NMN, NR, Resveratrol, Metformin & Other Longevity Molecules | Episode 4

I'm David Sinclair. I'm a professor at Harvard Medical School and co-director of the Paul F. Glenn Center for Aging Research. And I'm joined today by my lovely co-author and co-host, Matthew Lapland. Hey, how are we doing? -We're back at it again. -We are. We're here today to talk about how to live longer and better. -That's part of this podcast series. -Yeah, this series. -The deep dive into the things that you can do to slow stop and reverse aging. -That is true. -And today is going to be a really interesting one. -This is going to be the one that everybody. I mean, this is the one that everybody's been begging for. -That is true. We've been monitoring the responses to tweets and Instagram posts. And most of them are, David, just tell us what to take. -The nice ones. -Yeah. Some of those aren't very nice either, but. -Yeah. Please, please, please. Should I take NR? Should I take NMN? What should I do with Metform? And we're going to be talking about all of that today. -We are. And our research team has been spending weeks on this. And if you can't see, I'm actually sitting in front of many pages of notes here, we're going to deep dive into what is fact and what is not fact, what is known, what is not known. Because there's so much misinformation out there, especially with supplements. -Yeah. We do need to say. We usually take a moment to think our sponsors. We're going to do that, of course. But we also have to take a moment to say, we are not medical doctors. We are not medical doctors. -What he said. I'm a PhD. I'm a researcher. I can read the literature. I've been doing it for the last 30 years. I distill that for everybody. But, of course, if you want to try supplement or even change your diet radically, please talk to your physician before you change anything. Because some of the things we'll talk about today can affect your body in hopefully many good ways, but sometimes can be dangerous depending on the person. And everybody's different. -And what we want to do is give people the ability to have a more intelligent, informed conversation with their physician. -Exactly. -Okay. With that out of the way, now we should thank our sponsors. -Let's do that. Because this podcast is free to anybody who wants to watch or listen. Our first sponsor is Levels. Levels is an app that syncs with a continuous glucose monitor, which they provide. And it interprets your glucose data for you. I've been so impressed by levels that I've recently joined them as an advisor. Monitoring your blood glucose allows you to see how different foods impact you. I've used levels to see what foods impact me. I've learned that grapes spike my glucose, white rice, but actually potatoes aren't that bad. It's not just interesting. It's also a lot of fun to see what's going on inside your body. So if you'd like to try levels, you can skip the 150,000 person wait list. And you can join today by going to levels.link/sinclair. That's levels.link/sinclair. Today's podcast is also brought to us by InsideTracker. InsideTracker is a personalized nutrition platform that analyzes data from your blood and DNA, to help you better understand your body and reach your health goals. I've been using InsideTracker for over a decade and also serve as chair of their advisory board. I really like InsideTracker because they make it easy to get your blood test. Either someone can come to your home like they do for me, or we can go to a clinic. They then present the blood analysis in an easy to understand dashboard that provides recommendations for improving your health. There are interage 2.0 tests which I helped develop using an AI algorithm, even shows your biological age. If you'd like to try InsideTracker, you should go visit them at insidetracker.com/sinclair and you'll get 25% off every InsideTracker plan. You're Sinclair as the code at the checkout. 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Again, go to AthleticGreens.com/sinclair to claim this special offer. Okay Matt, let's dive in. There's a lot to get through today and I know everyone's waiting to hear what we have to say today. In the last episode, David, we talked about adversity mimetics. These are the things that we can do in our modern lives to mirror the sorts of stresses we faced across our evolutionary history. But even if you're engaged in doing these things like we've talked about already fasting, getting lots of exercise, getting out of your comfort zone, our modern lives are still designed around comfort and sedentary-ness. Sedentary life styles. And that's not to mention the fact that even before modern times, we age, right? So if we're going to combat aging, we may need an additional boost. Do you believe we may need an additional boost? Well, I do. And I've been doing this since my early 30s. We'll talk about my program at the end of this episode. But really, what we want to do today is to talk about some of the major supplements and medicines that are thought and have the greatest scientific evidence to be able to give you wellness now as well as long-term health in the future. Supplements and medicines, drugs and supplements, molecules and drugs are a lot of different terms that we're probably going to throw around. And we're going to use them fairly synonymously, but in fairness, let's define drug versus supplement at least. Right. Well, first of all, most drugs are chemicals, okay? But some are naturally occurring and some are freely available over the counter, OTC. And that's because they've been in our food supply before and the FDA doesn't regulate them. They fall under what's called generally recognized as safe or grass. And that's why you can pick up whole variety of molecules from the plant world because they're already in our food supply. Therefore, the government thinks, well, they're probably okay, even if there are a thousand times more concentrated than what you're eating. Which may or may not be the case. Right. Right. And so that's why you always have to be careful. You have to monitor yourself like I have been with my blood work for many years to make sure that you're not hurting parts of your body. Your liver particularly could be sensitive to some of these molecules, even if they are available freely at the pharmacy or the vitamin shop. Different story about drugs. Drugs are regulated molecules because they have the chance to actually cause damage. And many drugs actually do have serious side effects that need to be carefully monitored and discussed with the doctor. Even those that are very safe, like we'll talk about metformin. These are regulated by the government because they are not in the food supply. They are artificial molecules that could theoretically do damage. And there are literally thousands of drugs and supplements that someone somewhere will tell you will help you with health spans and longs, but life spans. We're not going to talk about thousands of drugs and supplements today. No, maybe in future episodes we'll come back, but we want to hit the high points today. And so that's why today we're going to move through some of the most popular and some of the most promising. These are things that most people can have access to or find a physician who, if the need exists, will prescribe. Right. And I get emails and I get all sorts of texts every day, DMs. What should I take? What about this? What about that? What's the dose? When should I take it? What should I take it with? Is it okay to take this drug with exercise or not? That's what we're going to cover today. Your most pressing questions answered here today. And so we're going to talk about NAD boosters. We're going to talk about metformin, burberry, rapamycin, spermidine, risk veritrol, fysadin and curesidine. And probably a few others. But those are sort of the highlight points. If you're only interested in one of these or if you watch this whole episode, you need a reminder that show notes are going to be timestamps. You can immediately go to burberry and find it and click on it. That's right. Included in the show notes are the scientific references that we now have in front of us that we're going to talk about. So that people can do a deep dive, even deeper than what we're going to do here today. There's one more thing that we'll link to in the show notes. That's on your website that I think is valuable for people to know about. You're involved in a lot of different companies. You're an entrepreneur, you're a researcher. You have, I don't know how many patents. There are plenty of people who would say, "Oh, this guy's just trying to sell stuff." If they suspect that you might have a conflict of interest, they can go and look at your disclosures. I do disclose everything that I do. My lab has a website. You can