Ashkenazi older subjects were characterized by an percentage of the apoE 2 allele and a decreased

Table 1

Summary of findings in the Ashkenazi ethnic group

Gene Polymorphism Ethnic group Sex Allele Change with ageing P ApoE Alleles 2,3,4 Ashkenazi M 2 (considered protective in AD) " 0.025 M 4 (risk allele in AD) # Ashkenazi F 2 $ 0.065 F 4 # MHTFR C677T Ashkenazi F C " 0.029 CC (note that TT = elevated homocysteine) " 0.045 SOD2 C9T Ashkenazi M T " 0.009 Ala (GCT) ! val(G TT) TT (Ala wt is risk for breast cancer) " 0.038 Leiden factor VII Arg/Gln R353Q Ashkenazi M A # 0.045 AA (QQ protective MI??) # 0.055 IGF2 ApaI A/G Ashkenazi F A " 0.063 AA " 0.004

effects are already observed at a considerably younger age than 100 both in the children of centenarians as well as in our 75-year-old cohort.

when corrected for multiple testing (IGF2 ApaI). Therefore, these results should be considered only suggestive. Never- theless, since some of the observed associations are both consistent with previous investigations (for example, ApoE) and moreover, make ‘biological sense’, we believe that overall the current investigation may serve as a useful roadmap towards unraveling the complex genetic architec- ture of human longevity.

4.4. Methylenetetrahydrofolate reductase (MHTFR)

The gene coding for MHTFR has been well characterized and subjects homogenous for the TT allele at position 677 display higher levels of plasma homocysteine and are at risk for cardiovascular disease (De Bree et al., 2002). The increased frequency of the C allele in older Ashkenazi women is consistent with a deleterious effect of TT homozygosity presumably mediated by high serum homo- cysteine levels.

4.2. Apolipoprotein E

The finding that there is an increase in the apoE2 allele and a decrease in the apoE4 allele in older Ashkenazi male subjects is consistent with a large literature demonstrating the protective effect of e2 and the deleterious role of e4 in conferring risk for Alzheimer’s disease (AD) (Blanche et al., 2001; Rea et al., 2001; Slooter et al., 2001; Smith, 2002; Wang et al., 2001b).

4.5. Superoxide dismutases (SOD)

Functional polymorphisms in the genes encoding SOD, superoxide scavenging antioxidant enzymes, may play an important role in the development of a number of diseases. SOD reduces intracellular damage caused by reactive oxygen species, a by-product of cellular metabolism that can build to toxic levels if not removed. Toxic reactive oxygen levels cause intracellular damage that is hypothe- sized to be a putative cause of aging. For example, the ala/ala polymorphism of the superoxide dismutase 2 gene may be a modest risk factor for prostrate cancer (Woodson et al., 2003), sporadic breast cancer (Mitrunen and Hirvonen, 2003) and colorectal cancer (Stoehlmacher et al., 2002). In the current study, we observed an increase in the TT (val/val) homozygotes in older Ashkenazi males consistent with a deleterious role for the ala/ala genotype.

4.3. ApoE and aging—a robust finding

The finding that e4 allele becomes markedly less frequent with advancing age is one of the most robust single gene findings in the human genetic studies of ageing (Schachter et al., 1994). It is of interest that the report of Schachter et al. (1994) compared centenarians to subjects aged 20–70 years old whereas in the present study, we observe the deleterious effect of e4 already at 75 years and also the protective effect of e2. These results suggest the notion that many of the genes contributing to longevity can be detected using subjects considerably younger than centenarians. Interestingly, children of centenarians had a 56% reduced relative prevalence of heart disease (odds ratio, a 66% reduced relative prevalence of hypertension and 59% reduced relative prevalence of diabetes) after multivariate adjusted analyses (Terry et al., 2003). These findings strengthen the notion that gene variants protective for major diseases such as heart disease and diabetes seem to play a particularly important role in exceptional longevity. Moreover, their

4.6. IGF2

IGF2, also known as somatomedin A, is a single chain polypeptide which shares an amino acid sequence homology of about 47% with insulin and about 31% with relaxin and with them comprise the insulin family of polypeptide growth

2003). The insulin-like growth factor (IGF) signaling system plays a critical role in the growth and development of many tissues and regulates overall growth, particularly prenatal growth. The IGF system has also been implicated in various pathophysiological conditions, and is thought to play a particularly prominent role in tumorigenesis. The IGF system is comprised of the IGF ligands (IGF-I and IGF-II), cell-surface receptors that mediate the biological effects of the IGFs, including the IGF-I receptor (IGF-IR), the IGF-II receptor (IGF-IIR), and the insulin receptor (IR), as well as a family of IGF-binding proteins (IGFBPs). IGFBPs affect the half-lives and bioavailability of the IGFs in the circulation, in extracellular fluids, and may exert IGF-independent effects under certain conditions. Not surprisingly, consider- ing the extensive homology between these two peptides, both IGFI and IGFII activate IGF1R receptors. To our knowledge, the current report is the first directly linking a SNP in the IGF2 receptor directly to longevity, as opposed to BMI-related measures, in humans.