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

11:44AM Jul 23, 2021

Speakers:

Allison Duettmann

Aubrey

Nir

Keith

Karl

Keywords:

metformin

trial

aging

people

study

jamie

drug

fda

question

disease

biomarkers

diabetes

showed

effect

data

itp

cancer

clinical studies

target

change

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.

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.

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.

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.

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

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,

we have that hypothesis that Metformin is one of those rare opportunities where it might act in a general fashion. It's an attractive hypothesis, the trial is required to see if it's true. It started with a conceptual innovation, that aging can be modified, then years of work by a growing number of scientists and labs around the world and years of convincing people of their ideas. Maybe this is what a breakthrough looks like.

If the FDA accepts that aging can be treated, the scientists believe it will forever transform healthcare and medicine.

I don't think that there are too many interventions in history that would rival the type of intervention that we're talking about your insolence almost everyone.

As a matter of policy, the FDA does not allow cameras into official proceedings. But they did agree to an interview immediately following their meeting. We have lots of experience was claimed to decrease the rate of heart attacks to decrease the degree of dementia drugs that prevent strokes, drugs that treat your diabetes, we have lots of experience with all that. But what's being sought and being talked about is a more broad claim to prevent a lot of the consequences of aging. So the question for us is, how do you show that we gauged their willingness to accept the general approach of targeting a Something that they said right off the bat, we've never done anything like this before, and they were very receptive. Their hope is that wide variety of page related problems, you know, loss of muscle tone, dizziness, fall, dementia, loss of eyesight, all of those things, to do them all at once with a single treatment, that might make a convincing case that you're doing something beyond just treating the disease. that would that would be something never done before. They didn't have any problem with the general approach. And I asked him specifically at the end, this is what I think I'm hearing you don't have any problems, the general approach? And they basically said yes. So I don't think we could have had a better outcome. If you really are doing something to alter aging. The population of interest is everybody. It surely would be revolutionary. If they can bring it off.

There's no doubt about it. I always thought that the promised land is not in our reach. I think that we are going to the promised land. Okay, so from the horse's mouth. Okay. You heard that the FDA said Bring it on it or bring it off? Not sure. So, the last thing that I want to do is on beyond 10 will happen. You know, there's a long story around that. That is frustrating, but and we can talk about it later. But it's going to happen a bit. We're beyond it, we are trying to actually sell the concept that there shouldn't be only 10 trial, but they should be tamed many more time like trial and error. Oh, I need to Sorry, I need to get my I need to get my slides here going again. And and what I've been doing with colleagues, including a George kachelle if you know him is a great, geriatrician and Philippe who you all know, is trying to see which other drugs FDA approved drugs can be used immediately in a clinical trial, based on a geroscience guided approach. Can you see that? Can you see the slide?

I can't see you.

Oh, sorry. So um, I must not have shared it.

Perfect.

Okay, so, so geroscience Okay, and FDA approved. And we did a huge amount of work. And let me show you the final table. We identified all the FDA approved trials that also had at least one longevity testing. Okay, whether it was ITP or not ATP, you get more points for ITP. And we looked at all the preclinical data in animals and the lifespan data in animals, okay, to a to assess the hallmarks and have a gr a geroscience. Understanding that those drugs are doing something that are our geoscientific and, and then look at all the human data in order to rank them. Okay, if it was the next three studies, who who would you study? A lot of n for the for the human studies, we looked at health span, meaning we we looked at the effects of drugs beyond one disease, which were they're designed to, okay, did they have effect on other age related disease and also on mortality? Did they have effect on mortality? Did they have effect on mortality that is not related to this specific disease? Okay, so review, we reviewed tons of papers and as you see, and you might be surprised, number one, okay, is stlt two inhibitor. That's the number one drug that has a giant geroscience identity identified. It's a glucose transporter inhibitor that is a really for the treatment of diabetes, but there's tons of literature that it prevents almost any age related disease and it gets more points than Metformin because Metformin in the ITP you know, Metformin head to head in the ITP didn't work although it was additive to rapamycin it was a it increased lifespan. mailed by 10%, but not in one center. So it wasn't significant. So we didn't give the ITP a point to a Metformin. So but but because of this NGlt tube, went over that, and you'll see that you see that the other drugs are rapamycin, ocra acarbose, an ACE inhibitor, the center latex one, we just don't have enough data to that, you know, many of those, we don't have enough data. But without enough data, it's hard to make a convincing a argument. But the idea is, we have to come from neuroscience, look at the clinical thing and see what we can repurpose fast, I just want to show you that this is the ITP result of the of a cannot lift zone, which is one of those drugs that increase a lifespan more significantly males than in females. And this is some of the clinical data were compared to placebo it a decreased here a death from cardiovascular or hospitalization, cause from a renal causes, and from death from any, any cause of mortality. And every class of this drug has basically shown the same thing infecting New England Journal of Medicine at the same issue, there are three studies by three different companies basically showing the same thing. So if you didn't know about this drug, then I'm introducing you to these drugs. And, and, and and telling you that we have we have to use all those data and think how creatively to show that there are several drugs like that. And we should have several team like studies so that we have, so we were belt and suspenders and make sure that we are there in time for the biotechs to start targeting aging better. So a, so I'm stopping here for questions. And I just wonder, and Alison, I don't know if you can help me.

