As noted back in the Fight Aging! archives, scientists have been picking away at the knot that is p66(Shc) for a while now, tying the activity of this protein to many of the other mechanisms of metabolism considered important to longevity and resistance to common age-related damage and disease. Here's more on the topic: "The notion that mice carrying a targeted mutation of the p66(Shc) gene display prolonged lifespan, reduced production of intracellular oxidants, and increased resistance to oxidative stress-induced apoptosis prompted a series of studies aimed at defining the biochemical function of p66(Shc) and its possible implication in cardiovascular diseases. Indeed, p66(Shc-/-) mice are protected against vascular, cardiac, and renal impairment attributable to hypercholesterolemia, aging, diabetes, and ischemia/reperfusion. ... On the whole, the evidence so far reported and here discussed supports the concept that pharmacological modulation of p66(Shc) expression and activity may be a novel and effective target for the treatment of atherosclerotic vascular disease as well as myocardial adaptation to hypertrophic, inflammatory and neuro-hormonal stimuli in the overloaded heart."