A possible weakness was that cases and controls had an average age difference of 10.8 years, so we cannot com- pletely exclude the possibility of confounding by birth cohort effects. There are several reasons why this is not likely: (i) There was only a 19-year difference in birth year from oldest to youngest participants; (ii) Subgroup analy- ses showed no differences in socioeconomic status (educa- tion and occupation) between cases and controls; and (iii) Contrary to typical cohort studies in which younger cohorts have longer survival, older participants at baseline were the most likely to have lived 95 and more years. Because our study was conducted in only one population, it should be replicated in other populations. Further research should also be directed at effects of the genetic variants with aging of specific organs.

tion between the SNPs in the mTOR pathway genes exam- ined and longevity, it remains possible that variants having a minor allele frequency less than 0.10 or variants in other genes in this pathway could have significant effect(s) on longevity or the health or rate of aging of specific organs or both. This is particularly relevant to a genetic study of the rare phenotype of attainment of extreme old age (>95 years of age in our study). As a result it is possible that at least some of the genetic variants that contribute to this pheno- type are themselves rare or were below the minor allele frequency of 10% threshold we set for selection of SNPs for testing. Further research is needed to examine the asso- ciation of uncommon and rare variants of mTOR pathway genes with longevity. Indeed, disruption of mTOR signal- ing has been associated with sarcopenia (47), and there is evidence that rapamycin treatment can reverse age-related

In conclusion, the present study has found no association of common genetic variation in MToR, RPToR, RicToR, and RPS6Ka1 with living to age 95 or older in American men of Japanese ancestry. Further studies of these and other TOR pathway genes in both sexes and in other populations may be warranted.

Supplementary Material

Supplementary material can be found at: http://biomedgerontology.

Funding

This research was supported by the National Heart, Lung, and Blood Institute (contract NO1-HC-05102), the National Institute on Aging (con- tract NO1-AG-4-2149; and grants U01-AG-019349, R01-AG-038707, and R01-AG-027060), and the Hawaii Community Foundation (grant 2004-0463).

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