I will get you with questions. I just want to remind you, I think that at the beginning of it. First of all, at the beginning of it, I think you were mentioning that you may want to call on Jamie or on Ronald, if they're here. I don't know if there was a particular item that we should get out of the way for or you would just want to take questions.

If it Jamie, what is the one thing that I didn't mention that you think is important? Oh, I see. Can you? Yeah, can you?

Can you all hear me? Yeah. Can you can hear me now? Okay, great. Sorry, everybody. I'm in the lab today. So I've got more mask near I think already mentioned a lot of really important things, there were a couple of questions just about, you know, sort of composition of an endpoint individual versus looking at some kind of a composite. And I think in general, one of the important points is, you know that, of course, individual diseases will be tracked and you know, will be announced, but when we're looking at an FDA indication is that the composite outcome is really important is that what we know and think about of aging is this larger kind of phenotype that can't be defined as any one disease or any one marker. And so I think for a typical first trial, like chain is looking sort of larger and collective so that we can begin to define what this should be in the future is incredibly important. And sort of make that data available for a larger community to use and develop. terrific, terrific. Thank you for joining me and, Jamie. If there's specific questions, I'm here as well.

Yeah, if there's any other question that you can answer it, don't be shy. Allison. I'm seeing a lot of those questions. And I'll tell you, we, we decided to use 1500 milligrams for a team study. Basically, you know, the argument was like, you know, it's for aging, maybe we should use more and then the argument that are you kidding, those are elderly people, you should lose less. Okay. And and we don't know, there was no dose response. So we don't know. And what we decided is to use the dose that was used by most of the clinical studies. And and that's what led us to this decision.

Okay, that makes sense. I have a variety of questions here. And if I go via upload first then cow would be first with this question. Then I think Mark net the first one and then always, I think it was uploaded by a call. So cow Martin Obie

says always near. So I want to my questions about sort of looking beyond team. If it fails, and we go, I'll get disappointed. What are the prospects for, you know, down the pike the next better candidate treatment and getting it, you know, getting another trial going on that? And can we even get, you know, a second team style trial going before the full team trial has finished? And in some ways, obvious question is somewhat related.

Yeah, look, for me, personally, and I'm saying personally, because I'm an optimist, okay. My, you know, the guys are saying, you know, we have a six year trial. And I think like, I felt in the DPP, that four years will be enough. I don't have any expectation, the team that this is not going to work, okay. But I'm also just presented the fact that if we had enough money, we should do more than attain a study, we should do some other drugs and maybe another time all over the world, because we cannot fail. We cannot fail. In this study. That's part of the reason why we chose Metformin, we cannot fail in this study. So I don't know what to tell you look for me, there. You know, there's this story of the two frogs that fell into a bucket of milk. And one of them was trying to figure out what's going on and drowned. And the other one starts rushing around and moving its arms and everything like that. And in the morning, the farmer came and saw a very tired frog sitting on a bucket of butter. Okay, I'm there. Okay. I'm very tired sitting on the on the on the bucket of butter. The Dame should have been happened long ago. But I don't think it's going to a to fail. So I cannot bring myself to tell you what if, what if is that we need something to succeed. It's like unity, failing with the one of this analytics, well doesn't mean the senescent is not a target, it means that we need better drug better approach better indication. Right.

Okay, so then the optimistic version is, are you going to work during these six years on starting a new team with a different treatment in parallel with shepherding this one through?

