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David Sinclair (00:00):
Welcome to the Lifespan Podcast, where we discuss the science of aging and how to be healthier at any stage of life. 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.
Matthew LaPlante (00:21):
Hey. Hey, welcome. How are we doing? Feel good today. We’re back at it again.
David Sinclair (00:24):
We are. We are here today to talk about how to live longer and better.
Matthew LaPlante (00:29):
That’s part of this podcast series. Yeah, this series. A deep dive into the things that you can do to slow, stop, and reverse aging.
David Sinclair (00:35):
That is true. And today is gonna be a really interesting one.
Matthew LaPlante (00:39):
This is gonna be the one that everybody, I mean, this is the one that everybody’s been begging for.
David Sinclair (00:43):
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 one.
Matthew LaPlante (00:53):
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 Metformin? We’re gonna be talking about all of that today.
David Sinclair (01:03):
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 gonna 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.
Matthew LaPlante (01:19):
Yeah. We do need to say, we usually take a moment to thank our sponsors. We’re gonna do that, of course. But we also have to take a moment to say, we are not medical doctors. We are not medical doctors. We are not medical doctors.
David Sinclair (01:33):
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 distilled that for everybody. But of course, if you want to try a 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.
Matthew LaPlante (01:58):
And what we wanna do is give people the ability to have a more intelligent and informed conversation with their physician. Exactly. Okay, with that out of the way, now we should thank our sponsors.
David Sinclair (02:10):
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 slash Sinclair. That’s levels.link slash Sinclair. Today’s podcast is also brought to us by Inside Tracker. Inside Tracker 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 Inside Tracker for over a decade and also serve as chair of their advisory board. I really like Inside Tracker because they make it easy to get your blood test. Either someone can come to your home like they do for me, or you can go to a clinic. They then present the blood analysis in an easy-to-understand dashboard that provides recommendations for improving your health. Their InnerAge 2.0 test, which I helped develop using an AI algorithm, even shows your biological age. If you’d like to try Inside Tracker, you should go visit them at insidetracker.com slash Sinclair, and you’ll get 25% off every Inside Tracker plan. Use Sinclair as the code at the checkout. Today’s episode is also brought to us by Athletic Greens, the all-in-one daily drink to support better health and peak performance.
Athletic Greens is a greens powder developed from a complex blend of 75 vitamins, minerals, and whole food-sourced ingredients. It’s filled with adaptogens for recovery, probiotics and digestive enzymes for gut health, as well as vitamin C and zinc citrate for immune support.
I’ve been drinking Athletic Greens in the morning for many years, and I do that because I don’t often eat perfectly and I travel a lot, and I can rest assured that I’m getting all the nutrients I need for optimal health. So if you’d like to try Athletic Greens, you can go to athleticgreens.com slash Sinclair to claim a special offer. They’re giving away five free travel packs, plus a year’s supply of vitamin D3 for immune support, and vitamin K2 for keeping calcium out of your arteries and putting it where it’s needed into your bones.
Again, go to athleticgreens.com slash 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.
Matthew LaPlante (04:53):
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 the world and 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 sedentariness, sedentary, is that a word? Sedentary lifestyles? Sedentary lifestyles. And that’s not to mention the fact that even before modern times, we aged, right? So if we’re gonna combat aging, we may need an additional boost. We believe we may need an additional boost.
David Sinclair (05:34):
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 wanna 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.
Matthew LaPlante (05:53):
Supplements and medicines, drugs and supplements, molecules and drugs, there are a lot of different terms that we’re probably gonna throw around and we’re gonna use them fairly synonymously, but in fairness, let’s define drug versus supplement at least.
David Sinclair (06:08):
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 a 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 they’re a thousand times more concentrated than what you’re eating.
Matthew LaPlante (06:36):
Which may or may not be the case.
David Sinclair (06:40):
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 a 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.
Matthew LaPlante (07:19):
And there are literally thousands of drugs and supplements that someone somewhere will tell you will help you with health spans and life spans. We’re not gonna talk about thousands of drugs and supplements today.
David Sinclair (07:32):
No, maybe in future episodes we’ll come back, but we wanna hit the high points today.
Matthew LaPlante (07:36):
And so that’s why today we’re gonna 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.
David Sinclair (07:50):
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 gonna cover today. Your most pressing questions answered here today.
Matthew LaPlante (08:10):
And so we’re gonna talk about NAD boosters. We’re gonna talk about metformin, berberine, rapamycin, spermidine, resveratrol, fisodin and curcidin, 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 watched this whole episode and need a reminder, the show notes are gonna be timestamped so you can immediately go to berberine and find it and click on it.
David Sinclair (08:35):
That’s right, included in the show notes are the scientific references that we now have in front of us that we’re gonna talk about so that people can do a deep dive, even deeper than what we’re gonna do here today.
Matthew LaPlante (08:45):
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, ah, 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.
David Sinclair (09:09):
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.
Matthew LaPlante (09:25):
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.
David Sinclair (09:34):
Right, I’ve actively kept myself away from the supplement industry because I wanna be able to talk about things without any bias.
