AGE

, Volume 35, Issue 2, pp 487–500

Evidence from case–control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity

  • Mette Soerensen
  • Serena Dato
  • Qihua Tan
  • Mikael Thinggaard
  • Rabea Kleindorp
  • Marian Beekman
  • H. Eka D. Suchiman
  • Rune Jacobsen
  • Matt McGue
  • Tinna Stevnsner
  • Vilhelm A. Bohr
  • Anton J. M. de Craen
  • Rudi G. J. Westendorp
  • Stefan Schreiber
  • P. Eline Slagboom
  • Almut Nebel
  • James W. Vaupel
  • Kaare Christensen
  • Lene Christiansen
Article

Abstract

In this study, we investigated 102 single-nucleotide polymorphisms (SNPs) covering the common genetic variation in 16 genes recurrently regarded as candidates for human longevity: APOE; ACE; CETP; HFE; IL6; IL6R; MTHFR; TGFB1; APOA4; APOC3; SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. In a case–control study of 1,089 oldest-old (ages 92–93) and 736 middle-aged Danes, the minor allele frequency (MAF) of rs769449 (APOE) was significantly decreased in the oldest-old, while the MAF of rs9923854 (CETP) was significantly enriched. These effects were supported when investigating 1,613 oldest-old (ages 95–110) and 1,104 middle-aged Germans. rs769449 was in modest linkage equilibrium (R2 = 0.55) with rs429358 of the APOE-ε4 haplotype and adjusting for rs429358 eliminated the association of rs769449, indicating that the association likely reflects the well-known effect of rs429358. Gene-based analysis confirmed the effects of variation in APOE and CETP and furthermore pointed to HSPA14 as a longevity gene. In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes, only one SNP, rs2069827 (IL6), was borderline significantly associated with survival from age 92 (P-corrected = 0.064). This advantageous effect of the minor allele was supported when investigating a Dutch longitudinal cohort (N = 563) of oldest-old (age 85+). Since rs2069827 was located in a putative transcription factor binding site, quantitative RNA expression studies were conducted. However, no difference in IL6 expression was observed between rs2069827 genotype groups. In conclusion, we here support and expand the evidence suggesting that genetic variation in APOE, CETP, and IL6, and possible HSPA14, is associated with human longevity.

Keywords

Human longevity Candidate gene association study Case–control data Longitudinal data 

Supplementary material

11357_2011_9373_MOESM1_ESM.pdf (65 kb)
ESM 1(PDF 64 kb)
11357_2011_9373_MOESM2_ESM.pdf (127 kb)
ESM 2(PDF 127 KB)
11357_2011_9373_MOESM3_ESM.pdf (56 kb)
ESM 3(PDF 56 kb)
11357_2011_9373_MOESM4_ESM.pdf (63 kb)
ESM 4(PDF 63 kb)
11357_2011_9373_MOESM5_ESM.pdf (107 kb)
ESM 5(PDF 107 kb)