Will a I'm trying a I'm trying to convince the new large foundations that are coming in to do several efforts. And I think that will modulate the risk. In particular particular, I think we'll get a lot of biomarkers from time, but some of the biomarkers might be emit forming specific. So even for this reason, we need some other a biomarkers.

Look satisfied? Okay, great. Martin, what's your question?

Um,

just a naive question. Following up on near, you know, you have all this data that there are positive effects, which is great, because then we can, you know, do stuff that we know will work and then make aging an indication as to me also haven't messaged me, are people following up, you know, the unenlightened who just care about answer and just care about different diseases? are they following up on this? data, human data for Metformin? And you know, if so, how? And can you include, you know, can you use that to support the same trial? And if not, you have any idea? Why not? Yeah,

well, the simple answer is no, look, we are doing the clinical trial we have to show we have to show that it works in a clinical trial. And I'm not selling Metformin to anyone because it will kind of ruin the trial. What happened when Wall Street Journal first talked about this trial. I got in the next week 3000 calls email from people who wanted to volunteer to this study, okay, Wall Street Journal. And I thought we're done recruiting for this study. And then I realize that a we you know, we didn't leave our name there or email so it's readers of Wall Street Journal, okay. So they have means they can get to us they know how to reach us. And, and, and they're not interested in the trial. They are interested in being in Bay on being on with forming anything. fact, they, they there are several emails that said, I'm broke. I'm ready to volunteer for the trial as long as I'm not in the placebo, right? So I have to distance myself from people who are saying why don't we take Metformin? Not because I don't believe that, but because I don't I want to have enough enough people out there in 14 different centers that can be recruited, not totally believing that I'm right. But it's worth testing, right?

Yeah, I didn't mean, sort of like just random people taking my format. I meant, are there any sort of like a colleges to see, oh, Metformin has an effect on cancer, let's start a trial for Metformin just for cancer.

Yes, there there are people who are doing it. NIH has multiple grants on Metformin, that are interesting, because they are not only on prevention, in fact, that's the hardest thing to do, not only on prevention of cancer, but of treatment in cancer. I noticed in the last few weeks, I got emails from people with cancers who are doing intermittent fasting and Metformin, before chemotherapy, and things like that in order to kind of upregulate the aging part and, and, and, and fighting the cancer better. Also for metastasis of case. So there are studies like that. But remember, we're talking about Metformin, not for not for the treatment of diabetes are not for the treatment of cancer, but for the prevention of variety of age related diseases.

I think Jamie wants to chime in or has your appointment. Okay, great.

Can you hear? Yeah. Oh, yeah, I was just gonna say near answered that is that that's correct. There are multiple studies going on right now multiple Institute's within NIH are really interested in this study. And the FDA is certainly interested in Metformin for individual diseases. came as as near said is in no way designed to test Metformin effect and individual diseases. That's simply not the purpose of the trial, though it will be trapped.

Okay, lovely. Okay, next one, we have obey.

Hey, um, so thanks. Um, so yeah, my question is a bit similar to Carl's. But that's a little more focused. So I am interested, I get asked about the time trial all the time, of course. And I want to really know whether I'm telling the truth or how close to the truth. What I'm saying is, when I talk about the impact of the time trial, on other trials, crime just just even before it begins, because what I like to try to argue is that now that the FDA has approved for the for the time trial to be conducted, that any big pharma company who has a drug that they had one patent, and they actually feel that it has broad ranging Azure AD rate effects. They can more or less just copy and paste the clinical endpoint that you guys negotiated with the FDA. And they're going to basically get their trial approved to be conducted as well. Now, I'm sure that that's another simplification, but I don't know how bad and oversimplification it is. So if you could speak to that,