Matthew LaPlante (09:41):
Not for lack of opportunity, though. There’s plenty of people who would love to put your face on a package.
David Sinclair (09:46):
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.
Matthew LaPlante (09:54):
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. Sirtuin’s, AMPK, and mTOR. Different drugs and supplements are thought to work on these different pathways in different ways. And we’ll sort of like categorize them in those three buckets today.
David Sinclair (10:14):
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 two. So it’s a network, and we’re still trying to figure out exactly what the optimal combination for each individual is. 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 gonna present the cutting edge science here today.
Matthew LaPlante (10:47):
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 a AMPK effect. There’s also an mTOR connection there.
David Sinclair (11:06):
Well, they definitely talk to each other. And because if you’re low on amino acids and it’ll turn on the mTOR 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 we’re 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.
Matthew LaPlante (11:32):
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?
David Sinclair (11:53):
Well, we’d be dead in 30 seconds. We need 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.
Matthew LaPlante (12:06):
And we didn’t say what that stands for, that’s…
David Sinclair (12:08):
So NAD stands for nicotinamide, which is vitamin B3 and adenine dinucleotide. 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 co-discovered in the 2000s. It activates the sirtuins, and the sirtuins are 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.
Matthew LaPlante (13:06):
And this is because NAD is a sensor for adversity.
David Sinclair (13:12):
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 gonna have lower NAD levels by the time you’re in the latter half of your life. So 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 younger. When you were young.
Matthew LaPlante (13:33):
Okay, so let’s talk about the first NAD booster, probably the most well-known. It’s definitely the most well-studied of the NAD boosters and probably the most taken, used. That’s NR.
David Sinclair (13:46):
Which stands for nicotinamide riboside. So 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, what, since 2014, either solely, just as a capsule, or there’s some companies that sell it in combination with other molecules.
Matthew LaPlante (14:11):
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.
David Sinclair (14:24):
That’s for sure. And 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. And in fact, you will raise NAD levels in blood tests.
Matthew LaPlante (14:38):
So I think this is an important distinction to make, though, like there’s a difference between safe and effective, right? Just because we say something is safe doesn’t mean it’s gonna work or not. And in fact, sometimes things that are the most safe aren’t gonna work at all. That’s why they’re so safe is they don’t have any effect. But we do know that NR is largely safe. You know, 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.
David Sinclair (15:09):
Go even further back. Okay, yeah. So that’s where it was first discovered. NR was a newly discovered molecule back in the early 2000s. It’s found a little bit in milk and other food stuffs. And if it was fed to yeast, they lived longer by turning on the yeast sirtuin pathway.
Matthew LaPlante (15:25):
Okay, how much longer were the yeast living?
David Sinclair (15:28):
Generally, yeast live 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 sirtuins and give increased genome stability and epigenome stability that really lengthens their life.
Matthew LaPlante (15:43):
And those kinds of findings make you really interested because you’re really interested in the sirtuin activation. And so you’ve been part of a group of scientists that have been looking at this.
David Sinclair (15:53):
Yeah, one of the first things that we discovered, this is now, we’re talking 2002, 2003 in my lab, is that there’s an NAD synthesis gene called PNC1. In our body, it’s called an amputee. 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 shown that you can mimic this effect with this NR. How does 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 taken up into your muscle, into your brain and other cells that by transport is called ENTs. 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.
Matthew LaPlante (16:56):
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?
David Sinclair (17:09):
Yeah, it’s going back a number of years ago, it was found that NR, when given to mice, extends their 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. And 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.
Matthew LaPlante (17:41):
Among the other health benefits that have been seen by researchers who have given NR to animals in the lab, enhanced oxidative metabolism.
David Sinclair (17:54):
So they burn more fat, 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.
Matthew LaPlante (18:04):
Let’s carry this now into the human studies, because what we don’t have for reasons that maybe are obvious, but I’m gonna 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 than 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.
David Sinclair (18:38):
Somewhat, I would say NR, there’d been 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 NAD levels anywhere near the level that NR does. And 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 to add on there before it becomes active. Okay, back to the human studies on NR.
Matthew LaPlante (19:22):
We have sought to see, by 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. I think it’s fair to say.
David Sinclair (19:50):
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, a gram a day, does raise NAD levels. But it takes about nine to 10 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 borne out just yet in these short-term studies with NR.
Matthew LaPlante (20:27):
Sorry, these are the things that were present in the mice who also lived longer.
David Sinclair (20:34):
Right, yeah. Now, it could be that you need a longer-term exposure of these people. These have been fairly short-term studies. Or that humans are not the same as mice.
Matthew LaPlante (20:44):
So would you say, I mean, if somebody 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.
David Sinclair (20:55):
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 terastilbene, which is a resveratrol-like molecule. We’ll talk about resveratrol next. That found that in ALS patients, Lou Gehrig’s disease, there was an improvement in their function, daily 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.
Matthew LaPlante (21:26):
It’s fair to say that in the SIRTU-inactivated compound research community, there’s kind of team NR, and then there’s team NMN. Your lab really focuses on NMN. And I think if people were sort of like following what you said earlier about how NR turns into NAD, they might go, oh, well, NR turns into NMN, NMN turns into NAD, so why don’t we just take NMN to begin with anyway? And you had mentioned earlier phosphate, and that’s an important component of this question.
