TAME & Biomarker Q&A with Nir Barzilai Institute for Aging Research

2:20PM Nov 26, 2020

Speakers:

Keywords:

aging

metformin

people

question

study

disease

fda

centenarians

proteins

drug

igf

biomarkers

trial

diabetes

effect

prevent

biotech

chances

targets

hallmarks

All right, well, it's really good to see so many. And I'm expecting a lot more folks to join via the waiting room, and I'll be accepting them. I think as we speak, I think we have a really quite fantastic and special and special session ahead of us today, not only because it's almost Thanksgiving, but also because I think near your presentation was much, much, much expected. How many people here in the group? Thank you so much for making time for joining us, I will try to keep my comments brief questions that I'll be asking you up front. And then I'm hoping that people can collect the questions in the chat.

So thank you for being such a good leader for us. And it's really good, you know, I really appreciate that somebody, and that's so much younger than me is starting to tell me where to go and what to do. I think it's very much needed. Thanks, thanksgiving for that.

Very nice. I'm very humbled. And, and, and, and I, I mean, I'm very much looking forward to you telling us a little bit of where this group may, may go outward, which makes sense. So I'm still accepting a few more folks into the conversation. But I think it would be really lovely to first. Okay, first of all, at the end of the session, I'm going to share with you what I'm hoping to be the program outline for next year. So there's an additional practice stay on even though I don't think that we have problems with people staying on for the session. But that's just an additional point. And then I'll be introducing next week's guest as well. But I think first and foremost, we will just have a q&a with Neil. And I will post the longer BIOS near here in the chat, but to keep it kind of very short and sweet. And near as a professor in the Department of endocrinology, medicine, and the Department of genetics at the Albert Einstein College of Medicine. He's also the Ingeborg and Leon Renner Chair of aging research at that very college. And he's the founding director of the Institute of aging research at that very college, and the director of the Nathan choc Center for Excellence in the basic biology of aging, which is funded by the National Institutes of Health. He's currently leading. And I think that's of interest to many people here in this group, the time trial, which is really a multicenter multicenter study to prove the concept, that multi, multi morbidities of aging can be delayed in humans, and have the very ambitious goal of changing the FDA indications to allow for next generation interventions. So yeah, I'm terribly excited that you're joining us today. I'm going to post your longer bio here in the chat. And feel free to already Ask, ask questions away that I'll be then collecting in the chat. And but for now, I think maybe we could just start with a very simple question, which is, can you tell us a little bit more about a team to bring people up to speed just in case they don't know what it is? And what made your phone table salt?

And, okay, let me let me share some slides from time to time just to make a point. And so I want to, I want to first make sure that we're all understanding the challenge. And the challenge is that for every other disease, we do it biological discoveries and, and there are biotech or pharmaceuticals that are trying to develop medicine. And then there are drugs to treat the disease. And by the way, it happens that those bio biotech or those pharmaceuticals are like they want better drugs, other pathway. So they feed back into the biological discoveries, and that's how we have a symbiotic relationship in that where we got stuck is the fact that regulatory bodies around the world certainly the FDA here doesn't recognize aging as something that you can target. And now if the FDA doesn't doesn't recognize a preventable condition, their health care providers don't really need to pay their clients it because you know, they'll say this is this is not a disease, the FDA doesn't recognize it, why would we give them money. And secondly, if that's happened, the pharmaceuticals are not going to jump on and get get those resources from the biotechs and develop better drugs, combination of drugs and other things. In order to accelerate how we treat we treat aging. So this is really how it this is really what happened. That led To design team, how, how do we design a study? And that if it's successful, the FDA will recognize that aging is something that you can be targeted. And just, that's another discussion. But one of the things we found and we went to the Senate and to the Congress, because we thought maybe we have to change the law, because the FDA has diseases that he targets Do we need to call aging a disease? And we found out that we don't know we don't need to call aging a disease. Okay. And I'll tell you what I mean, a later. And so, Ellison there, the question for me, let me stop sharing the question for me is, and we went to the FDA, and we sat with them, and it was documented. It was documented in her Ron Howard film, the age of aging, if you didn't see, it's the best movie about aging. Okay, and I think it'll take a year to get the producer like Ron Howard to do it again. But, Ellison, if you permit me, I'll give it three minutes or four minute clip of us going to the FDA, and they interview with Bob temple, who said Bring it off. Okay. Is it okay?

Please go ahead. I'd

love to see it. Okay, if it's because I think I think people are saying, you know, the FDA doesn't approve does not approve. Let me just show it on record here. Because we think that forming is the first one. But can you see better than Miss forming. 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 insolence almost.

