All other things being equal, more cells in the body undertaking more activity means a larger risk in any given period of time of one of those cells undergoing a cancerous mutation. Given this, larger and longer-lived species have necessarily evolved superior mechanisms of cancer suppression in order to avoid early death by cancer. The protein p53 is a cancer suppressor, produced from the gene TP53. Large mammals such as elephants maintain a low risk of cancer, despite having many more cells than smaller mammals, in part via having many copies of TP53 in the genome. It isn't just copy number, however. The sequence of p53 varies in small ways from species to species, and researchers here show that some of those differences appear to correlate with species longevity.
p53 is a critical sensor of cellular stress and thus, the dictator of cell fates. Depending on the types of stress, which include DNA damage, oncogene activation, nutrient deprivation, reactive oxygen species accumulation, and telomere shortening, p53 either (1) transiently stops cell proliferation, initiates the DNA repair machinery, and induces cell death when the damage cannot be repaired, or (2) pushes cells to replicative senescence, which is a permanent proliferation arrest.
Long-lived, cancer-free African elephants have 20 copies of the TP53 gene, including 19 retrogenes (38 alleles), which are partially active, whereas humans possess only one copy of TP53 and have an estimated cancer mortality rate of 11-25%. The mechanism through which p53 contributes to the resolution of Peto's paradox of cancer incidence remains vague. Thus, in this work, we took advantage of the available datasets and inspected the p53 amino acid sequence of phylogenetically related organisms that show variations in their lifespans.
We discovered new correlations between specific amino acid deviations in p53 and the lifespans across different animal species. We found that species with extended lifespans have certain characteristic amino acid substitutions in the p53 DNA-binding domain that alter its function. In addition, the loop 2 region of the human p53 DNA-binding domain was identified as the longest region that was associated with longevity. A 3D model revealed variations in the loop 2 structure in long-lived species when compared with human p53. We speculate that in long-lived species, L2 affects the p53 binding to DNA and/or other transcription factors and, consequently, affects the replicative senescence program.