbell H, Burtt NP, Bonnycastle LL, Boomsma DI, Boekholdt SM, Bergman RN, Barroso I, Bandinelli S, Ballantyne CM, Assimes TL, Quertermous T, Altshuler D, Seielstad M, Wong TY, Tai ES, Feranil AB, Kuzawa CW, Adair LS, Taylor HA Jr, Borecki IB, Gabriel SB, Wilson JG, Holm H, Thorsteinsdottir U, Gudnason V, Krauss RM, Mohlke KL, Ordovas JM, Munroe PB, Kooner JS, Tall AR, Hegele RA, Kastelein JJ, Schadt EE, Rotter JI, Boerwinkle E, Strachan DP, Mooser V, Stefansson K, Reilly MP, Samani NJ, Schunkert H, Cupples LA, Sandhu MS, Ridker PM, Rader DJ, van Duijn CM, Peltonen L, Abecasis GR, Boehnke M, Kathiresan S (2010) Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466(7307):707–713. doi: 10.1038/nature09270 PubMedCrossRefGoogle Scholar
  77. Vaupel JW (2010) Biodemography of human ageing. Nature 464(7288):536–542. doi: 10.1038/nature08984 PubMedCrossRefGoogle Scholar
  78. Vijg J, Suh Y (2005) Genetics of longevity and aging. Annu Rev Med 56:193–212. doi: 10.1146/annurev.med.56.082103.104617 PubMedCrossRefGoogle Scholar
  79. Wigginton JE, Cutler DJ, Abecasis GR (2005) A note on exact tests of Hardy–Weinberg equilibrium. Am J Hum Genet 76(5):887–893. doi: 10.1086/429864 PubMedCrossRefGoogle Scholar
  80. Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD (2008a) FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci USA 105(37):13987–13992. doi: 10.1073/pnas.0801030105 PubMedCrossRefGoogle Scholar
  81. Willcox DC, Willcox BJ, Wang NC, He Q, Rosenbaum M, Suzuki M (2008b) Life at the extreme limit: phenotypic characteristics of supercentenarians in Okinawa. J Gerontol A Biol Sci Med Sci 63(11):1201–1208PubMedCrossRefGoogle Scholar
  82. Williams PD, Day T (2003) Antagonistic pleiotropy, mortality source interactions, and the evolutionary theory of senescence. Evolution 57(7):1478–1488PubMedGoogle Scholar

Copyright information

© American Aging Association 2011

Authors and Affiliations

  1. 1.Center for Population Health and AgingDuke UniversityDurhamUSA

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