David Sinclair (22:03):
Well, it is. 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 Kaeberlein, who’s at Wash U, who treated a mitochondrial 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.
Matthew LaPlante (22:50):
When we supplement with NMN, when NMN is given to organisms in the lab, what’s happening?
David Sinclair (22:58):
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 actually are giving themselves NAD through the IV route. When it comes to NMN, what happens is, it was recently discovered by Shin Imai at Wash U, his team discovered that there’s a specific transporter that takes NMN out of the liquid outside the cells, inside the cell, and its name is SLC-128A.
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.
Matthew LaPlante (23:54):
So when it comes to NMN, there’s been a number of animal studies showing, for instance, similar to NR, it 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 an immense effect across analysis, entire lifespan yet. Well, we have half a lifespan.
David Sinclair (24:17):
Shin Imai showed that it actually was pretty good at slowing down the effects of aging, but he stopped the experiment because he ran out of NMN. 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 life. 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 NMN. The doses are about 400 mgs per kg.
How much longer? At this point, my recollection is about 10 to 15%, but particularly strong in females.
Matthew LaPlante (24:58):
Okay, so not particularly like wholly different than what we saw in the NR cases with the mice?
David Sinclair (25:04):
Right, a little bit better than that, but certainly those mice are healthier and more active and more youthful.
Matthew LaPlante (25:11):
And you said it’s more pronounced than the females, or at least according to the first phase of this, it’s more pronounced than the females? Right, so it’s more pronounced than the females.
David Sinclair (25:18):
Right, well, we had fewer females, so we have to repeat that. So we’ve now got a larger cohort of mice. We’re repeating the 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.
Matthew LaPlante (25:28):
And 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.
David Sinclair (25:45):
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 is another three or four. That’s a decade’s worth of work for one experiment. And your career only goes for about five of those times. So five experiments?
Matthew LaPlante (26:05):
Of course, you can run them parallel. Well, that’s how careers used to go. We’re gonna change that, right?
David Sinclair (26:08):
We’re gonna live a lot longer. We run things in parallel as well. That’s important. But we can also mimic things, not just in animals, but with growing tissues, and the dish will be the subject of a later episode.
Matthew LaPlante (26:20):
Okay, so far what I’m hearing is in animals, NR and NMN both have some similar effects, right? Lengthening 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?
David Sinclair (26:46):
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, 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.
Matthew LaPlante (27:22):
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.
David Sinclair (27:47):
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, and my clinical trials are 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 hallmark of longevity, keeping the glucose out of the bloodstream, keeping it low levels is a hallmark 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 note, are 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, even increased wound healing. I’d love to know if NMN does that in humans. That’d 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 NAD-boosting molecules that have been made that are even better than NMN, so-called NCEs, called new chemical entities, and those, I’m aware, probably in the next year will go into the first human studies.
Matthew LaPlante (29:17):
And that’s a, I mean, that can be in a whole episode of this podcast in and of itself, yeah? We should do it. Yeah, okay. Why don’t we just give NAD directly? We’re talking about like NAD boosters, NR creates NMN, NMN creates NAD. That boosts NAD, or NMN boosts NAD, but it all gets us to NAD, so why don’t we just, you know, set up the drip line and get it going?
David Sinclair (29:42):
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 over an hour of NAD.
Matthew LaPlante (29:54):
These are not in study settings. This is not in a research setting. This is like people trying this out.
David Sinclair (30:01):
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 wishful thinking or not. I 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 know, you cannot conclude anything unless you actually have one of these placebo-controlled trials. I’d love to be involved if anybody’s gonna do one. I’d love to help, but I’m asked this probably every day. NAD IVs, do they work? And my answer has to be, we don’t know yet.
Matthew LaPlante (30:34):
What do we think they might be? I mean, what are people trying them for?
David Sinclair (30:37):
Well, they’re used 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.
Matthew LaPlante (30:48):
Is it as good as the Australian hangover cure that you’ve given me a few times?
David Sinclair (30:53):
Oh, the raw egg and the Vegemite? I hope it’s better than that.
Matthew LaPlante (30:57):
But the idea- Because the truth is that doesn’t work. I just pretend it works because it makes you happy.
David Sinclair (31:03):
That’s true, and you’re one of the few people that eats my Vegemite. But the reason that it probably works is there’s an enzyme that’s too high in the body is an enzyme that detoxifies alcohol called alcohol dehydrogenase. And a lot of Asians are susceptible to high levels of alcohol because they lack a lot of this enzyme. Alcohol dehydrogenase needs NAD. And so what’s probably happening is when you wake up with a hangover, you lack NAD, your liver is depleted, and if you take NMN or NR, you can raise those levels back up, get your liver working again and get rid of the excess alcohol.
Matthew LaPlante (31:35):
So you think chances are that is actually, it’s not just like a placebo effect, that there’s a chance that like, it makes sense that that would work.
David Sinclair (31:43):
I think makes sense is the right word to use. You know, 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.