I, you know, it's fine. For me, one of the missions of of team was to have a template so that every pharmaceutical has kind of an idea of what is the design of a study to show you that. So with the FDA, we never mentioned the word Metformin, believe me Metformin? Yeah, it's in their web, that there were two questions. One is, what what do we call it? You know, what, what, what, what is it? What, what? Because we said, we're going to target aging. They said, No, we the agent is not a disease. I said, so what is it? He said, they said, Okay, we're going to change a composite, we're going to move a composite of age related disease, that's what we're going to call it and it's fine for me, they can call it whatever they want, it's still going to be aging. The second part was to ask them, Look, this is the study that we want to do. We don't want to get to the end of the study. And you'll say, No, you should have done something else. Right. So so we got a we got the feedback on that. It's interesting. They didn't want diabetes to have to be an endpoint which shocked me because under diabetologist, okay, their claim is diabetes is a chemical indication. And the complications happened in 40% of the people 10 years later, it's not as convincing as having a heart disease or Alzheimer or stroke or cancer. Okay. It's just interesting how the FDA thinks. So I think the template is really very important. And as far as I concern, they should do it. In fact, what I'm busy doing, I'm trying stlt two trials have ended recently. I want to get their hands on their plasma and DNA of those people and and look at their biomarkers. You know, we have one of the things of showing you those other drugs, if we can get to the people who did the clinical studies, and believe me, they store a lot of stuff. If we can get back and do it biomarker will be in biomarkers ahead of the time. And immediately.

So I had a second question, but Jamie's just answered it in the chat. So maybe Jamie could like, just read it out.

Sir. So Aubrey had had a question about inclusion criteria that we had a gate speed that was ahead of hard, lower and upper limits for inclusion in the trial, and yet, we just listed there that was a history of other disease classes that would be considered later. And all of our event rate projections, I want to emphasize this, and I can't emphasize it enough. Those are really based on gates, the projections out of the different trials and studies that we use, is that gates B criteria really was what was setting those projections, and that we actually ended up including history of those various diseases, primarily for ease of recruitment is that it eases some of the burden for entry and getting people in. And it had a lot less to do with whether or not they were going to experience an incident new disease. And we did not include gradations of those diseases for entry, primarily, because of the burden that that would put on the recruitment centers is that suddenly, if you're not just doing history, yes, no, you have to do a lot of tests. And that costs money and time to do that, in order to sort of date people in and out based on those really flexible criteria, where gates beats pretty simple, cost effective, easy to do.

Right, Jamie? And thanks in Aubrey, you So Andrew Scott, a paper right on, on the lunch, longevity dividend. And actually, Ellison, I think this would be a great a great hour with Andrew stop.

And I think in a few weeks,

okay, terrific. So we gave him all the time calculations. And he did in this study that showed that, you know, we're going to save 30% of the world GDP if we do team, if we if we we extend health spending 2.6 years or something like that really quite incredible. Because by the way, it's not about health care. For him, it's about Okay, you increase the you know, people are going to be healthier for 2.6 years more. So they're going to travel, they're going to have fun, they're going to contribute to the economy, it's going to be really great. So he did, he did a one about a Metformin. And we calculated that for every of every of our non placebo or mid forming user aware everybody of the 1500. And we save $80,000 in cost for the government, okay, over, let's say six years trials. So that means that the tank trial itself is going to save over $120 million. And it's cost only 50 million. So it's a pretty good even just the tape study is going to have millionaires effect.

Yeah, totally, and always reminds me of an early time that we gave and a father event, I think, four years ago or something when he was saying, Well, once I think, you know, we tip and and people will believe that they will live longer than I think you have a snowball effect of of the changes that they're making of the expectation of their increased longevity, even furthering almost a self fulfilling prophecy.

It's the interest on the interest, right? It gets to be really big, you know?

Well, hopefully. Okay, I think we had a few questions specifically about and fine. But maybe before we get there, because we're still in the trials. Carl, you want to ask your question, and then maybe spring and then we move into John's question. So

can we use team, regardless of outcome, post hoc to establish a new surrogate endpoint. biomarkers stand in for the team multimorbidity by having bank samples, and basically even if somebody comes up with a new test after the seven years are completely over, do we have enough data and biological samples to be able to basically go to the FDA and say, Look, this biomarker predicts the same multimorbidity the team used, we don't need to run a new seven year trial to establish that surrogate endpoint.

Exactly. And I think that was actually I think, Jamie, let me introduce you. I would, I would say I was just open with one thing. Part Part of our challenge, Jamie's challenging in writing the NIH biomarker protocol is we had to tell them, if tame fails, there's still a lot of data that can help us, Jamie go on.

