The p53 protein is one of the principal defenses against tumorigenesis. It integrates upstream signals from the DNA damage response and translates these signals into action: cell cycle arrest, apoptosis, or senescence. The specific outcome of p53 activation depends on a host of variables, including cell type, the extent and nature of DNA damage, and cell-cell signaling.
If p53 were to somehow go AWOL in a cell, it would bode poorly for cancer prevention. Lacking this critical checkpoint control, genetically damaged cells could go on cycling, perhaps developing additional genomic changes that further encourage unrestricted growth, and eventually becoming frankly neoplastic.
A recent study from Arnie Levine‘s lab shows that the p53 response to one form of genotoxic stress (ionizing radiation) becomes less efficient in of old mice. If this finding is general to other humans, it could partially explain why the risk of tumors increases exponentially with age . From Feng et al.:
Declining p53 function in the aging process: A possible mechanism for the increased tumor incidence in older populations
Cancer is a disease of aging. The accumulation of mutations in individual cells over a lifetime is thought to be the reason. In this work, we explored an additional hypothesis: could p53 function decline with age, which would contribute to an enhanced mutation frequency and tumorigenesis in the aging process? The efficiency of the p53 response to -irradiation was found to decline significantly in various tissues of aging mice from several inbred strains, including lower p53 transcriptional activity and p53-dependent apoptosis. This decline resulted from a decreased stabilization of the p53 protein after stress. The function of the Ataxia-telangiectasia mutated (ATM) kinase declined significantly with age, which may then be responsible for the decline of the p53 response to radiation. Declining p53 responses to other stresses were also observed in the cultured splenocytes from aging mice. Interestingly, the time of onset of this decreased p53 response correlated with the life span of mice; mice that live longer delay their onset of decreased p53 activity with time. These results suggest an enhanced fixation of mutations in older individuals because of the declining fidelity of p53-mediated apoptosis or senescence in response to stress, and they suggest a plausible explanation for the correlation between tumorigenesis and the aging process.
One important point that might get lost in the shuffle is the observation that the timing of p53 decline is related to the life expectancy of the mice. In an absolute sense, longer-lived mice have high (i.e., normal) p53 activity for a longer time; in a relative sense, however, they have high p53 for the same proportion of the lifespan as short-lived mice.
This gets at a question that biogerontologists like to ponder: Do age-related phenomena occur late in life simply because they take a certain amount of time to get going, or are they coordinated with the overall rate of aging? As with the finding that Aß aggregates form later in longer-lived worms, the p53 mouse finding argues for the latter interpretation (and supports the idea that a 15-year-old dog who happens to get cataracts, arthritis, heart disease, kidney dysfunction and incontinence all at the same time isn’t merely unlucky, but rather a living example of the as-yet-unidentified means by which evolution has synchronized the rate at which the various wheels start coming off the wagon).
Back to the central finding: What might cause such a decline in p53 activity over time? The authors of the paper point out that the signaling kinase ATM, one of the heavy hitters of the most upstream events in the DNA damage response, is also suffering a functional decline with age — but this just shifts the problem up one level. Why is ATM declining?
I wonder whether a contributing factor might be adaptation of the signaling pathways involved. Signaling pathways almost always involve some negative feedback; among other things, this serves to prevent inappropriate activation of a pathway in response to a low baseline level of stimulus, to preserve the dynamic range of the system and reset the threshold so that it can be triggered only by really noteworthy events. (Something like this happens at a circuit level in the olfactory system: ever notice how a really bad smell gets more tolerable over time?)
We know that aged cells accumulate DNA damage (an input into the p53 pathway) and other alterations that might increase their overall stress “tone.” One can imagine that increasing chronic stress might, via negative feedback, increase the thresholds for activation of the DNA damage response at multiple levels, from the upstream events like recognition of damage by ATM all the way down to the principal effector, p53. Consequently, aged cells simply wouldn’t register DNA damage in the same way as young cells: they’ve been hearing that signal too often for too long to get all excited about it. The problem, of course, is that a given amount of DNA damage is just as bad for an old cell as a young cell, and they’d be wrong not to listen.
This is wild speculation, but it makes a series of testable hypotheses, including the potential to turn young cells into old ones by tuning up their chronic genotoxic stress levels and seeing whether they start tuning down p53. It also raises the stimulating counterintuitive possibility that by somehow temporarily turning off the DNA damage signaling altogether, one could cause these thresholds to sink again — in essence, re-teaching an old cell its old tricks.