Abstract: Aging-related oxidative stress and free radical theory has become accepted increasingly as explaination, at least in part of the aging process. In murine models of aging, a genetic deficiency of the p66^Shc (66-kilodalton isoform of Shc gene products) gene, which encodes a phosphotyrosine signal adapter protein, extends life span by 30%, and confers resistance to oxidative stress. Upon oxidative stress, p66^Shc is phosphorylated at Ser36, contributing to inactivation of the forkhead-type transcription factors (FKHR/FoxO1), which regulates the gene expression of cellular antioxidants. The p66^Shc has a direct connection with the life span related signaling, which is conserved evolutionarily. Shc is basically not expressed in mature neurons of the adult brain and spinal cord. Instead, two Shc homologues, Sck/ShcB and N-Shc/ShcC, which have been proved to be effective on oxidative stress and aging, are expressed in neural system. The expression of Shc-related genes is affected in the aging process, which may be relevant to cellular dysfunction, stress response and/or cognitive decline during aging.