How Supplementing With NMN Can Increase NAD levels, Energy, Reduce Inflammation, And Improve Insulin Resistance - Transcript

Introduction: Coming up on this episode of the Doctor's Farmacy.

Dr. Andrew Salzman: There are inflammatory changes that are chronic or subacute where NAD is actually regulating the amount of inflammation in the cell. And that has a whole effect on the development of injury to our tissues, cancer development, lack of healing.

Dr. Mark Hyman: Welcome to The Doctor's Farmacy. I'm Dr. Mark Hyman, that's Farmacy with F, a place for conversations that matter. And if you are curious about longevity, which I imagine maybe listening are, and you may have heard about something called NAD or NMN or NR or sirtuins, or supplements that you can take to potentially extend your life and improve your health, you're going to love this podcast because we have an expert today, Dr. Andrew Salzman, who's a physician and inventor, professor. He's a biomedical entrepreneur.
He lives in Israel right now. He's received his medical degree from Harvard University and spent decades in drug discovery and development. He's raised over $165 million in the NIH grants for research, which is astounding. That's a lot of money, to give away that much. In addition to 50 patents, Dr. Salzman's credited with a breakthrough discovery in how cells repair their DNA, which led to the first clinical application in the world for successfully treating breast cancer caused by mutations in BRCA1 and BRCA2 genes.
So he's benefited so many people. Millions of people have benefited from his discoveries in areas including mitochondrial health, gastrointestinal microbiome, the damage caused by inflammation and oxidative stress to human cells and DNA, autoimmune disease and cancer, all the things we like to talk about on The Doctor's Farmacy. So welcome, Dr. Salzman.

Dr. Andrew Salzman: Welcome. Thank you. Thank you very much for having me here today.

Dr. Mark Hyman: Well, I'm really excited to talk to you because, as many of you listening today know, I wrote a book called Young Forever about how do we enhance our health span, increase the time we're healthy in our life, and potentially expand our lifespan. And there's been so much research on this lately, and that has really gone really deep into the understanding of the mechanisms of aging. We call the hallmarks of aging.
And in those hallmarks, there's a lot of data information there, but there is something that's really important, which is how we regulate energy in our mitochondria, which is really the key energy producing units of our body. When we eat and we breathe, we produce energy called ATP. And in the mitochondria, that's where we do it. And it has to be functioning well, they have to be actually efficient, effective. And as we age, they decline in their number and their function, their efficiency, and that's kind of why we get old and slow and tired.
So there's been an amazing compound that's been the subject of intense research, you might have heard about called NAD, or nicotinamide adenucleanide diribecide or something like that. It's a big fancy word and it's the driver of our health longevity in many ways. So can you tell us, what is NAD? Why is it so key as a driver of our health longevity? And just give people sort of a high-level background about what we're going to be talking about today, which is mostly about NAD.

Dr. Andrew Salzman: Okay. Sure. So when the cell produces energy, it's actually a complex mechanism. It starts of course with the food we eat. And ultimately, that fuel, that food that we ingest is changed and modulated until ultimately it provides molecules of energy that the cells can use throughout the body. And NAD and the mitochondria are absolutely central to that process. When the sugar or protein or whatever we eat enters the cell, it enters into various pathways. And in these pathways, the foodstuff, which typically as an example might be glucose, is then modified and cut and shaped. And NAD plays a critical role in this process. There are three separate sequential processes in the cell which produce the ATP. And in each one of these, NAD is generated, to a certain extent. And without that NAD, we ultimately cannot finish this sequence, this cycle, which leads to ATP.
So NAD is sort of the transfer agent that goes from the food to the final product, which is ATP, which we can use. In the absence of NAD, you can't make ATP. So NAD is [inaudible 00:04:33] central part of life. As we age and as we have various processes that reduce NAD, we're putting [inaudible 00:04:42] a number of factors in this process. For example, we can't make a ATP as well. So when you're 20 years old and you're running down the field with the football, you've got a lot of NAD and a lot of ATP. When you're 60 years old, you start to notice quite a difference of course.
And if look at the muscle of a 60-year-old or of an 80-year-old, 'cause when we're 80, we're still doing a lot of stuff today, but what you're going to see is there fewer mitochondria, these powerhouses of energy, they're fewer of them, that's a problem. But within each individual one, they're not making enough NAD. And of course they're not making enough ATP. Now, if you're a couch potato, you're sitting there and you're watching the 7:00 news, you're probably not going to notice that. But if you try to run up the stairs carrying some groceries, or God forbid, run down the football field, the age of 70 or 80, you don't have the capacity to ramp up and generate the NAD and ATP that would be required to be competitive with a youngster. So we start to feel it as we get older.
Now, in the overall picture, this NAD deficiency is much more than just energy, although energy, let's start with that discussion because that's the key point. But there are other things that I will come to which show the broad effect of having lower NAD. So it's not just energy. But focusing on energy, we now know in humans that with time, with age, every year it's a little less NAD available to us. We know in animal models, if we artificially suppress the amount of NAD, those animals can't perform as well. And we have even more data which show that if we supplement and restore and bring back the levels of NAD to where they were when we were younger, we can do a lot more. So NAD is a critical factor in our energy.
Now, what's interesting recently is that this whole story of NAD has been tied into other mechanisms and other pathways in the cell that we didn't realize. For example, we now know that NAD is involved in inflammation, it's involved in pain. And as we get older, we're all feeling a little bit more painful and we're also having loads of inflammation, we have more inflammatory diseases. So this deficit of NAD as we age is really causing a broad effect on our health.