References

  1. Abdollahi MR, Huang S, Rodriguez S, Guthrie PA, Smith GD, Ebrahim S, Lawlor DA, Day IN, Gaunt TR (2008) Homogeneous assay of rs4343, an ACE I/D proxy, and an analysis in the British Women’s Heart and Health Study (BWHHS). Dis Markers 24:11–17PubMedCrossRefGoogle Scholar
  2. Agerholm-Larsen B, Nordestgaard BG, Steffensen R, Sorensen TI, Jensen G, Tybjaerg-Hansen A (1997) ACE gene polymorphism: ischemic heart disease and longevity in 10,150 individuals. A case-referent and retrospective cohort study based on the Copenhagen City Heart Study. Circulation 95:2358–2367PubMedCrossRefGoogle Scholar
  3. Altomare K, Greco V, Bellizzi D, Berardelli M, Dato S, DeRango F, Garasto S, Rose G, Feraco E, Mari V, Passarino G, Franceschi C, De BG (2003) The allele (A)(−110) in the promoter region of the HSP70-1 gene is unfavorable to longevity in women. Biogerontology 4:215–220PubMedCrossRefGoogle Scholar
  4. Arias-Vasquez A, Sayed-Tabatabaei FA, Schut AF, Hofman A, Bertolli-Avella AM, Vergeer JM, Aulchenko YS, Witteman JC, van Duijn CM (2005) Angiotensin converting enzyme gene, smoking and mortality in a population-based study. Eur J Clin Invest 35:444–449PubMedCrossRefGoogle Scholar
  5. Asada T, Kariya T, Yamagata Z, Kinoshita T, Asaka A (1996) ApoE epsilon 4 allele and cognitive decline in patients with Alzheimer’s disease. Neurology 47:603PubMedCrossRefGoogle Scholar
  6. Atzmon G, Rincon M, Schechter CB, Shuldiner AR, Lipton RB, Bergman A, Barzilai N (2006) Lipoprotein genotype and conserved pathway for exceptional longevity in humans. PLoS Biol 4:e113PubMedCrossRefGoogle Scholar
  7. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265PubMedCrossRefGoogle Scholar
  8. 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 290:2030–2040PubMedCrossRefGoogle Scholar
  9. Bathum L, Christiansen L, Nybo H, Ranberg KA, Gaist D, Jeune B, Petersen NE, Vaupel J, Christensen K (2001) Association of mutations in the hemochromatosis gene with shorter life expectancy. Arch Intern Med 161:2441–2444PubMedCrossRefGoogle Scholar
  10. Bathum L, Christiansen L, Jeune B, Vaupel J, McGue M, Christensen K (2006) Apolipoprotein e genotypes: relationship to cognitive functioning, cognitive decline, and survival in nonagenarians. J Am Geriatr Soc 54:654–658PubMedCrossRefGoogle Scholar
  11. Bellizzi D, Rose G, Cavalcante P, Covello G, Dato S, De RF, Greco V, Maggiolini M, Feraco E, Mari V, Franceschi C, Passarino G, De BG (2005) A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages. Genomics 85:258–263PubMedCrossRefGoogle Scholar
  12. Bladbjerg EM, Andersen-Ranberg K, de Maat MP, Kristensen SR, Jeune B, Gram J, Jespersen J (1999) Longevity is independent of common variations in genes associated with cardiovascular risk. Thromb Haemost 82:1100–1105PubMedGoogle Scholar
  13. 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 324:129–135PubMedCrossRefGoogle Scholar
  14. Bootsma-van der Wiel A, Van Exel E, de Craen AJ, Gussekloo J, Lagaay AM, Knook DL, Westendorp RG (2002) A high response is not essential to prevent selection bias: results from the Leiden 85-plus study. J Clin Epidemiol 55:1119–1125PubMedCrossRefGoogle Scholar
  15. Brattstrom L, Zhang Y, Hurtig M, Refsum H, Ostensson S, Fransson L, Jones K, Landgren F, Brudin L, Ueland PM (1998) A common methylenetetrahydrofolate reductase gene mutation and longevity. Atherosclerosis 141:315–319PubMedCrossRefGoogle Scholar
