Relevance of the p53-MDM2 axis to aging

In response to varying stress signals, the p53 tumor suppressor is able to promote repair, survival, or elimination of damaged cells - processes that have great relevance to organismal aging. Although the link between p53 and cancer is well established, the contribution of p53 to the aging process is less clear. Delineating how p53 regulates distinct aging hallmarks such as cellular senescence, genomic instability, mitochondrial dysfunction, and altered metabolic pathways will be critical. Mouse models have further revealed the centrality and complexity of the p53 network in aging processes. While naturally aged mice have linked longevity with declining p53 function, some accelerated aging mice present with chronic p53 activation, whose phenotypes can be rescued upon p53 deficiency. Further, direct modulation of the p53-MDM2 axis has correlated elevated p53 activity with either early aging or with delayed-onset aging. We speculate that p53-mediated aging phenotypes in these mice must have (1) stably active p53 due to MDM2 dysregulation or chronic stress or (2) shifted p53 outcomes. Pinpointing which p53 stressors, modifications, and outcomes drive aging processes will provide further insights into our understanding of the human aging process and could have implications for both cancer and aging therapeutics.