p53: Pro-aging or pro-longevity?

continues to surprise biologists. For nearly a decade, it was thought to be an oncogene [1, 2], only to be subsequently declared a potent tumor suppressor [3, 4]. Initially characterized as a transcriptional activator, we now know p53 is also a transcriptional repressor [5]. And just as it seemed p53 activities were confined to the nucleus, it became apparent that p53 also functioned in the cytoplasm to regulate mitochondrial responses [6, 7]. As a tumor suppressor and regulator of hundreds of genes [5], it was perhaps not surprising that p53 was shown to regulate numerous cellular processes related to cancer-cell cycle progression, apoptosis, cellular senescence and DNA repair, among others. It was another surprise, however, to learn that p53 might also regulate aging. Half a dozen or so years ago, two landmark studies showed that, in mice, the constitutive expression of certain p53 mutants or naturally occurring isoforms resulted in chronically elevated p53 activity. These transgenic mice were extraordinarily cancer resistant-but they showed multiple signs of accelerated aging and died prematurely [8, 9]. This pro-aging activity of p53 was thought to result from chronic p53-dependent apoptosis and/or senescence, resulting in cancer-resistance at the price of tissue atrophy or dysfunction [10, 11]. Shortly thereafter, though, mice were engineered with extra copies of the wild-type p53 gene, and so they showed elevated p53 activity but in a normally regulated manner. These mice were also extraordinarily resistant to cancer, but in this case they showed no signs of accelerated aging and had a normal life span [12]. Further, transgenic mice that overexpressed regulated p53 together with its upstream regulator ARF (p19) were not only cancer resistant but they lived significantly longer than wild-type controls [13]. In these models, the regulated hyperactive p53 activity was shown to reduce age-associated DNA damage and the accumulation of damaged cells. Editorial Together, these studies indicate that p53 can promote or retard aging, depending on the context of its regulation and activity. One obvious mechanism by which p53 might exert both its pro-aging and pro-longevity effects is by driving cell fate decisions. As a pro-aging determinant and as discussed above, p53 might drive excessive apoptosis and/or cellular senescence. These cell fates can, in turn, cause tissue atrophy and degeneration (apoptosis) and loss of tissue renewal or regenerative capacity (senescence). As a pro-longevity determinant, p53 might eliminate damaged or dysfunctional cells (apoptosis) or prevent their proliferation and hence their …