Scientist Stories: Nir Barzilai, Aging and Pandemics

Okay, it's 10 o'clock. Hello, and thank you to everyone around the world for joining us for this week's lab meeting. My name is Kristin Aboud. I am the science editor at the Human Vaccines Project, and I will be your moderator today. Sabrina Welch, who did a fantastic job moderating this series over the past year, has accepted a new position. Although we will miss her terribly, we have an exciting lineup of speakers for you. And I am excited to continue these important discussions. Since our last lab meeting, COVID vaccination rates have continued to accelerate, both here in the US and globally. As of this week, all US adults are now eligible to be vaccinated, an important milestone. And globally, the COVAX facility has now delivered vaccines to more than 100 countries. But another vaccine story emerged last week when, out of an abundance of caution, The US FDA and CDC recommended pausing administration of Johnson Johnson's single-shot vaccine following 6 cases of a rare blood clot that were reported among the nearly 7 million individuals who received the vaccine. Other countries also acted on this news. South Africa suspended rollout of the J&J vaccine, the only one available in the country so far. The South African health regulator now recommends resuming vaccinations as long as there is improved monitoring of potential side effects. The European Medicines Agency recommended adding a warning about unusual blood clots to the vaccine's product information, adding that the rare clots were very similar to those observed with the AstraZeneca adenovirus-based vaccine. In the US, the CDC's Advisory Committee on Immunization Practices is meeting tomorrow and is expected to render a decision on whether to resume use of the J&J vaccine. We'll continue to watch this and other emerging vaccine stories closely. Just a note before we begin: the information presented today includes some pre-published data that is currently under peer review. At the request of the author, we ask that you not reproduce or disseminate the data presented. The session will be recorded and made available on our website and our social media channels for you to review. With that, I am happy to introduce today's speaker. Dr. Nir Barzilai is from the Einstein Institute for Aging Research at the Albert Einstein College of Medicine in New York City. Dr. Barzilai is a chaired professor of medicine and genetics and is director of the world's largest center studying the biology of aging. He was the recipient of an NIH MERIT Award aiming to extend the healthy lifespan of rodents by biological interventions, and also studies families of centenarians that have provided genetic and biological insights on protection against aging. Several drugs have been developed based in part on these paradigm-changing studies. Dr. Barzilai is a recipient of numerous prestigious awards, including the 2010 Irving S. Wright Award of Distinction in Aging Research and the 2018 Ipsen Longevity Award. He is currently leading the TAME multicenter study, which aims to prove the concept that multiple morbidities of aging can be delayed in humans. His book, Age Later, was published last June. In an article in the Washington Post last month, Dr. Barzilai said, We're not about the fountain of youth. What we are saying is that we can delay aging. Death is inevitable, but aging is not. That certainly piques my interest. Today, Dr. Barzilai will talk about aging later through this pandemic and the next. During the presentation, please send me your questions using the Q&A function in Zoom. I will ask our speaker a broad selection of your questions after the presentation, when we will have about 25 minutes for discussion. It is my pleasure to now introduce Dr. Nir Barzilai from the Albert Einstein College of Medicine.

