Dr. David Sinclair on Informational Theory of Aging, Nicotinamide Mononucleotide, Resveratrol &

: Welcome back, my fellow “FoundMyFitness” longevity fans. Today is a pleasure. My guest is Dr. David Sinclair, a professor in the Department of Genetics at Harvard Medical School, where he researches and attempts to understand the biological mechanisms that regulate the

aging

process and how to slow them down. I can't think of a more interesting question than understanding the biological mechanisms that regulate

aging

and how to stop it. I'm also very interested, for sure. : Well, thank you, Rhonda. Thanks for inviting me. : What then are the mechanisms? : What is the secret of the universe? Well, as you know, I've been studying this for over 30 years.

And when we started, we didn't know anything. And then we move on to small yeast cells and then we move on to worms and mice. And now, I and probably a couple dozen other researchers around the world have overcome a barrier of understanding about why we age and how we can reverse it. : Wow. So, what is the... : Detail? : What's the... Yeah, what's the trailer? : Well, there were several advances. Then, in the 1980s, the big breakthrough was that there are... and in the early 90s, that there are genes that control aging. We call these longevity genes, we don't call them anti-aging genes.

We're not talking about anti-aging, we're talking about longevity and life expectancy. And so these longevity genes were first found in organisms like a nematode worm, a tiny one, and yeast cells that we use to bake bread and that's where I started my career at MIT with Lenny Guarente running the lab. And those same genes are in our bodies and in virtually all life forms on Earth. And what we've found is that when you're out running or you're fasting, the reason they're actually beneficial is because they activate those longevity genes to repair your body and make sure you don't age as much. you would do it differently. : Just as a kind of side note, because you mentioned these longevity genes in yeast and worms, one of the first...

So in college, I went to UCSD in San Diego and studied chemistry. And I worked in biotechnology. At that time, it was kind of a start-up, it was Illumina. And I worked in the chemistry department. Now it is a very large company. But I was working there during my junior and senior year of college and, you know, it was like I was doing peptides and doing a lot of organic chemistry and after a while, I just didn't feel very interested. in it more. So I went to the Salk Institute to try biology a little bit because, believe it or not, I didn't have many biology classes as a chemistry major.

I had a few, but it was mostly just, you know, chemistry. And so, at Salk, I joined Andrew Dillin's lab and... which uses, you know, nematode worms to understand the genetics of aging. And I remember the first time I worked with these worms that had a decreased IGF-1 insulin signaling pathway, how they lived 100% longer and how they were young when they were supposed to be dead. And I saw it with my own eyes when I was doing the experiments and I thought, "Shit, this is cool. We have genes that are similar to these little worms and they are like this." You know, that interested me, at least, in the genetic side of aging. : Well, I'm not surprised.

Although I don't do all the experiments in my lab, you might be surprised to know. And people told me the results: "Oh, mice live longer down in the NMN," or whatever, or "We've accelerated aging in mice because we've modified the epigenome," and, you know, all this stuff. It sounds great and, you know, I go back to my email. It's not until I walk into the animal room and see them with my own eyes, and they are living creatures that are getting older and younger. It really is a shock to see them and hold them with your own hands.

So, yeah, that's the excitement. Even with the yeast studies I was doing in the late '90s, I was very intimate with yeast cells. It sounds strange that you can really worship the little microscopic organisms, but you look at them under the microscope and they live for about a week and you have to monitor these stem cells and their little daughter cells that you collect and that you used to eliminate. a microscope and a small pickaxe. You get to know those cells pretty well. You don't give them names, you give them numbers. But when they were getting big, fat, old, sterile and then dying, you know, it was a little pang of sadness that these little ones that you had been taking care of all the time or the women, in this case, were dying.

So I think we biologists get attached to these living organisms and it's really gratifying to see that we're not making them sick, but we're actually ending up making them live longer, healthier lives. : Good. So I became familiar with his work in those days when I was researching these little nematode worms. And I remember some of your work was on

resveratrol

and how

resveratrol

helped regulate one of these, I guess, longevity pathways. Sirtuin, sirtuins and how it was involved, and basically if you could activate them and some of them seem to slow aging. So maybe you could talk a little bit about sirtuins and also what resveratrol is. : Oh, of course.

Let's start with sirtuins. So when I got to MIT, it had just been discovered that there was a gene called SIR4 that, when mutated, made yeast cells live longer. After quite a bit of work, we discovered that the SIR proteins, which are enzymes that control gene expression, turning genes on and off, became deregulated over time, and we discovered that this was because they were being distracted by a lot of DNA. instability that was accumulating in those cells. But the lesson was that the sirtuin enzymes that controlled genes also controlled lifespan, which was a real breakthrough. In reality, no one expected to find genetic regulators that control aging.

