The Regulation of Aging and Longevity: A New and Complex Role of p53

Abstract

p53 plays a critical role in tumor suppression. As a transcription factor, in response to stress signals, p53 regulates its target genes and initiates stress responses, including cell cycle arrest, apoptosis, and/or senescence, to exert its function in tumor suppression. Emerging evidence has suggested that p53 is also an important but complex player in the regulation of aging and longevity in worms, flies, mice, and humans. Whereas p53 accelerates the aging process and shortens life span in some contexts, p53 can also extend life span in some other contexts. Thus, p53 appears to regulate aging and longevity in a context-dependent manner. Here, the authors review some recent advances in the study of the role of p53 in the regulation of aging and longevity in both invertebrate and vertebrate models. Furthermore, they discuss the potential mechanisms by which p53 regulates aging and longevity, including the p53 regulation of insulin/TOR signaling, stem/progenitor cells, and reactive oxygen species.

Keywords: ROS; TOR/insulin/IGF-1; aging; longevity; p53; stem cell.

Figure 1.

The coordinated regulation of p53, target of rapamycin (TOR), and insulin/insulin-like growth factor 1 (IGF-1) pathways. The p53, TOR, and insulin/IGF-1 pathways are three important pathways that regulate aging and longevity. The decreased TOR and insulin/IGF-1 signaling promotes longevity. p53 down-regulates the insulin/IGF-1 and TOR pathways through its transcriptional induction of its target genes, including IGF-BP3, PTEN, TSC2, AMPK β1, sestrin 1/2, and REDD1. AKT-MDM2-p53 forms a negative feedback loop to negatively regulate p53, whereas p53-PTEN-AKT-MDM2 forms a positive loop to positively regulate p53. The insulin/IGF-1 pathway interacts with the TOR pathway through the regulation of TSC2 by AKT.

Figure 2.

The regulation of stem/progenitor cells and longevity by p53. p53 may regulate longevity through its regulation of stem/progenitor cell functions. When properly regulated, enhanced p53 activity may prevent the emergence of cancer stem cells but not inhibit the function of stem cells or even have beneficial effects on stem/progenitor cells. Thus, enhanced p53 activity increases tumor resistance and does not affect life span or even extends life span in organisms, such as “super p53” mice, MDM2 hypomorphic mice, and “super p53/Arf” mice. In contrast, when aberrantly regulated, constitutively enhanced p53 activity may reduce the number of stem/progenitor cells and impair their functions, thus promoting aging, although it also increases tumor resistance, such as in p53+/m and p44 mice.

Figure 3.

The regulation of oxidative stress, reactive oxygen species (ROS), and longevity by p53. p53 exerts either pro-oxidant or antioxidant activity depending on the type and extent of stress signals, which may contribute to its role in both promoting and preventing aging. p53 selectively induces the expression of a group of antioxidant genes, such as sestrins, TIGAR, GLS2, GPX1, and ALDH4, to lower ROS levels in cells under the conditions of nonstress or low stress. This antioxidant function of p53 protects cells from oxidative stress–induced DNA damage and allows cell survival, which may prevent aging. In response to severe stress, p53 selectively induces the expression of a group of pro-oxidant genes, including PIG3, PIG6, FDRX, Bax, and Puma, to further increase ROS levels in cells. This pro-oxidant function of p53 leads to the p53-mediated apoptosis and senescence to eliminate damaged cells, including stem/progenitor cells, which may promote the aging process.