  16. Caliebe A, Kleindorp R, Blanche H, Christiansen L, Puca AA, Rea IM, Slagboom E, Flachsbart F, Christensen K, Rimbach G, Schreiber S, Nebel A (2010) No or only population-specific effect of PON1 on human longevity: a comprehensive meta-analysis. Ageing Res Rev 9:238–244PubMedCrossRefGoogle Scholar
  17. Candore G, Balistreri CR, Listi F, Grimaldi MP, Vasto S, Colonna-Romano G, Franceschi C, Lio D, Caselli G, Caruso C (2006) Immunogenetics, gender, and longevity. Ann N Y Acad Sci 1089:516–537PubMedCrossRefGoogle Scholar
  18. Capurso C, Solfrizzi V, D’Introno A, Colacicco AM, Capurso SA, Semeraro C, Capurso A, Panza F (2007) Interleukin 6 variable number of tandem repeats (VNTR) gene polymorphism in centenarians. Ann Hum Genet 71:843–848PubMedCrossRefGoogle Scholar
  19. Carrieri G, Marzi E, Olivieri F, Marchegiani F, Cavallone L, Cardelli M, Giovagnetti S, Stecconi R, Molendini C, Trapassi C, De BG, Kletsas D, Franceschi C (2004) The G/C915 polymorphism of transforming growth factor beta1 is associated with human longevity: a study in Italian centenarians. Aging Cell 3:443–448PubMedCrossRefGoogle Scholar
  20. Carru C, Pes GM, Deiana L, Baggio G, Franceschi C, Lio D, Balistreri CR, Candore G, Colonna-Romano G, Caruso C (2003) Association between the HFE mutations and longevity: a study in Sardinian population. Mech Ageing Dev 124:529–532PubMedCrossRefGoogle Scholar
  21. Cellini E, Nacmias B, Olivieri F, Ortenzi L, Tedde A, Bagnoli S, Petruzzi C, Franceschi C, Sorbi S (2005) Cholesteryl ester transfer protein (CETP) I405V polymorphism and longevity in Italian centenarians. Mech Ageing Dev 126:826–828PubMedCrossRefGoogle Scholar
  22. Christensen K, Johnson TE, Vaupel JW (2006) The quest for genetic determinants of human longevity: challenges and insights. Nat Rev Genet 7:436–448PubMedCrossRefGoogle Scholar
  23. Christiansen L, Bathum L, Andersen-Ranberg K, Jeune B, Christensen K (2004) Modest implication of interleukin-6 promoter polymorphisms in longevity. Mech Ageing Dev 125:391–395PubMedCrossRefGoogle Scholar
  24. Chung WH, Dao RL, Chen LK, Hung SI (2010) The role of genetic variants in human longevity. Ageing Res Rev 9(Suppl 1):S67–S78PubMedCrossRefGoogle Scholar
  25. Coppin H, Bensaid M, Fruchon S, Borot N, Blanche H, Roth MP (2003) Longevity and carrying the C282Y mutation for haemochromatosis on the HFE gene: case control study of 492 French centenarians. BMJ 327:132–133PubMedCrossRefGoogle Scholar
  26. Deelen J, Beekman M, Uh HW, Helmer Q, Kuningas M, Christiansen L, Kremer D, van der 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 10:686–698PubMedCrossRefGoogle Scholar
  27. Di Bona D, Vasto S, Capurso C, Christiansen L, Deiana L, Franceschi C, Hurme M, Mocchegiani E, Rea M, Lio D, Candore G, Caruso C (2009) Effect of interleukin-6 polymorphisms on human longevity: a systematic review and meta-analysis. Ageing Res Rev 8:36–42PubMedCrossRefGoogle Scholar
  28. Dietrich M, Hu Y, Block G, Olano E, Packer L, Morrow JD, Hudes M, Abdukeyum G, Rimbach G, Minihane AM (2005) Associations between apolipoprotein E genotype and circulating F2-isoprostane levels in humans. Lipids 40:329–334PubMedCrossRefGoogle Scholar
  29. Flachsbart F, Croucher PJ, Nikolaus S, Hampe J, Cordes C, Schreiber S, Nebel A (2006) Sirtuin 1 (SIRT1) sequence variation is not associated with exceptional human longevity. Exp Gerontol 41:98–102PubMedCrossRefGoogle Scholar
