Dr. David Sinclair on Informational Theory of Aging, Nicotinamide Mononucleotide, Resveratrol & More
Posted on November 6th 2019 (3 months)
David A. Sinclair, PhD, is a professor in the Department of Genetics at Harvard Medical School and co-director of the Paul F. Glenn Center for the Biological Mechanisms of Aging. He is the co-founder of the journal Aging, where he serves as co-chief editor.
Dr. Sinclair's work focuses on understanding the mechanisms that drive human aging and identifying ways to slow or reverse aging's effects. In particular, he has examined the role of sirtuins in disease and aging, with special emphasis on how sirtuin activity is modulated by compounds produced by the body as well as those consumed in the diet, such as resveratrol. His work has implications for human metabolism, mitochondrial and neurological health, and cancer.
Dr. Sinclair obtained his doctoral degree in molecular genetics at the University of New South Wales, Sydney, in 1995. Since then, he has been the recipient of more than 25 prestigious honors and awards and in 2014 was named as one of TIME Magazine’s 100 most influential people in the world. Dr. Sinclair recently authored the book Lifespan: Why We Age – and Why We Don't Have To.
Aging – a process that began the moment we were born – is generally thought of as inevitable. Although aging isn't a disease, it is the primary risk factor for developing many chronic diseases, including cardiovascular disease, Alzheimer's disease, and cancer. In turn, many of these conditions hasten the aging process, setting up a vicious cycle of cellular damage and systemic loss of function. A growing field of research, led by a few innovative scientists proposing radical, contrarian ideas, suggests that aging might not be as inevitable as once thought.
In this episode, Dr. David Sinclair discusses exciting new findings in the field of aging research, with special emphasis on the roles of sirtuins, resveratrol, and NAD+.
Burgeoning research identifies longevity genes
In recent decades, scientists have identified genes that control aging – so-called longevity genes – that are present in nearly every life form on Earth. One group of genes, the sirtuins, encode a class of enzymes that control gene expression to regulate a variety of metabolic processes essential to maintain proper cellular function, including the release of insulin, mobilization of lipids, and response to stress.
Sirtuins are among what is now appreciated to be a network that includes other familiar players like IGF-1 and mTOR to influence aging and longevity. The activity of these players is impacted by familiar healthspan interventions, even those actively researched among longevity scientists in the research community, such as caloric restriction and prolonged fasting, but also things we just generally think of as healthful, like exercise and more. Perhaps more importantly, sirtuins also modulate lifespan in lower organisms by interacting with pathways conserved in and relevant to human biology by directing the activities of multiple molecular pathways.
DNA damage interferes with the sirtuins' role in gene regulation in a manner similar to aging
A critical aspect of aging is genomic instability – a wide range of alterations that occur in our DNA and irreversibly change the information carried in our genome. In this episode, Dr. Sinclair describes sirtuins as some of the first responders to the site of DNA damage within a cell, where they direct gene expression to promote DNA repair. However, as DNA damage accumulates over time, sirtuins become distracted by having to facilitate DNA repair to properly regulate gene activity. As a result, this leads to a breakdown in the cell's ability to properly regulate which genes are switched on and off during the aging process. Accompanying the sirtuins' response is the activation of another class of enzymes, the poly-ADP-ribose-polymerases, or PARPs. Their activation depletes cellular levels of nicotinamide adenine dinucleotide, or NAD+, a coenzyme that participates in the production of cellular energy, serving as a kind of "double hit" that accompanies aging by potentially reducing other important NAD+ processes, like those required for healthy mitochondrial function.
Lifestyle behaviors facilitate a cellular reset
"What we've discovered is that when you go for a run or you're fasting, the reason that those are beneficial is actually because they trigger those longevity genes to repair your body and make sure that you don't get as old as you would otherwise.” - @davidasinclair Click To Tweet
Certain lifestyle behaviors such as exercise, intermittent fasting, and caloric restriction trigger the activity of sirtuins, restoring normal gene regulation, resetting the cell's activity, and slowing the aging process. These behaviors moderately stress the body and induce shifts in metabolism that drive changes in sirtuin gene expression – sometimes as much as five- to ten-fold – highlighting the links between sirtuins, nutrient levels, and key metabolic pathways.
Cellular energy stress drives sirtuin regulation
"If you have a lot of sirtuins, you get the benefits of calorie restriction or dieting and other types of little stresses on the cell like heat and a bit of a lack of amino acids. And if you get rid of the sirtuin or SIR2 gene, the real breakthrough was that calorie restriction doesn't work anymore." - @davidasinclair Click To Tweet
The mechanisms that drive sirtuin activity come into play when a cell senses changes in cellular levels of NAD+, a coenzyme that participates in the production of cellular energy. Low energy levels, such as would occur during exercising, fasting, or caloric restriction, stress the cell. In turn, NAD+ levels rise, switching on energy-generating pathways and activating enzymes such as sirtuins.
Caloric restriction – the practice of long-term restriction of dietary intake, typically characterized by a 20 to 50 percent reduction in energy intake below habitual levels – has long been associated with higher NAD+ levels and sirtuin activity. However, other forms of lifestyle modification likely have similar effects – and greater sustainability.
For example, intermittent fasting, a broad term that describes periods of voluntary abstention from food and (non-water) drinks, lasting several hours to days, may be sufficient to elicit cellular energy stress and drive sirtuin activation without the need for prolonged adherence to a highly restrictive dietary pattern. Similarly, exercise induces changes in skeletal muscle fuel utilization to preserve glycogen stores and blood glucose levels for glucose-dependent tissues, switching from glucose to fat as the primary energy source. This change in glucose availability stresses the cell, promoting alterations in gene expression via NAD+-dependent sirtuin activation.
Levels of NAD+ vary according to nutrient intake, activity, and even time of day. In fact, the body's circadian rhythms, which control nearly 15 percent of gene expression in the body, are subject to NAD+ levels, which drive the body's master "clock." Altered NAD+ levels may be the root cause of jet lag as well as the overall loss of energy we experience as we age.
Enhancing sirtuin activity with resveratrol, a sirtuin-activating compound
"These sirtuin pathways exist in plants as well and they get turned on in response to stress. And we call this xenohormesis, the idea that when we eat stressed plants, we get those molecules and they help our bodies.” - @davidasinclair Click To Tweet
Energy stress isn't the only activator of sirtuins. Some naturally occurring and synthetic compounds, called sirtuin-activating compounds, or STACs, may provide a way to tap into the benefits of this biology as well.
For example, resveratrol, a naturally occurring compound found in red grapes and other plants, is a potent STAC. It protects the plants in which it is found from environmental stressors and disease. When ingested by humans, resveratrol binds to sirtuins, altering their affinity for NAD+ and their protein substrates, thereby increasing sirtuins' activity. As such, resveratrol presents a promising therapeutic strategy to ameliorate age-related diseases and extend healthspan. Resveratrol is a "dirty molecule," however, known for its multiple cellular targets, so teasing out all the ramifications of this plant-based compound's use has proven problematic.
Manipulation of cellular levels of NAD+ as a strategy for slowing aging
As we age, however, the NAD+ levels in our bodies decline, reducing resveratrol's potency. A few candidates have emerged as a means to manipulate or "boost" NAD+ levels in the body. The most well-studied NAD+ boosters are nicotinamide riboside and nicotinamide mononucleotide, which have been shown to ameliorate age-associated diseases in animal studies. Some preliminary human studies have shown that nicotinamide riboside can raise NAD+ levels in plasma, but whether this will translate into health benefits remains to be determined.
The future of aging research
Understanding aging is a burgeoning field of research, rife with unanswered questions. A small group of scientists is currently working to identify the doses, targets, and potential complications associated with altering the aging process. Although much of the data comes from animal studies, substantial progress has been made in human trials, and many more discoveries will likely come in the next decade or so.
- Andrew Dillin
- Matt Kaeberlein
- Juan Carlos Izpisua Belmonte
- Steve Horvath
- Shinya Yamanaka
- Anne Brunet
- Shelley Berger
- Jessica Tyler
- John Gurdon
- R. Scott Turner
- Manuel Serrano
Learn more about Dr. David Sinclair
Rhonda: Welcome back, my fellow "FoundMyFitness" longevity fanatics. Today is a treat. My guest is Dr. David Sinclair, a professor in the Department of Genetics at Harvard Medical School where he researches and tries to understand the biological mechanisms that regulate the aging process and how to slow them. I can't think of a more interesting question than understanding the biological mechanisms that regulate aging and how to slow it. I'm very interested in it myself, for sure.
David: Well, thanks, Rhonda. Thanks for having me on.
Rhonda: So what are the mechanisms?
David: What is the secret to the universe? Well, I've been studying this, as you know, for over 30 years now. And when we first started out, we knew nothing. And then we went to little yeast cells and then we worked our way up to worms and mice. And now, myself and probably a couple of dozen other researchers around the world have broken through a barrier of understanding about why we age and how we can actually reverse it.
Rhonda: Wow. So what's the...
Rhonda: What's the... Yeah, what's the breakthrough?
David: Well, there were a number of breakthroughs. So in the 1980s, the big breakthrough was that there are...and early '90s, that there are genes that control aging. We call these longevity genes, do not call them anti-aging genes. We don't talk about anti-aging, we talk about longevity and healthspan. And so, these longevity genes were first found in organisms like a nematode worm, tiny little one, and yeast cells that we use for baking in 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 pretty much every life form on Earth. And what we've discovered is that when you go for a run or you're fasting, the reason that those are beneficial actually is because they trigger those longevity genes to repair your body and make sure that you don't get as old as you would otherwise.