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 with claims to decrease the rate of heart attacks to decrease the 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 gauge their willingness to accept the general approach of targeting aging, 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

a wide variety of age related problems, loss of muscle tone, dizziness, fall, dementia, loss of eyesight, all of those things, to do the old ones with a single treatment, that might make a convincing case that you're doing something beyond just treating the seas. That would be something never done before. They didn't

have any problem with the general approach. And I asked them specifically at the end, this is what I think I'm here and you don't have any problems, the general approach, and it basically said yes, so I don't think we're gonna have a better outcome. If you

really are doing something to alter paging, the population of interest does everybody surely be revolutionary? If they can bring it off? There's no doubt about

it. I've always thought that the promised land is not at all rich. I think that we are going to the promised land, the study will happen. The fact that FDA is going to be part of it is really a major achievement, and eventually will be the temporary effect has been in the next decade.

antastic Would you mind sharing a link to this because I like the video is quite long. So I'm sure that folks would love to watch the whole thing.

This is not The link, it's part of the video, it's in National Geographic, and I wasn't allowed to do any so far, maybe I should try again. So you can go and see it on National Geographic, maybe pay $2 and 39 cents, but you can see it, but I don't have the link,

I think we will, we will must have the cost. To watch that video,

I might, I'd like to just chime in here and say that that short little video actually did something that I've never seen done before, which you didn't capsulated FTA openness to an anti aging therapeutic with an actual FDA official on camera, which speaks to the doubt that a lot of people in, you know, surrounding us and maybe even within our group have had as to whether they're really open or not. So I think that short video is actually quite potent. If you could extract it. I don't know if you can do it legally. But if you could extract it from the National Geographic piece and share it, it's a powerful tool. Well, I did. And that's why I really suggested to Allison, that she should ask me to show that, you know, and I would I would suggest that if anybody can get a short clip of this is Alison, actually. So maybe maybe I'll ask you to help me. But But thank you very much. And that was the point. I think I can stop now. Because I really wanted you to know, we had this meeting with FDA, it was prepared, there were 24 people of all branches. And there's also an exchange of letters and follow ups in on that. So it is a process. And the idea was accepted as a while bring it off, right? Yes, Allison.

Thank you. Yeah, I'm just I'm just researching the link that was shared in the chat to see if that may actually be already a shorter version of that. And maybe maybe someone has already done the work. Just know. But I think you know, and I think too. Well, I mean, there's a host of different questions, and I'm already Yeah, definitely encouraging people in the chat to ask more. But I think, you know, for maybe to bring people just a little bit more on board, I would perhaps love for you to talk a little bit more about which kind of exact home or hallmarks of aging, and Metformin is targeting that you're addressing with team.

Okay, so let me let me share one slide then, that really addresses it very specifically, it's a paper that we published a year ago in a in cell metabolism. And what you see here below is all the hallmarks of aging, right? And the question for us, which of the hallmarks of aging Metformin targets, okay, and I'm not going to do a big tour of the biology I'm going to do a brisk tour of the biology but Metformin goes through an octa one, its own transporter binds to complex one of the mitochondria and on the left side, does a lot of metabolic thing like a MP kinase, activation and mTOR inhibition and changes insulin action on the receptor and in vivo. And at the end, there are papers that suggest that those five hallmarks of aging are being targeted by Metformin. But then there's other side of Metformin because when you decrease the complex one in the mitochondria, you decrease a reactive oxygen species, you decrease DNA damage. By the way, not all of the effects of Metformin are necessarily through complex one. And not all of them are through MP kinase. And there are other effects of Metformin that are related to cell ocers, seller, seller, cellular senescence, stem cell and inflammation. And all of a sudden, you see that Metformin affects all all the hallmarks of aging. Is it really so? No, I don't think so. You know, I don't think so. And I think it's a phenomenon that we have to all realize, it happens with rapamycin, it happens with a sirtuin genes. When you take the cell and you fix the aging, then you fix a lot of things, okay? And those hallmarks are not the mechanisms of aging, there are things that happen with aging, you fix them. And so, so we start getting into arguments, you know, he does this, he does that. Well, I don't know what he does first. You know, I think that, that that binding to complex one of the mitochondria is probably important. But the fact that I see that it affects the hallmarks and the hallmarks are interconnected with each other. It's just very reassuring that you Doing something that is relevant to aging.