We thought we would find producers of antioxidants and DNA repair proteins. That's not what we found, not initially. And then sirtuins became very interesting in yeast and Matt Kaeberlein, who is now in Seattle, is also a leader in the field. He came in and his first project in the lab was to put an extra copy of one of the SIR genes, number two, SIR2, into yeast and those yeast lived 30% longer, and later, Lenny's lab and mine at Harvard They showed that this was through a process of imitation of caloric restriction. If you have a lot of sirtuins, you get the benefits of calorie restriction or diet and other kinds of little stresses on the cells like heat and a little lack of amino acids.

And if we got rid of the sirtuin or SIR2 gene, the real breakthrough was that now calorie restriction no longer works. And that whole setup was the basis for most of the research that the field has been doing since then in the field of sirtuins. Trying to understand that concept from what we learned in the 1990s in our bodies and in mice. And I'm lucky and happy to say that a lot of this is very similar in our bodies too. : And when you say calorie restriction, do you usually mean that, like in mammals and humans, we eat 30% less than normal or something like that? : Yes.

Well, in the old days, we usually took 30%, sometimes even 40% of the mice's food and they were hungry all the time and it was not very pleasant. With yeast, if you're wondering how to restrict yeast calories, we simply lower the sugar level in the petri dish. I think it quintupled and that was enough for them to live longer, but they still grew up quite happy. Nowadays, as you know, intermittent fasting seems to put these longevity genes into action. The sirtuins continue to ring, but it is not always necessary to be hungry. You can eat, you know, four days a week or even six days a week and still have a fasting period that raises sirtuin activity to levels that we think would be beneficial. : Good.

Yes. And there's certainly a lot of overlap, at least in the scientific literature, between calorie restriction and intermittent fasting having beneficial effects, a variety of beneficial health effects. But, you know, some of the differences would obviously be, you know, when you do intermittent fasting, you're shifting your metabolism from carbohydrate metabolism, glucose, to fatty acid metabolism and you start, you know, ketogenesis can kick in. after. , at least if you're doing a longer type of intermittent fasting. So there are certainly some differences between them as well. : Good. Well, one interesting thing that connects everything is that we showed in 2005 in a Science paper that when you take a calorie-restricted rat and you look at its organs... we look at the liver and the muscle, the levels of one of the sirtuin genes, number one, we have seven of these genes.

So we looked at number one because in those days we only had one antibody against number one. It rose dramatically. I think the levels were five to ten times higher in the calorie-restricted livers. And then we recap calorie restriction in the petri dish. We grew cells in serum from calorie-restricted animals and found that this was also sufficient to stimulate this increase in sirtuin production. But going back to what you did in Andy Dillin's lab, we found out that the reason he rose on the plate was because he had low levels of insulin and IGF-1. Because when we returned to normal insulin levels in IGF-1, the sirtuins went back down.

And that was a nice link between... for the first time in mammals, sirtuins, caloric restriction and the insulin pathway. And in fact, in those days, we were all fighting among ourselves because we were going through a paradigm shift, which is always stressful. And Andy was like, "My path is more important to the sirtuins." And then there were the mTOR people saying, "No, no, we have the most important path." And I'm trying to say, "Hey, guys, all paths are important. In fact, they all talk to each other." We show that sirtuins and TOR communicate with each other.

So, fortunately, now in the field, we have grown a little bit and we are wiser and we agree that this network exists, it is not just a direct path from food to a long life and that you can modify one path and the others . will also come to help. : Something that comes to mind when... So you're talking, really, about this important role that calorie restriction or intermittent fasting plays in activating this sirtuin pathway and also in deactivating things like the sirtuin pathway. insulin signaling and the IGF-1 pathway. is the fact that sirtuins are regulated by something called NAD,

nicotinamide

adenine dinucleotide plus.

But that's something that those levels actually increase during a fasted state. : Surely so... Correct. And also in response to exercise. So the reason NAD is so exciting compared to the 1980s, when we thought it was just a household molecule for reactions, is that NAD levels go up and down depending not only on what you eat, but also whether you exercise and even what time of day it is. So during the day your NAD levels will go up and then you'll eat a lot and they'll go back down. And it's... We think it's one of the reasons you're also jet lagged, is that your NAD cycles are out of control. : Are you on a circadian rhythm?

