Mechanisms of Ageing and Development 126 (2005) 333-339 www.elsevier.com/locate/mechagedev genes associated with aging and life expectancy in the Jerusalem longitudinal study Jochanan Stessman, Yoram Maaravi, Robert Hammerman-Rozenberg, Aaron Cohen, Lubov Nemanov, Inga Gritsenko, Nelly Gruberman, Richard P. Ebstein a Department of Geriatric Rehabilitation, Hadassah Hospital, Hebrew University Medical Center, Mt. Scopus, Jerusalem b Department of Psychology, Scheinfeld Center of Human Genetics for the Social Sciences, Mount Scopus, Hebrew University, Jerusalem 91905, Israel Available online 22 October 2004 Abstract In an exploratory study, 11 common polymorphisms were examined for contributing to longevity including: apolipoprotein E (apoE), methylenetetrahydrofolate reductase (MTHFR), cathepsin D (CAD), superoxide dismutase 2 (SOD2), angiotensinogen (AGT), and insulin-like growth factor 2 (IGF2), Leiden factor 7, p53 oncogene, dopamine D4 receptor (DRD4), and the serotonin transporter (SERT). Genotype and allele frequencies of these genes were compared in 224 older (75 years) Jewish Jerusalem residents of Ashkenazi ethnicity to a group of 441 younger subjects (22 years). Nominally significant results provide suggestive evidence in the Ashkenazi group that apoE, MHTFR, SOD2, IGF2 ApaI and factor VII are risk factors for a single outcome, survival to 75. Overall, the more genetically homogenous Ashkenazi ethnic group showed evidence for association in five genes examined suggesting that future studies in this population would gainfully focus on this ethnic group. Keywords: Longevity; Polymorphisms; IGF2; Methylenetetrahydrofolate reductase; Apolipoprotein E; Superoxide dismutase; Angiotensinogen; D; Leiden factors V and VII; Dopamine D4 receptor; Serotonin transporter 1. Introduction The mechanisms contributing to human longevity are only now slowly being elucidated. 1.1. Genes and aging in humans Twin and adoption studies confirm a significant genetic component to human longevity (Carmelli, 1982). An oft-quoted Danish twin study (Herskind et al., 1996) estimated the heritability of lifespan to be 0.23 for males and 0.20 for females but a more recent Swedish study attributes perhaps as much as 50% of the variation in susceptibility to mortality to genetic factors (Yashin et al., 1999). Most researchers agree that heritability of lifespan in humans is modest, <50%. Moreover, the role of specific genes in The current case-control genetic study is based on the ongoing Jerusalem Longitudinal Cohort Study (JLCS) of 70-year-old (born in 1920/21) Jewish residents of Jerusalem initiated in 1990 (Bursztyn et al., 1999; Bursztyn et al., 1996; Cohen et al., 1995; Dresner-Pollak et al., 1996; Eliakim et al., 1996; Ginsberg et al., 1999; Maaravi et al., 1996; Stessman et al., 1995; Stessman et al., 1996; Stessman et al., 2000). The younger cohort was recruited from a non-clinical population in ongoing studies of normal personality (Ebstein et al., 2000; Zohar et al., 2003) and eating behavior (Bachner-Melman et al., 2004). * Corresponding author. Tel.: +/ ; fax: + E-mail address: ebstein@mscc.huji.ac.il (R.P. Ebstein). 0047-6374/$see front matter # 2004 Elsevier Ireland Ltd. All rights doi:10.1016/j.mad.2004.08.025 1.3. Candidate genes studied 2.3. Genotyping The SERT promoter region polymorphism was characterized as previously described by our laboratory (Ebstein et al., 1997). PCR amplification was carried out using the primers: SIL 1 50-ggC gTT gCC gCT CTg AAT gC-30 and SIL 2 50-gAg ggA CTg AgC Tgg AC A ACC AC-30. The reaction mixture was electrophoresed on a 2% metaphor gel (FMC) with ethidium bromide to screen for genotypes. ForThe following text has been processed:

HWE was calculated using a convenient website: (http://www.kursus.kvl.dk/shares/vet-gen/Popgen/genetik/applets/kitest.htm). Considering that 11 alleles were studied and that we compared controls versus an older cohort, a conservative stand would be to conclude that a difference is significant for P-values < 0.05/11 = 0.0045. Nevertheless, the P-values reported in the results were uncorrected for multiple testing. The only significant result was a decrease in the percentage (30.6% versus 19.2%) of the A allele in older Ashkenazi male subjects (chi-square = 4.027, P = 0.045, 1d.f.) and a corresponding marked decrease (9.7-21%) in the percentage of AA homozygotes (chi-square = 5.790, P = 0.055). 

3.5. Insulin-like growth factor 2 (IGF2) ApaI  

An increase in the A allele was observed in older Ashkenazi females (chi-square = 3.455, P = 0.063) and a highly significant increase (3.8-15.7%) was observed in AA genotype in these subjects (chi-square = 10.972, P = 0.004, 2d.f.). 

3. Results  

We examined allele and genotype frequency for each of these candidate genes using chi-square and logistic regression analysis, stratifying results by sex due to gender-specific associations between common polymorphisms and longevity (Bonafe et al., 2001; Ivanova et al., 1998; Lio et al., 2002a, 2002b, 2002c). Only significant findings are presented below.

As summarized in Table 1, we examined 11 polymorphisms for association with survival to 75 years by comparing a young Ashkenazi group to an older cohort. Although nominally significant associations were observed, it should be noted that only one is robust. Ashkenazi older subjects were characterized by a decreased percentage of the apoE 2 allele and a decreased percentage of the A allele in male subjects. 

Table 1 Summary of findings in the Ashkenazi ethnic group  

Gene Polymorphism Ethnic group Sex Allele Change with ageing P