Alright, thank you so much. And would you just perhaps maybe be able to give a little bit of background on to whether Metformin really is a Gera therapeutics from a clinical perspective on that?

Okay, so, okay, so from a clinical perspective, bold declaration, okay, and it's all written it, there's actually another paper in cell metabolism that has everything that I told you in more details, and it's part of our grants. And I can give you any data you want. I have, I have the slides for the FDA that we prepared, but they are clinical studies, okay, clinical studies mean placebo control or drug control studies and their association studies. Okay. So, the fact that Metformin prevents diabetes is a clinical study, it was called a diabetes prevention trial. Okay, you give a Metformin to people, it decreases diabetes by 30%. Another clinical study is the ukpds. It's not the only one, there are several studies where Metformin was given. And compared to other anti diabetic therapy, and it's only Metformin that delayed cardiovascular disease in the diabetic population in their association studies, but their association studies are pretty impressive. They're 200 studies or more, showing that people on Metformin have less cancers, all kinds of karke cancers, the cancer that is kind of questionable is cancer, actually, but all other cancers are affected with Metformin with Metformin really x. And to prevent the aging part of why cancer shows up with aging. There is an association study with Alzheimer's. And Alzheimer's is the only thing where there's association studies that shows that eat increase Alzheimer, but those are really, really bad studies. And what's common to them, they're all from China. And, and so it raises the possibility that maybe there's a race difference in the effect of Metformin. But it's more likely that, you know, if people on Metformin live longer, there's more chances at the end of their life to catch up other things. It's really complicated to do it if you don't do this studies, right. On the other hand, there are two clinical studies to suggest that Metformin m, prevents m MCI, declining MCI, oh, they're going from MCI to Alzheimer's. So the clinical studies are really better. And I think they're the best study. Really, the best study that came in the in the in the best time is just a minute, I cannot. For some reason, I cannot go now. Just a second. Just a second, I'm stuck here. Still, so Oh, here,

it worked.

Yeah, this study, this study from the UK went here at time, zero into pharmacies across the UK, and looked at people with diabetes. And without diabetes. Actually, it looked at people with diabetes that got either Metformin or sulfonylurea, which is another drug and match them to people without diabetes, but they were treated in the same pharmacy by the same doctors, you know, a lot of commonality there. And, and what and by the way, there are 180,000 people in this study, but what they looked at is survival. Okay, so in five years, more than 25% of the people with diabetes have died, which is kind of what expected in the age age range that they were looking on. And this is control in control. It's only 10% in in red. But the people on with Metformin had actually less mortality and it was significantly less mortality, it is 18% less mortality. Now, the people with diabetes also had, first of all, they had diabetes and the control didn't have diabetes. Okay, so they already had one major age related disease, but they're also more sick to begin with, with more than two diseases on average. And also they were mortal. geese, and yet they lived longer. So when you look at everything I said, with a cardiovascular diabetes, a cancer mortality, you see that there's a cluster of things that was proven in humans. And that was the base of what we were going to do.

ugly. Thank you. And is there a particular relevance to COVID?

And, yes, there are eight studies around the world. And this is an effort to look at five of them. But there are eight studies, China, Korea, Spain, Italy, United States, that showed that people on Metformin had less hospitalization, and had less mortality than people without Metformin. So there's a clear signal that comes out with with people like that, I'm just concluded this study at Einstein we had in the Bronx, we had a huge COVID strike, our first strike was amazing. And people with diabetes head to fold more chances of dying. And people on insulin had two and a half more chances of dying people on sulfonylurea head and almost to fall chances of dying. But people with Metformin had no increase chances of dying compared to people, other people without diabetes. So we haven't published that yet, but but I see that more papers will come. There's definitely anyone who analyzed Metformin, see the detail the protective effect?

Hey, by the way, isn't this just go back for one sec, if you don't mind near to that slide. It this unlike so many slides like this, that I've seen, this has a logarithmic scale on the bottom axis. So those are really big differences, aren't they?

Well, that's how when when you do those risk ratios, you usually do the scale? a, it's a it's a, it's like that it's a logarithmic scale. So, you know, one is no chance. And, and here, it's I think, in this it's 35% decrease. For for about for that, but yeah, it's not always look, look, you're right.

pastic Alright, um, thank you, if you don't mind, once the papers out, when you publish it, I would love to share

my paper. It's a paper diary I reviewed. And I it might be out I I didn't check recently, but I'm underwriting another paper with eight studies. So that when that sits out, or maybe nine studies, we'll see.