Yeah, that's essentially it is that that's one of the kind of the remarkable things about working on this is that we've been writing and trying to develop it as a no fail trial is that no matter what happened was the primary outcome we built in multiple safeguards and ways that these can be analyzed and used by the scientific community and those sorts of environmental development. So we're going to gain so much out of just making and building the infrastructure. And sort of, you know, the scaffolding for the framework of what this will be, is that it really is sort of a remarkable opportunity. And absolutely, that's part of what we're hoping to do is to build an enough sample collection of assets and tried to get enough other people engaged in the trial, that we can actually make sure that this is a failed proof endeavor. And we really are working on this. I've actually built out tables of if primary outcome fails, we'll get and I've been keeping track of all of these, and it's actually, it's becoming really apparent that there's no matter what happened is that this is going to be a really useful experience, not just for those running the trial, but for the rest of this community.

Lovely. Okay. Thank you. You're doing you had a quick question. I think that was piggybacking off of something that you said earlier.

Yeah. Hi. Hi, there. My question is, what kind of budget are we looking at? and related question to that? is, why are we focusing on the US? Why can't it be done an international? Why can't it be a multicenter international trial so that we can try to drive down the cost?

Em, so So look, it's again, a, we're looking at the target, okay. And the target is the FDA. Okay. And, and that's how we do everything. There are other people, there are other groups from all over the world that wanted to be a center in the tank, they're actually maybe three centers in Australia that can be tamed. But they're not going to be considered by the FDA. Because because they are is you know, phobic, you know, I don't because that's not how you do the trial. Okay, so we had to convince them that we have centers that our experience in, you know, in medicine in geriatric medicine, that we can follow the protocols, one of the challenges imagine we would be with any Australian center or Singapore center, we could never meet at a certain time, because they're exactly the other side of the world. And changing data, extend extend, you know, getting DNA to do clocks, right, is not simple from place to place. So it wasn't, you know, it was about how can we do this study and satisfy the FDA and not have it too complex, and the FDA is not going to believe anyone else, you know, if we did it, so it wasn't an option. As far as far as the prices are, our initial grant was 480 million dollars, over six years, which is really, it's, you know, it would be it would be much, much more expensive. It's a billion dollar to do a trial with a new drug for aging. Okay, so it's really a cheap, a cheap, cheap trial. But in the version that we have now, that is going to be paid, probably by a foundation, we have a budget of about $15 million. Because what we did, we took out the secondary endpoints that Jamie talked about last time. Because Because we tried, we tried to make it cheaper, and we tried to make it focus on the FDA. We're still hoping to get the NIH to do the biomarkers. And we still hope to have the secondary endpoint, this study spower such that it's true that we want to see before and after what happens in individual, but the groups are large enough. So at the end of the study, we can figure out lots of other things that are happening without doing longitudinal studies. So we have enough power no matter what and we're trying to be cost effective so that people will bite into this ID. Is that okay? judge?

Yes. Thank you. Yeah, just want to add, I'm sorry, just one additional point. What is the major stumbling block right now? Is it the money Or is it the approval?

Well, first of all, and I meant to say to Aubrey, Aubrey, the FDA doesn't have to approve any study. Okay? They don't approve time. Okay. FDA, we you consult with FDA, you can do whatever study they want a, at the end, they're going to discuss the result of this study. So it's it's not exactly it's not zero. So there's no rate limiting here. We're done with FDA, that rate limiting was the funding. And on top of that, and the funding could have been before on top of that. It's COVID. And even now, even if we had the money today, I'm not sure when will be the right time to start, Jamie, you're saying no.

Yeah, we could not start it right now.

Started right now. it no matter what, so so that was somewhat of the luck. Not to evertime study in the middle of COVID. It would have? And by the way, who knows? Because there is another paper 10th paper now from China that shows that mortality for people on Metformin was 50%. If they have COVID of others, a that's one of the worst because they're there to a reduction in 66%. Also, but, but so COVID, you know, maybe it would be interesting, but COVID would have been really, we would have to stop a lot of the things and a lot of the services.

Thank you. Thank you, Jamie. I want to make actually one really quick point just about international trials and the opportunity for for a team to spread globally, nears absolutely right, that the trial itself needs to be contained, for all the reasons that he mentioned. But I just I would feel bad if I didn't mention that we really are encouraging for other folks who are interested in running either parallel trials that would not be really included with teams, that could be coupled, whether they're run in different countries, we've had some inquiries around that, or in specialty sub populations, there's been some interest of folks perhaps like with HIV and aging or other groups, that they're not necessarily going to be included within the team trial or won't be recruiting enough is that we absolutely are encouraging that once Tim gets going please reach out to us if you're in an either a different a different country, other folks that we're working with specialty sub populations that you might be interested in maybe running a parallel or a sister study that could be linked.