Dr. Mark Hyman: Yeah, it's so important because I think as we're sort of unpacking the science of aging and longevity, which really has been neglected for way too long in medicine, we're understanding that there are underlying pathways that are in the body that are designed to repair, regenerate, renew, heal, and optimize our health. We just screw them up by how we live, what we eat, how we don't move, the stress we're under, environmental toxins, all mess up these ancient survival pathways. And there's thousands of genes that regulate the process of actually healing, repair, rejuvenation and renewal. And we see these decline as we age, but at any age it's possible to actually activate these pathways and reverse that process.
So NAD seems to be really a key part of the story. And one of the hallmarks of aging that I talked about in the book, and it's really an important one, I think, probably the most important, is the deregulated nutrient sensing in which there are four key pathways that are sensing your nutrient environment, mTOR, MPK, sirtuins and insulin signaling pathways. And NAD works specifically on the sirtuins to stimulates sirtuins when there's low energy states. Right?
So can you explain what NAD does in the process of helping us to regulate the sirtuins, what the sirtuins do and why that's so important in longevity and aging? 'Cause I think people need to understand the science behind why everybody's talking about NAD and NMN and NR and all these compounds that sort of have nice alphabet soup, but what the hell do they do and how do they work in the body on these ancient preserved pathways that can be activated to optimize our health?

Dr. Andrew Salzman: Well, there are a number of different pathways that are both immediate [inaudible 00:08:46], intermediate, and then long-term. And NAD seems to be playing an important role in all three of them. So in the most acute situation where you have an acute stress, where you've lost function or you've lost blood flow, like in a myocardial ischemia where you have a heart condition, or in a stroke where you've suddenly lost blood flow flow to your brain, these are instantaneous problems, these are immediate problems.
And in those settings, NAD plays the dominating role because it is regulating the ability of the cell to survive in an environment where oxygen's been suddenly removed. So we can classify a whole bunch of conditions that are instantaneous that we have to deal with. And that involves PARP, which we'll come back to later. But there are pathways that NAD is regulating or is a substrate for which we must have for an acute problem. So that those are the acute instant problems.
There are inflammatory changes that are chronic, or subacute, where NAD is actually regulating the amount of inflammation in the cell. And that has a whole effect on the development of injury to our tissues, cancer development, a lack of healing. So when we look at processes like diabetes, metabolic disease, liver disease, and where there's colitis, where there's chronic inflammation, as we age, that is also very important with NAD.
As we get into the longer-term changes, we're talking about genetic changes or regulation of genes. And I think this is where you were coming at. And in [inaudible 00:10:23] sirtuins and PARP are presently are known to regulate a lot of the different up-regulated or down-regulated expression of key genes. So in the case of sirtuins, for example, NAD is a necessary co-factor. They don't function without the presence of NAD or they function a lot less. They modulate genetic transcription so they can up-regulate and depress various genetic changes which become important in aging and disease. In the case of PARP, our own research showed that this-

Dr. Mark Hyman: Well, can you just define what PARP is? 'Cause I think most people have never heard of that before.