Is it completely regulated by food intake? : It's a combination. It will rise and fall with circadian rhythms, mainly, but you can adjust it within the... : What about macronutrient composition? Do you like it if you eat more fat than carbohydrates? : Yes, nobody knows. It would be a good experiment. As far as I know, the circadian field has not focused on nutrition. But what I can tell you anecdotally is that if I raise my NAD levels when I travel, I feel much better if I get a booster shot of NAD in the morning when I arrive in Australia, where I travel quite frequently. .

And so I don't know if it's really working, we need more than one person in a clinical trial. But it fits with the mouse studies, which is that you can use NAD to reset your clock. The interesting thing about this is that NAD is not being driven by the clock, the clock is being driven by NAD. : Well. Yes. So for people who see or hear, the clock, I mean, what regulates the circadian rhythm? : Yes. How your organs coordinate the time of day. And when you're jetlagged, your brain can tell that it's morning because your eyesight, you know, sees sunlight, but your liver still thinks it's midnight, so you feel dizzy.

And that's the feeling. : And the reason NAD is... I mean, NAD is really important for a variety of metabolic processes... I mean, it's necessary for metabolism, for metabolizing glucose, metabolizing fatty acids, your mitochondria need it. But it is also important for a variety of other tissues, activating sirtuins and then the DNA repair enzyme PARP. : Yes ok. One could argue that NAD is the most important molecule in the body, perhaps with the exception of ATP, but withoutThey actually ended up being healthier. The mouse model of premature aging that had lived, I think was more than 40 percent longer.

But it has also since shown that these factors can be used to improve wound healing and kidney healing. : So you were increasing your stem cell reserves and your... So you were, like, regenerating tissues or? : What I think it's doing is what we're doing in the lab, which is getting those proteins that have moved around and lost their way back to where they were when they were young and then resetting the methylation clock. And now a cell doesn't just think it's young. He is literally young. : Were you using CRISPR to make this? : Well, it could have, but it was a transgenic mouse, meaning it inserted those four genes into the mouse genome with an on-off switch. : Yes, good. : We don't do that.

We use viruses that we can transmit to old mice. It has to start with a single egg. We can analyze old mice and, within a few weeks, find out whether we have reversed aging in one tissue or in the entire mouse. And we have also discovered that it is better if those four factors are not used; We have to leave one of them because it is toxic. It's the Myc gene, Myc is an oncogene, but the other three worked very well. And the results that came today through technology use those three genes to protect neurons from death in the mouse but also in the dish.

And the gene that can restore Horvath's clock was needed. And I think we're very close to seeing the future where maybe eventually we won't use viruses, maybe we'll have molecules that can do this that we can put in a dropper or in a pill that can set us back another 20 years. : Wow. That's super exciting. I'm really excited about all this epigenetic clock research and its link to, you know, basically the ability to reverse aging. I mean, I think... You know? Is there any evidence that fasting has any effect on that epigenetic clock? That has been proven, you know? : I haven't seen that.

I think what I've seen in Steve's and others' work is that the clock rate can be slowed down, but I haven't seen a reversal yet. And I showed Steve the results that I just told you about and he's very excited that someone has discovered... We think we've discovered why the clock ages, what causes it, but also what's the first reset that's been found. But I suspect that fasting may help, but it's probably not enough to actually do what these powerful genes are doing. Someday we will figure it out, but... So I fast, I continue to do it as much as I can for one main reason, and that is that it is going to activate these defenses that, at least, slow down and stabilize in some way. the decay of the epigenome we call.

But we'll probably need something more powerful to go back 20 years. But do we slow down aging by fasting and running? Absolutely, there is no doubt. : Yes. I mean, we are affecting these pathways, AMP kinase, sirtuins, mTOR and then IGF-1 insulin signaling; all of those pathways of aging, certainly, are affected by fasting and calorie restriction. : The good thing about those routes is that they seem to be really safe, relatively safe. Metformin has been tested in millions of people, NAD boosters have been used in mice for many years and in some humans for a while, including in clinical trials that I am helping to run.

So that's good. But when it comes to the most powerful age reversal, what we call epigenetic reset, we're now playing with fire because we're actually setting cells back decades. And if you do it too much, you end up turning a mouse into a giant tumor, which is not what you want. And we would never do that to a human. Therefore, we need to find ways to make this new and very powerful effect safe. So, you know, theoretically you could come to my lab and I could inject you with this and you could take doxycycline and activate it for as long as you want, and that's all theoretical.

