On resveratrol and the beautiful mindset of Michael Faraday — Part 1

In recent months, life-science blogs and journals have pulsated with negative vibes about resveratrol, the red-wine ingredient reported to show anti-aging effects in various animal species. The bad vibes have also been directed at sirtuins, the enzymes thought to mediate resveratrol’s benefits and at David Sinclair, the Harvard scientist who first reported that resveratrol can induce effects resembling those of calorie restriction (CR). Sirtris Pharmaceuticals, the sirtuin-based biotech Sinclair cofounded that GlaxoSmithKline bought for $720 million in 2008, has also come under heavy fire.

My recently released book, which covers the resveratrol and Sirtris stories among many others in aging science, has lately placed me in the skeptics’ line of fire. According to one scientist who emailed me recently, the cautious optimism I express in my book about the promise of resveratrol and sirtuins comes off as naive hype. Here’s an excerpt from his email:

Sirtuins and resveratrol and the entire Sirtris enterprise are a house of cards that is in the process of crumbling badly. The Pfizer study is pretty devastating…The critique that resveratrol and the SIRT1 compounds do not even act via sirtuins is also fairly devastating to the enterprise…The executives of GSK who paid a billion dollars for Sirtris are the laughing stock of the drug industry and likely to lose their jobs…But I can understand why you took the stance of celebrating sirtuins and Sirtris—your book needed a narrative that was positive and interesting.

Reading these strong assertions made me think of Lionel Trilling’s memorable comment on Michael Faraday, the self-educated blacksmith’s son who became one of history’s greatest scientists—he made seminal discoveries on the relation between magnetism and electricity, and developed the first dynamo. Wrote Trilling: “Every personal episode [about Faraday in a classic biography of him] makes it plain that he undertook to be, in the beautiful lost sense of the word, a disinterested man.”

Disinterestedness is by no means lost in science. But the recently fashionable characterization of research on resveratrol and sirtuins as hyped-up junk science suggests that Faraday’s beautiful mindset is even more endangered than it was when Trilling penned his comment in the early 1960s. In fact, I think this fashionable dismissiveness is a prime example of how views informed by envy (in this case, of a cocky young scientist who achieved great renown early in his career) and Schadenfreude (about the fact that he and his research have come under heavy fire) get spread at light speed inside the global reverberation chamber of the blogosphere. As a result, the “small and rather untidy passions,” as Trilling put it, that all of us experience from time to time can get instantly amplified beyond all reason—this unfortunate, Web-engendered phenomenon is something new.

This isn’t to deny that there has been lots of unwarranted optimism and hype surrounding resveratrol—the hawking of resveratrol supplements on the Internet has spawned an ever-spreading spam slick. Nor is it to say that Sinclair is a paragon of objectivity about resveratrol and sirtuins. Naturally, he’s a passionate supporter of his professional baby—in particular, the idea that resveratrol induces CR-like anti-aging effects and that it mainly does that in mammals by stimulating a sirtuin called SIRT1. At times he’s gotten carried away when making the case for his work’s medical promise, and while watching him over the past six years I’ve been struck more than once by the thought that he’s sometimes too good on stage for his own good. His ill-fated decision to consult with Shaklee, the nutraceutical maker that enlisted him to help promote its resveratrol supplements, has been the most glaring example of Sinclair-the-enthusiastic-showman upstaging Sinclair-the-careful-scientist, and I suspect he’s still kicking himself about it. Moreover, as a cofounder of Sirtris, he’s manifestly stood to reap millions by convincing the world that he’s right. Disinterested he obviously isn’t. (Nor has he ever claimed to be.)

But unlike many eager to bash him lately, Sinclair is extremely well-versed on the formidably large literature on resveratrol and sirtuins—including studies conflicting with his—and his lab’s additions to that literature have repeatedly passed muster with peer reviewers for top science journals, who aren’t known for being pushovers or members of a global conspiracy to hype his discoveries. Based on conversations with various Sinclair bashers, I’m convinced that a remarkably large percentage of them have at most a passing acquaintance with the relevant literature, and in many cases only second-hand knowledge of it based on the latest buzz in the blogosphere. (I don’t mean the small subset of Sinclair critics who do sirtuin-related studies themselves.) I say remarkably large because many of these people are bright, otherwise knowledgeable scientists who presumably are dedicated to the proposition that you should look at data before drawing strong conclusions and voicing incendiary assertions about it. And although it’s plain that they’ve spent very little, if any, time going over the 3,400 studies on PubMed that mention resveratrol, or the nearly 1,500 ones concerned with sirtuins, it’s pretty clear that they fancy themselves far more Faraday-like than Sinclair while asserting that his scientific contributions lie somewhere between outrageous hype and total baloney.

Before I myself get trashed as a Sinclair apologist, let me say a few things about where I come from in this debate. I’ve tracked the unfolding resveratrol/sirtuins story as a science writer since 2004 and am on a first-name basis with a number of its major players, including Sinclair; Christoph Westphal, the venture capitalist who organized Sirtris; Lenny Guarente, whose research on sirtuins paved the way for Sinclair’s work on resveratrol; and Brian Kennedy and Matt Kaeberlein, the scientists whose research first raised doubts about Sinclair’s and Guarente’s findings on sirtuins and CR. In a Wall Street Journal front-pager in late 2006, I broke the news that Sinclair’s team had discovered that resveratrol induces some CR-like effects in mice on high-fat diets. In that same story, I also took pains to lay out the case for skepticism, noting that “resveratrol’s mode of action is still murky”; that multiple studies had “cast doubt on the idea that SIR genes are key actuators of CR”; and that contrary to Sinclair’s findings, Kennedy and Kaeberlein’s data suggest both that CR can exert antiaging effects independently of SIR genes and that “other genes are more central to CR—at least in yeast.” Underscoring the doubts, I quoted Kaeberlein’s stark assertion at the time “that CR probably has nothing to do with SIR genes.”

I also took pains to sketch the expanded case for skepticism as of early 2010 in my book, citing, for example, the Partridge lab’s report that resveratrol doesn’t significantly extend life span in fruit flies and and does so only inconsistently in nematodes; various reports suggesting that resveratrol may act on SIRT1 only indirectly, or perhaps mainly exerts its effects via AMPK; various Kennedy/Kaeberlein yeast experiments suggesting that neither resveratrol nor CR exert their effects via SIR2; and the Sinclair group’s 2008 report that resveratrol failed to extend life span of mice on normal diets. The very title of my resveratrol chapter—”Red Wine’s Enigmatic Dirty Drug”—was meant to draw attention to the uncertainties about the compound’s mechanism and anti-aging potential. I also state in my book that I don’t take resveratrol supplements because I don’t feel there are enough data on its effects in humans to justify my joining the early adopters. In sum, the assertion that I present a simple, positive narrative about resveratrol, Sinclair and sirtuins doesn’t seem to reflect a very close reading of my book. In fact, I think I’ve consistently been more of a disinterested centrist on resveratrol/sirtuins science than are people who’ve recently accused me of hype.