Rhonda: Just as a sort of a side note, because you mentioned these longevity genes in the yeast and the worms, one of the first... So, in college, I went to UCSD in San Diego and I was a chemistry major. And I worked in biotech. At the time, it was a sort of a start-up, it was Illumina. And I worked in the chemistry department. Now it's a very big company. But I was working there my junior and senior year in college and I, you know, it was sort of like I was making peptides and doing a lot of organic chemistry and after a while, I just didn't feel, like, very interested in it anymore. So I went to the Salk Institute to kind of get a little bit of a taste of biology because believe it or not, I didn't have a lot of biology classes as a chemistry major. Had a few, but it was mostly just, you know, chemistry. And so, at the Salk, I joined Andrew Dillin's lab and...who uses, you know, nematode worms to understand the genetics of aging. And I remember the first time I was working with these worms that had a decreased insulin IGF-1 signaling pathway, how they lived like 100% longer and how they were, like, youthful when they were supposed to be dead. And I saw it with my own eyes when I was doing the experiments and it was like, "Holy crap, this is cool. We have genes that are similar to these little worms and they are like this?" You know, so that kind of got me interested in, at least, on the genetic side of aging.
David: Well, I'm not surprised. Even I don't do all the experiments in my lab, you may be surprised to know. And people would tell me results, "Oh, the mice are living longer downstairs on the NMN," or whatever, or, "We've accelerated aging in mice because we've tweaked the epigenome," and, you know, this all sounds great and, you know, I go back to my email. It's not until I go in to the animal room and I see them with my own eyes, and these are living creatures that are getting older and getting younger. It really is an impact to actually see and hold them with your own hands. So, yeah, that's the thrill. Even with the yeast studies that I was doing back in the late '90s, I was very intimate with the yeast cells. It sounds weird that you could really adore little microscopic organisms, but you look at them under the microscope and they live for about a week and you have to monitor these mother cells and her little daughter cells that you pick up, used to pick off with a microscope and a little pick. 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 they died, you know, it was a little twinge of sadness that these little dudes that you'd been looking after all the time or females, in this case, were dying. So I think, we biologists, we get attached to these living organisms and it's really rewarding to see that we're not making them sick, we actually end up making them live longer and healthier lives.
Rhonda: Right. So I became familiar with your work back in those days when I was actually doing research on these little nematode worms. And I remember some of your work was on resveratrol and how resveratrol, like, helped to regulate one of these, I guess, longevity pathways. Sirtuin, the sirtuins and how that was involved, and basically if you could activate them and certain ones seem to delay aging. So maybe you could talk a little bit about both sirtuins and also what resveratrol is.
David: Oh, sure. Let's start with sirtuins. So when I arrived at MIT, it had just been discovered that there was a gene called SIR4 that when it was mutated, it would make the yeast cells live longer. In a fair amount of work, we figured out that the SIR proteins, which are enzymes that control gene expression, genes on and off, they would become dysregulated over time and we found out that's because they were being distracted by a whole bunch of DNA instability that was accumulating in those cells. But the lesson was that the sirtuin enzymes that were controlling genes were also controlling lifespan, which was a real breakthrough. No one had really expected to find gene regulators controlling aging. We thought we'd find antioxidant producers and DNA repair proteins. That's not what we found, not initially. And so the sirtuins became very interesting in yeast and Matt Kaeberlein who's now out in Seattle, he's a leader in the field as well. 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 my lab at Harvard showed that this was through a process of mimicking calorie restriction. If you have a lot of sirtuins, you get the benefits of calorie restriction or dieting and other types of little stresses on the cell like heat and a bit of a lack of amino acids. And if you get rid of the sirtuin or SIR2 gene, the real breakthrough was that now calorie restriction doesn't work anymore. And that whole setup was the basis of most of the research that the field has been doing since in the sirtuin field. Trying to understand that concept of what we learned in the 1990s in our bodies and in mice. And I'm lucky and happy to say that a lot of it is very similar in our bodies as well.
Rhonda: And when you say calorie restriction, usually, you're talking about for, like in mammals and humans like eating 30% less than you normally would or something?
David: Yeah. Well, in the old days, we typically would take out 30%, sometimes even 40% of the food with the mice and they'd be hungry all the time and it wasn't very pleasant. With yeast, if you're wondering how do you calorie restrict yeast, we just dropped the level of sugar in the Petri dish. I think it was fivefold and that was enough to make them live longer, but they still grew quite happily. These days, as you're aware, intermittent fasting seems to kick these longevity genes into action. The sirtuins still come on, but you don't always need to be hungry. You can eat, you know, four days out of a week or even six days out of week and still have a period of fasting that gets the sirtuin activity up to levels that we think would be beneficial.
Rhonda: Right. Yeah. 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 are intermittent fasting, you're shifting your metabolism from carbohydrate, glucose, to fatty acid metabolism and you start to, you know, ketogenesis can kick in after, at least if you're doing a more prolonged type of intermittent fast. So, there's certainly a little bit of differences as well between those.
David: Right. Well, one thing that's interesting that connects everything is, so we showed in 2005 in a Science paper that when you take a calorie-restricted rat and look at its organs...we looked at the liver and muscle, the levels of one of the sirtuin genes, number one, we have seven of these genes. So we looked at number one because we only had an antibody in those days to number one. It went up dramatically. I think it was about five to tenfold in levels in the calorie-restricted livers. And then we recapitulated calorie restriction in the Petri dish. We grew cells in serum from animals that had been calorie-restricted and we found that that was also enough to stimulate this boost of sirtuin production. But getting back to what you did in Andy Dillin's lab, we found out the reason it went up in the dish was because of having low insulin and IGF-1 levels. Because when we put back in normal insulin levels in IGF-1, the sirtuins went back down. And that was a nice link between...for the first time in mammals, the sirtuins, calorie restriction, and the insulin pathway. And actually, in those days, we were all fighting amongst ourselves that we were going through a paradigm shift, which is always stressful. And Andy was saying, "My pathway is more important to sirtuins." And then there was the mTOR people saying, "No, no, we've got the most important pathway." And I'm trying to say, "Hey, folks, all the pathways are important. In fact, they're all talking to each other." We showed that sirtuins and TOR are talking to each other. So, fortunately, in the field now, we've grown a little older and wiser and we are in agreement that there is this network, it's not just one straight pathway from food to long life and that you can tweak one pathway and the others will also come on to help.
Rhonda: Something that comes to mind when you... So you're talking about, really, this important role that calorie restriction or intermittent fasting plays in activating this sirtuin pathway and also deactivating things like the insulin signaling pathway and IGF-1 pathway, it is the fact that the sirtuins are regulated by something called NAD, nicotinamide adenine dinucleotide plus. But that is something that actually, those levels rise during a fasted state.
David: They sure do... Right. And in response to exercise as well. And so the reason NAD is so exciting compared to the 1980s when we thought it was just a housekeeping molecule for reactions, is that the levels of NAD go up and down depending on not just what you eat, but whether you're exercising and even what time of day it is. So, during the day, your NAD levels will rise and then you eat a big meal and they'll go down again. And it's... We think it's one of the reasons you also get jet lag, is your NAD cycles are out of whack.
Rhonda: Is it on a circadian rhythm? Is it completely regulated by meal intake?
David: It's a combination. It will be going up and down with circadian rhythms, mostly, but you can adjust it within the...
Rhonda: What about macronutrient composition? Like if you eat more high fat versus carbohydrate?
David: Yeah, no one knows. That would be a good experiment. The circadian field hasn't looked at nutrition as far as I'm aware. But what I can tell you anecdotally is that if I raise my NAD levels when I'm traveling, I feel a lot better if I have a shot of an NAD booster in the morning when I get to Australia, which I travel to pretty often. And so I don't know if it's truly 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. What's interesting about this is that NAD isn't being driven by the clock, the clock is being driven by NAD.
Rhonda: Okay. Yeah. So for people that are viewing or listening, the clock, meaning what's regulating circadian rhythm?
David: Yeah. How your organs coordinate what time of day it is. And when you're jetlagged, your brain might realize that it's morning because your eyesight, you know, sees sunlight, but your liver still thinks it's the middle of the night, so you feel queasy. And that's the feeling.
Rhonda: And the reason why NAD is... I mean, NAD is really important for a variety of metabolic... I mean, it's required for metabolism, for metabolizing glucose, metabolizing fatty acids, your mitochondria need it. But it's also important for a variety of other tissues as well, activating sirtuins and then DNA repair enzyme, PARP.
David: Yeah. Right. You could argue that NAD is the most important molecule in the body, maybe with the exception of ATP, but without either of them, you're dead in about 30 seconds. So NAD and ATP were probably the first two molecules that life on this planet used to survive. And it's, to me... And amino acids as well. And so isn't it interesting that the amino acid levels, ATP, and NAD are the three main molecules in our bodies that are sensed as to what our environment is like and whether we need to hunker down and survive or go forth and multiply? And those are the three main pathways. There's the sirtuins, there's AMP kinase, which is the metformin pathway. And then there's mTOR, which is rapamycin, which I'm sure you and many of your listeners are aware. But we're tapping into very early aspects of life that's found all over the planet and that's why I think we're having such big effects in the animals. Often, people say it's too good to be true. You know, you tweak one pathway and all this good stuff happens. Well, these are pathways that have existed for going back probably more than 3 billion years. And we're only just learning how easy and seemingly safe it is to tweak them.
Rhonda: So NAD levels decrease with age, and you think this is causal for...plays a causal role in the aging process?
David: Right, right. So why is NAD linked to sirtuins? So, sirtuins are enzymes.... And this is my picture of an enzyme, but think of like a Pac-Man that's chewing off chemical groups of other proteins, telling them what to do, like a traffic cop. And without NAD, they don't work. They're stuck shut. And so there's always NAD around, otherwise, you'll be dead. But if the levels go down as they do, as you get older, and I'm almost 50, so my levels probably are half what they were when I was 20, scary thought.