Google Sinclair Lab. And if you click through my bio, there's a link to all the work that I do outside of Harvard, as well as what we do at Harvard, of course. But importantly, I've never sold any supplement in my lifetime. And that's not because you're a bad salesman, it's because you haven't actually tried to sell. I mean, there's a difference between having not sold a supplement and having tried to sell a supplement and not sold a supplement. Right. I've actively kept myself away from the supplement industry because I want to be able to talk about things without any bias. Not for a lack of opportunity, though. There's plenty of people who would love to put your face on a package. Well, and they do without my permission. You can see my face on the internet. But if you see that, no, that it's not with my permission. And I do actively try to stop that. To get into this, let's use some of the same framing that we've used for the other conversation. And that's these three longevity pathways, three longevity genes that we've been talking about. Surtoins, AMPK, and M-Tor, different drugs and supplements are thought to work on these things. different pathways in different ways and we'll sort of like categorize in those three buckets today. Exactly. And the thing to also remember is that these three survival pathways that we've talked about and in episode one we talked a lot about are responding to our environment, whether you're exercising or fasting, they'll turn on, but also appreciate that they talk to each other and some drugs or supplements will activate one of these and talk to the other too. It's a network and we're still trying to figure out exactly what the optimal combination for each individual might be, whether to tweak it with this molecule and then exercise here and then fast that day. We don't know all the answers but we are going to present the cutting edge science here today. Well, and I think it's been really interesting. I've been working with you for what like about four years now and in that time a lot of the molecules that we knew to be working on one of these pathways, there's been further research that has said, oh, that's not just an AMPK effect, there's also an M-Tor connection there. We talked to each other and because if you're low on amino acids and it'll turn on the M-Tor protection pathway, that will then tell the other survival pathways to do their thing too. It's like the Pentagon where there's centrally coordinated defenses and basically what I'm trying to do is to make a prank phone call to the Pentagon to say there's an emergency and they'll send out the troops in various ways and protect the body even though there's no immediate threat. I like that analogy, that's fun. Let's talk about the class of molecules that you've worked most extensively on in your lab. These are known as NAD boosters. Talk a little bit about how why NAD is important in our bodies. It's really important, if it disappears we're screwed, right? Well, we did in 30 seconds. We needed it for energy and but it was discovered about a hundred years ago by Germans who were looking at extracts in yeast and there was this component called NAD that was necessary for chemical reaction. And we didn't say what that stands for, that's. So NAD stands for nicotinamide, which is vitamin B3 and adenine danucleotide. This is a sugar and a phosphate. The important part about it is that the cells, our cells use NAD to transfer hydrogen atoms between proteins and even DNA. That is really important for life and without it we can't make chemical energy which is in the form of ATP which we'll talk about later because that's important for metformin. NAD is found in abundance. There's many grams of it in the body. It's probably with the exception of ATP, the most abundant molecule we have in the body. It helps us make energy but it also has this other function that's just as important that we worked on and just co-discovered in the 2000s. It activates the serotones and the serotones at these defensive enzymes that like the Pentagon send out the troops. The problem is as we get older we make less NAD and we also destroy it more. For reasons that we don't fully understand but it leads to a decline in our ability to fight off aging and the diseases that it causes. And this is because NAD is a sensor for adversity. It is. If you exercise, it's known and fast, it's known to raise NAD levels. But even though even if you exercise and have the healthiest diet, you're still going to have lower NAD levels by the time you're in the latter half of your life. That's why these supplements are thought to help because they'll boost up those older levels of NAD to where they were when you were young. Let's talk about the first NAD boosts are probably the most well-known. It's definitely the most well-studied of the NAD boostsers and probably the most taken used. That's NR. Which stands for nicotinamide riboside. That's the vitamin B3 plus the sugar. Without the N part, which is a phosphate, we'll get to the phosphate. That's important later. It may make a difference. But NR has been taken over the counter or through websites for, since 2014, either solely just as a capsule or there's some companies that sell it in combination with other molecules. And because it's been pretty well studied in humans, there's been plenty of human studies, at least in the short term, that show little to no side effects. This is a pretty safe molecule. That's for sure. We know that if you take it as a supplement, just swallow the pill, either 250 milligrams per day or a gram, there's no apparent negative side effects. In fact, you will raise NAD levels in blood tests. I think this is an important distinction to make though. There's a difference between safe and effective. Because we say something that's safe doesn't mean it's going to work in it. In fact, sometimes things that are the most safe aren't going to work at all. That's why they're so safe, because they don't have any effect. But we do know that NR is largely safe. Millions of people around the world take it. NR has been well studied in animals as well. And let's start with that because we actually know more about what NR does in the bodies of animals that we do in the bodies of humans. But let's start with yeast. Go even further back. Okay. I was first discovered. NR was a newly discovered molecule back in the early 2000. It's found a little bit in milk and other foodstuffs. And if it was fed to yeast, they lived longer by turning on the yeast, sir, two, and pathway. Okay. How much longer were the yeast living? Generally, the yeast lived about 30% longer when you give them these molecules similar to caloric restriction. And that's what this was doing mimicking caloric restriction because both activate the Sir Tuins and give increased genome stability and epigenome stability that were linked in their life. And those kinds of findings make you really interested because you're really interested. This Sir Tuin activation. And so you've been part of a group of scientists that have been looking at this. Yeah. One of the first things that we discovered, this is now, we're talking 2002, 2003. And my lab was that there's an NAD synthesis gene called PNC1. In our body, it's called NMPT. And it gets activated by these mild stresses. In a yeast cell, it's low salt, it's low sugar, heat, and that turns on the synthesis of NAD. And we found that extended lifespan. And then a few years later, it was showing that you can mimic this effect with this NR. How does the NR turn into NAD? So NR has to go through an intermediate molecule. Let's start with the mouth. You swallow your NR. It'll go into the gut. Some of it will be metabolized by the gut bacteria. But most of it will go into the bloodstream and then flow around and then get to the gut. And then it's taken up into your muscle and into your brain and other cells that are by transporters called EMTs. And there it's converted into NMN by what are called NRKs. And then you add the phosphate and you've got this thing NMN. What's NMN? Nicotinamide mononucleotide. And then the cell puts two of those together to make NAD. And when we do this in laboratory animals, you mentioned in yeast, it extends life by 30%. What have we seen in mice which are a little closer to you and I than your yeast is? Yeah, it's going back a number of years ago. It was found that NR when given to mice extends to the lifespan by about 9%. But it was given to them late in life at about 700 days, which is a pretty old mouse. This has been like a 70 year old human. But it still worked. But there were also improvements in health. They had more mitochondria, which is the energy. They had more athleticism, less inflammation. So that was the first real study that said, okay, maybe supplementing with these