p66^Shc: At the crossroad of oxidative stress and the genetics of aging

The biology of aging has been mysterious for centuries. Removal of the p66^Shc gene, which encodes an adaptor protein for cell signaling, extends lifespan by ∼30% in mice and confers resistance to oxidative stress. The absence of p66^Shc correlates with reduced levels of apoptosis. Oxidants induce phosphorylation of serine36 on p66^Shc, 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 p66^Shc is regulated by the methylation status of its promoter. This leads us to hypothesize that increased methylation of the p66^Shc promoter might contribute to the absence of its expression and therefore extended longevity in particular individuals.