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. Nevertheless, 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 architecture of human longevity. 

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). 

4.3. 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 aging (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 inThe combined RQ (arg/gln) and RR (arg/arg) genotypes of Factor VII R353Q were correlated with a reduced risk for CVD in 2574 patients, whereas the QQ (gln/gln) genotype was not. The potential link between aging and insulin/insulin-like growth factor-I (IGF-I) signaling has attracted substantial attention based on several pieces of evidence showing that disruption of the insulin/IGF-I signaling cascade can significantly extend lifespan in diverse species, including yeast, worms, fruit flies, and rodents (Barbieri et al., 2003). Intriguingly, long-lived mutants ranging from yeast to mice share some important phenotypic characteristics, including reduced insulin signaling, enhanced sensitivity to insulin, and reduced IGF-I plasma levels. Reduced oxidative damage of macromolecules and increased stress resistance are likely the final common pathways of these effects. Such genetic homologies and phenotypic similarities of insulin/IGF-I pathway mutants raise the possibility that the fundamental mechanism of aging may be evolutionarily conserved from yeast to mammals.

Although initial findings for genetic studies are difficult to replicate, especially across cultural and ethnic groups, some of the polymorphisms associated with longevity in other studies or age-associated diseases likely to contribute to longevity were confirmed in the present study for a single outcome - survival to 75 years. These include apolipoprotein E, insulin-like growth factor 2, methylenetetrahydrofolate reductase, superoxide dismutase 2 and Leiden factor VII. However, none of the observed associations were uniform across different ethnic and gender categories. Additionally, while we examined the IGF2 receptor in this study, it should be noted that IGF2 and IGF1 display similar physiological properties and are both components within a family of insulin-like growth factors (Le Roith).

In this cohort consisting of two ethnic groups, one homogenous and the second characterized by heterogeneity, a more consistent pattern of association was observed in the Ashkenazi cohort. We genotyped approximately 400 DNA samples in our older cohort; however, stratifying this sample by ethnicity as well as gender resulted in considerable power loss. Future studies in this population would gainfully focus solely on the more homogenous Ashkenazi ethnic group. Moreover, a substantially larger population sample should be targeted to compare simultaneously the risk for all examined polymorphisms of considerable interest.

Acknowledgement: This research was partially supported by the Israel Science Foundation founded by the Israel Academy of Sciences and Humanities (RPE).

References:

Bachner-Melman, R., Zohar, A.H., Elizur, Y., Nemanov, L., Gritsenko, I., Konis, D. et al., Association between a vasopressin receptor AVPR1a promoter region microsatellite and eating behavior measured by a self-report questionnaire (Eating Attitudes Test) in a family-based study of a non-clinical population. Int. J. Eat. Disord., in press.

Barbieri, M., Bonafe, M., Franceschi, C., Paolisso, G., Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans. Am. J. Physiol. Endocrinol. Metab., E 833-839.

Bi, X., Head, E., Cotman, C.W., Lynch, G., Spatial patterns of mammalian brain aging: distribution of cathepsin D-immunoreactive cell bodies and dystrophic dendrites in aging dogs resembles that in Alzheimer's disease. J. Comp. Neurol., 391-408.

Blanche, H., Cabanne, L., Sahbatou, M., Thomas, G., A study of French centenarians: are ACE and APOE associated with longevity? C. R. Acad. Sci. III, 183-188.

Bonafe, M., Olivieri, F., Cavallone, L., Giovagnetti, S., Mayegiani, F., Cardelli, M., Pieri, C., Marra, M., Antonicelli, R., Lisa, R., Rizzo, M.R., Paolisso, G., Monti, D., Franceschi, C., A gender-dependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity. Eur. J. Immunol., 2357-2361.