molecules like NR or NMN might have some long-term health benefits as well in humans. Among the other health benefits that have been seen by researchers who have given NR to animals in the lab, enhanced oxidative metabolism. So they burn more fat. Yeah. They get thinner. And that also means that they're burning more oxygen. And that's thought to be really good at staving off diabetes, type 2 diabetes as well as improving lifespan. Let's carry this now under the human studies because what we don't have for reasons that maybe are obvious, but I'm going to state anyway, which is that humans live a very long life and it's really hard to put humans into a control group and a test group across a very long time, then control for every variable that's possible is longitudinal studies that show increases in lifespan as a result of taking NR. But we do have studies that have sought to show similar health benefits to what we've seen in rodents. Somewhat, I would say NR, there being a few positive results, not a lot. Before we get to that, I think it's worth talking about why can't we just take vitamin B3, which is a precursor to NR. And you can, but it doesn't raise any two levels anywhere near the level that NR does. NR doesn't seem to be as effective as NMN. So the closer you get to NAD with your molecule, the better it seems. And that's probably because you need to bring in other components. So if you just take vitamin B3, you need a sugar and the phosphate. If you just take NR, you need the phosphate. And phosphate is pretty rare in the body. It's in your bones, it's in your DNA. And maybe when you take NR, one of the issues is that you need to find the phosphate add on there before it becomes active. OK, back to the human studies on NR. We have sought to see it, but we, I mean the research community, I don't mean necessarily you and me. We've sought to see the same sorts of effects that have been seen in models, organism studies. Sometimes that's happened, sometimes it is not, is that fair to say? That's very fair to say. With NR, there have been a handful of studies in humans showing that low dose, 250 milligrams per day, up to a pretty large dose of gram a day, does raise NAD levels. But it takes about nine to ten days to get to those peak levels. What we've also seen is, or others have seen, is lower inflammation, as well as some other markers, such as minor changes in body composition. But these other things, which are lower blood sugar, improvements in insulin sensitivity, increased mitochondria, those haven't been born out just yet in these short term studies within our. It's not easy. Sorry, these are the things that were present in the mice who also lived longer. Right. Yeah. Now, it could be that you need longer term exposure. If these people, these have been fairly short term studies, or that humans are not the same as mice. So would you say. I mean, if somebody said it tells you, "Oh, David, I've been taking NR for so many times, you're not rolling your eyes, but you're not convinced at this point, the jury's still out." Well, it depends what you're asking. If it's to lower inflammation, yeah, it probably works. There's also a study that was put out by a group that combined NR with terrestrial vein, which is a respiratory like molecule. We'll talk about respiratory next. That found that in ALS patients' lugaric disease, there was an improvement in their function, deli function. So that is somewhat promising. I think that we, of course, we need more studies. That's what we really need here to be able to make any sort of conclusion about what the long-term effects of taking this supplement are. It's fair to say that in the Sur2 and activated compound research community, there's kind of team NR and then there's team NMN. Your lab really focuses on NMN. I think if people were following what you said earlier about how NAD, they might go, "Oh, NR turns into NMN. NMN turns into NAD." Why don't we just take NMN to begin with anyway? You mentioned earlier phosphate. That's an important component of this question. Well, NR is more popular because it's cheaper to make. It doesn't have that phosphate, which can be expensive to put on the molecule through chemistry. And that's why most people started using NR first in humans and in mouse experiments. I didn't have a horse in the race. I didn't care which one. In fact, I'd prefer if both worked according to my theories. But what we found through empirical studies, basically, we're looking at which ones work better. My lab and others, including Matt Kablein, who's at WashU, who treated a mighty Condrill disorder and we were treating regular mice on treadmills, we found that NMN just worked better at the same dose. We don't actually understand why it could be that this phosphate addition is one of the reasons. But just based on observations in our hands and in others, NMN works better than NR. Can we supplement with NMN when NMN is given to organisms in the lab? What's happening? Well, it's a little different. There's been an argument in the literature that NMN doesn't get into cells. And similarly, NAD is really a big molecule because it's got multiple components. And that also has a real struggle to get it into cells. Neurons take it up, but other cells typically need to break it down into its various components and then re-uptake it. And that's important because some people are actually giving themselves NAD through the IV route. When it comes to NMN, what happens is it was recently discovered by Shin M.I. at WashU. His team discovered that there's a specific transport that takes NMN out of the liquid outside the cells inside the cell and its name is SLC128A. Still debated. A lot of things to figure out. But I think it's just best to say, okay, we know what's happening when you give it to animals. We're starting to learn what happens to people. We of course want to understand how it's working, but the fact that it does work is the most important point. So when it comes to NMN, there's been a number of animal studies showing, for instance, similar to NR, Restores NAD levels. It enhances insulin sensitivity. One of the things that was surprising to me is that we don't have a study that shows NNM's effect across the NNNN's entire lifespan yet. Well we have a half a lifespan. Shin M.I. showed that it actually was pretty good at slowing down the effects of aging, but he stopped the experiment because he ran out of NNN. It used to be rare stuff. Now you can buy it. But we took up the challenge and we've been doing these studies for the last few years in my lab. Now, preliminarily, these mice have less frailty. We've reported that out in the scientific community. They seem to be younger, having better activity, better mitochondrial function. They run further. The lifespan looks promising. We've done it once and they do live longer on NNN. The doses are about 400 makes per gig. How much longer? At this point, by recollections, about 10 to 15 percent, but particularly strong in females. Okay. So not particularly wholly different than what we saw in the NR cases with the mice. Right. A little bit better than that. But certainly those mice are healthier and more active and more youthful. And you said it's more pronounced than females? Or at least according to the first phase of this, it's more pronounced than the females. Right. Well, we had fewer females, so we have to repeat that. So we've now got a larger cohort of mice for repeating a whole thing. We'll see how it goes. But right now, with the small number of females, yeah, they did do better than the men. And what even though mice live pretty short lives, what we have to understand here is that they still live two, three years on average, right? And so in order to see lifespan extension, especially if they live much longer, it takes some time to do these studies. Yeah, it's quite painful actually because you think about this. An average experiment takes three years. And then you have to repeat it. So that's now six years. Then to analyze the data and publish it as another three or four, that's a decades worth of work for one experiment. And you know, your career only goes for about five of those times. So you do five experiments. Of course, you can run that. Well, that's how careers used to go. We're going to change that, right? We're going to live a lot longer. We run things in parallel as well. That's important. Yeah. But we can also mimic things, not just in animals, but we're growing tissues in the dish will be the subject of a later episode. Okay. So, so far what I'm hearing is in animals, NR and NMN both have some similar effects, right? Like thinning lifespan, restoring mitochondrial activity, restoring NAD levels, enhancing insulin sensitivity. But in NR, the human studies haven't always confirmed that that's