Dr. Andrew Salzman: Yeah, PARP, it's actually the most abundant protein in our nucleus, but it is a protein that sits within the nucleus, which is the center of the cell where all the genetic material is housed. And there, it is responsible for ensuring that the DNA is in good health. So DNA is a very long, long molecule and it can be influenced or impacted by oxidants. We're always exposed to oxygen, we're in an oxygen breathing environment and we have defenses against those oxidants, but some of them slip through. And when they do so, they can go right into the nucleus of our cell and they can actually alter our DNA.
So our genes can actually be damaged after we're born by some kind of oxidant stress. And they're damaged in very different ways. But one of the most important ways is called ANIC, where the oxidant comes into the cell and it actually cuts like a scissors, one of the two DNA strands. We have two strands, it's a double helix, but if you cut one of them, it's called a single strand break. And this is a very damaging effect on the cell. If it accumulates, it can cause cancer. So we have all kinds of mechanisms in the cell to make sure that when we have [inaudible 00:12:17] damage to our genetic material, it's rapidly repaired, and PARP is the key enzyme that does that, it's a key enzyme.

Dr. Mark Hyman: And that's mediated through NAD?

Dr. Andrew Salzman: Well, when PARP recognizes, when the enzyme is recognizing that there's a break, it grabs onto that break and holds on for dear life and then it pulls in NAD around it and makes a long chain of that NAD, which helps do the repair, which is a good thing because you want to keep your DNA repaired. And if you have enough NAD, you can affect the repair and your cells stay in good shape. You're not allowing the DNA to be damaged. So having NAD around chronically is very good. We know that animals that are deficient in PARP, we can actually make animals now that don't have the enzyme. These are genetic mites and they are much more prone to cancer.
So having a constant way to repair your DNA as you get older is absolutely essential. And PARP is enzyme that takes care of that. So NAD is absolutely essential to having healthy PARP, having sirtuins operate at the right level, and causing the up-regulation and downregulation of various genes so that we stay balanced. And as we lose NAD, this balance falls apart and we start to see dysfunctional gene expression, we start to see injury to various tissues, which can kind of cascade as we age. So NAD plays the critical role in maintaining that NAD level all the time, becomes more and more of a challenge as we get old because we're starting at a lower point.

Dr. Mark Hyman: Yeah. So NAD levels decline with age. But what's really interesting about what you're saying is that that the body gets maybe 100,000 little nicks to its DNA every day. Right? Death by 1000 cuts. But the body has its own built-in repairer system, like a repair truck that goes out. And this PARP is a key part of this repair system. And the NAD is also involved in actually activating the sirtuins, which are part of this repair system. Is that fair to say?

Dr. Andrew Salzman: I think most people don't recognize that to be in health, it's not just a matter of the body doing a lot of good things to keep it. It's the defense. The body is on defense, like a football team. And in the case of defending ourself against oxidant stress and injury, the body [inaudible 00:14:48] host of mechanisms, and all of those are important. It's like losing somebody in the front, the tackle or something in a football team. If you don't have a good defense, you don't need a lot of offense to win, to get in trouble. So what are the defenses in the cell? How does the cell protect itself all the time?
Well, first of all, we have evolved mechanisms to take care of these oxidants directly. We have antioxidant enzymes actually sitting throughout the cell, around the nucleus and inside the nucleus. And those enzymes, when they see an oxidant, they come right in on it and they remove it. But in order for them to do that, they have to have ammunition, if you will, to diffuse the oxidant. And what is that ammunition? It's a special molecule called glutathione to neutralize and take out this oxidant stress. So glutathione, it's the weapon they're using.
Well, where does glutathione come from? It comes from a process in the cell, which is completely dependent on NAD. So if you don't have NAD in the cell, you cannot produce glutathione. And these enzymes, they may be there, but they can't work. So NAD is [inaudible 00:16:01] to protecting ourselves from the oxidants, the very oxidants themselves. Okay? So we have antioxidants, that's the first line of defense. It's immediate, very fast, very effective most of the time. Now-

Dr. Mark Hyman: So that's fascinating that NAD actually boosts the enzymes in the cell that actually can make glutathione. Right?