Matthew LaPlante (31:53):
Just so I’m clear on this, though, because it’s still a little fuzzy to me, like why we, 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.
David Sinclair (32:12):
Yeah, well, it all started in yeast when I was at Harvard in 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 want to do is back off in size. So the next smaller molecule behind NAD is NMN, and there we know there’s a transporter 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.
Matthew LaPlante (32:46):
This feels like a good time to talk about bioavailability and making things available to you. Making things available to our body’s machinery. How do we make NR and NMN most bioavailable?
David Sinclair (32:57):
Just swallowing it is enough in our studies to raise NAD by two to three fold.
Matthew LaPlante (33:01):
So if you buy the, for instance, the capsules that are often sold in capsules, just swallowing, that’s going to be-
David Sinclair (33:06):
Or the powder, just drink it. 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.
Matthew LaPlante (33:23):
But in terms of the research right now, it doesn’t seem like there’s a huge advantage one way or another.
David Sinclair (33:29):
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.
Matthew LaPlante (33:41):
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 no 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?
David Sinclair (34:06):
Well, so most of these studies, actually there’s only two main studies have been done in mice. So here’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, oh, 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, but there is one other study that came out in 2019 by Nacarelli and they found that NAMPT, this NAD boosting gene, it increases the number of senescent cells and makes them more inflammatory, giving out these SASP proteins as they’re called, the senescence associated secretory phenotype is the word.
But also there were mice that were predisposed to pancreatic cancer. And when given NMN, they developed more precancerous and cancerous growths when they consumed this NMN. Exactly how it works, we’re not sure, but it might be because it was down-regulating a tumor suppressor gene called p53.
Matthew LaPlante (35:07):
And this was a subgroup of mice that were already predisposed. They had a gene that made them more likely to get cancer.
David Sinclair (35:12):
Right, but remember we fed NMN to mice, the normal mice, not predisposed. And if anything, they live longer and healthier. So it’s questioned whether it’s this predisposition that’s the difference.
Matthew LaPlante (35:23):
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.
David Sinclair (35:30):
For sure, and another reason to consult your physician.
Matthew LaPlante (35:33):
Absolutely, okay. Now there are other NAD boosters sort of 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 resveratrol. You started working with resveratrol back when you were trying to understand Sirtuin activation in yeast.
David Sinclair (35:60):
Right, I was just a kid. I was in my early thirties and what I was, I’d just come out of MIT with Lenny Guaranti where we’d found that up-regulating the Sirtuin gene in yeast extends their lifespan. But of course we can’t up-regulate genes easily in our body. We’re not gonna genetically modify ourselves anytime soon. Not anytime soon. We can, but we’re not gonna. 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 SIRT1 activation. SIRT1 is the first out of seven of them in the body. And Conrad Howitz, 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 SIRT1 and found which ones raised the level of fluorescence.
Matthew LaPlante (37:05):
And you found a bunch of them. There were like 20 of them that did. We published 20, yeah, in Nature, 2003.
David Sinclair (37:08):
The one that was the best at the time, which activated 13-fold SIRT1 activity was resveratrol. And there were others, quercetin, fazetin, which are actually now used by others for longevity. But resveratrol got most of the attention because it’s found in red wine.
Matthew LaPlante (37:25):
And you’ve told me this a bunch of times, red wine stock went out the route, right? Like people started buying red wine like crazy. Even the SITP print.
David Sinclair (37:31):
Oh, 30% 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-
Matthew LaPlante (37:38):
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?
David Sinclair (37:48):
Right, you know, you can’t drink enough red wine to get the kind of doses that are efficacious. 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 recommend it. That’s not gonna extend your life? Probably not, no. But what you can do is you can purify it out of grapevines or polygonum cuspidatum, which is an herb, a plant, mostly grown in the United States, a herb, a plant, mostly grown in Asia.
Matthew LaPlante (38:15):
When you say that, can you just take your pen? Take your pen. All right, now say that word again and go like this when you do it.
David Sinclair (38:20):
Polygonum cuspidatum. Okay, thank you. I appreciate that. This is magic, I think, by Harry Potter.
Matthew LaPlante (38:25):
Yeah. How much resveratrol do we actually need to see an effect?
David Sinclair (38:29):
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.
Matthew LaPlante (38:38):
This is a CERT activator. Like the other NAD boosters we’ve been talking about, works a little bit differently, but like you said, really well studied, and for almost 20 years now, what’s happening when we put resveratrol, let’s start with the animal studies. What do we know?
David Sinclair (38:57):
Well, we know, first of all, if you just give it to them in their water supply, it’s not gonna 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 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.
Matthew LaPlante (39:24):
And this is actually why you suggested that maybe some resveratrol studies that have shown 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.
David Sinclair (39:42):
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.
Matthew LaPlante (39:52):
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 rodents. What are these things telling you?
David Sinclair (40:13):
Well, they’re similar to what we expected from the sirtuins. They defend the body. They raise the body. They raise the metabolic rate. They protect against free radicals. And when we see resveratrol 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 resveratrol, 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.
