TAME Q&A: Lessons for Progress on Aging | Nir Barzilai, Albert Einstein School of Medicine | Otter.ai

TAME Q&A: Lessons for Progress on Aging | Nir Barzilai, Albert Einstein School of Medicine

Allison Duettmann1h

Nir

00:00

So the first thing I'm going to do, I'm going to show you just three slides to kind of get you a updated about a time. And basically, I want to make few points, if there is a paper that I sent you before, that basically shows what you see here are all the hallmarks of aging, right? Or, or some version of it. If we had a paper that was published in cell metabolism, where we showed that each one of this pathway is targeted by Metformin, right? And and if you ask me, do I believe that Metformin has at least you know, nine different actions? The answer is that we all know that when you target to one of those hallmarks, you affect others. And I think this is really the bottom line of geroscience. And that's why we're kind of fighting about what sirtuin do, and what was very thrilled to because they seem to do everything. But the principle is if you take a young and old cell or organ or body and make them young, you're going to see improvement in all those hallmarks of aging. And I think that's the mechanism that's really happening. If you ask me, what is the most important mechanism of action? Or what is the most important Hallmark? We try to say those four are more important than the others, but I don't know that for sure. But please know that when you really target aging, you'll get confused with the mechanism. Everybody said, No, it's not this. It's that. Okay. Point 1.2. A Metformin has been there for 70 years or more. In fact, big one i that is the father of Metformin, that's the chemical that is extracted from the French lilac has been used. There's therapeutical advantage that were noticed before more modern medicine. And it was used mainly to prevent flu and Alzheimers and malaria, I'm sorry. And during the process of using Metformin, mainly in Europe, it was also found that it lowers glucose in diabetic patients, and now it's an anti diabetic drug. By the way, the effects on glucose might be independent, or impartial, independent from the effects on aging. Okay. So I can answer more question about it later. But the point is that it's used for so many years that we understand all the safety issues of, of this drug. And it, it's still one of the safest drugs ever invented. A, I went over that it's generic and cheap. Okay, so it's relevant, because if people are going to tell us, you know, you're just working for rich people who would just want to have this drug and live forever, will using Metformin is one of them this opportunity to say everybody can use it. It's not a burden on any healthcare provider. It's the cheapest drug in the market, you can get 900 pills for $40. From Mexico, it's called metformina. And something like that, from Canada to him. And so we because of those reasons, and and the next slide, we we use Metformin as a tool. And I'm saying it's a tool, because all we have to do is repurpose a drug that is available that is safe to show on principle that we can target aging and then delay a cluster of age related diseases.

Nir

04:22

Okay, the second slide is basically to tell you that everything that were studied, were stuck were clumping together in the tame trial has been done pretty much in isolated trials. Okay. So, for example, in the DPP trial, took non diabetic people and gave them Metformin and showed a 30% decrease in the rate of diabetes over four years. In fact, this study had to be terminated early in a so 30% decline. In the onset of diabetes in this drug, by the way, it's not because they're taking anti diabetic drug when they let when they took out the drug and look at what happened a month or so later. It was it was still a, they still were not a diabetic, but that's a clinical study. Okay, there is a, there are actually few arms in the DPP, but there's a placebo and there is a Metformin. And so that's intervention or clinical study. Another intervention study was the UK t p PDS where it showed that Metformin unlike in saline or other drugs, so funny Korea, other drugs, it decreased cardiovascular disease, by the way, it also decreased overall mortality by 36%. Not diabetes related mortality, not cardiovascular mortality, only, but overall mortality by 36%. And next, next, their association studies. Okay, so their association studies are not as good as as intervention studies. But if you have association studies, if you have 200 of them, and there are more, that are all showing, you know, when you're in Metformin, you have less cancers, and it's all cause of cancer, the only controversial one is prostate cancer. Okay, some said yes, some says no, but all the association studies show decrease in cancer. And this is in a diabetic population.