Dr. Andrew Salzman: Every cell in the body has to make glutathione or it parishes. And within the cell, there is a special donor electron donor called NADPH, which builds the glutathione. And this molecule, NADPHH, is absolutely essential to us, and it comes from NAD. So without NAD being around, we cannot defend ourselves from immediate threats in the oxidative sphere.
Beyond that, if one of these oxidants slips through the line, it's running towards the quarterback, so the front line failed, there has to be a defense, something there to protect that quarterback. And in that case, the next line of defense would be this repair mechanism. So the injuries happen, the quarterback got hit, but he has to get back up again fast and keep working. And so the cell has mechanisms built within it to repair the damage that's occurred. And PARP would be a classic example of that.
So NAD is at every stage, it's the initial stage on the front line preventing the rusher coming in. And then it's back farther, if there's injury that's happened, it's there to heal. When NAD levels fall, none of these things are there and the whole cell starts to run into trouble. And eventually, if it spirals out of control and it cannot recover, that's when the cell dies or perishes.
For example, give you a classic example. Someone has chest pain and they find out they're having a heart attack, so they're not getting enough blood flow into their heart. The muscle of the heart is suffering, it's ischemic. So that is an immediate threat to the viability of the heart itself. There's all these oxidants flooding in right now. So glutathione is right there, NAD is doing everything it can to get there, but if the NAD levels are not sufficient, the glutathione levels fall, and now the injury goes one step further, to the DNA, and you get these [inaudible 00:18:17], then PARP is activated, NAD rushes in, tries to help there.
Well, all of these things are good and they can keep you from having a full-blown heart attack. But if at any point the NAD levels go too low, that's it. And at that point, the ATP cannot be produced, the glutathione's not made, and you have cell death, that is an infarction where the tissue is actually died, it's necrotic and it won't recover. And this is the most severe situation. So NAD is playing a role at every level trying to protect us from that chronic stress. And then acute stress like stroke and heart attack.

Dr. Mark Hyman: Yeah, what you point out is so important because so many of the disease of aging, like heart disease, cancer, diabetes, dementia, those are just way downstream from all these mechanisms that go wrong that we can influence. And that's what scientists are now talking about. If we address the underlying root causes of aging, the hallmarks of aging, which NAD in part does a lot of, we can actually do a huge job in preventing and even reversing some of these diseases. And that's so exciting to me, I think we are reaching a turning point in healthcare and medicine where we're understanding the root causes. What's really interesting, I sort of want to unpack this a little bit cause you basically said that we need NAD, which helps us create energy in the cell, but also is involved in regulating antioxidant status, it's involved in DNA repair and our epigenetic programming, but it also has all these cross-purposes actions.
When you activate sirtuins, which NAD does, it's one of the main actions of NAD, is to activate the family sirtuins. These signaling proteins, they work on many of the other pathways that relate to aging like, for example, mTOR, which is regulating your protein synthesis and inhibiting and regulating autophagy. So it helps inhibiting mTOR and helps stimulate the self for cleaning and repair recycling called autophagy. It reduces inflammation by inhibiting a big transcription factor that turns on all the cytokines in your cells called NF kappa B. It activates FOXO, which is another regulator of antioxidants in your cells. It helps to reduce oxidative stress by the mechanisms you mention of increasing glutathione. But it also activates another family of transcription factors called FOXO, which increases antioxidant enzymes that are built into our system. It can reduce cancer by activating tumor suppressor gene called p53. It helps your mitochondria make new mitochondria and improves the efficiency. It helps improve insulin sensitivity and activates AMPK, it regulates our circadian rhythms and clocks.
So it's such a multifunctional substance. You think you take a drug for one pathway. I'm taking a cholesterol drug for lowering my cholesterol, blood pressure, drug for lowering my blood pressure. But the beauty of these natural compounds that are our bodies own medicines, is that they work across the board on all these different pathways and there are many redundancies in the system so that it's not the only thing that regulates these pathways, but that's what I think makes so powerful. What are your thoughts on how all these things connect and how NAD has these multiple functions?

Dr. Andrew Salzman: I think 30 or 40 years ago when I was in medical school, we went from class to class and we learned about different diseases.

Dr. Mark Hyman: Yeah, me too.

Dr. Andrew Salzman: We had a rheumatoid class, we had stroke class, and we were told that there are these diseases that people just get. Right?

Dr. Mark Hyman: Yeah.

Dr. Andrew Salzman: Suddenly you have Parkinson's disease or suddenly you have diabetes. And so we would study diseases and this is sort of how the specialties develop. Right?

Dr. Mark Hyman: Yeah.