All right, lovely. I'm gonna I'm going to try to research and share. And Okay, great, thank you. And could you perhaps, you know, to move into the q&a, and maybe discuss just, again, the general end points of team.

So the thing the way it is now, we originally had another secondary aim that we took away because of budget stuff. But but this is the study the studies taking people 65 to a tee between 65 and 80. And what those people should have, you know, we don't want people who will become centenarians, okay, we want people that the next five years have chances of getting a disease. So either they should walk slower, because that's a risk factor for diseases, or if they already had the disease, not in the last year already had one age related disease. So the chances of getting another age related diseases increase. In fact, let me go to another slide. Let me go to this slide. Because I think it's so revealing. Aging here is so incredible, because we asked this question, if you have a major cognitive deficit, what's your chances in the next years to have either cardiovascular disease, cancer or death? So look at men, it's about 10. Okay, 10 per hundred person per year. Okay, so now we ask it differently. If you have constant if you had cancer, what's your chances of having the other diseases right? cardiovascular or cognitive deficit or death? And the answer is the same. It's about 10. Okay, so but if you had cardiovascular disease, what's your chances of having the other disease it's the same and it's the same for men and for Women, and and therefore what we're saying here is Who cares what disease, if aging drives all those diseases, we are agnostic to the disease because if you have one disease, you'll get the other. If you age fast, you'll get the other faster, okay? And Metformin will take those, whatever disease you're going to go next is going to push it away. Because we have data that's that is suggested. Okay, so I'm just making sure that you understand why, why in this, we're agnostic. And we take those people, and we need about 3000 of them. And we do a double blind placebo control, Metformin, 1500 milligrams versus placebo. And placebo is the most expensive part of this intervention. And our clinical FDA outcome is the time to the incidence of any major age related diseases. And the diseases are cardiovascular cancer, and dementia, or death. And when you get to one point for everyone, it doesn't matter what you get first, or second, or or if you get any other In addition, it's whatever you get, we we are saying Metformin will push the time until your next disease. Okay, and this cluster, we call ag. Okay. So it's the cluster of diseases that defines aging, you don't have to call aging disease in order to show that you prevent it by looking here, then we have a second part. And that's what we'll talk about next, which is the biological, we have an NIH grant to look at the biomarkers and to see which biomarkers are changing a through this treatment.

Yeah, which other initial ones that your test?

Which others? This is our statistical stuff.

Sorry. Which other biomarkers that a typical test initially and other any any others you have in mind? I know that that's like a number one point of interest for this group.

Yeah, yeah, absolutely. So look, we went this is Jamie justice. She's in the executive committee on time she led the study. And, and in preparation for team, we basically did a she I should say, she did a huge job, and basically what she took, she took the 258 candidate biomarkers that people claimed they're showing something that's related to a to aging. And she tried to rank those biomarkers, by several ways, you know, a, is it reflective of biology of aging? Is it robust across populations? Is it consistent with the functional endpoints that we're looking at attain? And is there any evidence that they'll response to treatment? Okay, because it is possible that we have a great biomarker to tell our biological age, but but it's not going to change with treatment. And those are the ones that are kind right in team because we have high degree and it's the only ones that we're measuring from the beginning, okay, because those we have no doubt that they're going to change. Not only that they're related to aging, but they're going to change a with a treatment. Okay, so it's the AI, il six TNF receptor, the gdF 1516, a, a, the MT pro B and P and emulgel have been a one C. Okay, so those are in, but our grant is not because of that our grant is because we need to have an only approach and to find all the biomarkers that could potentially change. Okay, such as what we heard last week from a Morgan Levine right, and the methylome and their epigenetic one. So let me tell you what, the preliminary data it's now published. We published this in nature medicine and into aging cell paper just recently, but what we did is we used a Soma mayor and I don't Want to go over the technology now? Okay, we can do it later. But basically the solar mer is a technology where in single plasma, you can measure 5000 proteins and probably more It started with 1500. We use a 1500. And we took subjects between the age 65 and 90, and 65 and 95 1000 subjects and we measure 5000 proteins, okay? 5000 protein side, times thousand. Okay, so what are the results of that? So what you see here is vulcano a plot, I think we saw it before I'll just be brief. You're, you're putting these data into this lava mountain, and it spits out the hot lava stones, right? So the highest it goes, the more is the significance, and the significance here is 10 to the minus 80. Okay, it's like, huge, because we have so much a so many samples.