David: So my sirtuins are working maybe half as well as they did telling the troops to go out and fix my body. So when I go for a run, I get less benefit from that. I feel tired, I don't make as much energy. Mitochondria are down. But by raising up the levels of NAD to when I was young, what I think is going on based on the animal work we've been doing for many years now is to trick the body into thinking that it's young again, or it's been exercising, or dieting, and that allows the sirtuins to do their job the way they once did.
Rhonda: By just having that level of NAD higher, like, it's basically like a signal.
David: It is. So I think of it as the fuel in a car if the sirtuins are driving. And then the resveratrol that we worked on years ago works on the same enzymes, but it's the accelerator pedal. So, it actually... The NAD is making it work, but resveratrol will come along and make it work even faster. So the combination of those two, we find, is even better than just one alone.
Rhonda: Cool, really. Let me ask you this. This is kind of something that comes to my mind. I don't think it's often thought about this way, at least, in the field. But, you know, because NAD is required for cells that have a really high energetic demand like activated immune cells, for example, activated immune cells require a lot of ATP for energy and a lot of NAD. And if you think about like chronic inflammation, how, you know, especially as you get older, and you're unhealthy, and with age, you know, basically it is increasing. If you're having more activated immune cells, is there any way to test if, like, the NAD, like there's a triage where NAD is kind of being sucked away to these activated immune cells and, like, then your mitochondria are now suffering and you get, like, mitochondrial decay because you're sort of shunting all this NAD to, like, take care of, you know, what your body thinks is potentially an infection that could kill you, right? So there's probably some sort of evolutionary mechanisms at play that say, "Oh, yeah, immune cells need this NAD more than mitochondria," or something, I don't know. So it'd be kind of interesting. Do you follow what I'm saying where...?
David: Oh, I absolutely do. I think you're probably right in thinking along the same lines that as you get older, you're losing the ability to make NAD, but you're also chewing it up. And as it gets worse and worse as you get older, the immune system is a big drain on NAD, and actually, so is DNA repair with the activation of PARPs. And once you drain NAD a little bit, then your PARPs and your immune system won't work, but then they'll need more NAD because you'll get more damage. And this is a positive feedback in a bad way so that once you start going down the NAD decline, the cells just start to need more, and more, and more with accumulating DNA damage. And that's actually what happens in yeast cells, going back to those little critters that we found that they became overwhelmed with damaged DNA and the sirtuins were overwhelmed, they had to go over and repair that genomic instability, the DNA instability. And one of the reasons old cells became sterile, which is a hallmark of yeast aging, is because the sirtuins are keeping the cells fertile back here, but they're so distracted by all this other DNA damage that's going on over here that they lose their identity. And that's a theme that we've discovered is likely true in mammals as well, that accumulations of DNA damage distract the sirtuins from their normal job of keeping a cell with the proper gene expression, and cellular identity and we see the loss of cellular identity over time in mice, at least. And what we're trying to do is to raise NAD levels back up so that they can fix the DNA damage, but also get back to where they came from and make sure the cell doesn't lose its identity too much.
Rhonda: I didn't know sirtuins played a direct role, and I guess they're regulating so many genes that they're playing a role in DNA repair and DNA damage.
David: Well, they're one of the first proteins to get to a broken chromosome.
David: Yeah, we discovered that. It's a while ago, it was a cell paper in 1999, if anyone would like to look it up. Mills, myself, and Guarente published that. SIR2 goes to a broken DNA end and then helps recruit other proteins.
Rhonda: A single-strand break or...?
Rhonda: Double? Really? So, like gamma-H2AX?
David: Yeah. So the first thing that happens is gamma-H2AX gets lit up on the break and then within seconds, SIRT1 brings in HDAC1, helps remodel the DNA in the chromatin so that it's ready for the repair proteins to come in and without SIRT1 getting there, these other repair proteins are very inefficient...
Rhonda: Interesting, I didn't know that.
David: ...but they're distracted. Sirtuins should actually be regulating genes elsewhere.
Rhonda: Right. Wow. That's really important to know..
David: Right. This is all part of my idea, my hypothesis called the information theory of aging, is that we're really losing the information regulation over time and all of these other things that occur such as telomere loss, and mitochondria loss, and loss of proteostasis, as Andy would call it, loss of protein folding mechanisms, this could be upstream of all of that, that our cells lose their identity and don't turn on the right genes the way they did when we were young. But the trick is how do you get everybody to go back and reset? And that's what we've been working on.
Rhonda: Well, if you think about, as you know, Steve Horvath's work on this epigenetic clock and how he's shown now, I mean, in several different cell types, you know, including from humans, that there's this very distinct epigenetic aging clock that...
David: So, what... You know, I got to jump in because I get a little excited about this. What I've been telling you about the sirtuins and their movement, we've shown, is intimately linked to Horvath's methylation clock.
David: Yeah. It's all part of the same process. So this distracted protein DNA repair system, what's happening as that happens is that you get the methyls on the DNA that we use as a clock, but what we're finding is that clock is a way of resetting the proteins to go back to where they came from. That there are modifications on the genome that say, "Hey, sirtuins and these other proteins, go back to that gene because that's where you belong 20 years ago and ignore these other changes which have come on since you were 20." And we think we've literally found what the signal is to get them to go back. Now NAD is part of that. You need the fuel, but what's the genetic trigger to say, "Get off there and go back there"? And we think we've found that and it's got to do with the Horvath clock being reversed.
Rhonda: Is this in your publication?
David: It's something we were writing up right now for a journal.
Rhonda: That's super exciting. That's really exciting. Has there been any...and I know we're going on a tangent here, but has there been any evidence looking at, like, for example, like supercentenarians, what their epigenome is, like do we know?
David: Very... I mean, they've done the Horvath clock on it.
Rhonda: They have?
Rhonda: And is it different than, like, elderly?
David: For the same age, yes. Right. And actually, the Horvath clock has now been done on people who are smokers or obese and it's quite clear.
Rhonda: Cancer [crosstalk 00:22:18] or... [crosstalk 00:22:20] tumor tissue, yeah.
David: Is that right?
Rhonda: Yeah. Yeah. Tumor tissues, like, looks like 10 years older in the same person, like age match, normal tissue.
David: That's interesting because we're reversing the Horvath clock with our new found genetic trick and we're finding that we're having benefits on those cells as well. So I think this could be...
Rhonda: On cancer cells.
David: And damaged neurons.
Rhonda: That's so cool. I'm so excited.
David: It seems to be something radically new, but... So I know Steve well and his research is really interesting in that it is showing that it doesn't just predict your chronological age, it's predicting also how long you have to live, which is a really interesting thing that if you've abused your body and had a lot of smoking and been sedentary, Steve can take your blood and he can say, "Hey, you're 10 years older than you should be."
Rhonda: Even if you... Let's say you were a previous smoker, you know, and you hadn't smoked for 20 years and you've become active and eat healthy, do you think that epigenetic mark is there or do you think that....
David: I think it is.
Rhonda: It's there.
David: Yeah. Well, we know the rates of cancer go down, but all the other damage, the changes to the epigenome, what I'd been drawing with my hands, this movement of proteins, that's one-way street. It's not that if you suddenly start running in your 60s that it's all going to be reset.
Rhonda: Unless you can identify the signal.
David: Well, the signal, yeah. We've been putting that into animals and restoring eyesight in old mice and regrowing optic nerves in old mice and it seems to be safe. They're not getting any...no downsides there.
Rhonda: And this is by manipulating the epigenome?
David: Right. So, we use... We haven't published it yet. So my graduate student, Yuancheng, will probably kill me for saying too much. But we're both so excited. Even today, he sent me a text about, a new breakthrough is that we've found not only the genes that trigger them to move, but then the genes that reset the Horvath clock once they get there.
Rhonda: Really? You've identified the genes that can make them move...make the methyl groups move?
David: Methyl groups. Yeah, and reset the methyl groups and what gets them to go back.
Rhonda: Okay, okay. Wow.
David: Yeah. So, I'll give a hint to the viewers. And maybe this will be published and, shortly, we'll see. So we're using what's called the Yamanaka factors. And so, the first, person to do this...
Rhonda: Explain what that is.
David: Sure. Well, the first person to use these factors was Shinya Yamanaka, a Japanese scientist who looked through a lot of different genes and found a set of four factors that if you put them into an adult cell, say, a skin cell, they would go back to being very primitive, so primitive, what we call a pluripotent stem cell that you could then turn those cells into a nerve cell or even regrow an eye in the dish. It was a breakthrough that led to the Nobel Prize being awarded to him in 2012.
Rhonda: You just take a person's skin cell and turn it into a neuron. I mean, that's, like, amazing.
David: Why not? We do... I mean, a high school student can do that these days. It's not that difficult. Typically, with science, once you know how something works, it's pretty easy. Same with aging, I think. But what we've discovered is that... And first of all, I want to give a lot of credit to someone at the Salk whose name is Juan Carlos Belmonte, a professor there. A good friend of mine and he's...and he did the experiment that we were trying to do, so we were just slightly scooped on that. But he made a mouse where he could turn on these four Yamanaka genes. And that, for sure, they stand for O,S, K, and M. And that mouse, when he switched them on, died within a couple of days. So that's not great for those mice. But what he then cleverly did was he didn't give up or his postdoc didn't give up. What he did was he turned the genes on for a couple of days and then stopped, let the mice recover for a few days, and then turned them back on.
So, you know, I feel for the mice because they were headed towards death and they could recover and then they cycle, but actually, they ended up being healthier. The premature aging mouse model that he had lived, I think it was 40-plus percent longer. But also, he's shown since then that you can use these factors to improve wound healing and kidney healing.
