p66(ShcA): linking mammalian longevity with obesity-induced insulin resistance.

Traditionally linked to an accumulation of cell and tissue oxidative damage, the aging process is currently viewed as the result of a chronic metabolic imbalance and deranged body response to nutrients. This is in keeping with the pivotal role of the insulin/IGF pathway in longevity determination from model organisms to primates, with the association between obesity and age-related disorders, and with the dramatic acceleration of senescence by diabetes. Importantly, metabolic and oxidative damages concomitantly occur in aging as consequences of tissue hyperstimulation by insulin. With its double identity of generator of mitochondrial oxidant species and of signaling adaptor in the insulin receptor cascade, the 66Kd Shc protein (p66Shc) has drawn major attention as a negative determinant of life span and healthy longevity in mammals. We have demonstrated that these effects are related, at least in part, to p66Shc effect on the mTOR/S6K cascade that promotes obesity and insulin resistance and shortens life span.