And, and a, and how far and some of them are going down, and some of them are going up, mostly are going up. And they end terminal, probably NP, which already I mentioned before, is one of the biomarkers for de has the largest effect, it goes at 10 to the minus 40. But its effect size is really very high. Okay. And so the question here, what what are we looking at do are we look at mechanisms of aging? And are we looking maybe there are a protective mechanism, protective proteins, right? For example, PTM and mc 15, we see which is gdF 15, that is one of the team, okay? And if you do transgenic animals, they live healthier and longer. So I think those two proteins, the fact that are going up or trying to protect us, okay. But the interesting thing in those biomarkers is you do proteomic, you do pathway analysis, and there are many ways to do that. And it's interesting that the first one that comes out, and it comes into genetics, and proteomic and epigenetics and everywhere, is the incident IGF signaling pathway. Okay, those are always prominent because they're such part of our aging. But the interesting things for me, I felt they're terrible initially, but the interesting things for me, are those one in red, that are all breakdowns, they are breakdowns, protein, okay, they come from extracellular matrix, they're degradation of the extracellular matrix, they are platelet degranulation, collagen degradation, in neutrophil, their their regulation, a coil collagen modifying em, and initially I thought, doesn't help me much. But then I thought, no matter how we treat aging, we have to prevent the breakdown doesn't matter, what's the mechanism, this is the endpoint. And that's why we're so excited about them, because we think that they'll probably change more rapidly with treatment than methylation, okay, still to be proven for both methylation in this, but proteomic is less stable than a proteomic. Now, I didn't tell you the whole story, but in those thousand people 500 with them are from regular aging people. But 500 are children of centenarians. And we've showed that children of centenarians are incredibly more healthy than age match control. And you can see it here. I don't know if you can see here, but you see that here. Those are the offspring of parents with usual survival. And it's very rare to hear, and it's very pink here. And really, only here 585 proteins were significant in our control, but only 235 are significant in the offspring of centenarians. Now, they're aging is delay, they'll catch up but they'll catch up years later, okay. But But we think we depict a lot of the, a lot of the aging in in this proteomic. And this is another way to look at it. Those are the offspring of centenarians, okay? And they have 206 proteins that are common to the our control population, but they also have 20 proteins that only they have. So they're likely to be protective proteins and some of them are. Some of them we know are protective protein. So you can see that this proton is really an interesting and an interesting comics that come in is going to a, to really be very helpful to the biomarkers. And this is even without showing you or mytable metabolomic, a response that is also very specific to aging into longevity.

Okay, fantastic. Thank you so much. I'm seeing a lot of questions already locked here. And you mentioned the film that was the film that you showed at the beginning of this correct. Who, you mentioned that there was a movie, but that was the movie. And our previous conversation you mentioned there was also an additional movie that you may want to show. No, no, that we showed at the beginning of the Okay, just making sure I'm not missing more movies, because that was really fantastic. All right. So now I really just want to jump into the questions they've been collecting here. I think they like queuing up. Thank you so so so much for this presentation. And I know that a few of the things are unpublished on the slide, but if you can share the slide deck, I think it will be tremendously useful for the group. Thank you very much. Okay, lovely. I'm moving into the questions now. And and I think we have first one Tom Cleo. Yeah, I

had two questions. The first question was the status of the team trial. That is, what whether you have the funding that is needed to launch the trial? That's the first question. And then the second question, with respect to actions that both government agencies could take, and private funders could take. So on the government side, I'm talking about FDA, NIH and NIH, which is, you know, is easier than the NIH and in terms of public private partnerships, or private philanthropy. What do you think the actions are that they could take that would have the biggest impact, both with respect to the team trial, but the sort of broader field of of geroscience?

So first of all, Tom, I'm so appreciative of your efforts and your guidance here, and we've discussed that those question before, I really appreciate where where you are here. So let me tell you were telling me, so first of all, and we, you know, we feel lucky that we didn't start time a year ago, because it would be a disaster now. Okay. You never know, I didn't feel lucky a year ago. And so Jamie's not going to start until we started, anything's possible. With a month ago, we thought we were going to start at the two centers. But that's not happening anymore. So I don't know if 10 will start before the vaccination, or when it will start. There is a foundation that is going to come in in January, and I'm not allowed to talk much about this foundation. But I'll tell you that this foundation, is you know, this foundation wants to solve aging. And it is going to spend $1 billion a year on aging on aging research on biotech, on, you know, around the world, maybe clinical program. And, and this is organization that will fund a team also am, I'm, I'm I know the guy who's in maybe you also know the guy who is going to be the president or the CEO of this organization. But I cannot tell you without risking my life now is a good friend. And I know that I'm going to be on the sap of this organization. So I'm very excited for what's coming in for the acceleration. And that's why we're kind of focusing there and not doing a process that might take longer Look, the day I talk I thought of I conceived tame in my mind was eight years ago, and I'm so frustrated that it's not there yet. Although everybody tells me no matter which dragon approach you want, it takes 10 or more years, but I'm very frustrated. It didn't happen and we want to start it now because of the whole biotech and you know, everybody here who's involved. We need the team will be there when we're ready. Prime Time with whatever we're developing. Great, thank you.

