ouroboros

Antagonizing antagonistic pleiotropy

One theory that purports to explain the evolutionary origins goes by the handle “antagonistic pleiotropy”: the idea is that genes which benefit an organism early in life but hurt fitness later on can nonetheless be selected, since extrinsic causes of mortality and the inexorable logic of exponential population growth cause the strength of selection to decrease with time (though there are ways around the math, if your body plan allows you to produce higher numbers of higher-quality offspring as a function of time; see Mark Powell’s comments regarding rockfish, in our recent article about whales, The old man of the sea).

The theory is an attractive one that has gained popularity among biogerontologists, as more and more findings are announced that appear consistent with its predictions. In my opinion, the strongest evidence comes from recent observations regarding the apparent tradeoff between cancer prevention and regenerative capacity, as well as related phenomena such as the anti-social behavior of senescent cells within tissues. For a refresher course, see these posts:

But every theory has detractors as well as adherents, and it seems only fair to give the other folks some air time (see also Battle of the reviews: Do tumor suppressors contribute to aging?). In a recent opinion in Biogerontology, Parsons launches a spirited attack on the generality of antagonistic pleiotropy:

Antagonistic pleiotropy and the stress theory of aging

The ecological stress theory of aging incorporates the normally harsh environments of natural populations and hence restricted resources. Especially towards lethal extremes, positive associations are expected among fitness traits underlain by selection for energetic efficiency favoring genotypes for stress resistance. Positive pleiotropy is therefore expected for fitness traits across varying ages under these conditions. Furthermore, hormetic zones are regions of maximum energetic efficiency, also implying positive pleiotropy. Negative pleiotropy may therefore be mainly a phenomenon of benign environments.

The author’s main argument is that the requisite conditions for antagonistic pleiotropy are extremely rare in naturally occurring populations, and that environmental stress should be a major driving force in the evolution of longevity. Negative consequences of selectable traits should be less important at the levels of energy intake that actually occur in the wild, he argues; furthermore, he proposes that some of the data in favor of antagonistic pleiotropy are artifacts of the artificially benign environments we create in the lab.

It’s a dense article, to be sure, but even after a couple of readings I remain unconvinced. Some of the most compelling findings on the role of tumor suppressors in aging are ignored (the one reference on that point is an offhand comment from four years ago from Lenny Guarante, whom I daresay might have changed his mind in light of more recent work by Heidi Scrable and co-workers), as are new observations that fixed alleles of housekeeping genes appear to be optimized for early-life function at the expense of longevity (see Conditioned for aging: Antagonistic pleiotropy in essential genes). There are also a few moments when I feel like the boat is simply missed:

…antagonistic pleiotropy is unlikely to be of consequence under the environmental conditions of natural populations where restricted lifespans preclude most survival to old age.

Well, I agree: when extrinsic mortality dominates life expectancy, we don’t expect to observe phenotypes that are specific to old age, because the organisms capable of expressing those phenotypes will have already met their final fate. This is one of the main reasons why alleles that confer with early good traits and bad late traits can be positively selected: the old-age traits are masked from selection because the organism doesn’t live long enough to express them. The preclusion of survival to old age by extrinsic mortality, and the consequent invisibility of certain traits to natural selection, is one of the main assumptions underlying the theory of antagonistic pleiotropy. The value of the theory isn’t in explaining how old a mouse lives in the field, but why the mouse looks like hell after three years safe in a cage.

I still think that the article is worth a read, as an opportunity to refresh one’s immediate command of the underpinnings of the relevant arguments. Theories are only as strong as the tests to which we put them, both experimentally and logically. Knowing that you believe a concept is one thing; knowing why you believe that concept and not a competing one is another thing — a more important thing — altogether.