Rhonda: So was he boosting their stem cell pools, and their... So he was, like, regenerating tissues or?
David: What I think he's doing is what we're doing in the lab, which is getting those proteins that have moved around and lost their way to go back to where they were when they were young and then reset the methylation clock. And now a cell doesn't just think it's young. It's literally young.
Rhonda: Was he using CRISPR to do this?
David: Well, he might've, but it was a transgenic mouse, which means he inserted those four genes into the mouse's genome with an on-off switch.
Rhonda: Yeah. Okay.
David: We don't do that. We use viruses that we can give to old mice. He has to start from a single egg. We can go into old mice and within a few weeks, figure out if we've reversed aging in a tissue or in the whole mouse. And we've also discovered that it's best if you don't use all four of those factors, we have to leave one of those off because it's toxic. It's the Myc gene, Myc is an oncogene, but the other three worked great. And the results that came in through the tech today use those three genes to protect neurons from dying in the mouse but also in the dish. And the gene that can restore the Horvath clock was required. And so we're very close, I think, to seeing the future of where maybe eventually we don't use viruses, maybe we have molecules that can do this that we can put in a drip or in a pill that can send us back another 20 years.
Rhonda: Wow. That's super exciting. I'm, like, very pumped up about this whole epigenetic clock research and linking it to, you know, basically, like, being able to reverse aging. I mean, I think that... Do you know... Is there any evidence that fasting has any effect on that epigenetic clock? Has that been shown, do you know?
David: I have not seen that. I think what I've seen from Steve's work and others is that you can slow the rate of the clock, but I haven't seen reversal yet. And I've shown Steve the results I just told you and he's pretty excited that someone's figured out... We think we've figured out why the clock ages, what's causing it, but also what's the first reset that's ever been found. But I would suspect that fasting can help, but probably, it's not enough to really do what these powerful genes are doing. One day, we'll figure it out but... So fasting, I still do that as much as I can for one main reason, and that is that it's going to activate these defenses that, at least, slow down and somewhat stabilize the epigenome decay that we call. But we're probably going to need something more potent to really go back 20 years. But do we slow down aging by fasting and running? Absolutely, no question.
Rhonda: Yeah. We're, I mean, affecting these pathways, the AMP kinase, the sirtuins, mTOR, and then IGF-1 insulin signaling, all those aging pathways, certainly, are affected by fasting and caloric restriction.
David: What's good about those pathways is that they seem to be really safe, relatively safe. So metformin has been tested in millions of people, NAD boosters have been in mice for many years now and in some humans for a while, even clinical trials that I'm helping to run. So that's good. But on the more potent age reversal, what we call epigenetic resetting, now we're playing with fire because we're really 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're never going to do that to a human. So we need to find ways to make this new very potent effect safe. So, you know, you could theoretically come to my lab and I could inject you with this stuff and you could take doxycycline and turn it on for as long as you want, and that's all theoretical. But we're not crazy, we're not going to do that. We probably need another few years of clinical testing before I can say that this is going to be usable in a wider context. But if you're wondering why are we testing the eyes, we're testing glaucoma, and blindness in old mice, it's because that's already on the market for AAV, so viral use. And it's localized, so if there's any problem, it's not going to hurt the rest of the body, anyway.
Rhonda: Yeah, wasn't there a clinical study, Japan, maybe it was where they used induced pluripotent stem cells to, like, heal some...I don't remember if it was like macular degeneration or some other retinal problem. It was some kind of form of blindness or something, I think I remember reading that study. But just kind of to go back what you were saying about the epigenetic clock, and the aging, and I had always wondered about with the Yamanaka, you know, these transcription factors that are able to sort of take a already differentiated cell, like a skin cell, or 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?" Right? Is it like, do you have an older epigenome but you're like somehow, you know, like...
David: You actually reset the epigenome, and that's how it works. Yeah. So, think of the genome as the digital information. So this is zeros 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 hard to maintain over 80 years.
Rhonda: That has to be the key.
David: It's a loss of information.
Rhonda: It has to be.
David: Yeah. But how do you get back that information? So I'm going to geek out a little bit because your audience is a smart one. So back in 1938, there was a man, a brilliant person called Claude Shannon who was at MIT and he wrote a theory, mathematical theory on communication. And his goal was to correct the loss of noise during a transmission of a radio signal during World War II and beyond. And he came up with a mathematical theorem of how do you make sure that the signal that starts here is pristine when it gets to the actual receiver? And what he decided was you can either make it digital or you can have somebody who's observing the signal and then if it gets messed up, you then send a replacement signal. We now call that TCP/IP. It runs the internet. That's how it all works. That's why it works. And we wouldn't have an internet if it wasn't for Claude Shannon's work back in the '30s and '40s. I think that's a good recipe for understanding why we age, loss of noise over time, analog systems, very prone to noise. But that system of resetting aging, how do you get the original information back that it was when the signal was first sent, that's what we're working on. That's what we think the Yamanaka factors are able to do. They're the group that sits above and says, "Oh, that signal is degraded, use that signal."
Rhonda: Yeah. That's cool.
David: Well, so that's all part of...
David: Thanks, Rhonda.
Rhonda: I'm excited.
David: That, I've been writing up in a book, which is coming out later this year in September. And so I've been so busy writing a book, I haven't even put this out in scientific publications. So maybe one of the first times that a scientist puts his whole ideas and theories in a book before it comes out in peer review. So, we'll see. But, you know, I think it's there for people to judge. Maybe by September, I'll have some scientific papers written up as well.
Rhonda: What an exciting field. Do you think other scientists in the aging field will start working on this? I feel like this needs to be...there needs to be a big push, like there need...
David: Yeah. It's going fast. So right now, I mentioned Juan Carlos Belmonte in the Salk, he's the pioneer. Steve Horvath is part of our dream team. There's another guy...unfortunately, they're all guys currently, but hopefully not forever, is Manuel Serrano. He's been working on... He's in Spain, in Barcelona. He's been putting these factors into mice, but there aren't just men working on the epigenome of aging. So a couple of really top leaders. So Anne Brunet is at Stanford. She's been working on the epigenomic causes of aging. And we have Shelley Berger at UPenn who's 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 trying to work out exactly what I was describing earlier about the distribution of proteins between DNA breaks and controlling a cell's age. But that's it. That's basically the world's elite teams of epigenetics of aging, but it's exploding. Two, three years from now, we'll have hundreds of labs.
Rhonda: Yeah. It sounds... I mean, this is cool. It's something I've definitely... This whole idea, like, is definitely, in some way, come to my mind with the Yamanaka factor and using that to, like, reset, you know, for aging, not just about making... I mean, there's always the, okay, well, you can keep, you know, replenishing your cell types in different organs and kind of keep it going, but like, to like turn it back, to like think it's a young cell. Like, there's got to be a way, there's got to be a way.
David: Right. Yamanaka did us a big, a big favor. Actually, John Gurdon who won the Nobel Prize with Yamanaka, he really told us years ago, back in the 1980s, that reversal of aging is possible. And we didn't really get it. What he did was he took an adult cell nucleus from a tadpole, put it into a frog's egg, and made a new tadpole. What that actually tells you is that your genome can be reset to go way back, and aging is not a one-way street.
Rhonda: Yeah. The fact that you can take your adult cell and reset it to a stem cell is proof, right? I mean...
David: Right. But now we know the machinery, at least the beginnings of it, and it's a very exciting time.
Rhonda: Yeah. And I'm so excited right now. I'm like, there's all this other stuff we were going to talk about, you know? You've mentioned these NAD boosters and we probably should definitely get into that. But...
David: Well, they're central, too, because as I mentioned, the proteins, many of them like the sirtuins were moving around controlling the epigenome. You want to stabilize that as best you can. Animals like whales and naked mole rats have a very stable epigenome, so there's moving around of proteins and epigenomic noise accumulating. If we're exercising, we're taking NAD boosters, we do slow that process down, I believe.
Rhonda: Let's talk about what NAD boosters are, so the precursors for NAD. Right, we make NAD in our bodies, in our... So...
David: Yeah. We do. And so, NAD is recycled in the body because there's grams of it, you can't eat that much easily. And there's a cycle, it's called the salvage pathway of NAD. 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's got these three main components, and the dinucleotide is related to DNA. But that's beside the point. It's a big molecule so that if you give a big molecule to cells, it doesn't get taken up. So we don't feed animals NAD. And we don't just feed them nicotinamide, which is the little end part of NAD because it's too small in that you need these other parts.
So NMN and NR are two molecules. So it stands for nicotinamide mononucleotide, which is essentially the precursor, the immediate precursor to NAD. If you'd give a cell NMN, it will be taken up by a transporter, which was just discovered by my buddy Shin Imai, we used to work together at MIT. Now he's at WashU. A few weeks ago, he wrote about it. I wrote about it, that there's a transporter that sucks up NMN, and the NMN is converted within one step to NAD in the cell, and now it's locked. It's a big molecule, it's locked inside the cell. And that step is carried out by an enzyme. It's got a name, it's called NAMPT. And that enzyme goes up under stress and calorie restriction. And in yeast, it's the same step. And so we showed years ago that that step of conversion of NMN to NAD or in yeast, what is it? Nicotinic acid to NAD is the critical step for boosting NAD when you're going through your circadian rhythms, when you exercise, when your cells are stressed. And without that step, you don't get the benefits of calorie restriction, your organs start to get old.
So what is NR? So NR is fairly popular, a lot of people have heard of it. It stands for nicotinamide riboside and all it is, it's just a smaller version of NMN without a phosphate on there. So there's no phosphorus on it. So if you take NR, your body has to first put on a phosphorus and then it has to basically link two of them together to make the NAD. So with all that said...
