Late last year we learned that the p53 tumor suppressor response to DNA damage dwindles with age, possibly providing an explanation for the exponentially increasing risk of cancer in old mammals. Another recent paper visits the other side of the coin: Moore et al. (from Larry Donehower‘s lab) describe how hyperactive p53 could contribute to premature aging — thereby shortening lifespan even as it prevents tumors:

Aging-associated truncated form of p53 interacts with wild-type p53 and alters p53 stability, localization, and activity

Evidence has accumulated that p53, a prototypical tumor suppressor, may also influence aspects of organismal aging. We have previously described a p53 mutant mouse model, the p53+/m mouse, which is cancer resistant yet exhibits reduced longevity and premature aging phenotypes. p53+/m mice express one full length p53 allele and one truncated p53 allele that is translated into a C-terminal fragment of p53 termed the M protein. The augmented cancer resistance and premature aging phenotypes in the p53+/m mice are consistent with a hyperactive p53 state. To determine how the M protein could increase p53 activity, we examined the M protein in various cellular contexts. Here, we show that embryo fibroblasts from p53+/m mice exhibit reduced proliferation and cell cycle progression compared to embryo fibroblasts from p53+/− mice (with equivalent wild-type p53 dosage). The M protein interacts with wild-type p53, increases its stability, and facilitates its nuclear localization in the absence of stress. Despite increasing p53 stability, the M protein does not disrupt p53–Mdm2 interactions and does not prevent p53 ubiquitination. These results suggest molecular mechanisms by which the M protein could influence the aging and cancer resistance phenotypes in the p53+/m mouse.

The mouse mutation used in this study resembles the p44 allele characterized by Scrable and co-workers in the sense that it is constitutively active. It is therefore likely to stimulate apoptosis and diminish proliferative potential, thereby decreasing the regenerative capacity of a tissue, even in the absence of genotoxic damage. Consistent with this, the p44 mouse also shows signs of segmental progeria. In contrast, when p53 is present in an extra copy but regulated normally (i.e., only activated when the cell detects damage), both tumorigenesis and aging are slowed.

Taken together, results from these two types of mutants suggest that p53 is only a gerontogene when it is activated all the time (similar, perhaps, to the case of cells suffering from chronic DNA damage, as in DNA repair mutants).

Note the subtle clash with the idea, discussed here previously, that tumor suppression inevitably trades off with regenerative capacity: Although inappropriately active p53 does accelerate aging by prematurely culling undamaged cells, properly regulated (but high-copy) p53 appears to be able to block cancer without crippling cellular replenishment pathways.