Delayed aging via increased Arf and p53

A boiling controversy in biogerontology involves whether tumor suppressor genes are beneficial or deleterious with respect to lifespan and aging.

According to the “deleterious” model, tumor suppressors prevent cancer, which is good for survival, but only by eliminating cells (via senescence or apoptosis) required for tissue regeneration late in life — thus, cancer prevention itself bears the seeds of mortality (see our earlier piece, Devil’s bargain: Tradeoffs between stem cell maintenance and tumor suppression, especially the articles about p16 linked at the bottom of the post). Advocates of this position point to cases (e.g., Heidi Scrable’s p44 transgenic) in which elevated p53 axis activity results in accelerated development of aging-associated phenotypes.

In contrast, the “beneficial” camp points out that tumor suppressors detect and suppress damaged cells, whose altered function might have contributed to the aging process if they’d been allowed to persist and proliferate. It is from this perspective that Matheu et al. interpret the data from their transgenic mice carrying extra copies of both p53 and p19^ARF genes.

Delayed ageing through damage protection by the Arf/p53 pathway

The tumour-suppressor pathway formed by the alternative reading frame protein of the Cdkn2a locus (Arf) and by p53 (also called Trp53) plays a central part in the detection and elimination of cellular damage, and this constitutes the basis of its potent cancer protection activity. Similar to cancer, ageing also results from the accumulation of damage and, therefore, we have reasoned that Arf/p53 could have anti-ageing activity by alleviating the load of age-associated damage. Here we show that genetically manipulated mice with increased, but otherwise normally regulated, levels of Arf and p53 present strong cancer resistance and have decreased levels of ageing-associated damage. These observations extend the protective role of Arf/p53 to ageing, revealing a previously unknown anti-ageing mechanism and providing a rationale for the co-evolution of cancer resistance and longevity.

The paper shows that the transgenes cooperatively confer increased cancer resistance: s-p53 (“super”-p53) mice or s-Arf mice have lower tumor incidence than wildtype, and double-transgenic animals have an even lower rate of cancer. Even controlling for the presence of tumors at time of death, the double-transgenic animals show a significantly different lifespan curve: Age at earliest mortality (the time when the first animals in the cohort die) is 300% higher in s-Arf/p53 mice. Furthermore, certain gross functional measurements (tightrope walking, which measures neuromuscular coordination; and hair regrowth, a proxy for regenerative capacity) deteriorate much more rapidly in the wildtype than in the transgenics.

The authors observed that s-Arf/p53 mice generate reactive oxygen species (ROS) at a lower rate than wildtype mice, express higher levels of antioxidant genes, and exhibit lower-steady state levels of oxidative damage in late life. They hypothesize that this slower accumulation of damage protects the animals against the ravages of time and helps them age more gracefully. (Note the subtle difference between this hypothesis, in which the tumor suppressors act to delay damage, and the motivating idea enumerated in the abstract, in which tumor suppressor genes detect and eliminate damage. An alternate explanation of the same data might be that the transgenic animals are more enthusiastically purging damaged cells, leaving behind a surviving population with lower average levels of damage.)

A few qualifications: Maximum lifespan is not increased in the transgenics (in fact, the wildtype mice edge them out, though not significantly). In combination with the delayed earliest mortality, this means that once the s-Arf/p53 mice start dying, they do so faster than wildtype. The authors don’t address this issue, but it does seem relevant to the claim of “delayed aging.”

On another front, the Arf locus is quite complex, and contains at least two genes in addition to Arf (p15^INK4b and p16^INK4a, so the attribution of the phenotype to Arf seems a bit premature. The authors do address this issue, by pointing out that since p16^INK4a is likely to promote aging (again, see the articles linked at the bottom of this post), any delay of aging in their transgenic system is likely to be a consequence of the extra copy of Arf as such. I’m not satisfied by this explanation, since the papers they’re referring to involved knockouts of p16 rather than properly regulated transgenic expression of the gene. Hand-waving? You be the judge.

Finally, a word about the controversy. Do they or don’t they? The authors cite two studies in which higher levels of p53 resulted in accelerated aging and shorter lifespan, and a third that shows rescue of premature aging by elimination of p53. They argue (convincingly, in my opinion) that the apparent paradox between their results and the previous work can be resolved by appealing to a critical difference in the models: In the premature-aging papers, p53 was always turned on at high levels. In contrast, in the slow-aging s-Arf/p53 mice, the genes are present at higher copy number but regulated normally, so the increased dose of tumor suppressor activity is relevant only in the presence of endogenous damage.

(Hat tip to my baymate Francis, for valuable discussion about this article.)