Saturday, March 3, 2018

TP53: On a Knife Edge of Death

The difficult tradeoffs made by TP53, between tumor suppression and premature aging.

TP53 is a gene whose mutated forms are perhaps the most frequently found causes of human cancer. Its product is a transcription regulator and also interacts with a large number of other proteins to orchestrate a graded response to cellular stress. One job is to halt the cell cycle in the presence of DNA damage. But it can also order cell suicide, which makes it one of the key defenses against cancer, which is fundmantally caused by escape from these kinds of tight mechanisms of cellular surveillance and control.

Interestingly, some researchers have created over-active mutations of TP53, which in mice confer higher resistance to cancer, but also a rapid aging phenotype. By this point, there are many ways to make aging go faster, by eliminating various cell repair pathways. One lab has deleted SIRT6, a gene that is an upstream inhibitor of TP53, and has its own complex role in stress response and promoting proper DNA and other forms of cell repair. It was one of the regulators thought to be part of the "red wine" effect, such as it is. This deletion dramatically reduces the lifespan of mice, from three years to just under one year. Since some of this protein's effect goes through TP53, the researchers created mice with a half-dose of TP53, which substantially rescued the mutant mice's phenotype, increasing longevity to one and a half years and raising health and body weight.

Comparison of mutant mice. SIRT6 is part of several cellular repair pathways, and its deletion (Sirt6-/-) causes mice (middle) to have much shorter and less healthy lives, their cells going south at increased rates. This defect can be corrected in part by adding another mutation, partially reducing the amount of TP53, one key target of SIRT6 inhibition.

This all demonstates, in part, that there can be too much of a good thing, i.e. TP53. On the other hand, other studies have shown that simple over-expression of normal TP53 in otherwise normal backgrounds strongly decreases cancer rates while not affecting longevity. Thus if TP53 is under normal regulation, it does what it is supposed to do- signaling cell repair or suicide, while not attacking normal or slightly stressed cells, which seems to be the problem in aging, causing loss of tissue and especially stem cell reservoirs.

Some other clues come from naked / blind mole rats, which have evolved a subterranean and highly social existence, combined with great longevity (twenty years, which for such small animals is extremely unusual) and virtually complete resistance to cancer. Here, the TP53 genes have lost some function, becoming less capable of inducing cell suicide. This is thought to be connected to the longevity phenotype. Separate mechanisms have evolved to fight cancer, such as a dramatic and thorough necrosis of any cell population that over-proliferates, induced by interferon gamma.

The message at the end of all this is that there is great scope in human biology for manipulating our longevity and health in later life. The molecular mechanisms we currently have are good, since a life span of eighty-odd years is nothing to sneeze at. But there is room for improvement, though the complexity of the networks involved in our internal surveillance and repair processes is so high that it will be some time before we have a theoretical handle on what can be done, let alone practical interventions to implement such theories.


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