Rhonda: NR gets converted into NMN first and then into NAD?
David: Yes. Yes, it has to. Yeah. But NR and NMN have both been shown to raise the NAD levels in animals and in humans as well. And there's small nuances about the differences, but they both seem to be effective, not just in humans, actually, I should say, in mice. But in yeast, they work as well, which is nice. I suppose people are interested in the plant world and what we eat, these same pathways, these sirtuin pathways exist in plants as well and they get turned on in response to stress. And we call this xenohormesis, the idea that when we eat stressed plants, we get those molecules and they help our bodies. So resveratrol, going back to that old chestnut, it's a great molecule that is produced when the grapes get stressed and...
Rhonda: It's got fungus, right?
David: Well, fungus will stimulate it.
Rhonda: Fungus stimulate it, okay.
David: Yeah. Or lack of water. So when they harvest red wine, they hope for a dry season, that'll boost the resveratrol levels and other good polyphenol molecules. And we think that...I think that when you ingest those molecules, the sirtuins have evolved to sense the plant world and if your food is stressed out, your body will hunker down and become fitter as a result of sensing that because, you know, we can see crops that are dying or if the water table's drying up, maybe we can sense that, but little animals that we evolved from or even, you know, a squirrel, it's too dumb to know that its food supply's stressed out, its body has to take care of that message.
Rhonda: Yes. So the resveratrol is activating all these stress response pathways that are basically, you know, in our, you know, we have in our body and basically turning on all these genes that are helping you deal with stress. But they're, like, staying activated for longer. And so, when, you know, basically aging, which is a stress, you're basically dealing with aging better in a way. Right?
David: Couldn't put it myself. And then the opposite, if you spend your whole day sitting, or typing, or you're always satisfying your hunger, your sirtuins, and your other pathways, AMP kinase, mTOR, they say, "Hey, times are good. Let's just grow tissue, go forth, multiply and not build a sustainable body in the long run." Because there's always a tradeoff, which Tom Kirkwood called the disposable soma hypothesis. And it seemed to be very true. So you want to always have your body in a state of a little bit of stress, hormesis, we call that.
Rhonda: Yes. People that are listening to the podcast have heard me talk about hormesis quite a bit. My favorite is sulforaphane, the molecule in the cruciferous vegetables. But I've been... You know, the resveratrol field, when I first was following it back in, I guess, the early 2000s, you know, I was very skeptical that there would be any effect in humans taking resveratrol because, certainly not from drinking a glass of wine. But from supplementing, just because it seemed as though, like, the doses required to get some really beneficial effects, at least in some of the rodent studies seemed sort of, you know, high and it didn't seem very attainable. But as you know, there was a really sort of compelling primate study in rhesus monkeys. I forgot when that was published. It was like mid-2000s, or 2011, or something like that.
David: Right. Rafa de Cabo's group with NIH.
Rhonda: Yes, that's right. They gave these rhesus monkeys resveratrol, and I think they started out with a lower dose, like 80 milligrams per kilogram and they went up to, like, 480. Any reason? Do you know why they start with... I've seen more than one study do that.
David: Yeah. So just anecdotally, what Rafa told me, I think, is that they started at the low dose and didn't see a change in pulse wave velocity in the blood vessels, so they upped it and then that's where they saw the benefit.
Rhonda: Oh, okay. Well, this study was... You know, the doses were very doable on humans when you, you know, convert and basically, you know, feeding these monkeys, they're feeding them, like, this terrible high sucrose diet, high sucrose and high fat, and they, like, it caused them to have, like, 40% increased aortic stiffness, but the resveratrol completely ameliorated it, like... So I was like, "Holy crap, that's pretty cool." I think that was the one study that sort of changed my view and then I started to sort of get into the literature and read ones that there was, you know, there's been a variety of clinical studies, as you know, and...
David: Yeah. Well, I'm glad somebody is reading the literature. Because there was a "hate me" club with resveratrol because it got so much attention. And anything that gets a lot of attention gets the "hate me" club in reverse. But resveratrol, I still take resveratrol, probably a gram or so every morning.
Rhonda: A gram? Really?
David: Yeah. In my yogurt. I don't measure it out, I just shake it in. So it might be half a gram to a gram.
Rhonda: Is this from your own, like, stash or is it like a...
David: It's a stash in the basement. I've had it for years.
Rhonda: It's a private stash?
David: It is. I'm not a drug dealer.
Rhonda: Because I don't usually find doses of resveratrol above 250 milligrams, I think.
David: Yeah. Right. You made a good point, which is it's a really insoluble molecule and that's one of the... Well, there are two problems with resveratrol, one is it's really insoluble. So if you just give it as a dry powder to an animal or a human, it's less likely to get absorbed. We know that as a fact. Include it with a bit of fat, it'll go up five to tenfold in the bloodstream.
David: It's like a big effect we've seen in mice and monkeys, it was with a bit of fat in the diet as well. And then the second problem with resveratrol is that it's light sensitive. And so those people who...researchers who put it in a plate with worms or didn't treat the molecule with respect, it goes brown. It goes off. It's one of the reasons it's very hard to put in a cosmetic because your cosmetic will turn brown. If you use brown resveratrol, it won't work. So you've got to keep it in the dark, in the cold, and it'll be fine.
Rhonda: Okay. So...
David: Or in a basement.
Rhonda: ...cold, dark, and also I think there's various forms like trans-resveratrol.
David: I'd go for the trans because when we gave the cis form to the sirtuin enzyme, it didn't activate it, but the trans worked brilliantly. Yeah. Rafa de Cabo, actually, he's been a good friend over the years. A great colleague. He did the study with us on the mouse, resveratrol study that showed that on a high-fat diet, those mice were extremely healthy and longer lived and their organs, when they opened up the mice, they were pristine. So the mice were still obese, so we didn't give them a lot of resveratrol, it was pretty low dose, but their organs were so beautiful. Their arteries, when you stain them for oil or fat, it was night and day. The ones on resveratrol or the ones without resveratrol were stained with fatty lumps. resveratrol, clean. And that alone makes me say, you know, resveratrol's probably not going to hurt me and it may very well help my cardiovascular system.
Rhonda: It seems to be really important for a cardiovascular system, like... And I'm just kind of, do you know why, why is it...?
David: We have a number of ideas. And resveratrol is a dirty molecule, so there's not just one way it works. Sirtuins definitely are involved. We now have a mouse that's mutant for the resveratrol activation of SIRT1, so we now see that some aspects, like endurance, of resveratrol seem to be through SIRT1. So one of the effects is through SIRT1's anti-inflammatory actions in the lining of the blood vessels, the endothelial cells.
Rhonda: Oh. Okay.
David: Yeah. That seems to be important. And there's other aspects also in DNA repair as well. infiltration of macrophages in there seems to be dampened. And we also looked at oxidative stress in those arteries of those mice treated and it was way down in the resveratrol mice.
Rhonda: Yeah. With the rhesus monkeys, with the, you know, basically like, you know, completely reversing that 40% aortic stiffness, that's like pretty, it's a pretty dramatic effect. So I was...
David: It is. And so, yeah, I think resveratrol, it's... People are, you know, "Oh, is it true, is it not?" "60 Minutes" did a story and then there was an argument about how it was working. And so people are confused about the molecule, and I still stand by it because the results, like you say, in animals. And there are clinical studies now that are really positive in humans. Not all of them, sometimes it has no effect. There was one study where it interfered with endurance exercise. Don't understand that.
Rhonda: Metformin was kind of shown to do something similar where it prevented mitochondrial adaptations in [crosstalk 00:47:47] but who knows?
David: I mean, maybe... Rhonda, what's maybe happening is that if you're dampening free radicals too much, you're actually losing that benefit.
Rhonda: Hormetic effect.
David: Exactly. The mitohormesis. But I haven't seen any downside. You know, I'm a N-of-one, as you would say, in a clinical trial. I've had my heart checked out with a 3D movie MRI. My heart looks like it's 20, it's got no sign of aging. So, it doesn't seem to be doing myself and my dad any harm. So...
Rhonda: How long have you been taking it?
David: Oh, geez. Since 2003.
Rhonda: Wow. And you take about a gram [inaudible 00:48:22] or so a day. Yeah. There was a couple of studies, as you know, there's phase one and two clinical studies on Alzheimer's disease where they were given 500 milligrams or 1,000 milligrams of resveratrol a day and both of these studies found that there was a reduction in amyloid beta 42 in cerebral spinal fluid. There was an improvement in cognitive function and a couple of other parameters. So it was kind of interesting because I recently had Dr. Dale Bredesen on the podcast and he has this whole protocol where he's able to, with certain, you know, diet and lifestyle factors, you know, improve cognitive function and also by MRI, like, have shown to, like, reverse some of the atrophy in the hippocampus. And so resveratrol was on his... He's got this long list and I kind of like, everything in the kitchen sink where I was like, "Geez, like, what is all..." And resveratrol was on there. I never really knew why until I, very recently, was reading a little bit of the clinical studies. I thought that was super interesting as well. And then the other thing that was interesting, as you know, was the autophagy because resveratrol seems to be activating autophagy and I also interviewed Guido Kroemer on the podcast.
David: Oh, you did? Okay.
Rhonda: And he talks about these three signals that are important for autophagy, and one of them is the increase in protein... Oh, wait, decrease in protein acetylation?
Rhonda: Yeah. Because sirtuins are histone deacetylases. So that would lead to, right? A decrease in protein acetylation.
David: That's exactly right. So that's how these Pac-Man enzymes are working. And one of the enzymes that they work on is an autophagy protein that goes and destroys bad protein. So it's perfectly reasonable to think that if you take resveratrol, it might be clearing the body of those proteins.