Thank you for this very kind introduction, and good luck to you in sharing those sessions. And I don't know if I want to thank you for the fact that the line that you quoted from The Washington Post is how I wanted to start. So I'll say it in a different way. Look, aging has a biology, right? We all know that. We know who's older and who's younger, but this biology is what drives diseases, and this biology can be targeted, and apparently it's not very difficult to target this biology, and this is what I want to tell you because it's immediately relevant to this pandemic. So aging can be targeted, it can be delayed, it can be stopped in certain instances, and even reversed. So with this introduction, that is the most important thing I'm going to tell you, let me demonstrate what I mean. So, sorry, I switched this. So this is a picture of the pandemic from my point of view. Those are studies around the world— China and Italy and the U.S. and the U.K.— all showing exactly the same thing. If you're over the age of 80, your chances of dying is about 180-fold more than when you're in the 20s. Aging is really the major risk factor for death in the population. Um, and, and, you know, like in the United States, we say that 80% of the deaths are over the age of 70. I mean, all the data are saying the same thing: aging is a major risk of death. And this is not really new. This figure depicts the relationship of mortality according to age in all those diseases that we're interested in. And you see that, for example, with heart, the death goes from 500,000 to 400,000 as we go through the years, through age. And it's similar for cancer and for diabetes and for Alzheimer's, all of those diseases. And that, again, underlying the fact that it's aging that is the common risk factor for all those diseases. So what do we do? You know, if you have a heart attack, you go to the hospital, you get the stent, you get the bypass. That's a local treatment for the heart. But what actually happens to those people who survive the heart attack? Within 2 years, they're likely to get cancer or diabetes or Alzheimer's because we never treated the aging. And our point is, if you treat the aging, you prevent not one disease but variety of diseases. Now, let me say immediately, the genetic and environmental factors are, are important, but for me, they are important for what disease you're going to get first. So if you're obese and your mother is diabetic, you're going to get diabetic first. But remember, after the age of 60, we're starting to accumulate disease after disease, and and treatment after treatment, and the diseases are awful, and sometimes the treatments are awful, and there is an interaction. And this is what we're facing now and facing with the pandemic. So the real question is, can we target the biology of aging? And I'm representing a field that's relatively new in— with this name, it's geroscience.. And that's what we've been doing in the last several decades, trying to figure out if there is a hope on doing something for aging, going into actually the promise. And what we geroscientists agreed on, that there are hallmarks of aging, or knobs that you can turn on or off that will affect aging. How do you become a NOB? How do you become a hallmark? You have to show that this hallmark changes with aging and that if you target that, it improves aging. And I'm not going in now to all those. The slides will be available, but I'm going to make several points, and the first is that you see that they're interactive with each other. In other words, if you target one of them, you actually have effects on others. You don't really have to treat everything to get effects on everything. And the concept, if I would say just very plainly, is that if you take a cell or a tissue that is old and you make it younger, you fix a lot of things. And this is the kind of general protection that we're looking for. Relevant to our discussion is, of course, the immune dysfunction that happens with aging and also the inflammation, or we call it inflammaging, that is part of the severe diseases. But, but I'll, I'll take you out of your comfort zone and, and tell you something about proteostasis and give an example. So with age, we're starting to have much more problem with unfolded proteins and junk that is being accumulated in the cells. And there are several ways to get rid of that, but probably the most important is through autophagy. And autophagy is the garbage cleaning mechanism. It's actually a clean garbage disposal mechanism. It takes all the junk and make the proteins into amino acids and the fats into free fatty acids and recirculate them. And when you target autophagy, you have an improvement in healthspan and lifespan of animals. And more important, the junk really comes into effect when we talk about Alzheimer's and Parkinson's, when we have accumulating of those alpha, beta, and and other proteins that are a part of the major problem. And when we target proteostasis, there's actually improvement also in mitochondrial control and in metabolism. And I'll give you a little bit, one example of the immune function. But basically, a healthy Lifespan, and I'm emphasizing healthy lifespan. Okay, it's as I was quoted, it's not about fountain of youth. We are really trying to talk about healthspan rather than lifespan, although they're kind of connected. But healthy lifespan has been extended in numerous animal models in numerous ways, and what's kind of interesting is that when you do the manipulation that you do, if you use a drug, it will affect not only one model, you know, not only rodents, but also nematodes or flies. And relevant drugs have been used in humans, and I'm going to give you two examples that are really very relevant to this pandemic, and that's about metformin and rapamycin. So So what we need to do that's relevant to this pandemic is to restore the immune dysfunction so people don't get the disease and also don't have the inflammaging. But that's not really enough. We want to target aging itself because you need to sustain quite a severe disease. So the the, the situation of the body, the, the resiliency of the, of the body of aging person is