Funding

We appreciate the support of contract N01-AG-4-2149, grants 5 U01 AG019349-05 and 2R01 AG027060-05A2 (Hawaii Lifespan Study) from the National Institute on Aging and contract N01-HC-05102 from the National Heart, Lung, and Blood Institute.

Acknowledgments

Author contributions: T.A.D., B.J.W., Q.H., J.S.G., K.H.M., B.R., and J.D.C. designed research; T.A.D., B.J.W., Q.H., R.C., J.S.G., K.H.M., B.R., and J.D.C. performed research; T.A.D. contributed new reagents and analytic tools; Q.H. and J.S.G. analyzed data; and T.A.D., B.J.W., Q.H., J.S.G., K.H.M., B.R., D.C.W., and J.D.C. wrote the article.

In the future, when more evidence accumulates as to a functional SNP(s), rigorous assessment with model organisms and human studies will be needed. Work with model organ- isms has already provided some clues that might be helpful for mechanistic studies of the effects of FOXO3 variation in humans. For example, oxidative stress, still a leading theory of how we age (35,36), is one potential mechanism. Indeed, the PI3K/Akt signaling cascade, a downstream target of insulin signaling, is an important inhibitor of FOXO function. Important antioxidant enzyme expression, including manga- nese superoxide dismutase (MnSOD) and catalase, depend on PI3K/Akt/FOXO3 activity (37,38), and oxidative stress appears linked to human longevity (39). Yet, work to date shows that mice deficient in the FOXO target MnSOD do not exhibit changes in life span (40). Nor do mice overexpressing the FOXO target MnSOD exhibit changes in life span (41). Interestingly, Ferber and colleagues (42) recently found that FOXO3 activation results in the repression of nuclear- encoded genes with mitochondrial function, this mediated by inhibition of c-Myc (independent of SOD2). FOXO3 activation also reduced mitochondrial DNA copy number, mitochondrial protein expression, respiratory complexes, and mitochondrial respiratory complexes and activity. More work is needed to assess potential relations between FOXO3, oxidative stress, and longevity, such as whether expression of common antioxidant enzymes correlates with genetic variation in FOXO3 or with other factors that influence

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