But we're not crazy, we're not going to do that. We'll probably need a few more years of clinical testing before I can say this will be usable in a broader context. But if you're wondering why we're testing eyes, we're testing glaucoma and blindness in old mice, it's because AAV is already on the market, so it's virally usable. And it's localized, so if there is a problem, it won't hurt the rest of the body anyway. : Yes, wasn't there a clinical study in Japan? Maybe it was where they used induced pluripotent stem cells to cure something... I don't remember if it was like macular degeneration or some other retinal problem.

It was some kind of blindness or something, I think I remember reading that study. But going back to what you were saying about the epigenetic clock and aging, and I had always wondered about the Yamanaka, you know, these transcription factors that are capable of taking an already differentiated cell, like a skin cell, a neuron or a liver cell and turn it back into a stem cell, a pluripotent stem cell. You know, I always wondered, "What about the epigenome?" Good? Do you have an older epigenome but somehow, you know, like...? You actually reset the epigenome and that's how it works.

Yes. So, think of the genome as digital information. So it's zeroes and ones, or in this case, A, T, G, C. But the epigenome is the reader of that, and it's analog, and it's very difficult to maintain for 80 years. : That has to be the key. : It's a waste of information. : Must be. : Yes. But how is that information recovered? So I'm going to freak out a little because your audience is smart. Back in 1938, there was a man, a brilliant person named Claude Shannon, who was at MIT and he wrote a

theory

, a mathematical

theory

about communication. And his goal was to correct the loss of noise during the transmission of a radio signal during World War II and beyond.

And he came up with a mathematical theorem about how to make sure that the signal that starts here is flawless when it reaches the actual receiver. And what he decided was that you can make it digital or have someone watch the signal and then, if it breaks down, send a replacement signal. We now call it TCP/IP. Operates Internet. That's how it all works. That's why it works. And we wouldn't have the Internet if it weren't for the work of Claude Shannon back in the '30s and '40s. I think it's a good recipe for understanding why we age, the loss of noise over time, analog systems are very prone to noise.

But that system of resetting aging, how to recover the original information that was there when the signal was first sent, is what we are working on. That's what we think the Yamanaka factors are capable of doing. They're the group that sits on top and says, "Oh, that sign is degraded, use that sign." : Yes. That's great. : Well, then that's all part of... : High five. : Thank you, Rhonda. : I'm excited. : I've been writing that in a book that will be published later this year in September. And that's why I've been so busy writing a book that I haven't even published it in scientific journals.

So, perhaps it is one of the first times that a scientist puts all of his ideas and theories into a book before it is published for peer review. So, we'll see. But, you know, I think it's there for people to judge. Maybe by September I will also have some scientific articles written. : What an exciting field. Do you think other scientists in the field of aging will start working on this? I feel like this has to be... there has to be a big push, it's necessary... : Yes. It's going fast. So right now I mentioned Juan Carlos Belmonte at the Salk, he is the pioneer.

Steve Horvath is part of our dream team. There is another boy... unfortunately they are all boys now, but hopefully not forever, it is Manuel Serrano. He's been working on... he's in Spain, in Barcelona. He has been introducing these factors into mice, but there are not only men working on the epigenome of aging. So, a couple of really important leaders. So Anne Brunet is at Stanford. She has been working on the epigenomic causes of aging. And we have Shelley Berger at UPenn who has been studying, among other things, what makes the difference between a short-lived ant and a long-lived ant: They have the same genome, just different epigenomes.

And Jessica Tyler works on the epigenetics of yeast cells and is trying to figure out exactly what I described earlier about the distribution of proteins between DNA breaks and controlling the age of a cell. But that's all. It's basically the elite aging epigenetics teams in the world, but it's exploding. Within two or three years we will have hundreds of laboratories. : Yeah. It sounds... I mean, this is great. It's something that definitely... This whole idea definitely, somehow, comes to mind with the Yamanaka factor and using it to, like, reset, you know, to grow old, not just to do. ..

I mean, there's always the, okay, well, you can keep, you know, replenishing your cell types in different organs and keep going like that, but like, turn it around, think of it as a young cell. . There has to be a way, there has to be a way. : Good. Yamanaka did us a great favor. In fact, John Gurdon, who won the Nobel Prize with Yamanaka, actually told us years ago, back in the 1980s, that reversing aging is possible. And we didn't really understand it. What he did was take the nucleus of an adult tadpole cell, put it in a frog egg and made a new tadpole.