Thank you. Okay, Martin, your next.

Thanks.

Hi, Dan here. So my question is around sort of understanding what the end points lead to pertain. So. So you've already laid out sort of like this is what we're measuring time until the next morbidity slash the first morbidity. So part, one of the question is, is the philosophy there that you think the epistemological data is strong enough that there will be an effect? And we are just trying to show that there is an effect on multiple diseases? Therefore, it's a general general protector? Or is it more that we don't really know what might be affected? So we're going to put like eight things in there. And then we think that it'll affect at least one it might depend on the person and so forth. And then the other half of the question is, What is next? So let's say that we have, Metformin is shown to delay the onset of one or more diseases? How does that trigger? Every Big Pharma and biotech VC now wants to get into aging? Great, great questions.

And so M. So are Chuck. So first of all, I, I know that I did it in one slide. But every endpoint that we were looking for, had clinical studies, or significant association studies done in humans already, okay. It just wasn't done together. And it wasn't done in people who are 65 to 95. Although a lot of the studies, including the DPP had older people, okay, they included older people, but it didn't take those kind of people. And our challenge was not the statistical significance. It's actually kind of interesting. Our challenge was, we didn't want too many people in the study, that let's say, after three years, we show that Metformin prevented cardiovascular disease significantly. And the FDA will say, Stop this study, we cannot go on, you know, everybody else should be on Metformin to prevent cardiovascular disease. And we'll never be able to show the cluster of diseases, right, our primary aim, our primary outcome is not going to be achieved. So we had to design a study where there's a lot of events for 3000 people, but that we are not going to get stuck with a significant statistical significance of one disease, because we are after the cluster. And that's how we, we we calculated it.

Thank you. Oh,

so what happens next, right. So like, let's say, benefits all the cluster, how does that make company x? What are they developing now? Super Metformin, or? No, no, no, from a pure greed perspective, which is important to tap into,

look at, but it's, you know, what, what do we do with rapamycin? What will we do without drugs that one of the importance of time is we are here repurposing a drug, right? And, and, and if this is going to be successful, that's the template. If, if you're a drug company, and you want to show that your drug significantly, delays, aging, Okay, you know what to do. And by the way, this is much cheaper than most phase three trials, because we need only 3000 people because there are so many events that we're looking at, right? And if you if you had only diabetes as an event, then you'll need 12,000 people to get diabetes, but because we don't care which disease we're talking about your next disease, Willie, we need much less people. So it's going to be a cost saving to actually target aging than any specific disease like hypertension, cholesterol, all the other things that people are that pharmaceuticals are developing.

That's the first smarten Yeah, I

mean, we kept sorry about this for the rest of the call, but yeah,

because

All right, thank thank you. And okay kreon you up next.

Yeah, hello, again near wonderful to hear more about this. never tired. So I have a couple questions of let's say the order them up. Obviously from the chart you showed and other people showed Metformin has currently has a lot of mechanisms of action and modulates a lot of pathways, not just downstream. Have one but there's a bunch of parallel modulations going on is that the current thinking?

Right that that one of the things slow, you know, targets really an aging process and fixes a lot of the others. So we don't know, which is we in this paper in this paper I develop, which I think is primary and which is secondary, but it doesn't have to be right. Okay, well, I'll

definitely read that I was starting to pour the talk. But let me ask you two questions about the pathways. One is, um, Metformin is often spoken of as a caloric restriction mimetic, but when looking deeper, it seems to possibly fine understand its actions, be either a protein restriction, mimetic or even a branched chain amino acid restriction or medic medic in particular. Do you have any comments on that? Do you think that's important for what you're involved with? And do you think it's actually modulating just the sensitivity to branched chain amino acids rather than calories in general? And what do you think about that whole debate? Well, I

you know, I am, Aubrey has a better view about it, and which I kind of agree that it goes to the caloric mimetic kind of things. Not necessarily at the same, ma'am. You know, with it with a with exactly the same results? And I don't know, he doesn't, he doesn't really matter for me. As much as I mean, it's going so many things that you can pick whatever you want there. I don't really have a view, it was very confusing to start seeing everything that Metformin is doing and try to make a sense of it. So I don't know. But it's

one more follow along that line, though. I don't know. Are you familiar with the work of Thomas Seyfried and his sort of metabolic origins of cancer theory? And that would partially explain why Metformin might be anti cancer, because it's just turning down all this glucose basic stuff that feeds cancer, do you think there's merit there?