Dr. Andrew Salzman: But I think it's come full circle because what we really understand is that there's really one fundamental disease, which is called aging. And then these other manifestations which we see, which we call diseases, "Oh, I have Parkinson's." But no you don't. What you really have is this sequential accumulated process of aging that has dysfunction across multiple pathways, connected to each other. And then we suddenly have, oh, we're 65 and now we have diabetes. Well, where did that come from? But it's not just a hit or miss thing, it is a sequential process.
And as you get older and as this aging process inevitably drives forward, all of these mechanisms are at risk. And eventually, one of them or more of them, becomes a disease that we can categorize and call a disease. But really, it's a generalized process. And NAD is at the epicenter of all the process. So one different way to think about disease management, yes, we need diabetologists, we need all these good people who do all these good things, but fundamentally, we need to slow and arrest or reverse this overriding inexorable aging process that is starting to degrade all of these different pathways together.
And so the search is on now for more broad spectrum or more fundamental approaches than just disease specific ones. And as we look at the NAD story, what better candidate could there be than something that underlies energetics, pain, inflammation, immune response, DNA repair, tissue repair, signaling, and all of the... I mean, this is a fundamental currency. Right?

Dr. Mark Hyman: Cancer prevention. Yeah, insulin sensitivity, all that. Right?

Dr. Andrew Salzman: Right. Like we have currency. We carry a dollar bill in our pocket, we can buy many, many things, but they all go back, you better have that dollar bill. So NAD is a fundamental driver of all of these processes. And you just mentioned many mechanisms, but there are many others that we don't even know about yet. Over in our research, we're looking at new pain pathways that are related to NAD. We didn't even know about this until recently. There's a whole nother category of pain-related problems that have to do with NAD deficiency.
Recently, there's been a whole lot of research on prostaglandins and inflammation from NAD deficiency. We didn't know that. So all of these separate things that we talked about and that we see in our patients, they're starting to come together to a final common or final initiating pathway. And we better understand that pathway and then learn how to manipulate it, how to help it, how to restore it. And that's where my interest is in.

Dr. Mark Hyman: Well, I tell you, I'm barely able to sit in my chair right now and not jump up but down and scream, "Hello, hooray. Yay, finally, somebody's getting it." Because I've been singing this tune for a long time. And when you start to look at systems biology and network medicine, what we call functional medicine, it speaks exactly to what you're talking about. The diseases are just leaves on the trees. We need to go to the roots and the trunk of what's really going on with their biology. And it has to do with exactly this thing that you're talking about, which is this regulated function that accumulates over age that we can actually intervene with and create health. And then all these diseases, either we prevent them or they go away or get reversed.
So that's so beautiful about our understanding of longevity science now. It's sort of peeling back the layers and people are going, "Wait a minute, aging is a disease. These are processes we can treat. There's a way to think about this differently. The diseases aren't all these separate things. They're all connected by these common roots," and it has to do with everything you're talking about.
And so when you look at NAD, the mechanism of action, it does so many different things, from DNA repair, to the activation of sirtuins, to increasing energy production of the cell, to lengthening our telomeres, which shorten to making new brain cells and making new brain connections, reducing inflammation, boosting mitochondrial function, improving insulin resistance and exercise performance. It's really quite remarkable. I remember David Sinclair told me about a study where they had a mouse treadmill that only goes to, I don't know, one or two kilometers. And they never saw anybody, mouse go longer than that. And then when they gave them NMN the thing just kind of broke the treadmill because it went three kilometers or something.

Dr. Andrew Salzman: The secret now, or the trick now, that once we've recognized this, is how do we get NAD levels back up? How do we preserve them? How do we preserve people who are reasonably healthy and give them optimal performance? And how do we help people who have low NAD who are in trouble and get them back to a reasonable level? So to do that requires, like any medicine, it means giving something to somebody that they're missing.
So there's several ways that initially people started giving NAD. It made sense, you have low NAD, give the person NAD. The problem with that is that NAD is a chemical or a molecule that's made inside cells. And it's so valuable, it's so important to the cell itself that the cell is very clever and it embeds within NAD, it changes the molecule in such a way that it can't leak out. It's precious. And so NAD has been designed to stay inside the cell. And if you give a person NAD, it won't fall out of the cell once it's there, but the big problem is it won't get into the cell. So if you [inaudible 00:27:29] a lot of NAD, that's great, it's all floating around doing all this stuff. But in order for it to work, it needs to be inside the cell.
Now, getting NAD into a cell is no mean feat because you've got a problem there. It's designed not to cross cell membranes. So what do you do? So you see all these health products out there, "Take NAD. Take this pill, it's got a lot of NAD," but the problem is yes, you can get it into the body, but you can't get it where it needs to go, which is inside the cell.

Dr. Mark Hyman: Interesting.

