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Certain p53 Sequence Changes are Indicative of Species Longevity


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Posted 21 May 2020 - 10:22 AM


Scientists here expand upon prior research indicating that longer-lived species tend to exhibit certain types of sequence difference in the tumor suppressor gene p53 - a gene also involved in many other processes relevant to aging. One might compare this with past studies that examine the number of copies of this gene in long-lived, larger species. Elephants have many copies of p53, for example, which might go long way towards explaining why they don't exhibit higher cancer rates despite their great size, and thus greater number of cells.

The p53 protein is a well-known tumor suppressor and TP53 is the most often mutated gene in human cancers. On the cellular level, decreased p53 functionality is essential for cellular immortalization and neoplastic transformation. However, the role of variations in the p53 amino acid sequence on the organism level has not been studied systematically. Here, we presented an in-depth correlation analysis manifesting the dependencies between p53 variations and organismal lifespan to address the role of p53 in longevity. To date, p53 expression has been detected in all sequenced animals from unicellular Holozoans to vertebrates, with the lone exception of the immortal Turritopsis jellyfish.

The results from Protein Variation Effect Analyzer show that the variability in lifespan among closely related species correlates with specific p53 variations. Long-lived organisms are characterized by in-frame deletions, changes, insertions or specific substitutions in the p53 sequence. It is likely that the changes imposed on p53 in long-lived species enable p53 to interact with different multiple protein partners to induce gene expression programs varying from those induced in species with relatively normal lifespan.

We can anticipate that these gene expression programmes would enable following changes: 1. more efficient tissue repair through autophagy, 2. loss of senescence, 3. enhanced clearance of senescent cells by the immune system, 4. enhanced regulation of intracellular reactive oxygen species (ROS) levels 5. improved resistance of mitochondria to ROS-induced damage or 6. loss of immune senescence that occurs in humans with age. All of the mentioned processes have been previously described as significantly contributing to longevity. Thus, long-lived organisms apparently have a different mechanism of protection against cancer and their lifespan is not limited by somatic cell senescence caused by active p53 protein, which is the case for other species with shorter lifespan as mentioned above.

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.

Link: https://doi.org/10.1...20.05.06.080200


View the full article at FightAging




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