2004 年 34 巻 2 号 p. 69-76
The oxidative stress theory of aging has become increasingly accepted as explaining at least in part the aging process. In mammalian genetic models of aging, a genetic deficiency of the p66-shc gene, which encodes a phosphotyrosine signal adapter protein, extends life span by 30% in mice, and confers resistance to oxidative stress. Upon oxidative stress, p66-Shc is phosphorylated at Ser36, contributing to inactivation of the forkhead- type transcription factor (FKHR), which regulates the gene expression of cellular antioxidants. The p66-Shc signaling has a direct connection with the evolutionary conserved longevity-related signaling, involving FKHR located far downstream of the insulinlike growth factor receptor and phosphatidyl inositol 3-kinase. While Shc is a mostly constitutive protein, it is not expressed in mature neurons of the adult brain. Instead, two neurally expressed homologues, Sck/ShcB and N-Shc/ShcC, take over the roles of Shc. N-Shc has long and short isoforms, p68 and p52, and seems to be phosphorylated at several serine residues under oxidative stress conditions, suggesting that it too has a role in oxidative stress and brain aging. The expression of Shc-related genes is affected in aging, though only slightly, which may be relevant to cellular dysfunction and/or death during aging.