Dr. Andrew Salzman: But it created the interest in other ways to boost NAD. So what people did is they said, "Well, where does NAD come from naturally? How does the body make NAD?" Well, it turns out that there are two steps along the way. First, there's something they called NMN and then there's something they called NR and then there's something called NAD. And so they thought, well, if we give the molecule before you get NAD, that can cross the cell membrane more successfully, it can cross the gut when you swallow it. There are all of these good things that could happen maybe if you took a precursor, an earlier step layer. So you'll see all these products now that have something called NR. Right? So nicotin-

Dr. Mark Hyman: Riboside, yeah.

Dr. Andrew Salzman: There are studies and cell studies and human studies looking at NR and it seems to do good things. First of all, it gets in a little bit better than NAD, but more importantly and significantly, you can see the NAD levels go up in the cell when you take NR. So that was a good thing. And then people went out to the ultimate step, which was to give NMN and they asked, "Is this a good way to deliver NAD? Will this do it?"
First of all, when you swallow a pill with NMN, it crosses into the body a lot better than NAD and NR. And that's because the body has created a special shuttle in the cell that recognizes NMN when it's outside and provides a lovely tunnel, if you will, for it to slip right through the membrane and end up on the inside of the cell. So the body has neared a way for NMN to get in there. And of course, once it's in the cell, that's great because then it can be sliced up and form NAD and all is good. And that's been shown. So we now believe that the most efficient way to deliver NAD is actually not NAD itself, but it's in the form of NMN. And that's why our focus has been to use NMN to make these necessary changes to boost NAD.

Dr. Mark Hyman: Interesting. Now, just to kind of loop back for a minute before we want to get into the delivery forms and what does and so forth, is do you know why NAD levels decrease as we age? Is this inevitable? Is there a way to prevent it? Can we naturally increase them? Is there any understanding how that may work?

Dr. Andrew Salzman: No, there really isn't a lot understood on that.

Dr. Mark Hyman: Okay. Good. Because I thought I missed it, but I thought maybe you knew because you're the expert.

Dr. Andrew Salzman: Let's talk about where it's actually made. The first part is when you take sugar, and again, glucose is a good example, and that is broken down by glycolysis and there you get [inaudible 00:30:46] that's spun out. The next part is a cycle called the Krebs cycle. And then that, you take what comes out of glycolysis and you wizard around with all these different enzymes and you make more NAD. And then the last step is where it enters the mitochondria, which is the powerhouse of the cell, the ATP unit if you will, of the cell. Mitochondria, the NAD is grabbed a hold of and it is used to fuel the production of ATP, which is the ultimate thing which comes out of the mitochondria.
So those are the three different things. If I had to guesstimate where the deficit lies, it's almost surely in the last one. So we don't think that as you age you lose glycolysis and you lose the Krebs cycle. We think the mitochondria are really the point where with aging we start to see this degradation. First of all, it's in the number of mitochondria. Let's take a professional basketball player and they run up and down the court for 60 minutes. They're not even sweating. Okay, how on earth would that be? If you take the muscle out of someone like Michael Jordan, you'll be astonished what you see under microscope. It's not normal at all.

Dr. Mark Hyman: Yeah, the number of mitochondria means he can jump over the rim.

Dr. Andrew Salzman: And I'd imagine the amount of mitochondria in that [inaudible 00:32:11] self. So when he takes a quiet breath, he's producing so much more energy than I could ever even imagine. That's why he can run up and down the court for 60 minutes because he's just loaded with these mitochondria bulging out everywhere in the muscle cell. Now, if you then take the same guy and he's now 75 and he's still working out, still doing his thing, if you look at the number of mitochondria in his cell at that age, it's fewer.
Now, why is that? Well, in the last five years we've learned a lot about what controls the number of mitochondria in your cell. There's actually a pathway that tells us, tells the body how to make or when to make or how many to make of these mitochondria. So we now know that one of the stimuli, for example, is low oxygen tension. So if you were to exercise, you're using up your oxygen very quickly and the muscle is in a state where it doesn't have enough, it's hungry. And that is a powerful stimulus to make new mitochondria. That's why a guy who's 75 who works out every day, he will actually create new mitochondria. Whereas someone who's a couch potato, he has no stimulus, and so you won't see those mitochondria being formed. So the aging process diminishes our mitochondria. And that's probably, can't say for sure, but this is probably the prime reason NAD levels fall with age, it's fewer mitochondria.