Rhonda: Yeah. I have seen the study with resveratrol, so that's...
David: Yeah, Richard Turner, I believe. That's the study I think you're referring to and it looked really promising. And he did what looked like a very convincing study, but he actually is still trying to raise the money to do his larger trial. And I'm trying to help him with that, but I would love to see that repeated in women and more people.
Rhonda: Yeah. I know that Dr. Kroemer has published a study looking at biomarkers of autophagy in humans after they've been fasted. And I think one of those was looking at, like, the acetylation on lysine or something. So, it seemed to be working. So it's all very interesting.
David: The NAD boosters also help the brain. So, at least in mice, a couple of labs have published now in top journals like "Cell" that raising the NAD levels in the brain also improves memory and slows down the advancement of Alzheimer's. In mice, admittedly, I know we've cured Alzheimer's in mice [inaudible 00:51:23]...
Rhonda: Well, both nicotinamide riboside and nicotinamide mononucleotide have been shown to do that in animal studies, right?
David: Yeah. You've been... Yeah, I'm amazed how much you know. So that's true. I would love to do a human study. Actually, one of the benefits that we might see is also improved blood flow and that might be helpful for vascular dementia because, as I'm sure you know, we've shown that NMN and others have shown for NR that it also helps with blood flow and actually mimic exercise and regrow the vascular system. And we've done that for muscle. We've got some early results that it also helped restore blood flow in the brain, which is badly needed for a lot of elderly people.
Rhonda: Right. Yeah, I know that's a big... I mean, that's a big thing for cognitive function. So NMN was able to do that.
David: In mice, yeah.
Rhonda: In mice. Yeah. So with the clinical studies, you know, I've seen a couple with nicotinamide riboside, but I guess the, you know, the question is with the nicotinamide riboside, there's been a little confusion about like, you know, whether or not nicotinamide riboside's even really getting converted into NAD inside cells and different organs other than the liver. This was this NAD flux paper that was done by Rabinowitz?
Rhonda: Rabinowitz. Thank you. Yes, that study he recently published just a few months ago looking at nicotinamide riboside and how orally, at a dose half of what typically is used in all the other nicotinamide riboside animal studies. So typically, they do 400 milligrams per kilogram body weight per day. I don't remember how long, the duration they were doing it. But in the NAD flux study, he did 200 milligrams per kilogram 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...
David: Yeah, we use double that dose for a while.
Rhonda: Yeah, so maybe, you know, this NAD flux study that showed nicotinamide riboside given orally didn't form NAD in the muscle, but it did in the liver could have been a dose-dependent thing?
David: It would make sense because we've done a lot of this in mice and now in humans, and that there's a threshold that you need to cross, you need to take a certain amount to get over probably the body's clearance mechanisms and then you get up to a level that plateaus after about nine days. And they may have just been under that threshold, so the body was just clearing it out. But you have to seemingly overwhelm that clear-out system, so that's why we do at least 400 mgs per kilogram in mice.
Rhonda: And that's with nicotinamide riboside. The question is, I mean, that's like if you talk about a human equivalent dose for like a 180-pound man, that's like over two grams a day. And it kind of leads 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 had pterostilbene in it. This dose was like 1,000 milligrams a day and they looked at a variety of endpoints in addition to...I mean, they looked at endurance, looked at...
David: Right. It was Doug Seals' study.
Rhonda: Yes. And there was no statistical significance in anything. It raised NAD levels, but there was no statistical significance. There was trending improvement in the vascular system, but there was no effect on endurance. And I'm wondering again, well, if we go back to the human equivalent dose, what was given to the animals, that was still less than half. I mean, so the question becomes, is it not even making NAD in the muscle tissue at that dose or, you know, so...which brings me to the nicotinamide mononucleotide. You know, like now those studies have been done in animals at a much lower dose than 400 milligrams.
David: They have. Yeah. So we, in my lab, and at the company, Metro Biotech, we've been using a whole variety of different molecules and different... We're doing what's called pharmacokinetics. So there's a lot of literature that I could talk for another hour on. One of the big questions people ask me is, "Have you ever put NR and NMN head to head in a study?" And we need to do a lot more of those, typically they're not done. And I'm unaware of it being done in humans at this point. But in mice, what we see... And for all the NR folks out there, please don't be angry, this is just data. I don't run the experiments, I just deliver the message. That at the same dose, NMN will increase endurance. And I forget what that dose was. It might've been 200, 250.
Rhonda: Yeah, 200.
David: NMN didn't increase... Sorry, NR did not increase endurance, but NMN did. We do find that for some parameters, and Matt Kaeberlein, who I mentioned earlier who, he works on dog aging now after doing the SIR2 extension lifespan. So Matt also has published that, comparing NR and NMN, only NMN worked in his disease model, which was a mitochondrial disease where those animals really need a boost of NAD. So one of the issues could be that NMN is a better molecule in that regard. It could be that maybe the mice just worked better than humans and we need a bigger dose. But what I'm working on, which is not talked about a lot because it's in the commercial realm, is there's been a team of seven chemists working on much better molecules than any of these two that I'm talking about, super NAD boosters. And we have ones that work far better than NMN. And these are timed release. These are what we call prodrugs. And those are the ones that I'm really excited about for medicines of the future that don't just increase someone's endurance but could actually treat diabetes, and heart disease, and cancer, and Alzheimer's. That said, we are doing a clinical trial right now with a molecule called MIB 636. MIB is just Metro Biotech. And that's a couple of clinical trials that are being done at Brigham and Women's Hospital in Boston, separate group for me, it's all independent. And that's just a safety study. So when I come back on your show, if I come up back on your show, maybe I'll tell you if we see some actual efficacy, some results. We're going to be looking in the phase two study at strength and endurance in the muscle of people after some NMN dosing. So we're on the verge of knowing if this is real or not for people.
Rhonda: Is this the first NMN study that's being done in humans, clinical study that you're doing here? Or is...
David: So we've done a couple, but yes, as far as I'm aware, we're the only ones that... Actually, you remind me to say something important for the listeners. Make sure your NR and your NMN is kept in the cold. If it's just on the shelf and it's not in a stabilized form, then it will degrade into nicotinamide, which is something you don't want to take high doses of because we've showed in my lab many years ago that nicotinamide will inhibit the sirtuins, and PARP as well, and interfere with DNA repair.
Rhonda: What? Really?
Rhonda: Like the form that's in vitamins?
David: Right. It doesn't have a super long shelf life, that's not very well known. So keep it cool, in a freezer or the fridge.
Rhonda: But I mean, like, if you're buying nicotinamide riboside, you know, from a variety of companies that make it, it's certainly not shipped to you cold. So the question is how much of it's already degraded just on the shelf?
David: I don't know.
Rhonda: I mean, it's kind of the case with probiotics. You know, when you get probiotics, you want them to be shipped to you cold, you know, so that they're live.
David: Right. Same thing here. We have to also replace our mouse NMN. We put it in their water. We replace that every week because it goes off, but if it gets wet or it gets a bit of humidity in the bottle, it's only a short time before it's degrading.
Rhonda: Wow. And we were talking a little bit before the podcast about... I was super excited. I think it was the 2016 "Cell" paper, you mentioned the group that published the NMN, basically, that was given to normal mice without any...
David: Yeah. Shin Imai's study.
Rhonda: Shin Imai's study. That's right. And basically, I think it was about 200 milligrams per day, like that dose, because I remember looking at the dose and going, "This is significantly lower than a nicotinamide riboside dose. And it seemed to delay tissue aging in multiple organs where, I mean, it was like... I don't know, did it extend lifespan?
David: He didn't take it long enough. He ran out of material. And in those days, NMN was hard to get and it was very expensive. It still is very expensive. We're still paying tens of thousands per kilo. But what he showed was that over a year of treatment, pretty much all the parameters of health in these mice were improved. And if those mice didn't live longer, I'd be surprised. But we have done an NMN lifespan in my lab and it's still ongoing and it's being crowdsource funded. So thank you for your donations. But it, already, it looks significantly different. The group that's on NMN in their water supply. And also, it improves frailty. In other words, they're less frail. Looks like it improves heart function as well. The dose, I can't exactly remember what we're using. It's probably around the 400, which is what's our standard dose, but don't quote me. But yeah, NMN and NR seem to do remarkable things to rodents. But like you say, like you brought up the challenges, A, does it work in humans? And B, if it does, what dose is necessary to get those effects?
Rhonda: Right. And is it going to be side effects with, like if you read the most recent study, the clinical study where the dose of nicotinamide riboside was, like, 1,000 milligrams, there were a lot of people that dropped out because they had rashes and...I mean, there was flushing.
David: Oh, they did?
Rhonda: Yeah, there's some side effects. There were some side effects.
David: It might be with NR. We've never seen anything like that with NMN. And I take a gram of NMN every morning.
Rhonda: So the NMN is the reason why there are more studies with NR because NMN is so expensive?
David: Yeah. Well, historically, some companies started making NR early on and made it widely available and cheap to researchers, in fact, so cheap, they were giving it away to researchers. So, it became used much more often than NMN. But increasingly, and if any scientist, lab wants some NMN, let me know, I'm happy to subsidize it if they'd like. But, yeah. And NMN was late on the scene because it was harder to synthesize because it's a bigger molecule, needs that phosphate, and phosphate chemistry is quite difficult.
Rhonda: So you mentioned that the company that you're... Is this the company that is trying to get supplements of NMN or is this like...
David: So I don't do supplements and I don't endorse products. You can only do one. It doesn't work for both. So I've committed my career to making pharmaceuticals that are proven to work and are proven safe and are awarded, you know, marketability by the FDA.
Rhonda: So a drug, basically, from...