Matthew LaPlante (40:54):
Have those findings translated over as we’ve moved resveratrol into human studies?
David Sinclair (40:59):
Yes, somewhat. Not all studies have worked, but there are a number of them that have. And for instance, resveratrol has been shown to reduce fasting glucose and significantly increase insulin sensitivity. This was a study in 2019. And then again, in 2020, Battista 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.
Matthew LaPlante (41:37):
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.
David Sinclair (41:50):
Yeah, I think so. Even before I worked on resveratrol, it was known to be an agent that suppressed cancer.
If you put a carcinogen on the skin of mice and then rub resveratrol on it, a 1999 science paper showed that those cancers are much smaller in those treated mice. So the anti-cancer activity of resveratrol 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 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.
Matthew LaPlante (42:37):
Does it, is that right? 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.
David Sinclair (42:50):
There’s two considerations here. One is that, you know, 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 resveratrol, and it has some of these other xenohormatic polyphenols that we talked about in earlier episodes that could give a combination effect.
Matthew LaPlante (43:08):
There are two other molecules I wanted to mention. You mentioned them earlier, actually, by name. These were part of the group of molecules that were identified in those early experiments with the yeast that identified resveratrol as a potential sirtuin-activating compound. These are fisodin and curcidin. 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.
David Sinclair (43:40):
Right, they are what are called senolytic, killed senescent cells.
Matthew LaPlante (43:45):
And senescent cells..
David Sinclair (43:46):
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.
Matthew LaPlante (43:60):
Yeah, and so getting rid of those would be presumably a good thing. And that’s what fisodin and curcidin appear to do.
David Sinclair (44:08):
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.
Matthew LaPlante (44:18):
And these have been shown in the case of fisodin, at least, to extend lifespans in some model organisms.
David Sinclair (44:26):
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 fisodin 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 SIRT1 defenses.
Matthew LaPlante (44:56):
And there’s been human studies in both of these as well. I know we kind of talk about these in a group because they were discovered as SIRT2 inactivators and now they’re being seen also as potential senolytics, but maybe we can differentiate a little.
David Sinclair (45:12):
Well, a lot more is known about quercetin. That was discovered first as a senolytic by Jim Kochel under the Mayo Clinic, who combined it with a drug called dasatinib 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.
Matthew LaPlante (45:32):
And we’ve had some randomized controlled trials with humans in quercetin. The effects are?
David Sinclair (45:37):
Reduces liver steatosis, or fatty liver, 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 quercetin and dasatinib.
Matthew LaPlante (45:50):
Dasatinib is a drug that’s used to treat leukemia. It’s got a lot of promise as a senolytic too, it seems. As of right now, you can really only get it for treatment for leukemia.
David Sinclair (46:03):
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 Navetoclax. These are being tested. They’re not ready for prime time at all. But fasetin is the interesting one. That one is a plant molecule. It’s found in grapes, it’s found in apples, high levels, relatively high levels in strawberries. You can now buy that relatively cheaply on the internet.
Matthew LaPlante (46:28):
So if people are like, man, I really wanna get into senolytics, the gateway right now, the most accessible place for people is fasetin.
David Sinclair (46:37):
Well, it is. But it’s early days. There’s not a lot of data compared to quercetin and dasatinib. 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 Affirm Light study by Jim Kirkland with fasetin. He’s got a number of patients that are on 20 milligrams per kilogram of body weight. And this, over the next year or so, should tell us whether fasetin is truly a senolytic in humans and can have some health benefits too.
Matthew LaPlante (47:10):
Okay, so there’s a third class of drugs we wanna talk about today. We’re gonna spend too much time with them because broadly speaking, they’re not available for purchase or even prescription right now, except for in very, very narrow instances. I’m talking about rapamycin and these drugs that are rapalogs, drugs that are supposed to mimic the drug to mimic the effects of rapamycin, perhaps without all the toxicity. These drugs have a really interesting history.
David Sinclair (47:38):
Well, they do. These are drugs that inhibit mTOR, which is mimicking fasting. They were discovered a number of years ago on Easter Island, Rapa Nui, which is why they’re called, it’s called rapamycin. On the back of a statue, I believe, somebody found-
Matthew LaPlante (47:52):
Yeah, there’s like the mold and there’s some fungus and they scraped it off and lo 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.
David Sinclair (48:08):
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 to suppress your 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. So you have to be extremely careful and right now it’s not available.
Matthew LaPlante (48:38):
And rapamycin works by inhibiting mTOR.
David Sinclair (48:42):
Yeah. Yeah. Actually, TOR stands for target of rapamycin. So that’s how mTOR was discovered. And when you give animals rapamycin, you’re mimicking low protein intake. Which we know-
Matthew LaPlante (48:54):
You’re mimicking this adversity that we’ve been talking about throughout this entire series.
David Sinclair (48:58):
Right. So your body 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.
Matthew LaPlante (49:10):
And that brings us to another drug, spermidine, which is also working on this autophagy process.
David Sinclair (49:22):
It does. So spermidine is more recent. You’ve only recently been able to get it on the internet. It has an interesting history. Anthony von Leeuwenhoek, 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 getting a lot of information but he started to get crystals in the sperm. And that was spermidine, hence the name.
