S.P. Mooijaart et al. / Experimental Gerontology 39 (2004) 263–268

low, and therefore there is low power to find statistically significant differences. A previous study failed to associate the Met410Val variant to insulin secretion, insulin sensi- tivity, type II diabetes, birth weight and length (Almind et al., 1999). However, here also the low valine allele frequency may have prohibited detection of statistical significance. To date, no in vitro studies have been published on the functionality of the variant. It is surrounded by tyrosine residues that, upon phosphorylation, effect insulin signaling. Our data suggest that the p66SHC1 Met410Val polymorphism may be functional and associated with longevity.

activity (which stimulate ROS scavenging and repair of oxidative damage). Because activation of p66SHC1 decreases forkhead activity, we predict that the beneficial valine allele is associated with mildly decreased p66SHC1 activity levels. Taken together, this hypothesis would explain the potential role for p66SHC1 in human longevity.

the p66 specific region of the SHC1 gene and our data hint at an association of the Met410Val variant with longevity. However, further study on the functionality of the Met410Val polymorphism is needed.

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). Conversely, high expression levels of p66SHC1 have been related to metastasis and carcinogenesis in human tumor tissue (Jackson et al., 2000). This can be explained as a cellular reaction to tumor growth and an attempt to switch from growth to apoptosis. Furthermore, the function of p66SHC1 has been related to the function of tumor suppressor protein p53 (Trinei et al., 2002). Together they regulate steady state levels of intracellular reactive oxygen species and apoptosis. As recently shown by the comparison of p53þ/m (which possess overactive p53) and p532/2 mice, induction of apoptosis can have both beneficial and adverse effects (Tyner et al., 2002). Loss of p53 results in loss of genomic stability and predisposes cells to becoming cancerous: p532/2 mice develop normally but soon die of cancer. Conversely, p53þ/m mice are resistant to cancer, but age prematurely. Thus, excessive induction of apoptosis leads to premature ageing, possibly due to the exhaustion of division competent stem cells, while insufficient induction of apoptosis may cause cancer (Tyner et al., 2002). Following this line of reasoning, we speculate that major mutations in p66SHC1 may not be tolerated because they would disrupt the proteins function in induction of apoptosis and would consequently compromise its role in tumour suppression. Subtle mutations, however, 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

Acknowledgements

The investigators 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 Ministery of Economic Affairs (grant number IGE01014).

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