Well, I just don't think that the mechanism of action, and it's really interesting, because when I came to the United States in 1987, I was a fellow at Yale. And Metformin was just inserted to the actually, it wasn't in the US market, but it was investigated. And I looked at the mechanism of action of Metformin on diabetes. And I was like the first paper that showed that Metformin, specifically decrease the party glucose production, that's the mechanism it plays in in the liver, and it's believed to be so and i don't think that this is necessarily irrelevant to a the action of Metformin on em on aging. And and let me just tell you that Metformin in the 1940s and 50s, was used around the world, mainly in Europe, to prevent flu and in in the Far East to prevent malaria. And it's then at that time that somebody noticed that it lowers glucose in diabetics, and, and then, all of a sudden, everybody said, hey, it's an anti diabetic,

but what's antiviral and anti parasitic as well, jack of all trades. One last one? Um, well, no, two last ones, I'll ask them together. First one, no

one asked one more, we have a very

long list. I need to be out to three o'clock because I have a board member of my biotech.

All right. All right. Last one, Metformin, inhibits axon IGF one. And Metformin is thought to be an anti aging drug, many human growth hormone acts oppositely on IGF one, and is thought to be an anti aging treatment by Greg Fahey, among others. How do you square that?

Well, I I don't square that. I don't need to square that there. The data is out there. And let me tell you what we brought to the data. I have 750 centenarians, okay, that I'm, I'm doing a whole exome sequencing and genotyping and other things, measuring the IGF 60% of our centenarians have functional mutation in the growth hormone IGF signaling pathway. Okay, so those guys, they're, they're extended health span is consistent with low growth or mana action or low IGF or low IGF action, okay? which really means that if you could give growth hormone, you can claim whatever you want, but it's not in the hands of aging. Yes, growth hormone for for young people will increase their muscle for all people. It'll look like they increase their muscle although it doesn't increase their function because One of the things that Metformin does it melt subcutaneous fat. That's why people like what they have their face becomes thinner and their muscle seems that they're bigger. But it really is not an important drug in aging. It can be important only in certain cases where you need to be anabolic if there's an injury. Okay? Maybe even if there was stroke, if you get a growth hormone there, it could be eviction, but not for aging. It's the opposite of aging for aging, you need low growth hormone x.

All right, thank you. And now we have our way which I think ties into the comments that you made earlier.

Yeah, a little bit. Actually, since Nir only has eight minutes left, I'm going to slightly change what I wanted to say because Keith has asked a couple of questions, which are really, you know, better statements of what I was going to say. First of all, yes, absolutely. As Neil said, I think, you know, Metformin is broadly working in the calorie restriction mimetic, but of course, every day, every calorie restriction, mimetic has a segmental profile, in terms of which aspects it mimics, and because it doesn't, so yeah, no, um, the first thing that Keith asked, which was what I was going to ask originally, but he said it better is, in terms of the components, endpoints that are being looked at, for the time trial, death, obviously, the singular event. So it's binary either happens, or it doesn't. But the other event could, in principle, be defined quantitatively in terms of the severity of cardiovascular disease or severity of cognitive decline, or whatever. And Keith mentioned, gage speed is, of course, the same deal. And that's being used as one of the entry point criteria. So I'm wondering whether you've looked at the possibility or the quantitative design of the end point.

Yeah. And the good? Well, they are they, the answer is, is? Yes, we looked. So look, in that the first ones are only time, this is all calculated this time to the next single event, whether it's cardiovascular or death, or whatever. And so so this is this is a structure that's needed for a composite outcome. And, and we did it according to other studies, that composite outcome, of course, most of the composite outcomes are in the same field. If it's cardiovascular, it's heart attacks, and strokes, CHF, you know, things like that. This is a different composite kind of things. But for the qualitative outcomes, we had another another thing that I took out now, I took out now because we're not asking for money for that. But those are all the things that are related to function, such as walking speed, such as hearing, and seeing, and ADL and, and hospitalization, and all all the other things. And the reason we took them out now has to help with budget. A for now, but also because we are powered in a way that we don't need to do it from beginning to end in the groups of Metformin and placebo. We can do it all in the last year of the study, right? When, when a when we accumulate the data, we have enough power to see this. But so it's it's kind of technical answer to you. But and I didn't show you here, but we have everything that else that you want to see.

