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

Age

Volumn 35, Issue 2, 2013, Pages 487-500

  Soerensen, Mette ^a,b   Dato, Serena ^a,c   Tan, Qihua ^a,b   Thinggaard, Mikael ^a   Kleindorp, Rabea ^d   Beekman, Marian ^e   Suchiman, H Eka D ^e   Jacobsen, Rune ^a   McGue, Matt ^a,f   Stevnsner, Tinna ^g   Bohr, Vilhelm A ^g,h   De Craen, Anton J M ^e   Westendorp, Rudi G J ^e   Schreiber, Stefan ^d   Slagboom, P Eline ^e   Nebel, Almut ^d   Vaupel, James W ^a,i   Christensen, Kaare ^a,b   Christiansen, Lene ^a,b  

^a UNIVERSITY OF SOUTHERN DENMARK   (Denmark)

^b ODENSE UNIVERSITY HOSPITAL   (Denmark)

^c UNIVERSITY OF CALABRIA   (Italy)

^d UNIVERSITY OF KIEL   (Germany)

^e LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

^f UNIVERSITY OF MINNESOTA   (United States)

^g AARHUS UNIVERSITY   (Denmark)

^h NATIONAL INSTITUTE ON AGING   (United States)

ⁱ MAX PLANCK INSTITUTE FOR DEMOGRAPHIC RESEARCH   (Germany)

Author keywords

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

Indexed keywords

5,10 METHYLENETETRAHYDROFOLATE REDUCTASE (FADH2); APOLIPOPROTEIN A4; APOLIPOPROTEIN C3; APOLIPOPROTEIN E; APOLIPOPROTEIN E4; CHOLESTEROL ESTER TRANSFER PROTEIN; DIPEPTIDYL CARBOXYPEPTIDASE; INTERLEUKIN 6; INTERLEUKIN 6 RECEPTOR; SIRTUIN 1; SIRTUIN 3; SIRTUIN 6; TRANSCRIPTION FACTOR;

ACE GENE; ADULT; AGED; APOA4 GENE; APOC3 GENE; APOE GENE; ARTICLE; BINDING SITE; CETP GENE; CONTROLLED STUDY; DANISH; ETHNIC GROUP; FEMALE; FOLLOW UP; GENE EXPRESSION; GENE FREQUENCY; GENETIC ASSOCIATION; GENETIC LINKAGE; GENETIC VARIABILITY; GENOTYPE; GERMAN; HAPLOTYPE; HFE GENE; HSPA 14 GENE; HSPA 1A GENE; HSPA 1L GENE; HUMAN; IL6 GENE; IL6R GENE; LONGEVITY; LONGITUDINAL STUDY; MALE; MTHFR GENE; POPULATION BASED CASE CONTROL STUDY; PROTEIN BINDING; QUANTITATIVE ANALYSIS; SINGLE NUCLEOTIDE POLYMORPHISM; SIRT 1 GENE; SIRT 3 GENE; SIRT 6 GENE; SURVIVAL TIME; TGFB1 GENE;

AGED, 80 AND OVER; ALLELES; APOLIPOPROTEINS E; CASE-CONTROL STUDIES; CHOLESTEROL ESTER TRANSFER PROTEINS; DENMARK; FEMALE; GENE FREQUENCY; GENETIC VARIATION; GENOTYPE; GERMANY; HAPLOTYPES; HUMANS; INTERLEUKIN-6; LINEAR MODELS; LONGEVITY; LONGITUDINAL STUDIES; MALE; MIDDLE AGED; NETHERLANDS; POLYMORPHISM, SINGLE NUCLEOTIDE; REGISTRIES;

EID: 84880569861     PISSN: 01619152     EISSN: 15744647     Source Type: Journal    
DOI: 10.1007/s11357-011-9373-7     Document Type: Article

References (75)

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 24:11-17
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 95:2358-2367
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 4:215-220
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 35:444-449
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 47:603
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:e113
7. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263-265
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 290:2030-2040
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 161:2441-2444
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 54:654-658
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 85:258-263
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 82:1100-1105
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 324:129-135
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 55:1119-1125
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 141:315-319
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 9:238-244
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 1089:516-537
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 71:843-848
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 3:443-448
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 124:529-532
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 126:826-828
22. Christensen K, Johnson TE, Vaupel JW (2006) The quest for genetic determinants of human longevity: challenges and insights. Nat Rev Genet 7:436-448
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 125:391-395
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-S78
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 327:132-133
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 10:686-698
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 8:36-42
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 40:329-334
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 41:98-102
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) 12:77-84
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 13:57-65
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 19:202-210
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 97:319-323
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 47:1879-1884
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 119:312-321
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 126:417-418
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 9:1004-1009
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 357:319-324
39. Jylhava J, Hurme M (2010) Gene variants as determinants of longevity: focus on the inflammatory factors. Pflugers Arch 459:239-246
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 9:57
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 62:960-965
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 17:1515-1519
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 154:257-264
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 18:4897-4904
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 3:20-24
46. Luft FC (1999) Bad genes, good people, association, linkage, longevity and the prevention of cardiovascular disease. Clin Exp Pharmacol Physiol 26:576-579
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 173:1357-1364
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 102:7906-7909
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 132:324-330
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 9:85-92
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 13:32-46
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 14:35-44
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 102:10064-10069
54. Pedersen CB, Gotzsche H, Moller JO, Mortensen PB (2006) The Danish Civil Registration System. A cohort of eight million persons. Dan Med Bull 53:441-449
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 16:244-248
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 81:559-575
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 124:555-561
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 38:1065-1070
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 38:561-565
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 6:29-32
61. Seripa D, D'Onofrio G, Panza F, Cascavilla L, Masullo C, Pilotto A (2011) The genetics of the human APOE polymorphism. Rejuvenation Res 14:491-500
62. Singh R, Kolvraa S, Rattan SI (2007) Genetics of human longevity with emphasis on the relevance of HSP70 as candidate genes. Front Biosci 12:4504-4513
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 16:796-801
64. Skytthe A, Kyvik K, Holm NV, Vaupel JW, Christensen K (2002) The Danish Twin Registry: 127 birth cohorts of twins. Twin Res 5:352-357
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 9:1010-1017
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 126:333-339
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 19:651-656
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 29:1003-1009
69. Vitek MP, Brown CM, Colton CA (2009) APOE genotype-specific differences in the innate immune response. Neurobiol Aging 30:1350-1360
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 103:1747-1754
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 123:29-38
72. Weber O, Bischoff H, Schmeck C, Bottcher MF (2010) Cholesteryl ester transfer protein and its inhibition. Cell Mol Life Sci 67:3139-3149
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 65:4947-4954
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 10:115-118
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