Dr. Mark Hyman: Yeah, that makes sense. And it's interesting. You look at some therapies that are used for longevity. For example, there're like hypoxia therapies. And so when you look at Vilcabamba in Ecuador, they live a long time because they live at 17,000 feet. Maybe it's cause of that. Or maybe when you use this technology called the Cellgym, which essentially takes you up to Mount Everest and then back down, it makes you hypoxic, it activates your mitochondrial production. Or when you use these hypoxia masks that athletes do. Or when they go to the altitude to go train for running a marathon, they'll run it 7,000 feet when they're going to run at 1000 during the race because it actually helps them build more mitochondria.
So it's really all about little tricks and building muscle through string training, through the right amount of protein, through actually using some of these compounds like NMN, can actually help to maintain and actually activate mitochondrial biogenesis, making new ones, and mitochondrial bioenergetics, which is the efficiency through which we make energy in ourselves. Right? Is that fair to say?

Dr. Andrew Salzman: I think there's so many serious athletes who exercise at elevated altitude for that reason and it provides them, well, you'd get the same thing I suppose if you're doing a lot of activity even at sea level. But being at an elevated altitude forces you into this domain where you're already stressing your system with hypoxia. And athletes who train at an elevated altitude and then come down are in far better shape. So they have a lot more loading of mitochondrial. We call it mitochondrial biogenesis. And we now know how the hypoxia is actually influencing the creation of new mitochondria. We know the molecular pathway, we know the molecules involved, and those, they haven't yet, but those will become drug targets. So-

Dr. Mark Hyman: Inducible hypoxia factor or things like that?

Dr. Andrew Salzman: Hypoxia reduction factor, HIF, responds to low oxygen environment. But what would happen if you had a drug that could turn that on?

Dr. Mark Hyman: I wonder if that's how blood restriction exercise works, is this kind of blood flow restriction where you put, let's say, a blood pressure cuff equivalent on your arms or legs and then you weight train at much lower levels but you get far more exhaustion sooner and it actually increases muscle synthesis better than regular strength training, which is really interesting.

Dr. Andrew Salzman: Sure. Yeah. It's the same mechanism and I think that we can do that through being active by exercising. And ultimately, I think there will be nutrients that stimulate mitochondrial biogenesis. There should be research going on, both in the pharmaceutical space but also in the natural health food space.

Dr. Mark Hyman: Yeah, for sure.

Dr. Andrew Salzman: Things that we can eat on our own or drugs that we can take perhaps. But we can change our lifestyle through what we eat. If we can identify diets that potentiate HIF and other factors and [inaudible 00:36:46] turn on mitochondria. And I think that's a wonderful area of research.

Dr. Mark Hyman: Yeah. Amazing. So we're going to go into the forms of mitochondrial support with NMN, NR and NAD. Talk about the differences. But before I do, I want to talk about a few other topics related to NAD, which has to do with sleep. It seems like it's a benefit to sleep as well, which I think I've never heard about. And there's a new study that came out that basically found that people who were part of this study and took NMN had better sleep duration, better deep sleep, better REM sleep, and reported better all overall improvement in sleep quality. Can you kind of comment on how that would work? It's just I don't understand the mechanism.

Dr. Andrew Salzman: Well, I think there are two aspects there. First of all, there's the control of sleep. We know that sleep deficiency leads to a loss of energetics, loss of focus, a loss of peak performance. So some of that has to do of course with the brain, in terms of it going through the processes that it needs to. But also, we know that sleep is a systemic phenomenon and it allows muscles, really all of our tissues to recover during the day.
So NMN, and this is an early area of research, but if NMN can potentiate better sleep, that's going to translate in a better systemic response. You're more rested and you've had a better chance to recover. So there's that effect at the central level with NMN on the sleep process. And some of that may have to do with regulation of sleep centers. We know, for example, that sleep is highly regulated by metabolites that have to do with energy. The main driver of sleep is adenosine, and adenosine is accumulating during the day as we're thinking and we're doing all of these things.
Little by little we're breaking down ATP because the brain uses ATP in a way that no other organ does. The brain is consuming a vast quantity of ATP, way out of proportion to everything, including our muscles. The brain is an ATP consumer. Huge amount of [inaudible 00:38:57]. I think 25% of the energy in your body is in your brain. So that a prime area where you can't keep up. And you can't. By the end of the day, by 9:00 or 10:00 at night, it is well well-documented that you have not been able to regenerate all of the ATP you've used. There's always a continuous deficit. From the moment you wake up, you are not keeping up. So [inaudible 00:39:23] 9:00 or 10:00 or 11:00 at night, you have wasted enough ATP that you cannot regenerate, that the end product that, which is the adenosine, is the final breakdown product, has accumulated. And adenosine is what causes drowsiness and ultimately sleep. Ultimately, you-

Dr. Mark Hyman: So does NAD improve adenosine production, is that what you're saying?