What that really tells you is that your genome can be reset to go back a long way and that aging is not a one-way street. : Yes. The fact that you can take your adult cell and turn it into a stem cell is proof, right? I mean... : Right. But now we know the machinery, at least its beginnings, and it is a very exciting time. : Yes. And I'm very excited right now. I think there are other things we were going to talk about, you know? You mentioned these NAD drivers and we should probably address that. But... : Well, they are also central, because as I mentioned, the proteins, many of them such as sirtuins, moved controlling the epigenome.

You want to stabilize it as best you can. Animals like whales and naked mole rats have a very stable epigenome, so proteins move around and epigenomic noise builds up. If we exercise, take NAD boosters, I think we slow down that process. : Let's talk about what NAD drivers are, that is, NAD precursors. Well, we produce NAD in our bodies, in our... So... : Yes. We do. And so NAD is recycled in the body because there are grams of it, you can't eat that much easily. And there is a cycle, it's called the NAD rescue pathway. And it all starts with

nicotinamide

, which is a form of niacin, vitamin B3.

But you can't just... Well, you can, but it's not very effective, just overdose on vitamin B3 because you need other things to make the big molecule, NAD. So NAD, the reason it's called nicotinamide adenine dinucleotide is that it has these three main components, and the dinucleotide is related to DNA. But that's beside the point. It is a large molecule, so if you give a large molecule to the cells, it will not be absorbed. So we don't feed the animals NAD. And we don't just give them nicotinamide, which is the small part on the end of NAD because it's too small because you need these other parts.

So NMN and NR are two molecules. It stands for nicotinamide

mononucleotide

, which is essentially the precursor, the immediate precursor to NAD. If you hit a cell phone with NMN, it will be taken by a transporter, which was just discovered by my friend Shin Imai, we used to work together at MIT. He is now at WashU. A few weeks ago he wrote about it. I wrote about this, that there is a transporter that takes up NMN, and the NMN is converted in one step to NAD in the cell, and now it is blocked. It is a large molecule, it is enclosed inside the cell.

And that step is carried out by an enzyme. It has a name, it's called NAMPT. And that enzyme increases under stress and caloric restriction. And in yeast, it is the same step. And so we demonstrated years ago that this conversion step from NMN to NAD or into yeast, what is it? Nicotinic acid for NAD is the critical step in increasing NAD when you are following your circadian rhythms, when you exercise, or when your cells are stressed. And without that step, you won't get the benefits of calorie restriction and your organs will start to age. So what is NR?

So NR is quite popular, many people have heard of it. It stands for nicotinamide riboside and all it is, it's just a smaller version of NMN without the phosphate. So it has no phosphorus. So if you take NR, your body first has to put in phosphorus and then it basically has to put two of them together to make NAD. So, all that being said...: Does NR become NMN first and then NAD? : Yes. Yes, it has to be like that. Yes. But both NR and NMN have been shown to increase NAD levels in animals and also in humans.

And there are little nuances about the differences, but both seem to be effective, not only in humans, but, it shouldthat they were doing it. But in the NAD flux study, you got 200 milligrams per kilogram of body weight, which is significantly less than what all of these other studies like the one you mentioned with Alzheimer's disease and other studies that have shown improvements in mitochondrial function in Mitochondrial mutator mice, and also muscular dystrophy, and all that. So... : Yes, we used double that dose for a while. : Yeah, so maybe, you know, this NAD flux study that showed orally administered nicotinamide riboside didn't form NAD in the muscle, but it did form NAD in the liver, could have been a dose-dependent thing? : It would make sense because we've done a lot of this in mice and now in humans, and there's a threshold you have to cross, you need to take a certain amount to probably overcome the body's elimination mechanisms and then get to a level that stabilizes after a few nine days.

And they may have been below that threshold, so the body was just clearing it. But apparently you have to overwhelm that cleansing system, so we applied at least 400 mg per kilogram in mice. : And that's with nicotinamide riboside. The question is, I mean, if we're talking about a human equivalent dose for a 180-pound man, it would be like more than two grams per day. And this brings me to my next question, which was the most recent clinical study with nicotinamide riboside, where they actually used a much higher dose than the original study that was done with Basis, the Elysium that contained pterostilbene.

This dose was like 1000 milligrams per day and they looked at a variety of endpoints as well as... I mean, they looked at resistance, they looked at... : Right. It was Doug Seals' studio. : Yes. And there was no statistical significance in anything. He raised NAD levels, but there was no statistical significance. There was a trend for improvement in the vascular system, but there was no effect on endurance. And I wonder again, well, if we go back to the human equivalent dose, the one that was given to the animals, it was still less than half. I mean, so the question is, is NAD not even produced in the muscle tissue at that dose or, you know, so... which brings me to nicotinamide

mononucleotide

?

