Results from Human Clinical Trials Do Not Support Metformin as a Longevity Drug

The SENS Research Foundation staff have carried out the public service of extensively discussing and dismantling the evidence commonly cited in support of metformin as a way to modestly slow aging, showing that said evidence is problematic, to say the least. Metformin might make life modestly better for diabetics, but it doesn't slow aging. This view of the human data matches the poor quality of the animal model data, in which metformin makes a poor showing in comparison to the robust data for a modest slowing of aging that is produced by the use of, say, mTOR inhibitors, or the practice of calorie restriction.

Regardless of what you, I, the SENS Research Foundation staff, or just about anyone else thinks of the merits of metformin and the problems with human studies of metformin, the TAME trial to assess the use of metformin to treat aging will forge ahead. Regardless of whether it succeeds or (as I expect) fails, the point of the TAME trial is to pave the way, to have browbeaten the FDA into accepting a trial design in which the target is aging, not any specific disease of aging. That has essentially taken place. The next well-funded group will try that same trial design with mTOR inhibitors, or plasma dilution, or senolytics, or small molecule reprogramming agents. Sooner or later, it will become commonplace to run trials that target aging, rather than development programs sidetracking into the treatment of specific age-related disease while hoping for off-label use to take off.

More Studies on Metformin and Survival

In an earlier five-part series, I laid out the reasons to be skeptical that metformin would pan out as a longevity therapeutic. The centerpiece of the second post in the metformin series was a 2014 observational study, which is the one study that is most often cited as evidence that metformin slows aging in humans. A press release that accompanied the Bannister paper wrongly stated that it showed that "Type 2 diabetics can live longer than people without the disease" if they take metformin.

But as other scientists had pointed out before me, the study had a design flaw that first unintentionally selected only the healthiest diabetic patients (those on metformin) and compared them to patients whose blood sugar was harder to get under control (those on second-line diabetes medications) as well as to a random assortment of the nondiabetic population. Their study design then unwittingly but systematically pushed subjects who were taking metformin "off the books" as soon as their diabetes got worse. This methodological artifact created the illusion that metformin users lived longer lives than nondiabetics, because it meant that the study would only count metformin users as metformin users if they managed to stay healthy.

In the months since I wrote the original blog post explaining this, I've become aware of two other studies asking the same core question but using different methods - and they both find that, as you would expect, people on metformin for diabetes are shorter-lived than people without diabetes. Because these studies address this question more directly than any of the studies discussed in that blog post, we'll review them here. In summary, the metformin users were clearly dying more often than the nondiabetic population. The long-term effect on metformin was better than going untreated as a diabetic, but its benefits were clearly not even enough to get them back on the miserable course of "normal" aging, let alone to have a real anti-aging effect.

We shouldn't stop looking for hidden benefits in common medications - and if we find good evidence that such a drug might slow something as terrible as degenerative aging, it may be worth it to follow that signal up with clinical trials. But with metformin, a story that emerged in cell culture and some poorly-designed animal and human observational studies have led many smart people astray. And even if metformin had turned out to be as effective as it seemed to be in some of the early studies of metformin in abnormally short-lived animals, the implied potential benefits for aging humans would have been pretty modest. It would garner an aging humanity a far greater gain if the media, many advocates, and scientists would redirect the resources and attention that have gone into metformin into developing therapies that directly repair the damage in aging tissues.


"Longevity variants have little impact on longevity compared to lifestyle choices."

This is simply not true. Period. You are flat out lying. Why do you keep spreading this lie, Michael Rae? Lifespan is *primarilly* genetic. See the works of Vadim Gladyshev, Vera Gorbunova, Sofia Milman and others.
Do you really think that you can make an average person to live as long as a supercentenarian? Jeanne Calment was smoking cigarettes on her 100th Birthday, and she went on to live almost another 23 years after that. Conversely, most marathon runners don't live to the age of 90. My father never smoked, never ate junk food, ran over 20 marathons in his life, and yet at only 71 he had a heart ischemia and almost died. His dad had the same at exactly his age of 71. Shitty genetics.He is only alive because of a pacemaker and statins. None of those are "lifestyle choices"(unless you consider medication and invasive surgery as lifestyle choices). Conversely, Jeanne Calment waspuffing cigarette smoke and pumping blood at 100 without any surgery or medication.
To use a more extreme example to elucidate my point, do you think that you can make a mouse live as long as a Human Being with "lifestyle choices"? Or make an African killifish(lifespan 8 months) live as long as a Greenland Shark(lifespan 400 years). Can you pronlong lifespan 600 X with "lifestyle choices"? Are you THIS stupid?

Posted by: Neil Heartman at September 21st, 2023 11:14 PM

@Neil Heartman: There is a good argument to be made from the data that long-lived families are long-lived because of lifestyle factor transmission and not genetic transmission. E.g. Secondly, genetic studies using the UK Biobank and other large resources are continually failing to find sizable genetic determinants of longevity. E.g. While it is certainly possible that rare variants are producing large effects - such as PAI-1, - that doesn't appear to be going on in most long-lived families.

Posted by: Reason at September 22nd, 2023 9:40 AM

@Neil @Reason

Anecdotally, my aunt had diabetes and took Metformin and passed away at 93.

In any case, it does seem implausible that simple molecules will make a huge difference in lifespans. Considering that aging is most likely a genetically programmed process, more advanced methods such as, at minimum, the insertion of proteins designed to interfere with aging cascades (Such as telomerase, various transcription factors, etc) or modification or insertion of new of actual organelles (Such as Mitochondria) may bring some real results. Additionally, organ growth and replacement (including non invasive surgical techniques) are probably real solutions. I am sure more versed people have even better ideas.

I believe you are right that focusing on simple supplements and medications can help people reach the maximal lifespan that their genome will allow, which in humans seems to be about 120 (They already knew about this limit in biblical times).

Posted by: Daniel at September 22nd, 2023 2:33 PM

@niel heartman- yes genetics most important. But don't u think epigenomics too key? For example if African American your genetics have skin that better protects from excess sun that leads to skin cancer. If very pale skin and get sun burned many times epigenetics change andnthen to increase odds of skin cancer. But if stay out of sun and not get many burns then to delay chance of skin cancer and early death. So here environment could cause issue for one with pale skin. Also if to over eat with bmi increasing to over 40 and even if haven food genes this much weight to lead to early death. So here to extra weight is environmental with this changing epigenetics.

Posted by: Mike at September 22nd, 2023 4:22 PM

@Neil Heartman: where have I made this statement?

Posted by: Michael at September 23rd, 2023 12:08 PM

One of the things that has confused me about the TAME saga is, now that they have obtained regulatory approval for the clinical trial, why does it need to proceed at all? Can't the other, better treatments use the same clinical endpoints without TAME proceeding? Hasn't TAME already achieved the objective of getting the FDA to agree with an aging clinical endpoint, so other treatments can use the same endpoints whether or not TAME actually happens? Can anyone shed light on this?

Posted by: Neil at September 24th, 2023 11:36 AM

@Michael: I read your article and think I understand it better now. a) It is much easier for a company preparing to run a new trial to use as an example an already-well-run trial, b) If the trial doesn't run soon, FDA regulators may change their minds and this end point won't be available anymore.

I think your article also clarified for me that damage-repair treatments have a better time in traditional clinical trials than do the messing-with-metabolism types, but that everyone would benefit from better aging trial endpoints.

Too bad TAME isn't something like TADQ, testing a senolytic. Then, perhaps in addition to setting a precedent, it might actually give a very positive result.


Posted by: Neil at October 7th, 2023 12:15 PM
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