David: It's a drug. It's a drug. And that's because early in my career, I dabbled in the supplement world with resveratrol. And it only lasted about three weeks before I had to get out because of... It's incompatible for me, at least, me to be able to, without getting criticized, "This is what I think, this is the data," and I want to be able to say that without making any money off it. But also, I find that the supplement world, it's so controversial and litigious that I was scared away. It's a sad thing that I'm unable to talk about supplements by name because I obviously know a fair bit, but I just can't because, you know, I've already been dragged into lawsuits, I've lost a lot of money by that. I've done nothing wrong except open my mouth. And there are a lot of companies out there who have a lot of money who don't want me to say things. So, unfortunately, you know, I really am unable to do that. I do tweet out and do social media where I can. I've written blogs about it. Like, I'm probably one of the few scientists that tells the world what I do personally and use myself as a role model for people to judge. But I never recommend anything because, first of all, I'm not a physician. I'm just a scientist and I mostly study mice. So I don't really know yet how this is all going to play out in people.
Rhonda: It'd be nice if NMN could be available without a prescription now.
David: Well, it would, but it will also be nice if someone like me did a clinical trial so we knew what would happen and what dose to take.
Rhonda: Yes. Well, that would be... That's first and foremost. I mean, knowing the dose to take that's actually has any effect. Right? It's not just like, yeah... I mean, don't just take some X amount just because it makes you feel good. I mean, a placebo does something, it definitely is changing dopamine in the immune system and stuff. But I agree. Yeah. So you mentioned supplements, you take a gram of resveratrol... Sorry, not a... Yeah, a gram?
David: It is a gram of resveratrol, whatever I pour out into my yogurt.
Rhonda: And about a gram of nicotinamide.
David: And NMN. [crosstalk 01:04:29]
Rhonda: And that's also in your yogurt as well?
David: No, I can just take that as a capsule in the morning, down it with a cup of coffee. And that's a pretty big boost, I find, physiologically, those three things with caffeine included. You can ask my friends. Sometimes I have to temper it a little because I'm like a mouse on oxygen, running around the cage a little bit too much. But it works for me. It helps with... I believe it helps me with jet lag as well or a lack of sleep. I've got three kids, so sometimes I don't sleep well. I know you have a young one, so you know what that's like.
Rhonda: Thankfully, I'm starting to sleep well now, but sleep is really important for aging as well, particularly the aging brain, you know, so... In fact, I was wearing a continuous glucose monitor. I've been wearing one for a few months now. And my son, like around Thanksgiving time, started having teething and stuff and he started waking up in the middle of the night and he'd be up for like an hour and it was like... So I was basically having very fragmented sleep and my blood glucose levels, like my fasting blood glucose levels and my postprandial were, like, 15 to 20 units higher. And this was, like, repeatable, very... I was, you know, my diet's... Pretty much, I eat the same thing, so it wasn't like eating anything like a cookie or anything like that. I mean, it was just like... And doing some high-intensity interval training did help, and there are actually some research on that, but I was astounded by the effect sleep had or a lack of sleep.
David: Yeah. If you take a rat and deprive it of sleep, it will get diabetes within a matter of a month or so.
Rhonda: I mean, it's just like it was... You know, I'd read the studies. I had Dr. Matt Walker on the podcast, talked all about it. But when it happens to yourself and you see the data, I mean, of course, it's still just an N-of-one for me. But I mean, it was just like, it was very... To me, it made it very real. I was like, "This really is regulating my insulin level, my insulin sensitivity."
David: Right. I could see my age changing when I had young kids.
Rhonda: Oh, absolutely. I've aged for sure. I mean, I can see it, like the... You know, especially as a nursing mother in the early, you know, days of my son being born, it was just so hard. I mean, it was so hard.
David: Yeah. Just check out photos of me in my 30s and early 40s when it was lack of sleep and stress and my wife screaming at me for traveling, that kind of stuff. That wore me out. You can see that I aged rapidly. Since then, I don't think and others don't think that I've aged much since then. So it's sleep and stress. All important.
Yeah. How much do you sleep at night?
David: Well, often, I'm working up until 11:00, which is a bad habit, but I have found ways to get to sleep pretty quickly. Avoiding blue light, so I wear those yellowish glasses. What do I do? Occasionally, I take a nibble of a sleeping pill occasionally when I really have trouble sleeping because I used to be an insomniac. But what I've found is the doses that they prescribe for some of these medicines, I won't say which, but I'm way more than I need at least. And so I just nibble on it and it's enough to get me to calm down and I go to sleep. And then in the morning, I get my boost and I'm going again. But I typically get seven hours sleep. 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 be going at 100 miles an hour every day.
Rhonda: Yeah. Doesn't work. Have you ever heard of the Phillips Hue lights? Philips Hue is really...it's like they make these lights, we have them around our house, that you can program your phone and they turn red at a certain hour, so like ours go red at sunset and so there's no blue light coming. And it's really like, you know, to think about it, it really makes a difference. And developing children are really sensitive to light, like even more sensitive than adults. So, like I'll notice if we're traveling and we're in a hotel room or if we're visiting, like, my in-laws in, you know, another state and they have lights on at night that my son, it's like it's harder to get him to go to bed and it's...I mean, it's very obvious, and so I'm always like freaking out trying to turn off the lights. I'm like, "We're going to be in the dark."
David: Yeah, me too. And so, my kids and I, three of us, we got my wife for Christmas one of these indoor plant growth, like, hydroponics and the light for that hydroponic unit, it's about a foot long, maybe two feet. It's super bright and it's in the kitchen. And it was so bright that I was finding I couldn't sleep because it also comes on at night and it's just this intense light. So we've had to move it to the dining room and drape clothing over it because, otherwise, I wasn't getting...
Rhonda: Oh, yeah, like hotel rooms with the alarm clock. It's like blue lights, like, it's like lighting up the room, you know, or I'm like always throwing stuff. We've got a HEPA filter and there's, like, this right red light. I mean, I'm just like, "Who's designing this stuff?" You know, you don't want light when you're trying to sleep and stuff.
David: I'm with you. In my bedroom, our bedroom, we've got lights popping up. Everything is glowing now, and they like to put blue lights in these things now that they're trendy. Does anyone not think it's...
Rhonda: No. Yeah, I know. Anyways, that's a whole other topic. Super excited about all your research. The epigenetic clock stuff has me super pumped up, David. We'll have to, like, stay in touch. I mean, I'm super...
David: That sounds good.
Rhonda: It's an understatement how excited I am. Like I definitely want to talk to Steve. I want to get in touch with him as well. But, yeah. This is like...
David: Yeah, so the people I mentioned, so Steve Horvath, Manuel Serrano, and Juan Carlos Belmonte, have just formed an entity to fund research in this area and to go into human clinical trials, probably in glaucoma, which is a disease that's extremely hard to treat, you cannot reverse the damage that's been done and we think we might be able to. So it's exciting times. The research is going extremely fast, makes my head spin. I get texts every day of breakthroughs, which is a great, I guess, a privilege. But yeah, I'd love to come back and tell you more. I tweet out some results these days. I used to be very tight-lipped, but now, it's too exciting not to tell people about it as we discover it.
Rhonda: Right. Totally. I'm following you on Twitter, so that's definitely... If people want to find you on Twitter, your Twitter handle is?
David: A for Andrew.
Rhonda: A for Andrew. And you have a website, a book coming out.
David: Well, we have a lab website. We'll shortly launch a book website where there will be information and 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 talents for medical illustration, Katie Delphia, and so that's speckled in there. And we've got a cast of characters in there that range from Captain Arthur Phillip, who founded Sydney colony, who used to hang out in my backyard in Sydney 200 years before, all the way through to scientists in London who were making major discoveries that led us to today and then it projects forward. With me having a front row seat on this field, both in the biology and industry, what does the future look like? What does it look like if we don't succeed, which is pretty bad. What does it look like if our wildest dreams come true? What's that world look like for us and our descendants?
David: And maybe we get to see our descendants.
Rhonda: Yes. Definitely, I'm looking forward to the book, for sure. Thank you for connecting up with me. Big fan of your research for quite some time and I'm even more excited now about all the new stuff going on. I had no idea. I mean, you just started talking about it and was like, "Yes."
David: Well, thanks, Rhonda. It's really great to be able to talk about it with someone who literally knows as much as I do about the topic.
Rhonda: That's flattering. Thanks, David.
AMP Kinase (AMPK)
An enzyme that plays multiple roles in cellular energy homeostasis. AMP kinase activation stimulates hepatic fatty acid oxidation, ketogenesis, skeletal muscle fatty acid oxidation, and glucose uptake; inhibits cholesterol synthesis, lipogenesis, triglyceride synthesis, adipocyte lipolysis, and lipogenesis; and modulates insulin secretion by pancreatic beta-cells.
An intracellular degradation system involved in the disassembly and recycling of unnecessary or dysfunctional cellular components. Autophagy participates in cell death, a process known as autophagic dell death. Prolonged fasting is a robust initiator of autophagy and may help protect against cancer and even aging by reducing the burden of abnormal cells.
The relationship between autophagy and cancer is complex, however. Autophagy may prevent the survival of pre-malignant cells, but can also be hijacked as a malignant adaptation by cancer, providing a useful means to scavenge resources needed for further growth.VIEW AUTOPHAGY TOPIC
The practice of long-term restriction of dietary intake, typically characterized by a 20 to 50 percent reduction in energy intake below habitual levels. Caloric restriction has been shown to extend lifespan and delay the onset of age-related chronic diseases in a variety of species, including rats, mice, fish, flies, worms, and yeast.VIEW CALORIC RESTRICTION TOPIC
Caloric Restriction Mimetics (CRM)
Compounds that induce a similar biochemical milieu in the cell as starvation or nutrient deprivation, including the reductions in cytosolic acetyl CoA and increases in protein deacetylation that serve as a trigger for the cellular autophagic machinery. Popular examples of compounds that exhibit this type of effect include: hydroxycitrate (inhibits ATP citrate lyase), spermidine (inhibits Ep300, a protein acetyltransferase), and resveratrol (activates deacetylases called sirtuins).
