Structural and mechanistic diversity in p53-mediated regulation of organismal longevity across taxonomical orders

The accumulation of senescent cells induces several aging phenotypes, and the p53 tumor suppressor protein regulates one of the two known cellular senescence pathways. p53's regulation of senescence is however not clear. For example, p53 deficiency in some mice has been shown to rescue premature aging while others display significant aging phenotype when p53-deficient. This study seeks to elucidate, structurally and mechanistically, p53's roles in longevity. Through a relative evolutionary scoring (RES) algorithm, we quantify the level of evolutionary change in the residues of p53 across organisms of varying average lifespans in six taxonomic orders. Secondly, we used PEPPI to assess the likelihood of interaction between p53 or p53-linked proteins and known senescence-regulating proteins across organisms in the orders Primates and Perciformes. Our RES algorithm found variations in the alignments within and across orders, suggesting that mechanisms of p53-mediated regulation of longevity may vary. PEPPI results suggest that longer-lived species may have evolved to regulate induction and inhibition of cellular senescence better than their shorter-lived counterparts. With experimental verification, these predictions could help elucidate the mechanisms of p53-mediated cellular senescence, ultimately clarifying our understanding of p53's connection to aging in a multiple-species context.