  30. Franceschi C, Motta L, Valensin S, Rapisarda R, Franzone A, Berardelli M, Motta M, Monti D, Bonafe M, Ferrucci L, Deiana L, Pes GM, Carru C, Desole MS, Barbi C, Sartoni G, Gemelli C, Lescai F, Olivieri F, Marchegiani F, Cardelli M, Cavallone L, Gueresi P, Cossarizza A, Troiano L, Pini G, Sansoni P, Passeri G, Lisa R, Spazzafumo L, Amadio L, Giunta S, Stecconi R, Morresi R, Viticchi C, Mattace R, De BG, Baggio G (2000) Do men and women follow different trajectories to reach extreme longevity? Italian Multicenter Study on Centenarians (IMUSCE). Aging (Milano) 12:77–84Google Scholar
  31. Frederiksen H, Gaist D, Bathum L, Andersen K, McGue M, Vaupel JW, Christensen K (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 13:57–65PubMedCrossRefGoogle Scholar
  32. 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 19:202–210PubMedCrossRefGoogle Scholar
  33. Herskind AM, McGue M, Holm NV, Sorensen TI, Harvald B, Vaupel JW (1996) The heritability of human longevity: a population-based study of 2872 Danish twin pairs born 1870–1900. Hum Genet 97:319–323PubMedCrossRefGoogle Scholar
  34. Hessner MJ, Dinauer DM, Kwiatkowski R, Neri B, Raife TJ (2001) Age-dependent prevalence of vascular disease-associated polymorphisms among 2689 volunteer blood donors. Clin Chem 47:1879–1884PubMedGoogle Scholar
  35. Hjelmborg JVb, Iachine I, Skytthe A, Vaupel JW, McGue M, Koskenvuo M, Kaprio J, Pedersen NL, Christensen K (2006) Genetic influence on human lifespan and longevity. Hum Genet 119:312–321CrossRefGoogle Scholar
  36. 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 126:417–418PubMedCrossRefGoogle Scholar
  37. Jacobsen R, Martinussen T, Christiansen L, Jeune B, Ndersen-Ranberg K, Vaupel JW, Christensen K (2010) Increased effect of the ApoE gene on survival at advanced age in healthy and long-lived Danes: two nationwide cohort studies. Aging Cell 9:1004–1009PubMedCrossRefGoogle Scholar
  38. Jofre-Monseny L, Loboda A, Wagner AE, Huebbe P, Boesch-Saadatmandi C, Jozkowicz A, Minihane AM, Dulak J, Rimbach G (2007) Effects of apoE genotype on macrophage inflammation and heme oxygenase-1 expression. Biochem Biophys Res Commun 357:319–324PubMedCrossRefGoogle Scholar
  39. Jylhava J, Hurme M (2010) Gene variants as determinants of longevity: focus on the inflammatory factors. Pflugers Arch 459:239–246PubMedCrossRefGoogle Scholar
  40. Khabour OF, Abdelhalim ES, Abu-Wardeh A (2009) Association between SOD2 T-9C and MTHFR C677T polymorphisms and longevity: a study in Jordanian population. BMC Geriatr 9:57PubMedCrossRefGoogle Scholar
  41. Kuningas M, Putters M, Westendorp RG, Slagboom PE, van Heemst D (2007) SIRT1 gene, age-related diseases, and mortality: the Leiden 85-plus study. J Gerontol A Biol Sci Med Sci 62:960–965PubMedCrossRefGoogle Scholar
  42. Lescai F, Blanche H, Nebel A, Beekman M, Sahbatou M, Flachsbart F, Slagboom E, Schreiber S, Sorbi S, Passarino G, Franceschi C (2009) Human longevity and 11p15.5: a study in 1321 centenarians. Eur J Hum Genet 17:1515–1519PubMedCrossRefGoogle Scholar
  43. Li J, Niu W, Qi Y, Mayila W, Zhu P, Muhuyati CZ, Qiu C (2009a) Interactive association of heat shock protein 70 genes variants with natural longevity in Xinjiang Hetian Uygur ethnicity. Transl Res 154:257–264PubMedCrossRefGoogle Scholar
  44. Li Y, Wang WJ, Cao H, Lu J, Wu C, Hu FY, Guo J, Zhao L, Yang F, Zhang YX, Li W, Zheng GY, Cui H, Chen X, Zhu Z, He H, Dong B, Mo X, Zeng Y, Tian XL (2009b) Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Hum Mol Genet 18:4897–4904PubMedCrossRefGoogle Scholar
  45. Lio D, Balistreri CR, Colonna-Romano G, Motta M, Franceschi C, Malaguarnera M, Candore G, Caruso C (2002) Association between the MHC class I gene HFE polymorphisms and longevity: a study in Sicilian population. Genes Immun 3:20–24PubMedCrossRefGoogle Scholar