The body’s 24-hour cycles of biological, hormonal, and behavioral patterns. Circadian rhythms modulate a wide array of physiological processes, including the body’s production of hormones that regulate sleep, hunger, metabolism, and others, ultimately influencing body weight, performance, and susceptibility to disease. As much as 20 percent of gene expression in the human body is under circadian control including genes in the brain, liver, and muscle. As such, circadian rhythmicity may have profound implications for human healthspan.
A broad-spectrum antibiotic used in the treatment of bacterial infections. Doxycycline, commonly called “doxy,” is a bacteriostatic drug that slows bacterial growth by inhibiting protein production. The World Health Organization considers doxycycline an essential medicine because of its widespread applications and its use as a treatment against biothreats such as anthrax, tularemia, and plague.
A biomarker of aging based on alterations in an organism’s DNA methylation profile. Methylations (biochemical processes that alter the activity of the DNA segment without changing its sequence) occur naturally and regulate gene expression. With age, the methylation state of a gene may change. These changes are quantifiable and serve as a means to gauge biological age, which is often different from chronological age.
Genetic control by factors other than modification of the genetic code found in the sequence of DNA. Epigenetic changes determine which genes are being expressed, which in turn may influence disease risk. Some epigenetic changes are heritable.
Biological responses to low-dose exposures to toxins or other stressors such as exercise, heat, cold, fasting, and xenohormetics. Hormetic responses are generally favorable and elicit a wide array of protective mechanisms. Examples of xenohormetic substances include plant polyphenols – molecules that plants produce in response to stress. Some evidence suggests plant polyphenols may have longevity-conferring effects when consumed in the diet.
Informational theory of aging
A concept based on the assumption that the loss of function that accompanies aging is due to impaired cellular repair mechanisms caused by the accumulation of genetic damage in the cells.
A broad term that describes periods of voluntary abstention from food and (non-water) drinks, lasting several hours to days. Depending on the length of the fasting period and a variety of other factors, intermittent fasting may promote certain beneficial metabolic processes, such as the increased production of ketones due to the use of stored fat as an energy source. The phrase “intermittent fasting” may refer to any of the following:
- Time-restricted eating
- Alternate-day fasting
- Periodic fasting (multi-day)
A metabolic pathway in which organisms produce ketones. Ketogenesis occurs primarily in the mitochondria of liver cells via the breakdown of fatty acids and ketogenic amino acids. Insulin is the major hormonal regulator of ketogenesis; however, glucagon, cortisol, thyroid hormones, and catecholamines can induce greater breakdown of free fatty acids, thereby increasing the substrates available for use in the ketogenic pathway. The primary ketones used by the body for energy are acetoacetate and beta-hydroxybutyrate.
Mechanistic target of rapamycin (mTOR)
A genetic pathway that senses amino acid concentrations and regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription. It integrates other pathways including insulin, growth factors (such as IGF-1), and amino acids. mTOR plays a key role in mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain. It is dysregulated in many human diseases, such as diabetes, obesity, depression, and certain cancers. mTOR has two subunits, mTORC1 and mTORC2. Also referred to as “mammalian” target of rapamycin.
Rapamycin, the drug for which this pathway is named (and the anti-aging properties of which are subject to much study), was discovered in the 1970s and is used as an immunosuppressant in organ donor recipients.
A drug commonly used for the treatment of type 2 diabetes. Metformin is in a class of antihyperglycemic drugs called biguanides. It works by decreasing gluconeogenesis in the liver, reducing the amount of sugar absorbed in the gut, and increasing insulin sensitivity. A growing body of evidence indicates that metformin modulates the aging processes to improve healthspan and extend lifespan. Furthermore, metformin may prevent genomic instability by scavenging reactive oxygen species, increasing the activities of antioxidant enzymes, inhibiting macrophage recruitment and inflammatory responses, and stimulating DNA damage responses and DNA repair.
 Najafi, Masoud, et al. "Metformin: Prevention of genomic instability and cancer: A review." Mutation Research/Genetic Toxicology and Environmental Mutagenesis 827 (2018): 1-8.VIEW METFORMIN TOPIC
Dietary supplements that purportedly increase cellular levels of nicotinamide adenine dinucleotide (NAD+). Examples of potential NAD+ boosters include resveratrol (a plant-based dietary compound found in grapes), metformin (a type of diabetes medication), and nicotinamide mononucleotide (a derivative of niacin).
Nicotinamide adenine dinucleotide (NAD+)
A coenzyme that is required for the production of energy in cells. NAD+ is synthesized from three major precursors: tryptophan, nicotinic acid (vitamin B3), and nicotinamide. It regulates the activity of several key enzymes including those involved in metabolism and repairing DNA damage. NAD+ levels rise during a fasted state. A group of enzymes called sirtuins, which are a type of histone deacetylase, use NAD+ to remove acetyl groups from proteins and are important mediators for the effects of fasting, caloric restriction, and the effects of the plant compound resveratrol, a so-called caloric restriction mimetic.
Nicotinamide mononucleotide (NMN)
A precursor molecule for the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a coenzyme that participates in the production of cellular energy and repair. NMN helps maintain cellular levels of NAD+, thereby facilitating NAD+-dependent cellular activities, such as mitochondrial metabolism, regulation of sirtuins, and PARP activity. Animal studies have demonstrated that NMN administration is effective in increasing NAD+ levels across multiple tissues while improving the outcome of a variety of age-related diseases. Although NMN administration has proven to be safe and to effectively increase NAD+ levels in rodents, the safety and efficacy of NMN supplementation in humans remain unknown. NMN is available in supplement form and is present in various types of food, including broccoli, avocado, and beef. It is also an intermediate compound in the NAD+ salvage pathway, the recycling of nicotinamide into NAD+.VIEW NICOTINAMIDE MONONUCLEOTIDE TOPIC
Nicotinamide riboside (NR)
A precursor molecule for the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a coenzyme that participates in the production of cellular energy and repair. NMN helps maintain cellular levels of NAD+, thereby facilitating NAD+-dependent cellular activities, such as mitochondrial metabolism, regulation of sirtuins, and PARP activity. Animal studies have demonstrated that NMN administration is effective in increasing NAD+ levels across multiple tissues while improving the outcome of a variety of age-related diseases. Although NMN administration has proven to be safe and to effectively increase NAD+ levels in rodents, the safety and efficacy of NMN supplementation in humans remain unknown. NMN is available in supplement form and is present in various types of food, including broccoli, avocado, and beef. It is also an intermediate compound in the NAD+ salvage pathway, the recycling of nicotinamide into NAD+.VIEW NICOTINAMIDE RIBOSIDE TOPIC
Capable of developing into any type of cell or tissue except those that form a placenta or embryo.
A compound initially developed as an antifungal agent. This use was abandoned, however, when it was discovered to have potent immunosuppressive and antiproliferative properties due to its ability to inhibit one of the complexes of mTOR (mTORC1). Rapamycin has since shown interesting lifespan extension properties in animals.
A polyphenolic compound produced in plants in response to injury or pathogenic attack from bacteria or fungi. Resveratrol exerts a diverse array of biological effects, including antitumor, antioxidant, antiviral, and hormonal activities. It activates sirtuin 1 (SIRT1), an enzyme that deacetylates proteins and contributes to cellular regulation (including autophagy). Dietary sources of resveratrol include grapes, blueberries, raspberries, and mulberries.
Resveratrol Autophagy ↑ Deacetylases (especially SIRT1) → ↓ Protein Acetylation → AutophagyVIEW RESVERATROL TOPIC
A member of the sirtuin protein family. SIRT1 is an enzyme that deacetylates proteins that contribute to cellular regulation (reaction to stressors, longevity). It is activated by the phytochemical resveratrol as well as fasting.VIEW SIRTUINS TOPIC
A class of enzymes that influence that influence aging and longevity through multiple molecular pathways. Sirtuins regulate a variety of metabolic processes, including release of insulin, mobilization of lipids, response to stress, and modulation of lifespan. They also influence circadian clocks and mitochondrial biogenesis. Sirtuins are activated when NAD+ levels rise. The dependence of sirtuins on NAD+ links their enzymatic activity directly to the energy status of the cell via the cellular NAD+:NADH ratio, the absolute levels of NAD+, NADH or nicotinamide or a combination of these variables. There are seven known sirtuins, designated as Sirt1 to Sirt7.VIEW SIRTUINS TOPIC
An isothiocyanate compound derived from cruciferous vegetables such as broccoli, cauliflower, and mustard. Sulforaphane is produced when the plant is damaged when attacked by insects or eaten by humans. It activates cytoprotective mechanisms within cells in a hormetic-type response. Sulforaphane has demonstrated beneficial effects against several chronic health conditions, including autism, cancer, cardiovascular disease, diabetes, and others.
A person who is 110 years old or more.
Proteins that can reprogram differentiated (mature) cells into pluripotent stem cells. Yamanaka factors are highly expressed in embryonic stem cells in mice and humans. Five Yamanaka factors have been identified: Oct4, Sox2, cMyc, Klf4, and NKX3-1. In a mouse model of premature aging, short-term expression of Oct4, Sox2, Klf4, and c-Myc ameliorated cellular and physiological hallmarks of aging and prolonged lifespan .  Ocampo, Alejandro, et al. "In vivo amelioration of age-associated hallmarks by partial reprogramming." Cell 167.7 (2016): 1719-1733.
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