p53 As An Intervention Target in Aging and Cancer

The protein p53 is involved in many cellular mechanisms, and seems to be an important part of the evolved balance between cancer risk and degenerative aging. This balance manifests as an ongoing decline in the activity of stem cell populations, and thus a progressive failure of tissue maintenance - but the lowered activity of these cell populations reduces the chances of damaged cells spawning cancer. In recent years researchers have demonstrated clever ways to manipulate p53 levels that can both reduce cancer risk and slow aging, so it is possible to both have your cake and eat it too in the case of this mechanism.

p53 is well known for suppressing tumors but could also affect other aging processes not associated with tumor suppression. As a transcription factor, p53 responds to a variety of stresses to either induce apoptosis (cell death) or cell cycle arrest (cell preservation) to suppress tumor development. Yet, the effect p53 has on the non-cancer aspects of aging is complicated and not well understood. On one side, p53 could induce cellular senescence or apoptosis to suppress cancer but as an unintended consequence enhance the aging process especially if these responses diminish stem and progenitor cell populations. But on the flip side, p53 could reduce growth and growth-related stress to enable cell survival and ultimately delay the aging process. A better understanding of diverse functions of p53 is essential to elucidate its influences on the aging process and the possibility of targeting p53 or p53 transcriptional targets to treat cancer and ameliorate general aging.

There are multiple ways to target p53 as an anti-cancer therapeutic. However, directly targeting p53 to suppress aging phenotypes would be difficult considering the delicate balance that is needed among arrest, senescence, and apoptosis. Animal models highlight these complexities [and] imply that specific and narrow interventions to either up or downregulate p53 activity might be suitable for cancer but not effective for general aging. Instead, broad interventions that reduce growth (rapamycin, calorie restriction, resveratrol) or mimic reduced growth (metformin, AICAR) may be the best candidates to alter p53 function in a manner that ameliorates or slows aging.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794078/


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