New Scholar Award in Aging
Scripps Research Institute
The Role of p66shc in Cellular Senescence and Mammalian Aging
The adapter protein Shc, which couples mitogenic signals from cell surface receptors through the Ras/MAPK pathway, has recently been implicated as a determinant of mammalian longevity, as mice harboring a targeted knockout of p66shc live 30% longer than control littermates. In addition to long life, p66shc KO mice exhibit resistance to oxidative stress induced by paraquat, a phenotype that is also characteristic of longevity mutants in Caenorhabditis elegans and Drosophila, suggesting that the pathway(s) involved is fundamental.
To better understand the role of Shc in mammalian aging, my lab is pursuing two complimentary sets of experiments. First, we have begun to examine the tissues of mice of varying ages for changes in Shc expression. Interestingly, we can detect only a trace amount of the p66shc isoform in primary murine tissues even when stringent precaution is taken to avoid proteolytic degradation. This is in contrast to our ability to detect p66/52/46shc isoforms in cultured murine and human cell lines. Immediate goals of my lab are to purify and characterize a novel p60 protein whose expression increases as mice age, and to determine the relationship of this protein to p66shc. We will also determine whether p66shc mRNA is present in primary murine tissues, or if a species corresponding to p60 can be found.
Our second set of experiments concern the role of Shc as a potential mediator of human aging. In order to begin addressing this question, we have chosen to examine Shc expression in primary human cells as they senesce. We find striking increases in Shc expression in cells which have been induced to senesce via expression of activated Ras or upon reaching the Hayflick limit. These initial results, when combined with the data from p66shc knockout mice point to a critical role for Shc as a determinant of mammalian longevity, and provide an opportunity to directly link in vitro experiments on cellular senescence with mammalian aging in vivo. Our immediate goal is to determine whether expression of p66shc is necessary and/or sufficient for senescence induction in primary human fibroblasts.
Both sets of experiments suggest that changes in Shc expression will prove to be a valuable biomarker for the study of aging. The p66shc knockout mouse suggests that Shc is not only a marker, but also a key effector in a longevity-determining pathway. Our long-term goal is to understand control of Shc isoform expression in both primary cell culture and in vivo, as we believe that changes in Shc expression may be responsible both for age related functional declines in vivo and senescence in vitro.