The p66(shc) adaptor protein controls oxidative stress response and life span in mammals

Gene mutations in invertebrates have been identified that extend life span and enhance resistance to environmental stresses such as ultraviolet light or reactive oxygen species. In mammals, the mechanisms that regulate stress response are poorly understood and no genes are known to increase individual life span. Here we report that targeted mutation of the mouse p66(shc) gene induces stress resistance and prolongs life span. p66(shc) is a splice variant of p52(shc)/p46(shc) (ref. 2), a cytoplasmic signal transducer involved in the transmission of mitogenic signals from activated receptors to Ras. We show that: (1) p66(shc) is serine phosphorylated upon treatment with hydrogen peroxide (H₂O₂) or irradiation with ultraviolet light; (2) ablation of p66(shc) enhances cellular resistance to apoptosis induced by H₂O₂ or ultraviolet light; (3) a serine-phosphorylation defective mutant of p66(shc) cannot restore the normal stress response in p66 (shc-/-) cells; (4) the p53 and p21 stress response is impaired in p66(shc-/-) cells; (5) p66(shc-/-) mice have increased resistance to paraquat and a 30% increase in life span. We propose that p66(shc) is part of a signal transduction pathway that regulates stress apoptotic responses and life span in mammals.