Aubrey de Grey on the TAME Metformin Trial


Pioneer Founding member

As you may or may not have heard, the TAME metformin trial recently received the remaining 40 million in philanthropic funding that is needed to progress. The trial will cost 75 million in total, and to my eyes this is quite the waste of funding. Aubrey de Grey of the SENS Research Foundation is far more polite on this topic in today's editorial, which isn't too surprising given our respective views on regulation.

I'll set aside for the moment the point that metformin is a weak treatment with a small effect size on life span, unreliable animal data, life span data in humans arising from a single trial for diabetics rather than healthy individuals, and side effects that are significant in comparison to the small effect size. The point of the TAME exercise is convince the FDA to accept aging as an indication - or something close enough that people can work with it. That never needed a trial to exist in order to take place. The important work has been a process of Nir Barzilai, his collaborators, and fellow travelers such as the Longevity Dividend folk negotiating with FDA bureaucrats, against a backdrop of increasing patient advocacy and activism for aging to be classified as a legitimate target for therapy.

Further, this labor of filling in a ditch dug by the FDA isn't even needed. The same end could be just as well achieved by putting rejuvenation therapies through the FDA process for any relevant age-related indication, and then engaging in a running battle over the off-label use that will come to be the overwhelming majority of all use for these treatments. That is exactly what will soon happen for the dasatinib and quercetin combination, as the world wakes up to just how large and reliable the benefits are for patients undergoing this sort of first generation senolytic therapy. The way forward will be established for these very cheap, revolutionary therapies, and then can be followed by everyone else developing a rejuvenation therapy. Under this sort of pressure, the FDA will change because they have to.

Since the TAME trial is forging ahead, we can hope that the philanthropists involved may choose to do the same for senolytic therapies - which would have been a far better choice, had the required information been widely available back in 2015, when the TAME trial originated. Nonetheless, it remains the case that there are far, far, far better uses for 75 million in this field.

TAME: a genuinely good use of 75 million dollars

The TAME trial is an attempt to determine whether metformin, the well-known anti-diabetes drug, actually has much more wide-ranging benefits against the health problems of late life - so wide-ranging, in fact, that they could uncontroversially be described as addressing aging itself. But then, hang on, metformin is an old drug. I mean, a really old drug - it has been off patent since forever. There is no way in hell to make money out of it. So, how would we fund a clinical trial of it? Well, yes: the only way is philanthropic. This will only happen if there are people out there who are sufficiently convinced of the importance of such a trial that they will pony up the requisite capital even though doing so is completely bereft of financial upside.

But the logic is persuasive in another way: precisely because metformin is such an old drug, a trial can immediately focus on efficacy, in contrast to the need for stringent tests of safety to come first in the case of a new drug. And, sure enough, pretty much as soon as the idea of such a trial was formulated, nearly half of the required 75 million was pledged by the long-standing supporter of gerontology research, Paul Glenn, via (as has long been his custom) the American Federation for Aging Research (AFAR). At that point, however, the pursuit of funds stalled for a couple of years - in particular, the National Institute on Aging twice rejected applications for the remaining money - but, as noted above, the remaining support materialised very recently, courtesy of an anonymous donor.

A question remains, however: is this, in fact, the best use of 75 million in the crusade against aging? Well, that's a few times the total amount that SENS Research Foundation has raised in its entire history, so it will not surprise you that I cannot quite look you in the eye and answer that question in the affirmative. But it is certainly not a waste of money either: indeed, I do feel able to declare that it is a pretty good use.

First, I think there is a reasonable chance that the trial will succeed, albeit modestly. There's no way that a brief course of metformin will give people a decade of extra life, but all that's really needed here is a statistically significant improvement versus controls, and with that kind of money the study can be powered well enough to achieve that threshold. The other rationale for this trial is arguably even greater. It is that the description of the trial incorporates a de facto definitition of aging as the clinical endpoint, which has been more-or-less approved by the FDA, and which can thus be copied and pasted into any future trial for an intervention against aging. That endpoint was the result of a highly arduous negotiation with the FDA that was led by the inestimable Nir Barzilai.