Matthew LaPlante (49:41):
Kids, if you want to get into science. And what do we know about spermidine 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.
David Sinclair (50:01):
And even mice. There’s a new study that was really compelling. If you give spermidine to mice, either when they’re young or even late in life, they live longer and they have better heart function and other youthful capacities. There are two ways that spermidine is known to work in mammalian cells. One is it stimulates autophagy, just like rapamycin does in the mTOR 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.
Matthew LaPlante (50:31):
There’ve been a number of human studies on spermidine, particularly revolving around enhancing memory and dealing with memory loss in older Americans.
David Sinclair (50:40):
That’s true. We don’t know a lot about aging itself, but cognition has greatly improved in a number of studies. The one that stands out for me is the one by Schwartz et al. 2018. They were giving people 1.2 grams per day over three months, and there was significant enhancement of memory.
Matthew LaPlante (50:56):
I want to go back to the history of this stuff. You mentioned earlier that Anthony von Lomthoek discovered the crystalline structures that led us to spermidine by examining his own sperm, presumably his own sperm in a microscope. Is that still where we’re getting sperm, adene? No, not that I know of.
David Sinclair (51:17):
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.
Matthew LaPlante (51:27):
All right, we’ve talked about sirtuin 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.
David Sinclair (51:56):
Yeah, it’s been used since the 1950s as the frontline medicine to bring down glucose levels in type 2 diabetics, and it’s relatively safe as a drug goes. In half the world, it’s available over the counter at pharmacies. Here in the U.S. and in Europe and UK, Australia, you need a prescription.
Matthew LaPlante (52:13):
We know that metformin works by activating AMPK. Do we know how that process kind of unveils itself?
David Sinclair (52:21):
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 protein complex called complex 1, which is involved in making energy in mitochondria, and 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, and then you get mitohormesis, mitochondrial hormesis. What doesn’t kill the cell makes it stronger, and the reaction is twofold. One is to make more mitochondria, so you get more energy a few days later, but also by inhibiting mTOR, it’ll 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.
Matthew LaPlante (53:11):
And 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 impacted.
David Sinclair (53:21):
Yeah, similarly to all of these factors which are talking to each other, this is a good example. Metformin will lower energy inhibit mTOR. 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 sirtuin.
So metformin is a remarkable molecule, comes from the plant world, it’s very simple. The French hellebore or lilac plant produces what’s called guanidines, and these have been known to treat diabetes for many years, in fact, over a century. And then chemists have put methyls on them, chemically modified it so that it’s more stable, and we call this metformin, and that’s what we have as the drug today.
Matthew LaPlante (54:02):
And we’ve given this drug to animals and worms, it’s extended lifespans, 30 to 40 days, which is no small amount of extension for a worm.
David Sinclair (54:13):
Yeah, I was involved in the mouse study with Rafael de Cabo down at the NIH, and we found that the mice were healthier and longer-lived on metformin.
Matthew LaPlante (54:22):
And what are the other things, because again, what we wanna look for, if we wanna know if metformin is working in humans like it works in animals, we’re not necessarily just gonna look at the lifespan extension, because that takes a long time, what are sort of the intermediary things that we’re seeing with metformin? In humans, you mean? Well, in animals that we can look for in humans.
David Sinclair (54:41):
Well, the main one, of course, is glucose-lowering, but we also see more energy, more mitochondria, 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. And you can see that switch back when you give them metformin, like they’re more like an athlete. And we’re seeing all of these things in animals
Matthew LaPlante (55:01):
and also in humans. Right, and this is where we can speak to a lot of data,
David Sinclair (55:05):
because millions of people have taken metformin, and one of the most interesting things about it is you can do a retrospective study of tens of thousands of elderly people on metformin 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? And the answer that’s quite remarkable is that they’re not.
Matthew LaPlante (55:34):
So, when we control for everything else, what we see is that the people who are on metformin are living longer.
David Sinclair (55:41):
Than people who don’t have type 2 diabetes. It’s a remarkable fact.
Matthew LaPlante (55:45):
So, now the question becomes, okay, take the type 2 diabetes part of the equation out, will we still see an effect? And then we can say, okay, the question is, will we still see an effect? And then we can say, okay, will we still see an effect? And that is something that’s being investigated in this really large study that’s underway, the TAME study.
David Sinclair (55:59):
Yeah, you’re right. The Targeting of Aging by Metformin Study run by Neil Barzilai 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 a while to raise that money, but 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.
Matthew LaPlante (56:25):
Why is it taking so long to raise money for this? Because this is really, I mean, everybody I know in the aging space is excited about this, and yet the money is hard to come by because…
David Sinclair (56:36):
Well, this is where capitalism has a little bit of a downside, which is that Metformin is very cheap. It costs a few cents and it’s off patent. So…
Matthew LaPlante (56:44):
Which means anybody can make it, there’s no profit motive for making this drug, right?
David Sinclair (56:50):
Right, so Neera’s relied on the government and 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 and 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.
