M, major allele; m, minor allele.

4. Discussion

study. 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.

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Although a significant association was observed between the IN3-M/IN4-M haplotype in INSR and longevity, both SNPs are located in introns and the functional implication of this haplotype association remains uncertain. Very recently a polymorphic variation of IGF1R was reported to affect human longevity in the Italian population (Bonafe et al., 2003) but the functional implication of the polymorphic variation also remains to be elucidated. It is noteworthy that both INSR and IGF1R are members of the insulin receptor tyrosine kinase family. Further comprehensive studies of the INSR locus, especially on the region including IN3 and IN4, together with the IGF1R locus are needed to identify the causal variations that enable or prevent human longevity and to clarify the molecular mechanisms of human longevity.

Acknowledgements

We greatly appreciate involvement of the SSCs in this study and their family members for their time and assistance. This study could not have been performed without their kind cooperation. We thank Wakako Hashi- moto, Fumiwo Ejima, Aki Nishida, Yan Li, and other members of RIKEN HGRG for their contributions to this