The changes in the p53 protein across the animal kingdom pointing to its involvement in longevity

Abstract Recently, the quest for the mythical fountain of youth has turned into specific research programs aiming to extend the healthy lifespan of humans. Despite advances in our understanding of the molecular processes underlying aging, the surprisingly extended lifespan of some animals remains unexplained. In this respect, the p53 protein plays a crucial role not only in tumor suppression but also in tissue homeostasis and healthy aging. However, the mechanism through which p53 maintains the function as a gatekeeper of healthy aging is not fully understood. Thus, we inspected TP53 gene sequences in individual species of phylogenetically related organisms that show different aging patterns. We discovered novel correlations between specific amino acid variations in p53 and lifespan across different animal species. In particular, we found that species with extended lifespan have characteristic amino acid substitutions mainly in the p53 DNA binding domain that change its function. These findings lead us to propose a theory of longevity based on alterations in TP53 that might be responsible for determining extended organismal lifespan.