Right, I think people are cancer survivors, it can have a time trial. I think HIV people can be a time trial. Disabled people can be a time trial, maybe poor people who cannot afford good food and a good quality food or, or to exercise or regime, you know, maybe maybe Metformin for them, they're dying, actually the the highest rate in the United States. So I totally agree. There's a need for many people for image forming trial.

Okay, thank you. And we are now I think settling in with john forbus question on Metformin that got uploaded earlier.

I near and Jamie, can you hear me? Okay. Hi, john. Hi. I frequently hear from exercise enthusiasts that Metformin will either interfere with the benefits of exercise in general, or muscle building from resistance exercise. And I wanted to get the knowledge from from the experts. Is this true? And if it is, would it make a difference if I exercised in the morning and took Metformin later in the day?

Well, thanks for the question. I shouldn't I should have I should have done this. I guess I didn't anticipate that. But so I think I published recently in aging, the definitive trial. So just to recap, in, in, in clinical trial, where elderly were exercised, within without Metformin, Metformin prevented, the muscle mass went up in all the studies but significant less with Metformin. Okay. By the way, if you read the studies, they're showing you MRI data in muscle and this and that. But in supplement for in the study, they actually show that the force didn't change, okay, the function of the muscle didn't change. So if they have less muscle, and the function of the muscle didn't change, it means for that for gram muscle, okay, the muscle was better. Okay. So I looked at it I took the muscle from those two Miles because they had muscle biopsies. And we did a transcriptome. And we basically saw the following thing, that all the work to get hypertrophy, you have to activate mTOR. And remember when you activate mTOR, it's not good for aging, okay, so the muscle growth was associated with mTOR, which meant Metformin blunted because that's part of what Metformin does. On the other hand, people on Metformin had transcript that was a protective transcript for aging with genes for autophagy against inflammation, some, some some other things. So there was a trade off. And for me, and by the way, I'm exercising and I'm on Metformin, for me, it's not important to bouche my muscle, okay. For me, it's more about aging. So if you want to show muscles don't take much for me, I don't think Metformin protects your muscle from the aging effects. And so if I were you, I would say do it together. And the question of timing, it depends, look, I'm on extended release. So. So it's not that I have an effect. And I'm also exercising sometimes in the morning, sometimes in the evening. I'm just, I'm just happy with what I proved myself and published. So

thank you. Thank you. Next one up, we have aspirin.

Yeah, thanks. Um, I was wondering if you can speak to the age range that that was selected in the trial, which of course, makes sense that you selected older individuals 65 to 80. But I wonder specifically, if in the prior trials, particularly that you mentioned with Metformin if if the population had been segmented by age, and if we expect to see kind of similar benefits on health span, if we're thinking about it in that way?

That's terrific. That's a terrific question. And, and Jamie, I'll do some provocations. And you you follow, follow that. So the the major reason we went to this age, based on the fact that, you know, the geroscience hypothesis, still applying it in elderly is that we need to find an age where there are enough events in the five years, six years, okay? If you get if you start with 50 years old, or 40 years old, you can wait 20 years until you have all those events that you're monitoring, right. So we needed a lot of events, and we have a lot of events between 65 and 80, where elderly are starting to accumulate them. Okay. So that's, that's the main reason why, why we're saying it's going to work there. Because, for example, in the DPP, the 20 20% of the DPP, the diabetes prevention trial was paid by the National Institute of age in order to include 20% of the people over the age of 65. By the way, they failed there 20% over the age of 60. But still, we have, and they didn't have different results than others. So so we have from this study and other studies, and clear examples, that Metformin effect is not blunted. with aging. We also did a studies. And we published them in last years where we took elderly people and gave them at forming and deep biopsies to see what transcripts change with Metformin. But by the way, the exercise was in 75 year old, and we have data on 75 year old and there's a market change in Metformin on the biology of aging. So we think it's it's relevant, Jamie?

No, I have very little to add near describe that beautifully. And, you know, there were some discussions along the way about possibly having different age ranges for men versus women, whether that would affect event accumulation. And, you know, we eventually decided that it wasn't worth the challenge of recruitment to do that. And so we, you know, ended up keeping it simple, but certainly, you know, looking at different age ranges when we've talked to other groups who are interested in again, those really special sub populations, like HIV and aging or others, that that could potentially be, you know, worth consideration is revisiting for special sub populations, if there's going to be a change in age range, but that doesn't apply to the time trial. The time trial is for simplicity and to move forward. Is that that really was based on you know, feasibility, and you know, something that would be fairly easy to define, and going for FDA indication on the back end as well. Thanks.