You know, like now, those studies have been done in animals with a much lower dose than 400 milligrams. : They have. Yes. So we, in my laboratory and at the Metro Biotech company, have been using a wide variety of different and different molecules... We are doing what is called pharmacokinetics. So there's a lot of literature I could talk about for another hour. One of the big questions people ask me is, "Have you ever compared NR and NMN in a study?" And we have to do many more things, but usually they are not done. And I'm not aware of it being done in humans at this time.

But in mice, what we see... And to all the NR people, please don't get angry, this is just data. I don't manage the experiments, I simply deliver the message. That at the same dose, NMN will increase resistance. And I forget what that dose was. It could have been 200, 250. : Yes, 200. : NMN didn't increase... Sorry, NR didn't increase resistance, but NMN did. We found that for some parameters, and Matt Kaeberlein, who I mentioned earlier, is now working on aging dogs after doing the SIR2 lifespan extension. Then Matt also posted that when comparing NR and NMN, only NMN worked in his disease model, which was a mitochondrial disease where those animals really need a NAD boost.

So one of the problems could be that NMN is a better molecule in that sense. It could be that maybe mice worked better than humans and we need a higher dose. But what I'm working on, which isn't talked about much because it's in the commercial space, is that there has been a team of seven chemists working on molecules that are much better than either of these two that I'm talking about, super NAD boosters. . . And we have some that work much better than NMN. And these are scheduled releases. This is what we call prodrugs. And those are the ones that really excite me in terms of drugs of the future that not only increase a person's resistance but could also treat diabetes, heart disease, cancer and Alzheimer's.

That being said, we're doing a clinical trial right now with a molecule called MIB 636. MIB is just Metro Biotech. And those are a couple of clinical trials that are being done at Brigham and Women's Hospital in Boston, a separate group for me, everything is independent. And that's just a safety study. So when I go back to your program, if I go back to your program, maybe I'll tell you if we see some real effectiveness, some results. In the phase two study we will look at the strength and endurance in people's muscles after a few doses of NMN.

So we're about to find out if this is real or not for people. : Is this the first clinical study of NMN to be performed in humans? Or is it... : So we've done a couple, but yeah, as far as I know, we're the only ones who... Actually, you're reminding me to say something important for the listeners. Make sure your NR and NMN are kept cold. If it's on the shelf and it's not in a stabilized form, then it will degrade to nicotinamide, which is something you don't want to take high doses of because many years ago we showed in my lab that nicotinamide inhibits sirtuins and PARP as well, and they interfere with DNA repair. : That?

Actually? : Yes. : Do you like the way the vitamins are found? : Good. It does not have a very long lifespan, that is not well known. So keep it cool, in the freezer or refrigerator. : But I mean, if you buy nicotinamide riboside, you know, from a variety of companies that make it, they certainly don't ship it to you cold. So the question is how much of it has already degraded just on the shelves? : I don't know. : I mean, it's kind of like the case with probiotics. You know, when you get probiotics, you want them to be shipped cold, you know, so they're alive. : Good.

The same here. We also need to replace our NMN mouse. We put it in their water. We replace it every week because it breaks down, but if it gets wet or a little moisture gets into the bottle, it will take a short time before it degrades. : Wow. And we were talking a little bit before the podcast about... I was super excited. I think it was the "Cell" article from 2016, you mentioned the group that published NMN, basically, which was given to normal mice without any...: Yes. The Shin Imai study. : Shin Imai's studio. That's how it is. And basically, I think it was about 200 milligrams per day, like that dose, because I remember looking at the dose and saying, "This is significantly lower than a dose of nicotinamide riboside.

And it seemed to slow tissue aging in multiple organs." where, I mean, it was like... I don't know, it extended the shelf life? It didn't run out of material enough and in those days, NMN was hard to get and it was still very expensive. paying tens of thousands per kilo. But what it showed was that over a year of treatment, almost every health parameter in these mice improved. I won't live any longer, I'd be surprised. But we've done a lifetime of NMN in my lab and still. It is ongoing and is being crowdfunded. So thank you for your donations.

But it already looks significantly different in their water supply. And it also improves the fragility. cardiac function. The dosage, I don't remember exactly what we are using. It's probably around 400, which is our standard dose, but don't quote me on that. But yes, NMN and NR seem to do extraordinary things with rodents. But as you say, as you mentioned the challenges, A, does it work in humans? And B, if so, what dose is necessary to achieve these effects? : Good. And will there be side effects? If you read the most recent study, the clinical study where the dose of nicotinamide riboside was 1000 milligrams, there were a lot of people who dropped out because they had rashes and. ..I mean, there was blushing. : Oh, they did? : Yes, there are some side effects.