Nir

06:34

There are clinical studies that are small and short, and and associations that are on MCI. Okay, which is halfway to Alzheimer or risk for Alzheimer, mild cognitive impairment, and an Alzheimer studies that have shown significant decline with Metformin. And except some studies from the Far East that I totally I don't totally understand that. But it's really complicated. Because if Metformin keeps you from dying, even if you have the disease, you kind of have to adjust for the life. In other words, more people with Metformin are staying alive and getting to Alzheimer's, you know, I mean, it's the whole science when when we're going to target aging, it's going to be very weird for us, because we have to take into account the gain the gain of life, that was the gain of years that we had. Anyhow, that's a side issue. And then the really a very impressive data on almost 200,000 people from the UK where people looked into the pharmaceuticals, and identify those 80,000 people who are newly diabetics and on Metformin, comparing them to other diabetes and non diabetics, and, and the basically the people with diabetes who were also more obese, and had more diseases to start with an end diabetes had lower mortality, significant lower mortality than people without diabetes, okay? So when you have all those aging stuff, and you take Metformin, you still live longer than people without diabetes. So, so that was interesting, but all that a, just justify why we use it at the tool. And again, amazing, basically showing you those studies, all those things are part of taking, you know, that diabetes, although not quite but a cardiovascular disease, Alzheimers, mortality cancers are all part of, of the construct of tain or, or which diseases were going to delay. So. So those were done, all we have to do it is together. Okay. And, and, and that's, I think the point. And Jamie showed you a little bit different slide, Ted, the secondary outcome, which I took out because a the study that is designed here is basically for the FDA. And what I want to point here is that we don't really care. And I'm know that I'm getting a good getting off, but you hear me all the time, right? Sometimes I'm freezing but you hear me all the time.

Nir

09:38

So the point here is, we are agnostic to the diseases, okay, we don't we don't care which diseases you had, and which specific disease you're going to get. Because what we're targeting is aging, okay. We have no idea what will be your next disease, okay. If your mother is there abetik and you're obese, you're going to get the next disease, we're going to get his diabetes. Okay? We don't know what this is you're going to get, but the geroscience hypothesis is whatever it is, we're going to move it away, like we showed in all those preliminary data in, in, in lots of association and clinical studies. So those and the second thing, we're doing it in a little bit older population. And the challenge here is that we need to understand exactly the power and not overdo it. Okay. So for example, if we're going to give Metformin and we're going to have significant result in cardiovascular disease and not in the other, even if they're trending, the FDA will say, Okay, stop, we can we cannot go on with a study a when there's such some so much benefit for a specific disease, you know, we have to stop the study and offer the people on placebo, Metformin, right. So it's very hard, it was very challenging to design a study where we have lots of events, and we want to have all causes of those of those major age related diseases. But we don't want to be significant in one of them, because we want to do the geroscience part. And then I'm skipping that, because because Jamie talked about it last week. And we're hoping that there was a delay, so we're hoping that then I will fund it. We'll find the bio marker, one later on. Okay, so this is this is part one. And part two, is I want to share the movie, I think that's what I did before I want to share the movie from Howard a. From Ron Howard's film, the age of aging, just that you all hear, okay, just you all hear what the FDA response was for the major work we've done. And the meeting that we had with them about a sorry, I didn't. I'm sorry, I need to stop this. Okay, and maybe close it. And now.

Speaker 1

12:31

Eli and his colleagues will try to convince the FDA to consider their study in advance of their critical meeting, and gather to prepare.

Nir

12:42

We are here representing the field of the science of aging. And we think that this is a historical day for us, because we're going to offer something that will be paradigm changing. I really want to frame the discussion today, as what would we need to show in a clinical trial that would allow the FDA to approve a new indication from it for me for delaying multiple morbidities related to aging, because we think Metformin is the first one. But there are others that could be better than Metformin. And we want to make sure that that's the template,

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