Insights into aging obtained from p53 mutant mouse models

Cancer suppression is an integral component of longevity in organisms with renewable tissues. A number of genes in the mammalian genome function in cancer prevention, and some of these have been directly implicated in longevity assurance. One such longevity assurance gene is the tumor suppressor p53, a transcription factor that is mutated or dysregulated in most human cancers. Early studies have linked p53 to the induction of cellular senescence, whereas recent reports implicate it as a potential regulator of organismal aging. We have shown by gene inactivation studies that loss of p53 function enhances tumor susceptibility and reduces longevity in the mouse. A recent serendipitously generated p53 mutant allele resulted in a hypermorphic version of p53 that displays increased cancer resistance, yet also mediates decreased longevity. The reduced longevity is accompanied by the accelerated onset of a variety of aging phenotypes. These include a 20% decrease in median life span, early osteoporosis, lordokyphosis, organ atrophy, delayed wound healing, and a reduced regenerative response after various stresses. Since the initial characterization of these mutant mice, we have attempted to elucidate the underlying molecular and cellular mechanisms that could be influencing the early aging phenotypes. Molecular studies of the p53 mutant allele product indicate that it induces an increase in p53 activity in both in vitro and in vivo contexts. The age-associated loss of organ cellularity and reduced tissue regenerative responses in the mutant mice are consistent with an accelerated loss of stem cell functional capacity. Our model is that enhanced growth inhibitory activity of p53 produces an earlier loss of the ability of stem cells to produce adequate numbers of progenitor and mature differentiated cells in each organ. Currently, we are performing stem cell functional assays from p53 mutant and wild-type mice to test this model. One challenge for the future will be to find ways to manipulate p53 function to provide increased cancer resistance, yet still enhance overall organismal longevity.