Numbers within the parentheses indicate the percentage of subjects with each genotype within the indicated age group. The 607 white female subjects of age B80 described here represent all of the women of age B80 participating in the large epidemiological study described in Section 2. / / a P(cid:4)0.0762 by Fisher’s exact test. /



Fig. 2. Quantile(cid:1)quantile plots for ages of Indy genotypes G/G, A/A, and G/G(cid:2)A/A vs. Indy wildtype (A/A) by sex. The 458 line on the plots / / indicates where the points would fall if the distributions of the ages of the two populations were identical.

nine at amino acid 62 is conserved between Drosophila Indy 2 and rat SDCT1 but not with Drosophila Indy (isoleucine) and rat SDCT2 (leucine) (Rogina et al.,

between Drosophila, rodent and human Indy genes, suggesting that they were less likely to compromise the Indy protein. One of the mutations, F62L was observed only once, and then in a young individual. It was not detected in 1390 other alleles, and therefore, its effect on aging could not be determined. Another mutation V80L seemed to be limited to African(cid:1)Americans, and in the / sample of 600 African(cid:1)American alleles examined no / relationship to aging was apparent. One polymorphism, the 1648 A0G (I550V), which initial studies suggested / were in excess in the older population, was considered more extensively for its association with lifespan and body weight. An examination of 1338 female and 684 male white subjects demonstrated that the 1648 A0G / (I550V) mutation was not associated with an increase in lifespan and not related to lower body weight suggesting an effect on caloric restriction.

3.4. Height and weight

Because of the proposed catabolic effects of Indy mutations we calculated the average heights and weights of white subjects with different genotypes. The results, shown in Table 6, did not demonstrate an association of genotype with height and weight.

4. Discussion

We have identified three mutations in the human Indy gene that result in an amino acid changes. None of the

Height and weight of white subjects with different Indy nt 1648 genotypes

Female Male A/A (559) A/G (593) G/G (182) A/A (303) A/G (297) G/G (83) Height 63.3990.12 63.1990.11 63.5290.21 69.6590.16 69.6090.15 69.4990.36 / / / / / / Weight 151.3291.45 150.3591.30 154.5692.42 193.4091.97 191.0291.89 195.7694.31 / / / / / /

Values given are mean9standard error. /

Fund. The authors would like to acknowledge Dr Jill Waalen and Carol Halloran for their expert assistance.

Our study involved a small number of elderly subjects (age 90(cid:1)99) and thus only the presence of a high / frequency ‘‘longevity promoting’’ mutation would have been observed. The examination of a larger elderly population would be necessary to identify less common ‘‘longevity promoting’’ haplotypes or polymorphisms in the Indy gene. Furthermore, since our study involved only unrelated subjects in a normal population, it remains possible that mutations in the Indy gene might play a role in the increased longevity seen in familial centenarians.

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Acknowledgements

This is manuscript number 14417-MEM from The Scripps Research Institute. Supported by grant DK53505-04 and funds from the Stein Endowment