the exact same thing that's happening in humans. What are we seeing in the human studies for NMN? I know a fair bit about the effect of NAD boosters in humans because I'm helping a group that is actually doing clinical trials at Harvard Medical School. And they've been giving a molecule that's similar to NMN to subjects for many years now. First of all, there's importantly, there's been no evidence of any negative side effects. That's important. And we're about to learn whether it actually does anything that's similar to the mice. We don't have results in yet, but hopefully by 2022, we'll actually know if people have more energy, more mitochondrial function, better blood flow, more endurance, which is what we saw in those mice. There's been a little bit less human research on NMN than in NR. But we're starting to see just in the last couple of years, especially sort of a flood of studies being published. Early results, for instance, from Yoshino et al. in 2021 showed increased insulin-stimulated glucose disposal. We talked about this a little bit when this study came out. You were pretty excited about it. Tell me why. It's one of the first real proofs that NMN does something in humans the way. It works in mice. So this was a 10 week study. It's well done. It's randomized, placebo controlled. It was 250 milligrams, which is a relatively low dose. Remember, I'm taking in my clinical trials or a gram and two grams. This is 250 milligrams. Nevertheless, it improved what you said, insulin-stimulated glucose disposal. That's basically insulin sensitivity. And that's a whole mark of longevity. Keeping the glucose out of the bloodstream, keeping it low levels is a whole mark of wellness and ultimately longer life. So that's the beginning, but we have a lot more to figure out. We need to figure out if that increased endurance that we see in my lab with NMN treated mice is true for humans. We also want to know, our organs protected, other labs not mine, but other labs have shown that NMN protects the organs when they're damaged, kidney and heart. The two main ones are even increased wound healing. I'd love to know if NMN does that in humans. That would be a big deal. Kidney injury is huge. And particularly, I don't know if you know this, but most surgeries on the heart end up damaging the kidneys. And there's not much you can do about it. So ultimately, we've seen a glimpse with Yoshino et al. My studies that I'm involved with at Harvard Medical School are looking promising. We'll know more next year. But yeah, there's a lot more in the works. And there are other NED boosting molecules that have been made that are even better than NMN, so-called NCEs, called new chemical entities. And those I'm aware are probably in the next year will go into the first human studies. And that can be a whole episode of this podcast in and out of itself. We should do it. Okay. Why don't we just give NAD directly? We're talking about like NAD boosters. And our creates NMN. And NMN creates NAD. That boosts NAD. Or NMN boosts NAD. But it all gets us to NAD. So why don't we just set up the drip line and get it going? Well, we don't, but others do. There's a lot of activity going on in Florida and LA particularly of having large drips, long drips of an hour of NAD. These are not in study settings. This is not in a research setting. This is like people trying this out. Well, they're done under medical supervision. But I haven't yet seen a placebo controlled trial that would tell us for sure if it's just wishful thinking or not. don't think so given how many people have been now treated and there's a serious amount of anecdotal data on this, better mood, better energy. But you cannot conclude anything unless you actually have one of these placebo controlled trials. I'd love to be involved if anybody's going to do one. I'd love to help. But I'm asked this probably every day in ADIVs, do they work? My answer has to be, we don't know yet. What do we think they might be going? What are people trying them for? They use for various things. It's been used for many years to treat addiction, whether it's drug or alcohol. It's also used for depression and also increasingly for hangovers. Is it as good as the Australian hangover cure that you've given me a few times? Oh, the raw egg in the vegemite. I hope it's better than that. But the idea. Because the truth is that doesn't work. I just pretend it works because it makes you happy. That's true. You're one of the few people that eats my vegemite. But the reason that it probably works is there's an enzyme that toxifies alcohol called alcohol dehydrogenase. A lot of Asians are susceptible to high levels of alcohol because they lack a lot of the enzymes. Alcohol dehydrogenase needs NAD. What's probably happening is when you wake up with a hangover, you lack NAD, you're liver is depleted. If you take in a men or in our, you can raise those levels back up, get your liver working again and get rid of the excess alcohol. So you think chances are that is actually it's not just like a placebo effect. That's just a chance that it makes sense that that would work. I think makes sense is the right word to use. I'm a Harvard professor. I'm not going to say something works unless I've seen hardcore proof. And I hope that'll come in the next year or so. It's just so I'm clear on this though. Because it's still a little fuzzy to me. I can understand why we might want to use NAD. I'm not understanding why we're not starting, for instance, all the research with NAD and then moving backwards to NMN and then moving backwards to NR. Yeah, well, it all started in yeast when I was at Harvard the early 2000s. Even in yeast, if you give them NAD, it doesn't work because it's too big. It doesn't get taken up into the cells. So what we wanted was back off in size. So the next smaller molecule behind NAD is NMN. And there we know there's a transport or protein that sucks it into cells. And NR is even smaller and it gets taken up even better into cells. And so that's the reason why it may be that NMN is at the sweet spot of the right size, but also has the right components to make just the right amount of NAD. This feels like a good time to talk about bioavailability and making things available to our body's machinery. How do we make NR and NMN most bioavailable? Just swallowing it is enough in our studies to raise NAD by two to three fold. So if you buy the for instance, the capsules, they're often sold in capsules, just swallowing that's going to be or the powder. Just drink it. That's we make tablets and give it to the patients that way, the subjects. But there are others, there is a sublingual version. I have heard there's evidence that works. I haven't yet seen it. It makes sense that it would be absorbed under the tongue. Or you can inject it. But in terms of the research right now, it doesn't seem like there's a huge advantage one way or another. No, I haven't seen any reason for saying that you need to put it under your tongue versus swallow it. What I can say for sure is that I've seen so much data on swallowing it that it definitely works to raise NAD levels. There has been some concern around the use of NAD boosters when it comes to the potential that it might stimulate cancer growth. And obviously that's something that we don't want to be dismissive of. It does you know good to be boosting your NADs and extending your lifespan if you're just giving yourself cancer. What's the latest research on that and how concerned should people be? Well, so most of these studies, actually there's only two main studies have been done in mice. So he's what they are. There was one again out of Washington University by a different group that found that knocking down the levels of NAD in brain tumors slowed the growth of the tumor. And unfortunately the new story ended up being all NAD causes cancer, which is not the same. That's the complete opposite. So that study, I wouldn't put a lot of stock into it, but there is one other study that came out in 2019 by Naccarelli. And they found that NAMPETE, this NAD boosting gene, it increases the number of senescent cells and makes them more inflammatory, giving out these SASP proteins as they called the senescent associated secretory phenotype as the word. But also there were mice that were predisposed to pancreatic cancer. And when given NAMPETE, they developed more precancerous and cancerous growths when they consumed this NAMPETE. Exactly how it works, we're not sure, but it might be because it was down regulating a tumor suppressor gene called P53. And this was a subgroup of mice that were already predisposed. They had a gene that made them more likely to get cancer. Right, but remember we fed NAMPETE to mice, but normal mice not predisposed. And if anything, they live longer in a