important beside the specific things we're trying to improve. And of course, this is important in the COVID-19, as the data shows. It's also important for vaccination, and I'll make a point about it later. And it is important for the next virus and for next diseases, because what we're talking about is about fortifying the host. It's not a viral-specific thing. It's about fortifying the host. It's about taking this host and making it young again. And one of the ways— and I just give an example— one of the ways we are looking at it in a standardized way is if you have any drug that you think is going to affect lifespan, you can write to the Intervention Testing Program, and they— that's a program that is a multicentral rodent program in 3 different locations where you can use the drug and look at the effects on healthspan and lifespan. The animals are not— are a mixed genetic model because the idea is it works on aging. It doesn't work on a specific model. And I'm just giving you several examples from the ITP, from the Intervention Testing Program, with anti-inflammatories like aspirin, with arachidonic acid, with alpha-estradiol, with rapamycin, with rapamycin with metformin. And in each example, you see what happens to the control and then the life extension that happens So that's a survival curve, right? Everybody's alive and those are dead, and there's kind of a right shift in the survival curve as you see in all those examples. And just several points to point out. First of all, in aging, there's a gender-specific effect, not only in the biology but also in the treatment.. And those drugs, for example, the first one, the NDGA and aspirin and acarbose, works mainly on males and not as well or not at all in females. The second point I want to make is that you can start, like here, the drug at a later age and you still are going to get a significant effect. In other words, it's never too late really to target aging. The animal model that lived the most significantly longer by 24% is animals that had a combination of those two drugs that I'm going to talk about, rapamycin and metformin. So just to tell, to give an example, there's a lot going on in our field to standardize our method and really see what we're talking about. And this is only lifespan, this is not including the parameters that are more important, that are healthspan, that are actually usually much better. So I want to make this point that is so important, and I think you intuitively know that. I think you know that we age at different rates, okay? Some of them are aging faster, and some of them, as I'm sure all of you, are aging more slowly.. And in the beginning of the pandemic, there was a paper in Nature that talked actually about the multimorbidities and showed that basically at age 65— and by the way, this is in Europe. In the United States, it's much worse. But in Europe, at age 65— sorry, what it shows you is by age how much diseases we're accumulating. The lights are less than 3 and the dark are in increasing number up to more than, right, than 7, than 8 diseases. And so you see at age 70, for example, you know, almost half of the population has more than 4 diseases. Now, at age 65, half of the population have less than 2 diseases and half of the population has more than 2 diseases. And for me, it's just an indication of the biology of aging. Those guys who are accumulating diseases are aging faster than those guys. So the chronological age is not really important. And why is it so important to understand? Because when I read the Pfizer or the Moderna papers, and I'm looking at the aging subgroup, and they do have people over the age of 75, and when I count the multimorbidities, it is clear that it's about one multimorbidity per person. So for me, age 75 with one morbidity doesn't tell me if the vaccine is effective, and I suspect that it's not as effective. I, I do want to say those vaccines are just terrific, okay, but I don't think you're going to immunize all the people you think you do. I can just tell you that I had coronavirus in April last year, had very mild symptoms. The only thing that lingered is my sense of smell, where— and then I got the Pfizer vaccine and I was sick by the second dose of the Pfizer vaccine much more than during the corona. But at the same time, my mother-in-law, who's 88, got the vaccine and she had no side effects, no local and systemic side effects. And I think in her case, she's probably not well immunized. So I'd like you to think about it. The multi— the multimorbidities are part of aging, and those that have more multimorbidities are probably going to have more failure with vaccines. One of the ways for me to understand the difference between biological and chronological age is really to look at exceptional longevity. And what you see here is the poster child of my study. Those are 4 siblings who were born in New York between 1910 and 1920. And the interesting thing about them is that they all reached over the age of 9— of 102. The little sister died at 102, 110, 107, and 109. I actually met Helen when she was 100 years old in a New York apartment. She opened the door for me and she was smoking. And I asked her, Helen, 'Nobody told you to stop smoking?' And she said, 'You know, all the 4 doctors that told me to stop smoking, they died.' Okay, and the point here, they're resilient to many effects of the environment, and that's why they're so unique. And I have studies where I have 750 centenarians and their families, their offspring, and a control without— survived without exceptional longevity, and I'm following them longitudinally.. And the important thing about them is not that they got diseases when all of us got diseases and live longer, but rather their healthspan was increased and not only the lifespan. And this is combination of two studies, the New England Centenarian Studies control in green and black, and our study— I'm sorry, black and red— and our study in green and blue. And, and they're harmonized for those diseases. And as you see, and the— again, this is a survival curve, so 100% have no disease to begin with, and then, you know, in our study at age 60, about 50% of them have disease, and