  46. Luft FC (1999) Bad genes, good people, association, linkage, longevity and the prevention of cardiovascular disease. Clin Exp Pharmacol Physiol 26:576–579PubMedCrossRefGoogle Scholar
  47. McKay GJ, Silvestri G, Chakravarthy U, Dasari S, Fritsche LG, Weber BH, Keilhauer CN, Klein ML, Francis PJ, Klaver CC, Vingerling JR, Ho L, De Jong PT, Dean M, Sawitzke J, Baird PN, Guymer RH, Stambolian D, Orlin A, Seddon JM, Peter I, Wright AF, Hayward C, Lotery AJ, Ennis S, Gorin MB, Weeks DE, Kuo CL, Hingorani AD, Sofat R, Cipriani V, Swaroop A, Othman M, Kanda A, Chen W, Abecasis GR, Yates JR, Webster AR, Moore AT, Seland JH, Rahu M, Soubrane G, Tomazzoli L, Topouzis F, Vioque J, Young IS, Fletcher AE, Patterson CC (2011) Variations in apolipoprotein e frequency with age in a pooled analysis of a large group of older people. Am J Epidemiol 173:1357–1364PubMedCrossRefGoogle Scholar
  48. Nebel A, Croucher PJ, 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 S A 102:7906–7909PubMedCrossRefGoogle Scholar
  49. Nebel A, Kleindorp R, Caliebe A, Nothnagel M, Blanche H, Junge O, Wittig M, Ellinghaus D, Flachsbart F, Wichmann HE, Meitinger T, Nikolaus S, Franke A, Krawczak M, Lathrop M, Schreiber S (2011) A genome-wide association study confirms APOE as the major gene influencing survival in long-lived individuals. Mech Ageing Dev 132:324–330PubMedCrossRefGoogle Scholar
  50. Novelli V, Viviani AC, Roncarati R, Guffanti G, Malovini A, Piluso G, Puca AA (2008) Lack of replication of genetic associations with human longevity. Biogerontology 9:85–92PubMedCrossRefGoogle Scholar
  51. Nybo H, Gaist D, Jeune B, Bathum L, McGue M, Vaupel JW, Christensen K (2001) The Danish 1905 cohort: a genetic-epidemiological nationwide survey. J Aging Health 13:32–46PubMedCrossRefGoogle Scholar
  52. Olmos Y, Brosens JJ, Lam EW (2011) Interplay between SIRT proteins and tumour suppressor transcription factors in chemotherapeutic resistance of cancer. Drug Resist Updat 14:35–44PubMedCrossRefGoogle Scholar
  53. Otto H, Conz C, Maier P, Wolfle T, Suzuki CK, Jeno P, Rucknagel P, Stahl J, Rospert S (2005) The chaperones MPP11 and Hsp70L1 form the mammalian ribosome-associated complex. Proc Natl Acad Sci U S A 102:10064–10069PubMedCrossRefGoogle Scholar
  54. Pedersen CB, Gotzsche H, Moller JO, Mortensen PB (2006) The Danish Civil Registration System. A cohort of eight million persons. Dan Med Bull 53:441–449PubMedGoogle Scholar
  55. Pes GM, Lio D, Carru C, Deiana L, Baggio G, Franceschi C, Ferrucci L, Oliveri F, Scola L, Crivello A, Candore G, Colonna-Romano G, Caruso C (2004) Association between longevity and cytokine gene polymorphisms. A study in Sardinian centenarians. Aging Clin Exp Res 16:244–248PubMedCrossRefGoogle Scholar
  56. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, Daly MJ, Sham PC (2007) PLINK: a toolset for whole-genome association and population-based linkage analysis. Am J Hum Genet 81:559–575PubMedCrossRefGoogle Scholar
  57. Rea IM, Ross OA, Armstrong M, McNerlan S, Alexander DH, Curran MD, Middleton D (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 124:555–561PubMedCrossRefGoogle Scholar
  58. Rose G, Dato S, Altomare K, Bellizzi D, Garasto S, Greco V, Passarino G, Feraco E, Mari V, Barbi C, BonaFe M, Franceschi C, Tan Q, Boiko S, Yashin AI, De BG (2003) Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly. Exp Gerontol 38:1065–1070PubMedCrossRefGoogle Scholar
  59. Ross OA, Curran MD, Crum KA, Rea IM, Barnett YA, Middleton D (2003) Increased frequency of the 2437T allele of the heat shock protein 70-Hom gene in an aged Irish population. Exp Gerontol 38:561–565PubMedCrossRefGoogle Scholar