healthier. So it's question whether it's this predisposition that's the difference. Something to watch for and to think about and to work into anyone's calculations if they're going to be considering an NAD booster in any case. For sure. And another reason to consult your physician. Absolutely. Okay. Now there are other NAD boosters, sir to inactivating compounds. One of the ones that you've been really interested in that I think a lot of people are interested in probably really widely used is RESTFERATRAL. You started working with RESTFERATRAL back when you were trying to understand sir to inactivation in yeast. Right. I was just a kid. I was in my early 30s. And what I was I'd just come out of MIT with Lenny Gorenti where we'd found that up regulating the sir to in gene in yeast extends their lifespan. But of course we can't upregulate genes easily in our body. We're not going to genetically modify ourselves any time soon. Not not anytime soon. We can, but we're not going to. It's easier to find a safe natural molecule that does the same thing. And so our goal back in the early 2000s at Harvard was to look for any molecule that we could find that was safe. That would activate the protein, not the gene, but the protein. It's an enzyme that controls other proteins remember. And so we set up an assay that looks for what's called SERT1 activation. SERT1 is the first out of seven of them in the body. And Conrad how it's my collaborator and I were using an assay in a test tube that would fluorescent, it would fluoresce when you had more activity. And so we added these chemicals, we added a dozen, then we added thousands and eventually tens of thousands to SERT1 and found which ones raised the level of fluorescence. And you found a bunch of them. They were like 20 of them that did. We published 20. Yeah, in nature 2003. The one that was the best at the time, which activated 13 fold. SERT1 activity was resveratrol. And there were others, of course it infositen, which are actually now used by others for longevity. But resveratrol got most of the attention because it's found in red wine. And you've told me this bunch of times red wine stock went out the right, like people started buying red wine like crazy. All 30 percent sales and they've stayed up ever since. And I've started drinking more red wine as a result as well. But when I look the truth is though, how much red wine would you actually need to drink in order to increase your levels of resveratrol and get an actual effect out of this? Right, you know, you can't drink enough red wine to get the kind of doses that are efficacious in men. You can't. Well, you can try, but I don't recommend it. You'd need hundreds of glasses of red wine a day, which I don't recommend, even if your doctor says so not recommended. That's not an extendial life. Probably not. No. But what you can do is you can purify it out of great vines or polygona cuspidatum, which is an herb, a plant, mostly grown in Asia. When you say that, can you just take your pen? Take your pen. Yeah. All right. And I say that word again and go like this when you do it. Polygona cuspidatum. Okay. Thank you. I appreciate that. It's magic, I think. Yeah. A per Harry Potter. Yeah. How much resveratrol do we actually need to see an effect? Well, there are a lot of human studies now. The minimum that I've seen is 250 milligrams a day. And some people take 1,000 or 2,000 milligrams a day. This is a cert activator. Yeah. Like the other NAD boosters we've been talking about, uh, works a little bit differently. But like you said, really well studied and for almost 20 years now, what's, what's happening when we put resveratrol? Let's start with the animal studies. What do we know? Well, we know, first of all, if you just give it to them in their water supply, it's not going to work. You can't just swallow it and expect it to get in easily. Why not? Well, resveratrol is the equivalent of brick dust. It's, it's really insoluble. If you put it in a glass of water, it'll fall to the bottom. So what you need to do is we found in both mice and humans, mix it with some food. You can use yogurt, you can use that kind of olive oil, that kind of oily food, and it will dissolve. It's hydrophobic. This is the problem. It's scared of water. And this is actually why you've suggested that maybe some resveratrol studies that have shown, uh, that it doesn't work as well as other studies show, those studies may have involved people who were feeding mice, resveratrol without that additional fat. Yeah, that's the case. Some of these studies didn't include food. We found that early on in the mid 2000s that if we gave it with a meal, the levels in the blood went way up. There have been a number of animal studies on resveratrol going back almost 20 years now. We're seeing extended replicative lifespan in yeast. We're seeing activation of AMPK in R&D. rodents, what are these things telling you? Well, they're similar to what we expected from the certuans. They defend the body. They raise the metabolic rate. They protect against free radicals. And when we see resverteral given to these rodents, what the biggest surprise was was that they were protected against a high fat, so-called western diet. Those mice on resverteral, even though they were really obese on this really chunky meal, they lived as long as the lean mice that we had as the control group. And that was really, as far as I know, the first study of any that showed that you could mimic caloric restriction with a molecule and be fat, but live as healthy as a lean animal. Have those findings translated over as we've moved resverteral into human studies? Yes, somewhat. I'm not all studies have worked, but there are a number of them that have. And for instance, resverteral has been shown to reduce fast in glucose and significantly increase insulin sensitivity. This was a study in 2019. And then again, in 2020, Batista and George et al showed that a randomized control study with 25 individuals ranging from 30 to 60 year olds with a slightly high BMI of 30, were able to lower their cholesterol levels, their urea levels, which is important for kidney function as well as raise their good cholesterol, the HDL. But once again, we don't know long term what this is going to do, but the trajectory seems good when we consider it in the context of what we've seen in animals and what we are seeing in these early human studies. Yeah, I think so. Even before I worked on resverteral, it was known to be an agent that suppressed cancer. If you put a carcinogen on the skin of mice and then rubber is veritable on it, in 1999 science paper showed that those cancers are much smaller in those treated mice. So the anti-cancer activity for resverteral has been known before I came along. And since then, we've seen effects on body composition, on metabolic rate, mitochondrial boosting, glucose levels. The list goes on. There's probably a thousand papers now showing at least the benefits in animals and there are a dozen in humans. Cardiovascular disease, I haven't mentioned, but that's a big one. May help explain the French paradox. The French can eat high fat foods. And with this glass or two of red wine every day, it helps mitigate the effects. Does that, I mean, like, but you've just said, like, you actually have to drink so much red wine in order to get this effect. But then we're thinking maybe the French who don't drink that much red wine, even though they do drink a lot of red wine, but they don't drink that much red wine. There's two considerations here. One is that drinking red wine over 30 years could have a cumulative effect and it builds up in the body. And the second is that red wine has more than resverteral in it, has some of these other xenoharmetic polyphenols that we talked about in earlier episodes that could give a combination effect. Okay. There are two other molecules I wanted to mention. You mentioned them earlier, actually, by name. These were part of the group molecules that were identified in those early experiments with the yeast that identified resverteral as potential sirtuin activating compound. These are fysodin and chercidin. And both in addition to being sirtuin activators potentially also seem to have this other property to them that is making them sort of like a hot number now. Right. They are what are called senolytic, killed senescent cells. And senescent cells are zombie-like cells. The ones that accumulate over time in your body, probably because their epigenome gets screwed up. But what they do is they shut down, they stop dividing, and they start secreting inflammatory factors and also factors that cause cancer. Yeah. And so getting rid of those would be presumably a good thing. And that's what fysodin and chercidin appear to do. They do in the dish and in mice. And there are