There were some side effects. : It could be with NR. We have never seen anything like this with NMN. And I take a gram of NMN every morning. : So NMN is the reason there are more studies with NR because NMN is very expensive? : Yes. Well, historically, some companies started producing NR from the beginning and made it widely available and cheap to researchers; in fact, so cheap that they gave it away to researchers. Therefore, it was used much more frequently than NMN. But more and more, and if any scientist or lab wants anything from NMN, let me know, I'll be happy to subsidize it if you want.

But if. And NMN came late on the scene because it was harder to synthesize because it's a larger molecule, it needs that phosphate, and the phosphate chemistry is quite difficult. : So you mentioned that the company that you are... Is this the company that is trying to source NMN supplements or is this... : So I don't make supplements and I don't recommend products. You can only do one. It doesn't work for both. So I've committed my career to manufacturing pharmaceutical products that have been proven effective and safe and are given, you know, marketability by the FDA. : So a drug, basically, of... : It's a drug.

It's a drug. And that's because early in my career I ventured into the world of resveratrol supplements. And it only lasted about three weeks before I had to leave for... It's incompatible for me, at least, to be able to, without being criticized, "This is what I think, this is the data," and I want to be able to say that without gaining money with it. But I also find the supplement world to be so controversial and litigious that it scared me. It's sad that I can't talk about supplements by name because I obviously know a lot, but I can't because, you know, I've already been dragged into lawsuits, I've lost a lot of money over it.

I haven't done anything wrong except open my mouth. And there are many companies that have a lot of money and don't want me to say things. Unfortunately, I can't really do that. I tweet and social media where I can. I've written blogs about it. I'm probably one of the few scientists who tells the world what I do personally and use myself as a role model for people to judge me. But I never recommend anything because, first of all, I'm not a doctor. I'm just a scientist and I mainly study mice. So I still don't know how all this will play out for people. : It would be nice if NMN could be available without a prescription now. : Well, it would be, but it would also be nice if someone like me did a clinical trial to find out what would happen and what dose to take. : Yes.

Well, that would be... That's first of all. I mean, knowing the dosage to take really has some effect. Good? It's not just like, yeah... I mean, don't take X amount just because it makes you feel good. I mean, a placebo does something, it definitely changes the dopamine in the immune system and stuff. But I agree. Yeah. So you mentioned supplements, you take one gram of resveratrol... Sorry, not a... Yeah, one gram? : It's one gram of resveratrol, which I put in my yogurt. : And about a gram of nicotinamide. :And NMN. : And that's also in your yogurt? : No, I can take it in capsule form in the morning and accompany it with a cup of coffee.

And that's a pretty big boost, I think, physiologically, those three things with caffeine included. You can ask my friends. Sometimes I have to restrain myself a little because I'm like a mouse on oxygen, running around the cage too much. But it works for me. It helps with... I think it also helps with jet lag or lack of sleep. I have three children and sometimes I don't sleep well. I know you have a young one, so you know what that's like. : Fortunately, I'm starting to sleep well now, but sleep is also very important for aging, especially for the aging brain, you know, so...

I actually wore a continuous glucose monitor. I've been using one for a few months. And my son, around Thanksgiving time, he started teething and stuff and he started waking up in the middle of the night and he was awake for like an hour and it was like... So basically he was having a very fragmented sleep. and my blood glucose levels, like my fasting blood glucose levels and my postprandial blood glucose levels, were like 15 to 20 units higher. And this was repeatable, very... I was, you know, my diet... More or less, I eat the same thing, so it wasn't like eating anything like a cookie or anything like that.

I mean, it was like... And doing some high-intensity interval training helped, and there's actually some research on that, but I was surprised at the effect that sleep or lack of sleep had. : Yes. If you take a rat and deprive it of sleep, it will get diabetes in about a month. : I mean, it's just how it was... You know, I had read the studies. I had Dr. Matt Walker on the podcast and talked all about it. But when it happens to you and you see the data, I mean, of course, to me it's still just an N of one.

But I mean, it was like, it was very... For me, it made it very real. I thought, "This really regulates my insulin level, my insulin sensitivity." : Good. I could see my age change whenI had small children. : Oh, absolutely. I sure have gotten older. I mean, I can see it, like... You know, especially as a nursing mother in the first few days of my son's birth, it was very difficult. I mean, it was very difficult. : Yeah. Just look at pictures of me when I was in my 30s and 40s, when it was lack of sleep and stress and my wife yelled at me for traveling, that kind of thing.

