The Sirtuin Scam (Part 1)

Dreams of Perpetual Youth (2)

At no point in human history have so many Americans been so old. Not just with respect to absolute numbers, but as a proportion of the total population as well. Naturally, the amount of money devoted to the study of aging has also increased. Donald Trump and his new sidekick Robert Kennedy Jr. have virtually destroyed the National Institutes of Health (NIH), eliminating most institutes. But the National Institute of Aging, was one of only three that was spared, so universal is the demand to do something about the aging process and its sequelae. To date the payouts of this investment have been unimpressive. But media coverage may lead you to believe otherwise, that significant life-extension is just around the corner, that the deterioration of body and mind associated with aging will soon be a thing of the past. At least for the affluent.

In this yearning environment any research that claims even a marginal advance in these regards will be highly publicized. The scientists involved are incentivized to hype their results for that reason alone. (Scientists are not immune to the allure of prestige.) Compound this form of self-aggrandizement with the allure of the wealth to be made in collaboration with the private sector and you have a recipe for the proliferation of misinformation. (For an excellent and detailed review of this sorry saga, see this excellent scientific review by Charles Brenner: 37035412). (I also am eager to acknowledge the outstanding coverage of the sirtuin scam by Derek Lowe in his column for Science magazine (see, for example, https://www.science.org/content/blog-post/speaking-illusions-sirtuins-and-longevity. Lowe, who has followed the story from the early days, is an exemplar of independent journalism. He is employed by one of the two most prestigious journals in all of science, one in which some of the problematic sirtuin research has been published. Which he has not hesitated to note.)

It all began just before we entered the 21^st century, with a study on the budding yeast, Saccharomyces cerevisiae, the same yeast species employed to make beer, bread, and wine, among many other applications. But you wouldn’t want to use these laboratory strains for the manufacture of any food or beverages, because the lab strains have been engineered for other functions.

Yeasts are single celled fungi. Budding yeasts are named for their primary mode of reproduction, called budding. The budded individual is called the daughter cell, the individual that did the budding is called the mother cell. It has long been known that an individual budding yeast is limited in the number of buds it can sequentially produce. This fact stimulated some to search for genes that influence the length of the yeasts reproductive lifespan as measured by budding. One early candidate was a sirtuin gene, called SIR2. When one copy of SIR2 was deleted, the amount of budding a yeast could do was cut in half. If, on the other hand, an extra copy of SIR2 was spliced into the genome, budding capacity increased by about 30%. This is the foundation of all claims that sirtuins increase longevity (37035412.

You may wonder at this point how a study of yeast life extension could have such profound implications for longevity in more complex creatures, like you and me. But there is a more fundamental issue here: what does the expansion of yeast budding capacity have to do with the expansion of yeast lifespan? Not much, it turns out. If anything, budding and longevity seem to be inversely related, at least as they relate to sirtuins. For increased sirtuin expression reduces the lifespan of budding yeast (10.1016/j.cell.2005.08.042).

By the time it was discovered that SIR2 actually reduces longevity in yeast the sirtuin train was already out of the station. Laboratories around the world were mobilized for sirtuin research, any grant proposal with the word sirtuin in it was funded, and a plethora of review articles were written. That was on the academic side. On the public side, the print press was all in, as was social media, including prominent podcasts. And popular books of course, best sellers on. David Sinclair led the charge and became the face of the the movement, coauthoring a popular book with the title Lifespan: Why We Age—and Why We Don’t Have To (46). Sinclair was also the first to monetize the hype. He created a company Sirtris, soon bought by Glaxo Smith Kline for over $700,00. GSK soon invested billions more in sirtuin research--to their great regret. GSK came to realize, too late that Sinclair had sold them snake oil; they tried, unsuccessfully, to claw their money back in court, claiming to have been deceived. Once the lawsuit was lost, GSK went to great lengths to rescue their investment and became part of the hype machine.

The initial results re the lifespan enhancing effects of sirtuins were promising, when extended to other model organisms, first on the nematode, Caenorhabditis elegans. If the yeast, Saccharomyces cerevisiae is the most important model organism in biology, C. elegans is second. (These tiny (1 mm) creatures consist of about 1,000 cells, all of which are now individually characterized.) So, it was certainly noteworthy—and newsworthy—When researchers reported that an extra copy of SIR2 extended nematode lifespan by 50% (10.1038/35065638).

Next step flies, specifically fruit flies, Drosophila melanogaster, the third most important model organism in biology. Drosophila are a big step up in complexity relative to nematodes. And, as in nematodes, the overexpression of SIR2 was reported to increase longevity in fruit flies (PMC528752).

But others reported quite the opposite, and the evidence against SIR2 as an anti-aging gene increasingly mounted. In addition to the research demonstrating a negative effect of sirtuins on lifespan in yeast, others went back to retest fruit flies and nematodes and found that sirtuin boosts had no effect on lifespan (PMC3188402: 10.1139/gen-2015-0213). By 2011 the tide had turned against the Sirtuin hype within the scientific community (DOI: 10.1126/science.334.6060.1194). That message failed to penetrate the popular media. And those scientists most invested in sirtuins doubled down and began to look beyond SIR2 to the antiaging effects of other sirtuins. (There are seven sirtuins in mammals). Other research, sometimes by the same scientists commenced a quest to find chemicals that act as sirtuin activators and hence life extenders.

In the next wo posts I will discuss this dubious and gratuitous research, beginning with sirtuin activators, most infamously, resveratrol.