even some human studies now that show that killing off these senescent cells in the body can improve health. And ultimately we think could extend lifespan. And these have been shown in the case of fysodin at least to extend lifespan since some model organisms. Like fruit flies? Yeah. And even in mice recently. I was particularly impressed by the mouse studies. A couple of colleagues out at the University of Minnesota were able to show that fizzitin put in either in the food of the mouse when it's young or even late in life. After 700 days, which is like a 75-year-old human, was able to extend lifespan quite dramatically up to 30% including improving their health. And that's ostensibly because both it's removing those senescent cells and activating the CERT-1 defenses. And there's been human studies in both of these as well. I know we kind of talk about these in the group because they were discovered as CERT-2 in activators and now they've been seen also as potential synolytics. But maybe we can differentiate a little. Well, a lot more is known about chercitin. Okay. That was discovered first as a centolytic by Jim Kocl under the Mayo Clinic who combined it with a drug called the satinib. And together those two molecules are potent killers of senescent cells. And those have been put into mice and into humans where they are showing really remarkable effects in treating age-related diseases. And we've had some randomized controlled trials with humans in chercitin. The effects are. Reduce is liver steatosis, a fatty liver. And as well as other effects like inflammation in the body. You can actually see that the number of senescent cells in the body goes away when you treat with chercitin and to satinib. The satinib is a drug that's used to treat leukemia. It's got a lot of promises as a centolytic too. It seems as of right now you can really only get it for treatment for leukemia. That's right. You can only get it if you're part of a clinical trial. You can't just go buy it on the internet. It's a regulated drug. As well as another drug that's senolytic, which is called nevitoclax. These are being tested. They're not ready for prime time at all. But fizzetin is the interesting one. That one is a plant molecule. It's found in grapes. It's found in apples, relatively high levels in strawberries. You can now buy that relatively cheaply on the internet. So if people are like, "Man, I really want to get into senolytics. The gateway right now, the most accessible place for people is fizzetin." Well, it is. But it's the only days. Not a lot of data compared to a Chorsitan and a Dissatenib. Really, we know that it reduces inflammation. That's about it in humans. I think we still have to wait to see whether it's really, truly safe before people rush out and try this. I'm excited about this affirmed light study by Jim Kirkland with fizzetin. He's got a number of patients. They're on 20 milligrams per kilogram of body weight. And this over the next year or so should tell us whether fizzetin is truly a senolytic in humans and can have some health benefits too. Okay. So there's a third class of drugs we want to talk about today because it's been too much time with them because broadly speaking, they're not available for purchase or even prescription right now, except for very, very narrow instances. I'm talking about rapamycin and these drugs that are rapologues, drugs that are supposed to mimic the effects of rapamycin, perhaps without all the toxicity. These drugs have a really interesting history. Well, they do. These are drugs that inhibit mTOR, which is mimicking fasting. They were discovered a number of years ago on East Ryle and Rappinui, which is why they're called, it's called Rappamycin. On the back of a saturated, I believe somebody found some mold and they have some fungus and they scraped it off and low and behold, we have a drug that actually has been used for other purposes. Immune suppression? Yeah. Cancer. Like really, I mean, this is a life-saving drug. We just don't know yet if it's a life-extending drug that's going to be useful in humans. Well, I'd put good money on it. The reason is that it's extended the lifespan of every organism it's been given to, in low doses, not immune-suppressing doses. In humans, it's considered around 10 milligrams per week. But you definitely don't want a suppression immune system. But even from yeast to worms to flies and mice, if you give it late in life, it still extends lifespan. It's really quite potent. The only downside is that it could be toxic. You have to be extremely careful. And right now, it's not available. And rapamycin works by inhibiting amdor. Yeah. Yeah. Actually, Thor stands for target of Rappamycin. So that's how amdor was discovered. And when you give animals Rappamycin, you're mimicking low protein intake. You're mimicking this adversity that we've been talking about throughout this entire series. He says, "Oh my goodness, I'm running out of protein. I need to scavenge protein from within." And so the body starts recycling old proteins in this process we talked about earlier called autophagy. And that brings us to another drug spermedine, which is also working on this autophagy process. It does. So spermedine is more recent. You've only recently been able to get it on the internet. It has an interesting history. Anthony von Lee-Wonhock, the inventor basically of microscopy, was looking at his sperm. No one believed him that there was these swimming things down there. But he started to get crystals in the sperm. And that was spermedine. Hence the name. Kids, if you want to get into science. And what do we know about spermedine now? Because this is a really old, I mean, this has got an old history, but like really new research that's showing potentially extensions of lifespan. Well, we know it extends lifespan in yeast and flies and worms. And even mice. And mice. There's a new study that was really compelling. If you give spermedine to mice, either when they're young or even late in life, they live longer and they have better. a heart function or other youthful capacities. There are two ways that spermedine is known to work in mammalian cells. One is it stimulates autophagy, just like rapamycin does in the emtore pathway. There's another really interesting property that seems to be true, which is it also stabilizes changes to the epigenome, which as you know is one of the major causes of aging. There have been a number of human studies on spermedine, particularly revolving around enhancing memory and dealing with memory loss in older Americans. That's true. We don't know a lot about aging itself, but cognition has greatly improved a number of studies. The one that stands out for me is the one by Schwarzele 2018. They were giving people 1.2 grams per day over three months, and there was significant enhancement of memory. On to go back to the history of this stuff you mentioned earlier, the Antony von Lohenhoek discovered the crystalline structures that led us to spermedine by examining his own sperm. Presumably his own sperm in a microscope. Is that still where we're getting sperm, Adin? No, not that I know of. Where are we getting it from? We're getting it from wheat germ. It's a lot easier. It's much more abundant. You can also find it in soy products. That makes me feel better about it. All right. We've talked about certain activators. We've talked about mTOR inhibitors, but really one of the most exciting classes of drugs is also sort of actually kind of the most boring because it's been around for so very long an AMPK activator called Metformin, which hundreds of millions of people around the world already take for diabetes. Yeah. It's been used since the 1950s as the frontline medicine to bring down glucose levels in type 2 diabetics. It's relatively safe as a drug goes. In half the world it's available over the counter at pharmacies here in the US and in Europe and UK, Australia, you need a prescription. We know that Metformin works by activating AMPK. We know how that process kind of unveils itself. Well, there are a lot of theories and it's been debated for over 50 years. One thought is that the microbiome changes, but a leading school of thought that most scientists agree on is that it inactivates a protein complex called complex one, which is involved in making energy in mitochondria. What it does is it lowers the amount of energy that the cell has in the form of ATP, this chemical that we use for energy. Then you get myto-hormesis. Mitochondrial hormesis, what doesn't kill the cell, makes it stronger. The reaction is twofold. One is to make more mitochondria, so you get more energy a few days later. But also by inhibiting AMPK, it will improve what's called insulin signaling so that the blood sugar that's in your blood, and if you're a