Matthew LaPlante (57:26):
We’re seeing a lot of doctors get a lot more comfortable with the idea of prescribing Metformin off label. Just a few years ago, the constraints of what Metformin was actually approved for was keeping it out of the hands of a lot of people who thought that it might be good for them in their efforts to slow their aging. There’s starting to be a little bit of a shift there.
David Sinclair (57:49):
Well, yeah, I’m seeing a lot more people taking Metformin 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 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 Metformin has some downsides. One is that it can cause lactic acidosis, which is quite a severe condition. It can be fatal. So you have to be very careful there. But most people are fine on Metformin. The biggest thing that happens to them is that they have an upset stomach, lack of hunger, lack of hunger, which can actually be a good thing if you want to lose weight as well.
Matthew LaPlante (58:34):
But doctors now are saying, okay, advising their patients as 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 the medications, and they’re prescribing it to pre-diabetic people and pre, what we might call pre-pre-diabetic people.
David Sinclair (59:08):
Well, 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.
Matthew LaPlante (59:19):
The one other thing that people should talk to the doctors about if they’re considering trying to get on metformin is the concerns about the connection between metformin and muscle loss.
David Sinclair (59:34):
Right, particularly in the elderly, this is an issue. But actually, if you look at the data in a couple of human studies, metformin doesn’t make a big difference to muscle size. It probably makes a difference in the 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 a 5% difference. And actually a 5% difference, I’ll give up 5% body size for longevity any day. But the other important thing is that those muscles on metformin were just as strong as the others and had less inflammation. So there’s other benefits to that. What 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 does it affect exercise? 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.
Matthew LaPlante (01:00:27):
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 with them, 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 berberine.
David Sinclair (01:00:50):
That’s right. This is a molecule from the plant world, bark and roots. You can find it’s a yellow substance. Again, it’s fairly insoluble. So if you want to take it, take it with some food, yogurt, olive oil, 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 mitohormesis is to amplify up 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, one to two grams per day, but it does seem to work.
Matthew LaPlante (01:01:30):
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.
David Sinclair (01:01:44):
Yeah, actually it’s really interesting. In mice, berberine 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.
Matthew LaPlante (01:02:01):
And I think you said you got to take quite a bit of this stuff though.
David Sinclair (01:02:04):
Yeah, the clinical studies, it’s at least a gram. There’s one that worked with two grams, but it does seem to work just like metformin in improving the body’s sensitivity to insulin and lowering the blood glucose levels, which is a good sign that it’s going to have future health benefits.
Matthew LaPlante (01:02:18):
Any concerns about side effects with berberine?
David Sinclair (01:02:20):
I’m not aware of any downside of berberine.
Matthew LaPlante (01:02:23):
We should say berberine does have some of the similar side effects of metformin. We don’t know in different groups of people, it might be different, but you’re looking at diarrhea, constipation, gas, potentially upset stomach.
David Sinclair (01:02:34):
Right, yeah, no molecules, 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.
Matthew LaPlante (01:02:43):
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 a chronology. When you started investigating resveratrol, you also started taking resveratrol. How did you know how much to take though? Because you were giving resveratrol to yeast and eventually to mice. Well, it’s not a one-to-one.
David Sinclair (01:03:27):
It’s not like you should take 3,000 times as much as the mouse had.
Matthew LaPlante (01:03:32):
It’s more 3,000 times bigger than a mouse.
David Sinclair (01:03:34):
Right, 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 allometric 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 a very small amount of human blood that’s about 1.2 grams per human. One to one, turns out we have about the same surface area as a mini pig.
Matthew LaPlante (01:03:58):
And so you take about a gram of resveratrol every day?
David Sinclair (01:04:01):
I do, and I’ve been taking that since about 2004. And, but like I said, you can’t just put it in water and drink it.
Matthew LaPlante (01:04:08):
You gotta add some fat to it.
David Sinclair (01:04:10):
Yeah, so I typically have some yogurt, a couple of spoonfuls, not a lot, because I’m trying to fast until dinner. 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 sirtuins, but also you can dissolve resveratrol in it. Do you get a twofer? 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 mix it with a bit of vinegar and basil leaves and it doesn’t taste too bad.
Matthew LaPlante (01:04:36):
Okay, so resveratrol, you’re taking about a gram a day in the morning. Also in the morning, you take NMN.
David Sinclair (01:04:43):
I do, and there 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? Again, it’s gram, but that’s not a 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.
Matthew LaPlante (01:05:02):
And that’s sort of the dosing amount that we’re seeing in a lot of the human studies now. And it’s both the past studies and the current studies.
David Sinclair (01:05:09):
Yeah, I take one gram of NMN every morning, along with my resveratrol. 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 SIRT1 activity should happen. And we actually know this, that the SIRT1-NAD cycle is part of our body’s natural 24-hour clock. SIRT1 regulates a protein called BMAL that controls the genes that tell us whether it’s night or day, should we be hungry or not, 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 sensibly through the SIRT1-BMAL pathway.
Matthew LaPlante (01:06:00):
You’re also taking Metformin? Yeah.
David Sinclair (01:06:03):
How much, when? I take 800 milligrams at night.