That exhausted me. You can see that I aged quickly. Since then, I don't think nor do others believe that I have aged much since then. So it's sleep and stress. Everything important. Yes. How much sleep do you get at night? : Well, I often work until 11:00, which is a bad habit, but I've found ways to fall asleep pretty quickly. I avoid blue light, that's why I wear those yellowish glasses. What should I do? Every once in a while, I take a bite of a sleeping pill when I'm really having trouble sleeping because I used to have insomnia.

But what I have found are the doses they prescribe for some of these medications, I won't say which ones, but at least they are many more than I need. So I just nibble on it and it's enough to calm me down and fall asleep. And then in the morning I get my boost and start again. But I usually sleep seven hours. And if I don't get more than that... sorry, if I get less than that, I'm in trouble because my brain needs to run at 100 miles per hour every day. : If it does not work. Have you ever heard of Phillips Hue lights?

Philips Hue is really... it's like they make these lights, we have them in our house, that you can program your phone and they turn red at a certain time, just like ours turn red at sunset and there's no blue light. . And it's really like, you know, thinking about it, it really makes a difference. And developing children are really sensitive to light, even more sensitive than adults. So, I'll notice if we're traveling and we're in a hotel room or if we're visiting my in-laws in, you know, another state and they have lights on at night so my son, it's like it's harder to get him to out to bed and it's...

I mean, it's very obvious, so I always scare myself trying to turn off the lights. I say, "We're going to be in the dark." : Yes me too. So my kids and I, three of us, got my wife for Christmas one of these houseplants, like she hydroponics, and the light for that hydroponic unit, it's about a foot long, maybe two feet. It is super bright and is in the kitchen. And it was so bright that I realized I couldn't sleep because it also comes on at night and it's a bright light. So we had to move him to the dining room and cover him with clothes because otherwise he wouldn't understand... : Oh yeah, like hotel rooms with the alarm clock.

They're like blue lights, like lighting up the room, you know, or I'm always knocking things over. We have a HEPA filter and there is a red light on the right. I mean, I'm just saying, "Who's designing this?" You know, you don't want light when you're trying to sleep and stuff. : I'm with you. In my room, our room, lights come on. Everything shines now and they like to put blue lights on these things now that they are fashionable. Does anyone not believe that it is...? No. Yes, I know. Anyway, that's another topic entirely. Very excited about all your research.

The epigenetic clock thing has me very excited, David. We'll have to keep in touch. I mean, I'm super... : That sounds good. : It's an understatement how excited I am. I definitely want to talk to Steve. I also want to get in touch with him. But if. This is like...: Yes, so the people I mentioned, Steve Horvath, Manuel Serrano and Juan Carlos Belmonte, have just formed an entity to fund research in this area and to conduct clinical trials in humans, probably in glaucoma, which It is an extremely difficult disease to treat, the damage that has been caused cannot be reversed and we believe we could do it.

So these are exciting times. The investigation is going extremely fast, my head is spinning. I get texts every day about progress, which I think is a great privilege. But yes, I would love to come back and tell you more. I tweet some results these days. I used to be very secretive, but now it's too exciting not to tell people as we find out. : Good. Completely. I follow you on Twitter, so I definitely... If people want to find you on Twitter, what's your Twitter username? : @

david

a

sinclair

. : @

david

a

sinclair

. : A for Andrés. : A for Andrés. And you have a website, a book about to be published. : Well, we have a lab website.

We will soon launch a website for the book where there will be information and we will build a community around the book. The book comes out in September. It's an unusual book, it's illustrated by one of America's greatest medical illustration talents, Katie Delphia, and that's speckled in there. And we have a cast of characters ranging from Captain Arthur Phillip, who founded the colony of Sydney, who used to hang out in my backyard in Sydney 200 years earlier, to scientists in London who were making important discoveries. That took us to today and then projects forward. If I have a front row seat in this field, both in biology and in industry, what will the future look like?

What happens if we don't make it? Which is pretty bad. What would it be like if our wildest dreams came true? What is that world like for us and our descendants? : Awesome. :And maybe we can see our descendants. : Yes. I'm definitely looking forward to the book, for sure. Thanks for connecting with me. I've been a big fan of your research for quite some time and now I'm even more excited about all the new things happening. I had no idea. I mean, you started talking about it and you said, “Yeah.” : Well, thank you, Rhonda. It's really great to be able to talk about it with someone who literally knows as much about it as I do. : That's flattering.

Thanks, David. : Thank you.