Okay. Well, we have two minutes. Nia, do you remember broadly the challenge that you submitted and to me before the call when I asked you to submit a health extension Oh,

I gave you I gave you a lot of them. Do you want to show that?

phase one, phase two and phase? I shared it already. And I shared the link to the document in the chat, but I'll share it again in the chat. I thought if you could remember to be nice ever spoken out, but I think otherwise people can can read on it as well.

Yeah, yeah, people can read it just the tie a I ended. At the end, I think that the differences between aging of men and women is incredible. It's actually it's male and female mice. It also a is incredible. And I think we have to have a better handle of that, because certainly, it can apply to general therapeutics, I would say that we have no evidence that Metformin or GLP, two inhibitors have a specific role in male and female. But I would also say that sometimes you adjust for male you adjust for female, and he doesn't change much. But that's not as much as to do the initial, you know, the initial assessment in male and female and see the differences. So I didn't want to forget that. But I think it's probably not relevant for a format for me. And then I was just talking about doing time doing a mortain like study and making more significant advance in the targeting aging and increasing health span.

Lovely. Do you have time for one more question? We have more more in the chat. Okay, lovely. Thanks, Keith.

Sure, again, here. This is a follow up of a previous question. But you have mentioned here that, you know, certain, you know, endpoints and data collection was pared down on this to keep things simple for the FDA or, you know, keep the budget streamlined. And that this is mitigated by having enough statistical power to do analysis after the trial. That being said, certain kinds of physiological longitudinal data, like the six minute walk tests are essentially kind of free and easy to collect using like Apple's healthkit. It doesn't just collect pedometer data does like the six minute walk test and everything. Can those sort of things be added without, you know, disrupting the budget or anything easily? Or is that still too difficult to add in to the team protocol?

JAMIE?

Yeah, oh, I would love to add functional measures back end, I would love to see it back included. And we're really, you know, as soon as we get launched reach out to us, I mean, this is the way that we've structured Our team is so that we can try to include as much as we feasibly can, and try to work out plans to you know, for for trying to expand is that we have sort of a minimal team that's going to get launched and started. But you know, we welcome your ideas and opportunities, and especially for function, I would love to see that going back. And if there's any way that we could afford it, or re are included again,

yeah, one point of context here is when I've talked to people, you know, in the NIH, etc, I feel like there's a disconnect there where I don't think they understand how easy and cheap it really is to collect. I think they're thinking that maybe these things are just pedometer photometers. And you'd still have to, like have a doctor walk them through like, no, the whole six minute walk test is like prefabbed in here. You know, maybe, you know, any conversations to be had there. Like let me know if there's anything I can do to talk to someone to convince them that this is like way easier than they think I cheaper.

Just remember that. We have centers all over the United States. And generally, the people that will be in the studies are less informed. I don't think that many of those people will come because they heard something on Metformin, they'll will advertise that there is a drug that might have the health benefits because we also don't want them to lose the plus right, the placebo effect. And and those people also don't have a access or knowledge or use the technology. So they're so we need to do some of it ourselves no matter what. Probably but, but I agree with Jamie, if we could put back the other $20 million. We're talking about, you know, 2 million, 3 million Moore's eight more a year, it'll be good to have the longitudinal one.

Okay, lovely. Am I just asked for any other questions, but I think we're good. And we're finishing broadly on time. And I wanted to just really take the time, Jamie, you're in the lab and you're here as aggressions. Thank you so so so much really, really appreciated. Near it's always been a pleasure. I won't. I won't sugarcoat it evermore,

Jamie, it's always nice to be the warming act for you. I'm sorry, I ended up glomming onto your son. Oh, no, no, I see. I asked you You're, you're in everything you're doing better job than me. So thank you so much, Jamie. By the way, Jamie is I think Jamie is going to be as we all are doing the next thing Jamie is going to be, I think the one who knows tame and and and be the leader of Team A, I'm actually stepping to be because a far is basically supervising. So I'm going to be the a far a principal investigator and team but in the field people are going to be a Jamie and her in her group.