Great. And the other question, which is also echoed by case, the interaction between the 10 trial and its progress or lack of progress, and the pandemic, whether the pandemic may be helping you in terms of the political side, you know, in terms of being persuasive to get people involved, whether that was influential in getting this new foundation involved, you know, how is it working, you said that, it would have been a nightmare if you started a year ago, but now that people are looking beyond and asking the question, you know, how do we avoid the next pandemic? How do we others, the health of the elderly relate to that, you know, what do you find it?

Well, is Tom Collins still on? And the, you know, the frustration here that everybody I think heard us about aging and COVID. I think we made an important point, and I think he tailed the geroscience hypotheses and we pushed very much of how to hearable this virus that has no eyes, and knows exactly who's old, and attacks them, and sees through our eyes, how we look at those people and are not going to help them. But our problem is somebody like Antony Fauci that we all love and adore because he was at the head of one Institute at the National Institutes of Health. And believe me, he doesn't know that aging can be targeted. It's our failure to get to the people who count and convince them to listen to us. And that's why we're struggling. But But, you know, john Manik has an aging study with a RBT 101. And we have a Metformin study also, that's George kushiel. Started and with Metformin and COVID. So the NIH has allowed us to go in to go with more studies, but hasn't really grasp what we're saying very well. And but I will always use it as an opportunity and reminder that next time we have to be better prepared,

just to mention Eric Burdon trained in factory flab. So we have an end there. Who did? Eric gladden?

Oh, okay.

That'd be Tom is still here on the call, in case you would like to chime in. Otherwise, we have Lynn. Lynn with a question. Linda, are you here?

I guess I'm here. yet. Hi, Nan. lovely to see you yet. Again. Another brilliant talk. And one thing that I'm slightly concerned about is, um, you mentioned that Chinese population and the mild cognitive decline stuff may indicate that there might be genetic differences. Have you considered that there might also be diet, lifestyle, BMI differences? And in particular, you're giving a fixed dose to everybody in your study group? Is that correct? Because I know that I, for one have very low blood glucose. If I took Metformin, I'd probably pass out. Whereas if I had to BMI, double what mine is, then maybe it would be fine. So how are you tackling this issue of heterogeneity within your target population?

Okay, that's very important point. So first of all, I want all of you to know that Metformin is not an anti hypoglycemic agent, it's not in by the way under diabetologist, okay, it's not the only thing it's doing it will lower your insulin, okay, your glucose is not going to be low, your insulin levels are going to be low. Okay, so there are plenty of people, by now plenty of non diabetic people that are getting insulin, they don't get hypoglycemia, you're unlikely to get hypoglycemia, it doesn't matter that people don't have side effects. If they take insulin, you know, three 3% of the people will not tolerate insulin for variety, and Metformin for variety of reason. So I really don't want to confuse people would think that only with a certain bi BMI, they have Metformin. The reason we chose the dose, and it was this discussion, when some some thought we shouldn't give 1500 milligrams, you know, they're older, let's give them less. And someone said, Are you kidding? If we want aging, we should give them more? Okay. And we pretty much decided we'll give whatever they gave him the studies that led to our preliminary data. Okay. And, and maybe we'll discover, you know, by other methods with time, the dose effects. I also want to say another thing, this study is not going to answer us. When should you be on Metformin? Okay, we do 65 to 80, because we are going to have lots of events. But I would bet, you know, the diabetes prevention trial was on people who are 50 years old and got a 30% effect. So it's not going to answer that, and it's certainly not going to the heterogeneity is going to be there. But the preliminary data with this dose in people like that suggests that we're going to have a major effect and we're, we're powered for much less effect than we are hoping that we think we'll get

Okay. Oh, you made it just Oh, sorry. I didn't want to cut you off. But I think Neil has to hop off now. We would hate to get you from A to prevent you from going to your board meeting. Is that correct?

Right, because my board meeting will have a drug that when 10 is done, we'll go to phase three trial on the template. Oh, man, I will. Thank you very much. back.

Thank you. Thanks.

I love this group. And Ellis Ellison. I think I have some ways of how to move things to you. Thank you. Thank you so much, guys, and I'm ready for other question. You can email me if you if you need.

All right, there are still a lot Thank you near thank you from all of us. Thanks for joining and have a great board meeting.