by age 80, only 10% don't have disease. But our centenarians live 20, 30 years longer free of disease. And in fact, at age 100, almost 30% of them don't have a disease. Some of them just don't wake up one day. But this is not the fascinating thing about our study. The fascinating thing is their, uh, contraction of morbidity. In other words, they die very soon after the disease. They don't linger like us for years. And the CDC actually confirmed that the medical cost in the last 2 years of life of somebody who dies at 100 is a third of that who dies at 70, and we're calling it the longevity dividend. Like, we cannot afford not to increase our healthspan when we're contracting morbidity so severely. Now, the immune response is deficient in older adults. Now, I'm going to show you some slides with immunology, and please understand, it's not my expertise, so don't ask me a specific question about transcripts. I'm going to to show you. Those are data from other people, but the concept is that the innate immunity and the adaptive immunity are deficient in elderly. So like on, on the whole, the whole process. And, and again, it's relevant because, um, because you want those vaccination— because those vaccination are actually using some of the machinery that is defective in aging. So that's a, that's a But let me again give you an example of the longevity or the biological versus chronological age. And I'm showing you just one slide on T cells response in people who are at the same age, but I have a study on the offspring of centenarians and people without survival, and they have different diseases and they are very resilient for longer.. And if you do macroautophagy studies, you see that the macroautophagy is increasing in the T cells, lymphocytes of our offspring, and also the cytokine concentration is higher for provocation in the offspring of centenarians that are age-matched to control, and there's a relationship between gamma interferon, and the macroautophagy flux. Just give you an example that's relevant to immunology and showing you that biological age is important. I will also tell you that the longest-living centenarians that had COVID was 117 years old. So those centenarians are healthy for a long period of time, and I know from the literature that at least 20 centenarians survived COVID. I don't know how many died, they are at the end of their lives, but they have really pretty unusual immunity as well. So what, what is the evidence that we can fortify those adult hosts? I mean, we, we want to take elderly and give them— older adults— and give them gerotherapeutics and look and see if we improve the vaccination.. And the example I want to give is, is on mTOR inhibition. Rapamycin is an mTOR inhibitor. Actually, mTOR is— the TOR is the target of rapamycin, and this is a major nutrient sensing in the body. And inhibition of mTOR, as I showed you before, increase healthspan and lifespan tremendously in many animal models, where mTOR inhibition is important in many steps of viral replication. And I'm showing you that without going through that because I even don't know how you pronounce many of those things, but mTOR is really controlling a lot of the immune response., and what a company by the name of Restrobio, and John Manick was their scientific director, and she gave me those slides. This is actually all published papers that show that if you use this RAD001, which is an mTOR inhibitor, you increase the immunity for flu. So this is the flu on, on the red is the flu titer in the placebo, and you got a 20% significant increase that's thought to be clinical. And you could, you can see it in the paper by giving this mTOR. And this was part of a phase 1 study, and they went on to a phase 2 study. In the phase 2 study, there was a dose-finding effect where you gave the mTOR inhibitor once a week for 6 weeks, and then you took this mTOR inhibitor out for 2 weeks and then looked at the effect on vaccination. The 2B study looked for a year effect, and I'll show you some, some of those data. So this is, you know, a clinical study with an mTOR inhibitor. Let me just say something that I— it's very important. Rapamycin in clinic now is used as an immunosuppressor after transplantation, and that's in a dose that is log different than the dose of rapamycin that gives pretty good inhibition in other cases. So rapamycin, when you give in low dose, increasing your immunity, and in high dose it's a suppression. So just to keep it in mind, if somebody wanted to ask, hey, rapamycin is actually immunosuppressor, it's not in those doses. And also that's why the treatment that will restore aging was in 6 weeks, and there is no rapamycin on board after 2 weeks when you do the vaccination. The assumption is that you rejuvenated the cells anyhow. Anyhow, in the Phase 2a study that was 264 healthy adults, there was a 42% reduction in the rates of confirmed respiratory tract infection. The anti-defense system was regulated. I'll show you a slide of that, and it was well tolerated. But I think more important to see the 2b study, because the 2b studies was with 652 high-risk elderly. So those are the people that are— that have more diseases and risk factors. And in this study, again, it was published in Science Translation, there was a 30% reduction in patients with confirmed laboratory tract infection. There was a 52% reduction in percentage of subjects with severe laboratory-confirmed respiratory tract infection. Imagine if we could have a 52% reduction in COVID cases. There's also 5 days reduction in the time of, um, of, of, you know, how long did that that last. And it was also well tolerated. In fact, it's kind of interesting that when you rejuvenate aging, then there are less serious adverse effects than in other groups, but it's really, it's very similar to placebo. And here is the effect of increasing transcripts. Of innate antiviral genes. And I would just leave it for a few seconds for you to see what transcript we're talking about. And the upregulation went from 25% in placebo to 95%, and some are not upregulated. So there is evidence both in the lab and in the clinic that this is really a major way to target infection. And as, as