TP53

TP53 is a tumour suppressor involved in cell cycle regulation, apoptosis, and DNA repair. Several lines of evidence from model organisms link TP53 to ageing, in agreement with its DNA damage protection role. In flies, expression of a dominant-negative version of TP53 extends lifespan. Mice with a permanently activated form of TP53 display signs of premature ageing starting at about 18 months of age, as do mice heterozygous for TP53 that lack BRCA1. Overexpression of p44 (one of the short isoforms of p53) also causes a progeroid phenotype, including phosphorylation of tau, synaptic deficits, and cognitive decline. Additionally, levels of p44 increase with age in the mouse brain. However, increased but regulated TP53 and CDKN2A activity has been found to ameliorate age-associated central nervous system functional decline in mice, acting to maintain the stem cell pool. This regulated TP53 activity provides a mechanism for extended lifespan and also health span in mice. Human mutations in TP53 have been associated with cancer. People with a polymorphism that decreases the apoptotic potential of TP53 have increased survival despite a higher proportional mortality from cancer. The myriad of functions and interactions of TP53, as well as the findings from model organisms, make it a possible player in human ageing.