Discussing the State of the TAME Clinical Trial, Metformin to Slow Aging
The TAME clinical trial, still not started, intends to assess the ability of metformin to marginally slow aging in humans. Back at the start of this initiative, it required a long process of negotiation on the part of the trial organizers with the FDA to produce an endpoint that was agreed upon to sufficiently represent aging. To my mind, the TAME trial initiative has already achieved what needs to be achieved: to get the FDA to agree that there is a way to run trials to treat aging. One doesn't actually need to run the trial, and there is in fact little point in running the trial. Metformin is almost certainly a marginal treatment, and attention should be directed instead towards senolytics and other approaches that have much, much better animal data to support their effects on the mechanisms of aging and late life health.
In 2013, Nir Barzilai and two other researchers got a grant from the National Institute on Aging to develop a roadmap to conduct, for the first time in history, a clinical trial that targets aging. They planned to test metformin, a drug that had been approved in the '90s for treating diabetes, and that was shown in epidemiological studies to prevent against conditions like heart attacks, cancer, and Alzheimer's. It also turned out to be very safe, with few, generally mild side effects. And it's dirt cheap: just six cents per dose.
The biggest obstacle they had was the Food and Drug Administration. The federal regulator adheres to a "one disease, one drug" model of approval. And because the agency does not recognize aging as a disease, there's no path forward for a drug to treat it. And even if there was, it's impractical to do a lifespan study - it would take decades and be astronomically expensive. The solution then would be to use biomarkers as a proxy, as researchers have with other treatments. Barzilai's plan was to launch a new kind of gold-standard trial, designed to prove that the onset of multiple chronic diseases, or comorbidities, associated with aging can be delayed by a single drug: metformin. The ambitious effort aimed to track 3,000 elderly people over five years to see if the medicine could hold off cardiovascular disease, cancer, and cognitive decline, along with mortality.
In 2015, he and a group of academics from more than a dozen top-tier universities met with the FDA to get its blessing for their Targeted Aging with Metformin, or TAME, trial. And to many people's surprise, the agency agreed. All that was left was funding it. Because metformin is a generic drug from which no one could make any money, the trial's sponsor wouldn't be a pharmaceutical company, but AFAR. A trial of the scale researchers were proposing would cost between $30 million and $50 million. The National Institutes of Health offered up just a small portion, about $9 million, toward the difficult but important task of screening for the best biomarkers for assessing if the aging process is actually being slowed. The rest of the money, Barzilai was convinced, could be raised from philanthropists. But despite interest from several people - at one point, Barzilai said, the Israeli American businessman Adam Neumann offered to pay for it all, before his WeWork empire evaporated - the required funds never materialized. "Those big billionaires, they want moonshots, they want a scientific achievement that will make people say 'wow'. TAME is not a moonshot. It's not even about scientific achievement really, it's more about political achievement. Metformin is a tool to get aging as an indication."
Link: https://www.statnews.com/2022/08/09/anti-aging-projects-funding-much-discussed-trial-overlooked/
From 2013 to now - it was 9 years and the trial did not even start !
And even if there is a trial, FDA may reject the results of it - a big waste of money , which can be spent on more promising, potentially more effective treatments of degenerative AGEing.
In general : considering all research and trials to slow and reverse AGEing- all of it is happening too slowly.
The AGEing process in each human is happening faster than the progress in research,
So most humans alive now, will die of AGEing before there will be any effective treatment of AGEing.
I am not an optimist , i am a realist and to be a realist is to be pessimist- expecting the worst outcome - suffering and death. Death is final and irreversible - eternal non-existence.
@nicholas You don't get the point of this TAME trial. We all know, including Barzilai, that it will have a modest effect on slowing aging. The point is to change FDA's view on aging. Of course it takes time. Elon Musk took 15 years to change car manufacturers view on electric vehicules. It took 15 years rocket companies to realize that reusable rockets are the only way. It will take several more years for the FDA to realize aging is the main problem. I'm confident that FDA will recognize aging as a condition by 2030.
"I have no credibility anymore..."
Sad
"Metformin is almost certainly a marginal treatment, and attention should be directed instead towards senolytics" - I wouldn't be so sure. I'm middle age, in no perfect health and tried many popular "longevity" drugs over the last years, with no visible improvements, but with plenty of side effects. That includes senolytics - fisetin and grape seed extract, separately and in combination.
Metformin though showed considerable improvement practically straight away. If it can do the same to many other people with declining health, and can do it cheaply and easily, why not to do it? Why wait for a new "moonshot" drug if many people need something right now?
Diabetics on Metformin do slightly better than non-diabetics, which is very significant considering that they should be doing far worse. . Nir has stated that there are better candidates like Rapamycin etc… but Metformin has a very long safety profile and is a good starting point. So Metformin along with exercise, some supplements that boost mitochondria like PQQ and CoQ19, eating a nutrient dense diet with occasional extended fasts is VERY significant. And of course people can add intermittent Rapamycin and/or Senolytics. No one here has to wait for this trial to maximize what is now available.
@Chyck - all good points, except 99% of people would have no idea what metformin is and even less would risk taking it without medical advice. It needs to go though human trials as anti-aging, get approved by FDA and then distributed to over 50 by their local GPs.
I have heard and read enough about metformin to convince me I would like to begin taking it for its anti-aging benefits. The question is-how can you get a prescription for it if you don't have DM or PCOS. Interested in any comments
what about glucosamine? It's life extension effect is suggested elsewhere to be about the same as metformin but more reliable, and without metformin's side effects. And it's prescription-free.
@Leona - I searched online and found some dodgy-looking websites selling metformin. I don't know if I'm allowed to post web links here, just search, it's not very hard to find.
Instead of a clinical trial, why doesn't AFAR consider a prospective observational registry where non-diabetics in the target age group of 65-79 are prescribed a standard dose of metformin and followed until death, by having routine labs from doctor visits, new diagnoses and cause of death entered into a database and outcomes compared to diagnoses, age and cause of death for non-metformin treated patients in this age range? Data for the non treated group could be obtained from the Medicare and Epic electronic medical records databases. If the treated group was large enough, statistically significant results on safety and effectiveness could be obtained without the high expense of a randomized clinical trial.
Why can't the experts like Barzilai say if a person should take metformin (yes or no) and if yes at what dosage (is 500 mg OK?). Why is an FDA-OK so important, that having spent 10 years on obtaining it is considered an achievement in the interest of mankind? There will be those like in the case of COVID who will say they would decline even in case of a flaming FDA-recommendation. So let them. Those who are interested should not be left with wishi washi statements. If the experts think Metformin is not more than a medium term thing until something really effective (Rapamycine or Rapalog ?) has been approved then say so (even though we all know that will take another 20 years at least).