I said, it's just by fortifying the host. It has nothing to do with the specificity of, of the flu. And another interesting thing I thought is that although this study was designed to see the effects on the flu, the monitoring was on many other viruses including coronavirus, not this one, the, the other common coronavirus. And you see there was a significant decrease in, in, in, in the number of coronavirus as well as other viruses that were, that were looked at during this period. Again, I guess that, that was the point I said before, it's not a viral-specific response. It's a host response. So now I'm going to the second drug, and that's metformin. And the interesting thing on metformin, when you give metformin, it actually targets all the hallmarks of aging. It's been in use for 70 years. In fact, metformin was used to prevent flu and malaria initially when it was found that it also lowers glucose in diabetic patients. So the whole field is on metformin. 70 years of studies are for diabetes. And, and so we know a lot about metformin. We know really, really, really a lot about metformin. Lots of studies have been done on, on metformin. And the nice thing with metformin, it's generally cheap. It's the cheapest drug in the pharmacy of the, the United States. And I'm leading a study, as was mentioned before, TAME, that is taming aging or targeting aging with metformin to show that we can move a cluster of aging-related disease. I'll, I'll say something about it later. Metformin through the years has shown substantial effects on human health. On one hand, it prevents diabetes in those that are not diabetics, but, but also In clinical studies, metformin delays cardiovascular diseases. In association studies, people who take metformin have about 30% decreases in all cancers. In both intervention and association studies, metformin delays cognitive decline and also Alzheimer's disease. In non-diabetic. And I think one of the coolest things about metformin, looking at 200,000 people in the UK, those who take metformin have significantly less mortality than people without diabetes who are using the same pharmacies and the same doctors and, and all that. So In fact, if you're diabetic and obese and have more diseases than average and take metformin, your mortality is significantly decreased. So if you look all at all of that, you understand that this is not that metformin just happens to have some specific effect on, on every disease. It's really something that targets aging, and that's why you see so many effects. So metformin for me is a tool to target aging, and it's a tool because we need to show to the FDA that we can do it in order to pave the road for other drugs, better drugs, combination of drugs. Okay, now as for immunity, and we published this paper in Geroscience to show that metformin— sorry, that metformin has many effects on many parts of the immune system, and some of them even through microbiota, through AMPK, through mTOR inhibition. But neutrophil numbers are increased, CD8, T memory and regulatory are increased by metformin. Macrophage M2 is increased, macrophage M1 is decreased. So lots of immune effects on metformin. But the interesting news is that there are 9 studies around the world that basically are showing 2 things: there's a decrease in inflammation, there is a decrease in hospitalization, and decrease in mortality. In fact, it's a very significant decrease. The latest paper came from the United States in diabetic patients, and it shows that age is a risk factor for death, as we know. Race was not here. Gender, yeah, male is a risk. Obesity is a risk. But the important data is people who were on metformin had 67% less mortality, suggesting that, you know, metformin has— I mean, I, I, I'm really trying to excite you and for you to think about it. There's no other drug that have showed 67% decline in mortality, and it's not just one study, you know. This is a study from nursing home, and, and people were infected with COVID and 30-day mortality in those taking metformin is much less, is more than 50% less than people who are not taking metformin. The study that I'm doing, that we're doing, is we're taking 3,000 people in a double-blind placebo-controlled fashion and looking at the primary outcome is time to the incidence of any major age-related disease. We're moving the clusters, and we're also looking at biomarkers for longevity. So I want to end with 3 thoughts. First of all, the CDC has published the risk for severe CVD disease. Okay, those are the conditions that are at increased risk for CVD, and aging is not mentioned. Okay, when I called the CDC, they said, well, you cannot do anything about aging. But you know, you cannot do anything with sickle cell or, or, or other things, or, or you're unsuccessful with obesity. This is not the reason. And in fact, it's worse even in conditions that might be an increased risk. Aging is not here. So please, guys, aging is the major risk factor, and aging can be targeted, and even in, in a way that's relevant to this pandemic. A second point is a more futuristic point. You can take a sperm of a 70-year-old man, and we can measure the biological age, and fertilize an egg of a 50-year-old woman, and when the blastocyte is formed, the aging is erased. Okay, we all start at zero. We don't remember the age of our parents, and there's a lot of research in biotech using Yamanaka factors and other in rejuvenating. You know, the idea is that when you're from— when you're 20 or something, you'll get a monthly therapy that will erase the aging. And that's the way we're thinking about the future. So I want to just end by saying that current COVID vaccinations are using the same machinery that fails with adults, and I'd like to remember that. And I hope that it's not relevant for those vaccines, but I really doubt it. Vaccinations so far have not tested the biological and chronological age, and gerotherapeutics such as rapalox and metformin, I think, should be implemented, especially now when so many people around the world are hitting COVID, are not vaccinated. And, and if you ask what you could do, well, this is what you could do. Metformin is available and cheap.