type 2 diabetic, it's too high, it gets sucked out of the bloodstream and utilized, which is why it's used to treat type 2 diabetes. This is another one of those cases where there is perceived diversity and then not just one of these pathways, but multiple pathways in this case are infected. Yeah. Similarly to all of these factors which are talking to each other. This is a good example. Mettformin will lower energy inhibit emtore. It will activate AMPK, obviously. We talked about that's what it's mainly doing, but it also raises NAD levels, which, as we all know, will activate the serotonin. Mettformin is a remarkable molecule, comes from the plant world. It's very simple. The French hellebore or lilac plant produces what's called guanadines, and these have been known to treat diabetes for many years, in fact, over a century. Then chemists have put methods on them, chemically modified it so that it's more stable, and we call this Mettformin. That's what we have as the drug today. We've given this drug to animals in worms that's extended lifespan, 30 to 40 days, which is no small amount of extension for a worm. Yeah. I was involved in the mouse study with Raphael de Carbo down at the NIH, and we found that the mice were healthier and longer lived on Mettformin. What are the other things, since again, what we want to look for, if we want to know if Mettformin is working as humans, like it works in animals, we're not necessarily just going to look at the lifespan extension because that takes a long time. What are the intermediary things that we're seeing with Mettformin? In human, you mean? In animals that we can look for in humans. The main one, of course, is glucose lowering, but we also see more energy, mohmarkandria, less inflammation, and muscle switching. We haven't talked much about muscle type switching, but muscles, as you get older, become more glycolytic. They start to use more anaerobic mechanisms. You can see that switch back when you give the Mettformin, like they're more like an athlete. We're seeing all of these things in animals and also in humans. Right. This is where we can speak to a lot of data because millions of people have taken Mettformin. One of the most interesting things about it is you can do a retrospective study of tens of thousands of elderly people on Mettformin and ask, "Okay, their type 2 diabetes may be reduced and slowed down." But what about other diseases that they're susceptible to? Cancer, heart disease, Alzheimer's, frailty? The answer that's quite remarkable is that Mettformin lowers the risk of all those other diseases. When we control for everything else, what we see is that the people who are on Mettformin are living longer. Then people who don't have type 2 diabetes, it's a remarkable fact. But now the question becomes, "Okay, take the type 2 diabetes part of the equation out. Will we still see an effect?" That is something that's being investigated in this really large study that's underway, the tame study. You're right. The targeting of aging by Mettformin study run by Neobarzoly down at Albert Einstein College of Medicine. This is a very large study of many different institutes and hospitals. It's costing tens of millions of dollars. It's taking the world to raise that money. And ultimately, the goal is to show to the American FDA that you can target aging with a drug and slow it down. The ultimate goal being having aging a treatable medical condition. Why is it taking so long to raise money for this? Because this is really. Everybody I know in the aging space is excited about this. And yet, the money is hard to come by because. Well, this is where capitalism has a little bit of a downside, which is that Mettformin is very cheap because of a few cents and it's off-pattern. Which means that anybody can make it. There's no profit mode of making this drug right now. Right. So, Near is relied on the government. They've given half the money and the rest of the half he's relying on donors and he's still raising that money. But he's getting started. Fortunately, he's off to the races. We should know in the next few years if he's seeing signs of slowing aging and he's looking at a number of things, not just diseases, but also things like stability, ability to walk, strength, these kinds of things, mental acuity. These are things that would indicate that aging itself is being slowed down and he's even now able to measure the human biological clock with accuracy. And that should also be slowed down if this is truly an anti-aging medicine. We're seeing a lot of doctors get a lot more comfortable with the idea of prescribing Mettformin off-label just a few years ago. The constraints of what Mettformin was actually approved for was keeping it out of the hand of a lot of people who thought that it might be good for them in their efforts to slow their aging. They're starting to be a little bit of a shift there. Well, yeah, I'm seeing a lot more people taking Mettformin under the approval with the approval of their physician. And part of it is education, typically when a doctor sees the evidence and there's an extensive literature. And sometimes the patient takes the information to the doctor or our book. The doctor, in most cases, is convinced that this is worth the risk. Now it's not risk-free. We should mention that Mettformin has some downsides. One is that it can cause lactic acidosis, which is quite a severe condition. It can be fatal. You have to be very careful there. But most people are fine on Mettformin. The biggest thing that happens to them is that they have an upset stomach, lack of hunger, which can actually be a good thing if you want to lose weight as well. But doctors now are saying, okay, they're advising their patients out to these potential side effects and also saying, yeah, either because that doctor is sold on the idea that there's a potential aging benefit here or anti-aging benefit here. Or one of the other things you and I have talked about before is doctors are increasingly getting sick of waiting until patients are full-blown sick to prescribe them medications and they're prescribing it to pre-diabetic people and pre- we might call pre-pre-diabetic people. So there's a shift in medicine and the way doctors are looking at their patients, more and more doctors are saying, okay, let's not wait till the patient is so sick that we have to treat them. Let's get ahead of that and let's start treating them earlier. The one other thing that people should talk to the doctors about if they're considering trying to get on Mettformin is the concerns about the connection between Mettformin and muscle loss. Right. Particularly in the elderly. This is an issue. Actually, if you look at the data and there've been a couple of human studies, Mettformin doesn't make a big difference to muscle size. It probably makes a difference if you're trying to win Mr. Universe, but other than that, the difference is really slight. If you look at the graphs, it's only 5% difference. And actually 5% difference. I'll give up 5% body size for longevity any day. But the other important thing is that those muscles on Mettformin were just as strong as the others and had less inflammation. So there's other benefits to that. But some people are doing just in an abundance of caution, is taking metformin on days that they don't exercise. And if you're wondering why is it effect exercise, well really it's pretty obvious. It reduces the body's ability to make energy. And so you don't feel as strong on the days that you take metformin. So you do less reps, fewer reps. And so what you could really do is just put a little bit of extra effort in and probably make up that 5% difference. If people are interested in the effects of metformin but are not able to work with a doctor to get a prescription for it, or if they've tried out metformin and it just doesn't sit well within, which is the case with about 20% of people, there's another alternative that works on some of the same pathways activating AMPK. That's burbring. That's right. This is a molecule from the plant world. Bark and roots, you can find it's yellow substance. Again, it's filly insoluble. So if you want to take it, take it with some food, yogurt, olive oil, all this kind of stuff. But it's been remarkable what's been found in animals and even in people that it can mimic the effects of metformin. Specifically, what it does is, again, it binds to this complex one and reduces chemical energy in the body. And in reaction, this mitochondrhoemesis is to amplify mitochondria and make the body more sensitive to insulin and lower the blood glucose. We've seen this in my lab in mice and human studies have actually validated this as well. The doses are high, 1 to 2 grams per day, but it does seem to work. And when you say it does seem to