  60. Schachter F, Faure-Delanef L, Guenot F, Rouger H, Froguel P, Lesueur-Ginot L, Cohen D (1994) Genetic associations with human longevity at the APOE and ACE loci. Nat Genet 6:29–32PubMedCrossRefGoogle Scholar
  61. Seripa D, D’Onofrio G, Panza F, Cascavilla L, Masullo C, Pilotto A (2011) The genetics of the human APOE polymorphism. Rejuvenation Res 14:491–500PubMedCrossRefGoogle Scholar
  62. Singh R, Kolvraa S, Rattan SI (2007) Genetics of human longevity with emphasis on the relevance of HSP70 as candidate genes. Front Biosci 12:4504–4513PubMedCrossRefGoogle Scholar
  63. Singh R, Kolvraa S, Bross P, Christensen K, Bathum L, Gregersen N, Tan Q, Rattan SI (2010) Anti-inflammatory heat shock protein 70 genes are positively associated with human survival. Curr Pharm Des 16:796–801PubMedCrossRefGoogle Scholar
  64. Skytthe A, Kyvik K, Holm NV, Vaupel JW, Christensen K (2002) The Danish Twin Registry: 127 birth cohorts of twins. Twin Res 5:352–357PubMedGoogle Scholar
  65. Soerensen M, Dato S, Christensen K, McGue M, Stevnsner T, Bohr VA, Christiansen L (2010) Replication of an association of variation in the FOXO3A gene with human longevity using both case–control and longitudinal data. Aging Cell 9:1010–1017PubMedCrossRefGoogle Scholar
  66. Stessman J, Maaravi Y, Hammerman-Rozenberg R, Cohen A, Nemanov L, Gritsenko I, Gruberman N, Ebstein RP (2005) Candidate genes associated with ageing and life expectancy in the Jerusalem longitudinal study. Mech Ageing Dev 126:333–339PubMedCrossRefGoogle Scholar
  67. Tan Q, Christiansen L, Christensen K, Kruse TA, Bathum L (2004) Apolipoprotein E genotype frequency patterns in aged Danes as revealed by logistic regression models. Eur J Epidemiol 19:651–656PubMedCrossRefGoogle Scholar
  68. Todesco L, Angst C, Litynski P, Loehrer F, Fowler B, Haefeli WE (1999) Methylenetetrahydrofolate reductase polymorphism, plasma homocysteine and age. Eur J Clin Invest 29:1003–1009PubMedCrossRefGoogle Scholar
  69. Vitek MP, Brown CM, Colton CA (2009) APOE genotype-specific differences in the innate immune response. Neurobiol Aging 30:1350–1360PubMedCrossRefGoogle Scholar
  70. Wan T, Zhou X, Chen G, An H, Chen T, Zhang W, Liu S, Jiang Y, Yang F, Wu Y, Cao X (2004) Novel heat shock protein Hsp70L1 activates dendritic cells and acts as a Th1 polarizing adjuvant. Blood 103:1747–1754PubMedCrossRefGoogle Scholar
  71. 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 123:29–38PubMedCrossRefGoogle Scholar
  72. Weber O, Bischoff H, Schmeck C, Bottcher MF (2010) Cholesteryl ester transfer protein and its inhibition. Cell Mol Life Sci 67:3139–3149PubMedCrossRefGoogle Scholar
  73. Wu Y, Wan T, Zhou X, Wang B, Yang F, Li N, Chen G, Dai S, Liu S, Zhang M, Cao X (2005) Hsp70-like protein 1 fusion protein enhances induction of carcinoembryonic antigen-specific CD8+ CTL response by dendritic cell vaccine. Cancer Res 65:4947–4954PubMedCrossRefGoogle Scholar
  74. Yang JK, Gong YY, Xie L, Lian SG, Yang J, Xu LY, Gao SJ, Zhang YP (2009) Lack of genetic association between the angiotensin-converting enzyme gene insertion/deletion polymorphism and longevity in a Han Chinese population. J Renin Angiotensin Aldosterone Syst 10:115–118PubMedCrossRefGoogle Scholar
  75. Zajc PM, Skaric-Juric T, Smolej NN, Tomas Z, Krajacic P, Milicic J, Barbalic M, Tomek-Roksandic S (2012) Angiotensin-converting enzyme deletion allele is beneficial for the longevity of Europeans. Age (Dordr). doi:10.1007/s11357-011-9270-0 CrossRefGoogle Scholar

