The Sirtuin Scam (Part 2): The French Paradox

Dreams of Perpetual Youth (3)

(Note): For those not familiar with sirtuin research there is inevitable confusion about how sirtuin genes are designated and named. The initial research, which created the excitement, was conducted with yeast (a fungus), and the sirtuin gene under consideration was designated SIR2. The animal equivalent (ortholog) of this yeast gene is designated SIRT1, which is a recipe for confusion. Not only are different numbers attached to the sirtuin gene, but the letters are different as well, SIR versus SIRT. In what follows, I will simply use “sirtuin” to refer to both. Mammals have seven sirtuin genes, but I’ll cross that bridge when I come to it.

The French Paradox refers to the relatively low incidence of heart disease among the French despite diets high in saturated fats. Obviously, any number of lifestyle differences could be responsible for this interesting observation that could interact in complex ways. But from the outset researchers zeroed in on diet. No statistics were presented as to the relative mount of saturated fats consumed by French versus Americans. Moreover, fatty acids (lipids) are diverse, many of them healthful; this is especially true of saturated fatty acids. Nonetheless researchers chose to focus on other dietary elements. The amount of plant versus animal products consumed would seem the most obvious place to start. Instead, researchers zeroed in on wine, specifically red wine. The French, it was alleged, drink red wine with their high fat meals.

A group, led once again by David Sinclair, screened red wine for various chemicals and found that several of a class called polyphenols acted as sirtuin activators, resveratrol most notably among them. The answer to the French Paradox, it was declared is the resveratrol in red wines. Quite an inferential leap. But not nearly is impressive as their other claim, called Xenohormesis.

Hormesis is a phenomenon whereby a stressor, say a toxin, can have positive physiological effects at low doses by challenging an organism to respond adaptively (in a physiological sense), thereby reducing the subsequent effects of higher doses of the stressor. So, bad at high doses, good at low doses. Xenohormesis, a term coined by David Sinclair, himself, is allegedly a benefit derived in one species on the tree of life from consuming another species on that tree that has experienced hormesis. Xenohormesis is hormesis at one remove. No need to experience stress yourself, just eat—or drink—something that has.

With respect to red wine this idea jibes nicely with the conventional wisdom that great wines come from stressed vines. That is, vines that struggle to find water and nutrients. (Somehow ignored re the French Paradox is the fact that only a very small minority of French people consume great, or even good wines. The great unwashed are condemned to vin ordinaire from non-stressed vines.) More generally, stressed plants allegedly produce more sirtuin activating polyphenols that coddled ones. Any remotely well-tuned bullshit detector should have set off alarms when confronted with this nonsense.

Instead, the two most prestigious publications in all of science embarrassed themselves in their coverage of resveratrol and xenohormesis. From Nature (published in the U.K. and where the original article appeared) came this editorial gem: “Aging: a toast to long life” (10.1038/425132a). From Science (published in the U.S.): “Longevity: in vino vitalis? (10.1126/science.301.5637.1165). At least Science covered its ass somewhat with the question mark, for which posterity will reward it. For the tide has changed. Subsequent studies have shown that resveratrol is not a sirtuin activator (10.1111/j.1747-0285.2009.00901.x); It doesn’t even bind to sirtuins (10.1074/jbc.M500655200). The evidence that resveratrol activated sirtuins turned out to be what is commonly known as an artifact, a false positive born of a correlated signal. In this case, the artifactual signal was the fluorescent marker by which resveratrol activity was tracked (https://www.science.org/content/blog-post/speaking-illusions-sirtuins-and-longevity).

It was the fluorescent chemical tag, not resveratrol, that was attracted to sirtuin. Glaxo Smith Kline, which went all in on sirtuins and sirtuin activators, once it couldn’t back out of the deal for Sirtris, admitted this when confronted by evidence from their competitors, Amgen and Pfizer, who were of course gleeful to embarrass GSK. Not so, scientists in the public sector, some of whose reputations were at stake. You would think that of David Sinclair would have suffered the most, but he continues shamelessly on. As we will see when I turn to the next generation source for a “fountain of youth”, it is Sinclair once more unabashedly leading the charge.