Variation in the human TP53 gene affects old age survival and cancer mortality.

Longevity may depend on a balance between tumor suppression and tissue renewal mechanisms [Campisi, J., 2003. Cancer and ageing: rival demons? Nat. Rev. Cancer 3 (5), 339-349]. Mice with constitutively activated p53 are almost cancer free but their life span is reduced and accompanied by early tissue atrophy [Tyner et al., 2002. p53 mutant mice that display early ageing-associated phenotypes. Nature 415 (6867) 45-53]. Replacement of arginine (Arg) by proline (Pro) at position 72 of human p53 decreases its apoptotic potential [Dumont et al., 2003. The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat. Genet. 33 (3), 357-365] providing a tool to test for a similar trade-off in humans. Using a formal meta-analysis of the published literature we show that carriers of the TP53 codon 72 Pro/Pro genotype have an increased cancer risk compared to Arg/Arg carriers (p<0.05). Next, in a prospective study of 1226 people aged 85 years and over we show that carriers of the Pro/Pro genotype have a 41% increased survival (p = 0.032) despite a 2.54 fold increased (p = 0.007) proportional mortality from cancer. It is suggested that human p53 protect against cancer but at a cost of longevity.

Variation in the SHC1 gene and longevity in humans.

Mice in which the p66(SHC) specific region of the SHC gene is deleted live 30% longer without apparent disease. These mice have lower levels of oxidative stress and apoptosis, both of which have been linked to old age survival in man. This makes SHC1 an important candidate gene for longevity in humans. We found no variations in the p66 specific region of the SHC1 gene in 30 young and 30 extreme long-lived subjects. Thus in man, no common sequence variations occur in p66 specific region of the SHC1 gene. In two independent cohorts of respectively 730 and 563 subjects aged 85 and over, we tested the only known non-synonymous polymorphism, Met(410)Val, for association with longevity using a prospective follow-up design. In the first cohort, we found increasing valine allele frequency in three strata of increasing age at death (2.8-5.2%). Moreover, compared to Met/Met carriers, mortality rate was a factor of 0.71 (95% CI 0.45-1.13) reduced for Met/Val carriers in the combined cohorts, with similar risk estimates in both cohorts. Low valine allele frequency resulted, however, in low power to detect statistical significance. These data suggest that an association between the Met(410)Val polymorphism and longevity in humans may exist.