The traditional view of the p53 tumor suppressor gene is that it is a representative mechanism in the evolved trade-off between suppression of cancer on the one hand and harmful buildup of senescent cells on the other. Specifically p53 is an important part of the machinery that induces cellular senescence in response to potentially cancerous mutational damage. A senescent cell ceases replication and secretes inflammatory signals in order to attract immune cells to destroy it and any other problem cells in the immediate vicinity. Unfortunately immune mediated clearance of senescent cells becomes less effective with advancing age, allowing a build up of a lingering senescent cell population. Their signaling is harmful to tissue structure and function.
So a lesser degree of p53 activity implies a lesser burden of cellular senescence in later life, and thus a slower pace of aging, but also a greater risk of cancer. More aggressive p53 activity impedes cancer, but then leads to greater cellular senescence and a shorter life span. This is an oversimplification of a more complicated picture, however. Once one starts to look into the biochemistry of diverse species, one finds all sorts of different variations on how p53-driven mechanisms relate to aging and cancer. For example, elephants have many copies of p53 and aggressive anti-cancer activity in general, but are nonetheless long-lived mammals. There is a great deal more to consider than just p53 when it comes to understanding the relevance of p53.
Usually, aging is a gradual process characterized (in humans and mouse models) by molecular biomarkers such as a decrease in leukocyte telomere length, decreased levels of IGF-1, and increased inflammation. Several molecular mechanisms have been purported to regulate aging and determine lifespan – many of which have been linked to p53 tumor suppressor activities. In low or high-stress conditions, p53 binds to several target genes – including those that encode PML, PAI-1, and DEC1 – which then induce cellular senescence. The link between aging and its ability to push cells to senescence is of particular interest to this study. In a senescent state, a damaged cell resists apoptosis and ceases to replicate. An accumulation of these cells triggers the aging process by creating a senescence-associated secretory phenotype (SASP) which creates a chronic inflammatory microenvironment. It has been shown that a programmed clearance of senescent cells delays aging phenotypes.
While p53 consensus sequences for most of these targets have been elucidated, few studies have explored regulatory mechanisms and structural features of p53 that could be implicated in organismal aging. Residual changes in the DNA-binding domain of several orthologs of p53 in Cetaceans have been linked to longevity. This supports findings that p53-mediated cellular senescence could be mediated directly by DNA binding. Additionally, there has been an extension exploration of the role of the mouse MDM2 gene in the aging process of mice. MDM2 is the most well-studied negative inhibitor of p53 tumor suppressive activity; disruption of the MDM2-p53 axis accelerates aging in some mice, suggesting the importance of the MDM2-p53 axis to the aging process.
However, p53’s link to organismal aging may not be easily explainable just by the MDM2-p53 axis. MDM2 has only minor regulatory effects on the levels of p53 in the naked mole rat. And, interestingly, the naked mole rat lives an average of 30 years compared to an average of 2-4 years for most rodents. This is thought to be due in part to a hyperstable p53 – the source of this stability remains largely unknown. In another case, the African elephant despite being predisposed to cancer due to prolonged UV-radiation and large body mass lives comparably long lives and displays a significantly lower frequency of cancer when compared to humans. The unique presence of 20 copies of p53 in their genome is thought to be responsible for this.
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 the PEPPI protein-protein interaction predictor 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.
