Antagonistic pleiotropy and p53.

George Williams' antagonistic pleiotropy theory of aging proposes that cellular damage and organismal aging are caused by pleiotrophic genes, or genes with multiple phenotypic effects [Williams, G.C., 1957. Pleiotropy, natural selection, and the evolution of senescence. Evolution 11, 398-411]. According to this theory, genes that exhibit antagonistic pleiotropy increase the odds of successful reproduction early in life, but have deleterious effects later in life. The tumor suppressor p53 confers protection against cancer (and death) by interrupting the abnormal proliferation of cells. When control of proliferation is applied to normal stem cells, however, it can impair tissue homeostasis and accelerate aging. We use data from recently developed models of accelerated aging in mice to determine if the deleterious effects of p53 on aging reflect antagonistic pleiotropy of the p53 gene or are attributable to genes that can modify p53 activity but are evolving independently.