p66Shc: at the crossroad of oxidative stress and the genetics of aging

The biology of aging has been mysterious for centuries. Removal of the p66Shc gene, which encodes an adaptor protein for cell signaling, extends lifespan by 30% in mice and confers resistance to oxidative stress. The absence of p66Shc correlates with reduced levels of apoptosis. Oxidants induce phosphorylation of serine36 on p66Shc, contributing to inactivation of members of the Forkhead transcription factor family, some of which appear to regulate the expression of antioxidant genes. The expression of p66Shc is regulated by the methylation status of its promoter. This leads us to hypothesize that increased methylation of the p66Shc promoter might contribute to the absence of its expression and therefore extended longevity in particular individuals.