Matthew LaPlante (01:06:08):
Okay. And you take that at night because?
David Sinclair (01:06:10):
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 and my body has all the benefits of stimulating those repair pathways, those survival genes.
Matthew LaPlante (01:06:26):
And that’s the most recent thing that you’ve added to your regimen?
David Sinclair (01:06:29):
It is, actually what happened was I had terrible blood biochemistry, 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 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.
Matthew LaPlante (01:06:47):
We mentioned earlier some concerns about exercise in Metformin. Your practices were that concerned?
David Sinclair (01:06:56):
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.
Matthew LaPlante (01:07:05):
And then there’s also Spermidine?
David Sinclair (01:07:08):
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 Insight Tracker.
Matthew LaPlante (01:07:19):
Okay, so that’s not something that 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.
David Sinclair (01:07:27):
I am, and I 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.
Matthew LaPlante (01:07:37):
How much of that are you taking?
David Sinclair (01:07:38):
A gram as well.
Matthew LaPlante (01:07:41):
Oh. You are also periodically taking fisetin, curcidin aimed at senescent cells.
David Sinclair (01:07:50):
There are clinical trials being run out of the Mayo Clinic for fisetin and for curcidin. These are high doses. They’re 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.
Matthew LaPlante (01:08:05):
Let’s take this morning through night just really quickly. Risperatrol, one gram.
David Sinclair (01:08:09):
In the morning with yogurt or olive oil.
Matthew LaPlante (01:08:11):
NMN as well. A gram, yep. Fisetin and curcidin.
David Sinclair (01:08:14):
Half a gram in the yogurt. Spermidine. Definitely spermidine, yeah, in the morning. About a gram.
Matthew LaPlante (01:08:20):
And then in the evenings, if you’re not working out the next day, metformin, how much? 800 milligrams.
David Sinclair (01:08:27):
Okay. Okay, that’s it.
Matthew LaPlante (01:08:28):
That’s it. Now, you’re not most people. A lot of other people are gonna 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?
David Sinclair (01:08:40):
Well, I think so. Most doctors are open to looking at, say, inside tracker data and hearing about the latest science. It’s very difficult for them to keep up with it. It’s one of the reasons we’re doing this podcast in the first place.
Matthew LaPlante (01:08:52):
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 a future season of Lifespan 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 wanna bring into their lives, and if so, how, of course, again, in consultation with their physician.
David Sinclair (01:09:24):
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 AST, ALT. I do that routinely just to make sure nothing’s going wrong in that regard.
Matthew LaPlante (01:09:37):
Our next episode is :
David Sinclair (01:09:38):
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 gonna 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. That’s probably the best way to support the show. We also have a Patreon account. That’s patreon.com slash David Sinclair, 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.
In this week’s episode, Dr. David Sinclair and co-host Matthew LaPlante zero in on drugs and supplements that have been reported to combat aspects of aging. They share the latest experimental and clinical data for NAD boosters, resveratrol, fisetin, quercetin, rapamycin, spermidine, metformin, and berberine. Given the abundance of data available, a special focus is placed on the NAD precursors nicotinamide riboside and nicotinamide mononucleotide. Known mechanisms, limitations, and/or side effects associated with these molecules are additionally highlighted.
Correction and clarification: At time point 1:07:37, Dr. Sinclair says he takes 1 gram of Spermidine, but the active ingredient in the capsules is 1-2 milligrams. We apologize for the confusion.
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Dr. David Sinclair Social:
To stay up to date with David's work to democratize biological age testing and insights, visit tallyhealth.com.
Matthew LaPlante's Social:
(00:00:00) Kicking Off Episode Four: Longevity Molecules
(00:02:15) Thanks the Sponsors
(00:04:46) An An Additional Boost Beyond Adversity Mimetics
(00:05:52) Drugs vs. Supplements and Highlight Points
(00:09:54) Longevity Molecules Target the Survival Circuit
(00:11:33) NAD Boosters
(00:13:32) Nicotinamide Riboside
(00:21:26) Nicotinamide Mononucleotide
(00:29:22) NAD Intravenous Drips
(00:32:45) Bioavailability of NAD Boosters
(00:33:40) NAD and Cancer
(00:42:26) Red Wine and the French Paradox
(0043:08) Fisetin and Quercetin
(00:47:09) Rapamycin and Rapalogs
(01:02:43) Dr. Sinclair’s Protocol for Longevity Molecules
(01:08:51) Wrap-up and Next Week’s Episode: Interventions on the Cutting Edge
(01:09:52) Options for Subscription and Support
For the full show notes, including the peer-reviewed studies, visit the Lifespan podcast website.
Please note that Lifespan with Dr. David Sinclair is distinct from Dr. Sinclair's teaching and research roles at Harvard Medical School. The information provided in this show is not medical advice, nor should it be taken or applied as a replacement for medical advice. The Lifespan with Dr. David Sinclair podcast, its employees, guests and affiliates assume no liability for the application of the information discussed.
Title Card Photo Credit: Mike Blabac
Special thanks to our research assistants, Adiv Johnson & Sarah Ryan.