期刊名称：Journal of Clinical Biochemistry and Nutrition
印刷版ISSN：0912-0009
电子版ISSN：1880-5086
出版年度：2004
卷号：34
期号：2
页码：69-76
DOI：10.3164/jcbn.34.69
出版社：The Society for Free Radical Research Japan
摘要：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.
