4. Discussion
This work was supported in part by a grant to RIKEN GSC from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

To date, many genetic variations in the INSR locus have been reported to be associated with diseases including diabetes mellitus, leprechaunism, and Rabson-Mendenhall syndrome (Online Mendelian Inheritance in Man #147670). To our knowledge, this is the first report showing associations between genetic polymorphisms of INSR and human longevity. Through a study of Japanese centenarians, we found the prevalence of diabetes mellitus in centenarians to be significantly lower than that in the general population (manuscript in preparation). A common variant in the PPARGC1A gene has been reported to be associated with type II diabetes mellitus (Ek et al., 2001). The PPARGC1A protein interacts with FOXO1 in an insulin-regulated mechanism of gluconeogenesis (Puigserver et al., 2003). The risk variant (PP1 in Table 2) present frequently in both SSCs and controls (about 50%) and no association with the common variation and longevity was found in this study.

References
Bluher, M., Kahn, B.B., Kahn, C.R., Extended longevity in mice lacking the insulin receptor in adipose tissue. Science, Bonafe, M., Barbieri, M., Marchegiani, F., Olivieri, F., Ragno, E., Giampieri, C., Mugianesi, E., Centurelli, M., Franceschi, C., Paolisso, G., Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide-kinase genes affect IGF-I plasma levels and human longevity: cues for an evolutionarily conserved mechanism of lifespan control. J. Clin. Endocrinol. Metab., Clancy, D.J., Gems, D., Harshman, L.G., Oldham, S., Stocker, H., H