Let me end here and welcome your questions. Thanks so much. Thank you so much, Dr. Barzilai, for the presentation. We have some questions coming in specifically about the correlation between the antibody or cellular-mediated immunity levels and feeling poorly after vaccination. So someone asking, is there a known correlation? And we had another question saying that they were not aware of any studies that have actually showed that the reactogenicity indicates a better immune response to vaccination.

Could you talk about that? Yeah, yes, sure. So I think, let me tell you what I think is behind one. I showed you phase 1 study and phase 2 studies, but actually a phase 3 trial have failed on a primary outcome. And I think the reason it failed the primary outcome is because they actually asked how do the patients feel, okay? Do they say that they were healthier? Did they have better year with less diseases, etc. And this is okay when you have young people and treat psoriasis. They'll tell you how it's going. But to use those same criteria in older adults is wrong, okay? They're complaining no matter what, okay? We tell our geriatric patients, if you wake up in the morning and you have no complaints, you're dead, because, because those are tools that are adapted from other things. But actually, when you analyze the secondary points and tertiary points, which will come soon in a paper, I think you'll see that as far as the immunity, the immunity was achieved. I don't know specifically about antibodies to a response because I don't, I don't think those studies have been done. There is a study now on mTOR inhibitor that is supported by the NIA.

I don't think there's any preliminary data on that at all. Right. Okay.

