The actuarial survival curve for the Leiden 85-plus Study is shown in Fig. 3. The genotypes are indicated as follows: Met/Met, white dots; Met/Val, black dots. Survival in both cohorts of the Leiden 85-plus Study from age 85 to 90 years is shown in Fig. 3. The precision weighted pooled mortality risk was a factor of 0.71 (0.451.13) decreased for Met/Val carriers compared to Met/Met carriers based on the combined observations in both cohorts. Heterozygote carriers had lower mortality in two independent cohorts with an average decrease in mortality of 29%. These findings suggest a beneficial effect of the valine-allele.

No common sequence variation was found in the 941 bp domain specifically coding for the p66SHC1 isoform and its core promoter. This, together with the fact that in the rest of the gene (1505 bp) only one coding variant was found at a low frequency, a methionine to valine change at position 410 of p66, suggests that major variations in the SHC1 gene may not be tolerated. Our findings implicate that such sequence changes with strong effects on gene functionality do not occur naturally at high frequency in the p66 specific part of the human SHC1 gene, thus raising the possibility that evolution may have selected against their occurrence.

Our data suggest that the p66SHC1 Met410Val polymorphism may be functional and associated with longevity. In reaction to oxidative stress, p66SHC1 becomes activated by phosphorylation that takes place in the region specific to p66SHC1 (Le et al., 2001), causing decreased activity of the Forkhead Transcription Factor FKHRL1 (Nemoto and Finkel, 2002; Alvarez et al., 2001). This results in a higher level of apoptosis and a lower level of cell cycle arrest and DNA repair (Alvarez et al., 2001). Cells defective in apoptosis tend to survive with excess DNA damage and thus allow DNA replication despite DNA damages, ultimately leading to carcinogenesis. On the other hand, methylation of the p66SHC1 promoter decreases the expression level of p66SHC1 (Ventura et al., 2002), which has been suggested to play a role in longevity (Purdom and Chen, 2003). Our results suggest that subtle mutations may have a life prolonging effect because reduced apoptosis may lead to a greater reserve capacity in terms of number of division competent stem cells. Life extension may result from increased resistance to oxidative stress due to up-regulation of forkhead activity. Further study on the functionality of the Met410Val polymorphism is needed.

The investigators would like to thank C. de Koning-Treurniet, M. van Schie, and M. van Kersbergen-van Oostrom for technical assistance, and R.A. van Soest for useful suggestions concerning TaqMan assays. This work was supported by an IOP grant (Innovative Oriented Research) from the Dutch Ministry of Economic Affairs (grant number IGE01014).

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