Copyright information

© American Aging Association 2012

Authors and Affiliations

  • Mette Soerensen
    • 1
    • 2
    • 3
  • Serena Dato
    • 1
    • 4
  • Qihua Tan
    • 1
    • 2
    • 3
  • Mikael Thinggaard
    • 1
  • Rabea Kleindorp
    • 5
  • Marian Beekman
    • 6
    • 7
  • H. Eka D. Suchiman
    • 6
    • 7
  • Rune Jacobsen
    • 1
  • Matt McGue
    • 1
    • 8
  • Tinna Stevnsner
    • 9
  • Vilhelm A. Bohr
    • 9
    • 10
  • Anton J. M. de Craen
    • 11
  • Rudi G. J. Westendorp
    • 11
  • Stefan Schreiber
    • 5
  • P. Eline Slagboom
    • 6
    • 7
  • Almut Nebel
    • 5
  • James W. Vaupel
    • 1
    • 12
  • Kaare Christensen
    • 1
    • 2
    • 3
  • Lene Christiansen
    • 1
    • 2
    • 3
  1. 1.The Danish Aging Research Center, Epidemiology, Institute of Public HealthUniversity of Southern DenmarkOdense CDenmark
  2. 2.Department of Clinical GeneticsOdense University HospitalOdense CDenmark
  3. 3.Department of Clinical Biochemistry and PharmacologyOdense University HospitalOdense CDenmark
  4. 4.Department of Cell BiologyUniversity of CalabriaRendeItaly
  5. 5.Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein and Christian-Albrechts-UniversityKielGermany
  6. 6.Department of Molecular EpidemiologyLeiden University Medical CenterLeidenthe Netherlands
  7. 7.Netherlands Consortium for Healthy AgeingLeiden University Medical CenterLeidenthe Netherlands
  8. 8.Department of PsychologyUniversity of MinnesotaMinneapolisUSA
  9. 9.The Danish Aging Research Center, Department of Molecular BiologyAarhus UniversityAarhus CDenmark
  10. 10.Laboratory of Molecular Gerontology, National Institute on AgingNational Institute of HealthBaltimoreUSA
  11. 11.Department of Gerontology and GeriatricsLeiden University Medical CenterLeidenthe Netherlands
  12. 12.Max Planck Institute for Demographic ResearchRostockGermany

Personalised recommendations