We had one question wondering if the mTOR will increase the antibody titers following vaccination.

No, I, I don't know that. Okay. I just don't know that. Yeah.

So do you think that metformin will increase acidosis in patients with obesity? Well, acidosis— the story of acidosis and metformin started with a cousin of metformin that was called fenformin that in several cases initiated severe lactic acidosis, which is something that people remember. It's called It's really called a metformin association lactic acidosis, MALA, and it's about patients who have lactic acidosis because other diseases, for any, for instance, for example, their kidney shut down or they're hypoxic and they're also on metformin. But the cases of true lactic acidosis are really, really very rare in metformin. Saying that, metformin is not for everyone, and, and this is a whole conversation, but it's one of the most safest drugs that we ever used, and the lactic acidosis is not really a concern. There, there is one thing though, you know, we're talking about fortifying the host before you get the disease. Okay, so if you're in the hospital and you think you should give metformin, I would, I would not do it because you're going to have lactic acidosis too if you're in intensive care unit and things. So I'm talking about what we can do now to fortify the host so they don't get the disease, or if they get the disease, they don't die, they don't get hospitalized or die.

Right. And then that's important. Thank you for asking this question. Okay, I think in a related question to what you were just speaking of, someone was asking about the side effects of metformin and rapamycin that might be of concern and how you balance that with the benefits of the combination.

Okay, so I didn't— I showed the combination just for the preclinical data and interest in the aging. And I have not suggested to use both in combination in humans because the data on rapamycin or rapalogs, the analogs of rapamycin, are, you know, we haven't, we don't have enough clinical studies to suggest what are the side effects. When you give rapamycin to animals, and you increase aging for it and you increase lifespan, for example, there's more cataracts in the animals, there's a testicular atrophy that happens sometimes. So the safety issue of rapalog and those things have not been shown in humans, but those even with higher dose, but those issues are still need to be resolved.

So I wouldn't use the combination of both of them at this time. Okay. And can you tell us if vaccines are being evaluated in the TAME study to assess the immune age versus the biological age versus chronological age?

Right. So, what we're planning to do with the TAME considering the COVID is to immunize. So we have ancillary studies to immunize against the flu, or as it happens, against a second vaccination or adjuvant for the COVID-19, and looked at the immune response. It's part of what we're going to do in TAME, and this is kind of a moving target all the time. So, so, but, but immunology is going going to be a major part of not maybe the major outcomes but of what we're going to establish in this study.

Okay, wonderful. So we had a question on your position on the suggestion that vitamin D, magnesium, and zinc should be administered to improve health among the elderly.

So there's more on that in my book if you want to see, but My complaint about all supplements is that there's no clinical data to support them. You know, supplements are good for the economy, and that's very important. A lot of people are using that, and they're mostly not harmful, either because they don't have what they claim to have, or they're not harmful. Some of them are harmful, but the lack of a clinical study is something that I cautious again. In fact, all clinical studies except one clinical study, and that's for osteoporosis, are negative for vitamin D. So vitamin D is low in association with lots of condition, but it hasn't been shown that supplementing vitamin D changes anything. So I, I, so I, I can, you know, I'm, you know, in medical school they teach us first do no harm, and then there's not always or never. So we're very conservative and we really don't know what to do. But I, I don't have any evidence that vitamin D or zinc is really important to humans aging except in certain situations. As I said, in aging, a lot of people have osteoporosis, and if they have vitamin D, they should get vitamin D.

But I wouldn't say it to the population. Okay. And in these studies, how do you, how do you account for the role of other factors that influence aging, like diet and exercise?

Very good question. So absolutely, look, the most important thing to do to delay aging is exercise. In men, in women, in every age, exercise has huge benefits. Okay, so let's not forget that. But, but let, let me now say differently, and I'll talk about diet in a second, but let me say differently. You know, I was talking about aging, but people who are surviving chemotherapy and radiation for cancer treatment They age rapidly, in particular the young people, because we're actually, by doing the chemotherapy and radiation, we're helping these hallmarks of aging. So they need help. People with HIV have age-related disease 10 years younger than other ages. People who are debilitated or on wheelchairs and they don't move and they eat more, they need help. I would say even poor people in the United States that cannot go to the gym, cannot afford going to the gym, and can afford only high-fat food, that they should be helped. And if we ever go— want to go to Mars, um, we need to stop aging. Look, we're not going to go to Mars because we'll get cancer on the way there and we'll never come back, okay? We need to solve aging. So let's, let's make it bigger. And so exercise is important. Not everybody wants or can exercise, so we need geroprotection or gerotherapeutics as well. So I can't take Metformin and skip my run today, in other words. Well, that's a different issue, but right, basically right. The diet— so let me just tell you an experiment that we've done in our lab. In our lab, always caloric restriction increased lifespan in animals. That's our positive control. You give animals 70% of the food that ad libitum animals are having, and they live 30-40% longer and much, much healthier. And this was taken as you should have less for breakfast, lunch, and dinner. But that's not what we did. We gave the animals the food in the morning. They were hungry. They finished the food in 20 minutes, and now 23 hours later, they are fasting. So it's not only the calories, it's the fasting. And in fact, when we try to give them this food throughout the day, they are thinner, but they don't live longer. So from a diet perspective and aging, okay, and I'm saying just from the aging point of view, Fasting is important. I, for example, and many of my colleagues are doing what's called the 16:8-hour fast. We're doing variety of fasting, but I'm doing the 16:8-hour fast, which means I'm basically skipping breakfast but without cheating for 16 hours. No, no calories in those 16 hours in order to get the effects, the benefits of fasting, which has to do with the autophagy that I mentioned before, with lower insulin, with ketones. And, and there's ketogenic diet that increase lifespan. So this is the diet that I suggest. And I'll tell you just one thing, I never dieted before, but if you would give me a diet for 3 months, I could break any day. But I'm not going to break if I'm hungry, if I have an hour to go and then I can eat or whatever I want. So, so this is my diet advice. Think of the fat for an aging Think not for diet, okay? Think, or if you want to think of the aging, try to fast. And, and you can do it 16:8, or you can fast once a week or twice a week, or you can fast like Michael—

