Sirtuins come under fire

Over the past few years, sirtuins have generated great excitement — both in the basic study of biogerontology and (more recently) in the private sector. In just over a decade, the field has moved from its founding observations in yeast to wide-ranging results in mammals. Among the adherents of a widely held theory, it is believed that sirtuins act to extend lifespan via similar mechanisms to calorie restriction (CR), and that small-molecule activators of sirtuins (such as resveratrol) are CR mimetics — therefore, the sirtuins are the first molecular target to guide drug design in a bona fide anti-aging pharmacopoeia.

As theories reach maturity (and middle age), they are naturally subject to challenge, and the sirtuin story is no exception. The role of sirtuins in CR has been challenged, sometimes by the very founders of the field. The mechanism(s) of action of resveratrol are also under close scrutiny. Even some of the most famous studies of sirtuins — specifically, regarding effects on median lifespan and exercise tolerance — used animals eating such horrifyingly fatty diets or ingesting such gigantic doses of resveratrol that their relevance to humans must be questioned.

It’s therefore high time that we turned a skeptical eye to the sirtuin story. Ken Garber, reporting for Nature Biotechnology, has assembled a very accessible short review of the subject that lines up the arguments regarding sirtuins’ role in aging, the relationship between sirtuin activity and CR, and the value of “known” sirtuin activators as preclinical leads (link):

… But there is another sirtuin narrative that has received much less attention. To begin with, there is no published evidence that resveratrol or sirtuin activators can extend lifespan in normal mammals. Calorie restriction does extend lifespan in many organisms (though not all), but its effects in mammals may have little to do with the sirtuins: other pathways may be more important. And resveratrol may not be a general sirtuin activator in the first place—the compound’s beneficial effects may arise from completely different mechanisms. Finally, credible research in yeast suggests that sirtuins may actually function to limit chronological lifespan, not increase it.

The piece summarizes, thoroughly and fairly, the arguments for and against the competing narratives regarding sirtuins’ importance; in the process, it gives a nice historical overview of the evolution of the sirtuin field since its foundations in yeast.

By pointing out the importance of narrative, Garber reminds us that sometimes we tend to preferentially remember facts that improve the consistency of a story, and conversely, to preferentially forget completely valid observations that add rough edges and sharp corners to a favored view. This field is rife with examples. Here, we are reminded of some of the prima facie weaknesses of some of founding studies, including ones that led to such fundamental beliefs as the idea that resveratrol activates sirtuins. We’re also pointed toward the work of dissenting scholars who find that sirtuin mutations and resveratrol have minimal, if any, effect on lifespan — raising the possibility that any such effects observed in other studies are sensitively dependent on the choice of culture conditions and the genetic backgrounds of the animals used.

On the balance, the piece doesn’t argue that sirtuins aren’t involved in aging or that they’re not worth further study — but after reading it, I found myself realizing that some of the parts of the big machine don’t fit together as smoothly as I thought they had. Especially when a theory is widely accepted — and widely used as an inspiration for future studies — it’s crucial to be regularly reminded of what we know for sure, why we think we know it, and (most importantly) of the magnitude of what we don’t yet know.