work, you mean not just showing the activation of AMPK and increased mitochondrial energy, but we actually, in mice, have seen increases, pretty substantial increases in lifespan. Yeah, actually, it's really interesting. In mice, Berber and Will extend the lifespan of mice treated with chemotherapy and have a pretty big lifespan extension of normally aged mice. That's also true in fruit flies. So it seems to be a common mechanism that you lower the energy in an animal and it responds by living longer. And I think you said you got to take quite a bit of this stuff, though. Yeah. In my lab, I think it's a good way to do that. And I think it's a good way to do that. You know, molecule is perfect. But this one's really interesting because it's a natural and commonly available one that you can try at home. Of course, talk to your doctor first, though. Yeah. All right. Well, that kind of brings us to try at home. And again, with the caveat that we're not telling anybody what to do. We're not giving them medical advice. You're not a doctor. I know you have been really open about what you do that has changed over the years. But let's just sort of take it through the things that you started doing 20 years ago, 10 years ago, five years ago, just start from the sort of chronology. When you started investigating risk veritrol, you also started taking risk veritrol. How did you know how much to take, though, because you were giving risk veritrol to yeast and eventually to mice? Well, it's not a one-to-one. It's not like you should take 3,000 times as much as the mouse had. This is about 3,000 times bigger than a mouse. Right. It's not just proportional. It's actually more related to our surface area and how much the drug can get into our bodies versus the mouse. And the calculation for a mouse, which is called the "alometric scaling," is about 12. So you multiply it, let's say, if the mouse has 100 milligrams, 1.2 grams for a human. For a rat, it's three. For a mini pig, it's one-to-one. Turns out we have about the same surface areas as a mini pig. And so you take about a gram of risk veritrol every day? I do. And I've been taking that since about 2004. But like I said, you can't just put it in water and drink it. Yeah, add some fat to it. Yeah. So I typically have some yogurt, a couple of spoonfuls, not a lot, because I'm trying to fast until dinner. But I could mix it with olive oil. Olive oil recently, as we mentioned earlier, in a previous episode, seemed to be really good for activating sartones, but also you can dissolve it as veritrol in it. Do you get a tooper? You do. I don't have a lot of it. There's a lot of calories in olive oil. I don't want to break the fast severely. But it makes it with a bit of vinegar and basil leaves, and it doesn't taste too bad. Okay. So, risk veritrol you're taking about a gram a day in the morning. Also in the morning, you take NMN. I do. And now you don't have to worry about food. It's dissolved easily. You can put it in water or swallow it, put it under your tongue. And so I do that. That's my main combo in the morning. How much NMN are you taking in the morning? Again, it's gram, but that's not, I guess, that's actually based on the human studies that we've done that show that a gram over 10 days raises your NAD levels about twofold. And that's sort of the dosing amount that we're seeing in a lot of the human studies now. And that's both the past studies and the current studies that we're going. I take one gram of NMN every morning, along with my res veritrol. The reason is in humans, we know that that doubles NAD levels, which is important because someone my age has half the levels of NAD than I did when I was 20. But you can go as high as two grams and triple the amount. It's important to mention that I take these at a certain time of day based on science as well. I take these in the morning because that's when the natural rise in NAD and certain one activity should happen. And we actually know this that the certain one NAD cycle is part of our body's natural 24 hour clock. So it one regulates a protein called B-Mail that controls the genes that tell us whether it's night or day, should we be hungry or not, whether we should have, whether we have jet lag or not. And I do find anecdotally that NMN is remarkably good at preventing jet lag as well. I can reset my body's clock, ostensibly through the sort one B-Mail pathway. You're also taking that form. Yes. How much when? I take 800 milligrams at night. Okay. And you take that at night because? Well, because doctors tell me that it's a good time to simulate a fast. I take it with my dinner just after. And then through the night, I'm presumably having low levels of glucose. My body has all the benefits of stimulating those repair pathways, those survival genes. And that's the most recent thing that you've added to your regimen? It is. Actually, what happened was I had terrible blood by chemistry. I was eating badly, I gained weight. I wasn't sleeping, I was stressed. And those numbers just went through the roof. And I said, I've got to do something. So I went on NMN and things were somewhat rectified. And then I added metformin and they really got back to my optimal. You mentioned earlier some concerns about exercise metformin. Your practices were that concerned? Yeah, I pulse metformin. It doesn't sit well in my stomach anyway. So on days where I know next day I'm going to exercise and lift weights, I might skip metformin that night before. And then there's also spermini. There is. You can buy it now. There's a company that makes it in pure form, very low levels of gluten. And just the last few months, I've added that to my protocol. And we'll have to see how my numbers look on inside tracker. Okay, so that's not something you've adopted. And you're like, I'm definitely sticking with it. This is, I'm adopted and I'm testing it out to see how it works. I am. And actually I advise that company. It's the first supplement company I am advising. And I did that because I wanted to look at the human clinical trials. And they look really promising as well. How much of that are you taking? A gram as well. Okay. You are also periodically taking facetin, curesidin, aimed at scents itself. There are clinical trials being run out of the Mayo Clinic for fizzidin and for course and these are high doses that typically two grams taken one day a week for a matter of months. I'm myself, I'm on a maintenance dose. I take about half a gram of each every day. Let's take this morning through night just really quickly. Resveratrol, one gram. In the morning with yogurt or olive oil. NMN as well. A gram, yep. Fizzidin and curesidin. Half a gram in the yogurt. Spurmedin. Definitely, spermidin, yeah. In the morning about a gram. And then in the evenings, if you're not working out the next day, metformin, how much? 800 milligrams. Okay. That's it. That's it. Now, you're not most people. A lot of other people are going to be different. You don't advise people, but it might be a good place for people to start their conversation with their doctor though, yeah. I think so. Most doctors are open to looking at, say, inside track or data and hearing about the latest science. It's very difficult for them to keep up with it. One of the reasons we're doing this podcast in the first place. So David, this has been a really comprehensive conversation. Even still, we could have gone deeper on any one of these drugs or supplements. Maybe we'll do that in future episodes, in future season of Lifesweam podcast. But what we're trying to do today is really give people an opportunity to really start thinking about whether this might be something that they want to bring into their lives. And if so, how, of course, again, in consultation with their physician? And monitoring. This is important. You don't know if you're doing good or harm to your body unless you measure it, particularly your liver. You can measure what's called ASTALT. I do that routinely just to make sure nothing's going wrong in that regard. Our next episode is. Things that are not supplements. Things. Maybe you could regard them as being on more of the cutting edge. Things like testosterone, growth hormone, exosomes, peptides. We're going to dive deep into those as well. All right. Sounds like fun? Yeah. Let's do it. If you're enjoying this podcast and would like to support us, please subscribe on YouTube, Apple Podcasts and Spotify. On Apple, you have the opportunity to leave us up to a five-star review. Also check out the sponsors that we mentioned at the start of the episode. probably the best way to support the show. We also have a Patreon account. That's patreon.com/DavidSinclair, and there you can support the show at any level you'd like. Thanks again for joining us on this episode of the Lifespan Podcast.