some of my colleagues are doing 4 times a year for 4 days, things like that. That's very, very interesting. Uh, we have another question on metformin, and it's being demonstrated to help TB patients, but yet your data shows downregulation of inflammation. Is that an apparent contradiction?

And would you just be able to comment on that? No, I think it's up to you guys to determine that. I'm talking more— the inflammaging is not really apropos. It wasn't meant as part of the immunity. What happens When we're old, we have breakdown, okay? We're going from, uh, from, you know, getting stronger and getting to reproduction to starting having breakdown. And part of this breakdown is associated with inflammatory response. Just like if you have virus, you have an inflammatory response, the aging has an inflammatory response. That actually is dysregulated and causes part of the problems with aging. And I think it might be relevant just for, you know, the fifth day of COVID in the hospital where people have this cytokine storm or something, that it's not helpful to have inflammaging as you enter that. But I cannot really—

I don't know the specific answer for this question. So what advice might you have for vaccine developers to design their studies if they want to address the aging immune system?

Well, I, I think my major point is you have to include people who are old with multimorbidity and, and discover the limitation, because maybe it's a dose effect Or, you know, first of all, I hope that it's still very effective. I believe it's still very effective. But, but I, I clearly don't believe that this is effective from the data that is missing to me, the people that we need to help most. So I, I think you should consider to do this vaccination, you know, in old age home, in people with multimorbidities, to see really the effect on this population. Look, If we could have just decreased mortality in the elderly by 67%, I don't think this epidemic would have been as frightening as we see it.

Yeah, absolutely. Well, thank you so much. I think that brings us to the end of our time for questions. But what an interesting and provocative discussion. So thank you so much for your presentation and for sharing your work with our audience. I'd also like to thank the attendees for participating in today's webinar. We are fortunate to have such an engaged audience in these lab meetings, and I want to thank you for spending your time with us and for submitting such great questions for our speaker. I invite, invite you to join us 2 weeks from today on May 6th for the next Global COVID Lab Meeting. Our speaker that day will be Dr. Laura Walker from Adimab, who will speak about the generation of broad and potent neutralizing antibodies to speed pandemic responses. I also wanted to note that the application portal is now open for the Michelson Prizes Next Generation Grants presented by the Human Vaccines Project and the Michelson Medical Research Foundation. The Michelson Prizes are given to support promising young researchers who are applying disruptive concepts and inventive methodology to advance human immunology, vaccine discovery, and immunotherapy research for major global diseases. We're posting the link to the Michelson Prizes in the chat, so please visit that site for more information or to apply. And if you're interested in more research on COVID-19, please sign up for the HVP COVID Report, a biweekly newsletter that provides insights from experts around the globe and highlights the latest scientific articles and data. In next week's COVID report, I will be speaking with Heidi Larson, founding director of the Vaccine Confidence Project at the London School of Hygiene and Tropical Medicine, about COVID-19 vaccine acceptance. Finally, please visit our website and follow us on LinkedIn, where we will upload a recording of today's webinar. And with that, I will say thank you again for participating today. A special thank you to Dr. Barzilai for his wonderful presentation. Stay safe, and we hope that you'll join us again on the next Global COVID Lab meeting. Thank you so much.