Dr. Andrew Salzman: No, the NAD is responsible for taking the adenosine that's forming during the day and driving it back and getting rid of it and keeping it low by pushing it back to ATP. Adenosine is used to make ATP. So when you have ATP, it breaks down to ADP and then to AMP, and then the AMP, it's broken down to adenosine.

Dr. Mark Hyman: Oh, adenosine. Oh gosh, I can't believe I just got that. Adenosine monophosphate. Adenosine triphosphate. Yeah. That's ATP, AMP. Okay. Adenosine, right, of course. Yeah. I never put that together.

Dr. Andrew Salzman: If you looked at the brain at 6:00 in the morning, what is there? It's ATP. Everything's fine. You wake up, you feel good, you can conquer the world. By 4:00 or 5:00 in the afternoon. You've already got adenosine there. Some people even take naps as they get older. But by the time it's 10:00, 11:00 at night, your ATP levels are low and your adenosine levels are super high, and adenosine directly influences the, it's a part of the brain in the midbrain which controls your arousal, how awake you are. And the adenosine directly causes you to feel sleepy.
When you're driving down the road in the morning and you can hardly keep awake, your brain is flooded with adenosine, very dangerous to drive. And so what you need, is to do one of two things. Either get rid of the adenosine, which is called sleep, is the best way to do that. Or you can take a drug which blocks the adenosine from binding to its receptor. So even though you're swimming in adenosine, you can block the adenosine from activating adenosine receptor. And I would say that 99% of the American public does this every day 'cause it's called coffee.

Dr. Mark Hyman: Coffee. Coffee. Right.

Dr. Andrew Salzman: So some people even have a problem in the morning [inaudible 00:41:45] get going to work. They get up and they drink two cups of coffee and it's really unnecessary, frankly, because you don't have much adenosine at six in the morning, if you get a good night's sleep that is. Now, if you haven't had a good night's sleep, you haven't had time to remove all the adenosine and you need your coffee at 6:00 in the morning to block it. The better thing to do is to get some good sleep. But if you want to stay awake and alert and bright and bushy-tailed, people drink coffee. It's a natural adenosine blocker. So that is the whole adenosine story. Now, NAD is there in the brain to take adenosine, one of [inaudible 00:42:25], and turn it back to ATP. So if we had efficient NAD around, we would be able to go through the day with a whole lot more energy and a lack of sleeping.

Dr. Mark Hyman: And then when we want, we reduce sleep, it improves the quality of our sleep?

Dr. Andrew Salzman: Yes. Because it's helping us to get rid of the adenosine. Sleep, it's a about many things. Fundamentally, we got to get rid of the adenine that accumulates during our day. That's our job.

Dr. Mark Hyman: Got it. Interesting. All right. So okay, next question has to do with a research paper that came out in mice. It got a lot of play which basically got everybody in a kerfuffle, which is that NMN, NAD causes cancer. Can you speak to that study, the challenges with it, what's true? 'Cause you are an expert in cancer, a lot of your research has been on cancer, you know this stuff inside out. So can you unpack this for us and help us either understand why there's a problem or why there's not a problem?

Dr. Andrew Salzman: Well, look, it's one lab that's very focused on this, God bless them, but they're doing the Lord's work looking at this. But still, it's one lab and it hasn't disseminated to other labs which have shown this. "Oh, okay, let's take this guy and give him all the credit in the world that he's doing good job." But let's walk through those. Okay. If you give NMN in cells that you have the potential to actually stimulate tumor agenesis.
Well, what he later shows, and it wasn't discussed initially, but is that it's not the NAD levels that are causing the... It's not the NMN element that's causing the cancer per se. It's that he created artificially a very unusual metabolic scenario. He dumped a bucket of NMN into the cells and there was so much NMN that it overwhelmed the NAD. So you had a ratio of NMN very, very high and NAD was normal, but the ratio was crazily in favor of NMN. And that can't happen.
And later studies have shown that if you have very low NAD and very high NMN, yes, that has the potential for causing tumor agenesis. But can that really happen? No. [inaudible 00:44:46] if you ingest NMN, it doesn't hang around and mind its own business. It's converted to NAD. That's what happens to NMN. It's not just saying, "Hello, I'm here." It is rapidly transformed because it's a precursor into NAD. So you don't get this wide abnormal ratio of high NMN, low NAD, it's not going to happen in nature.
Now, maybe he speculated there could be people with a genetic defect where they can't convert NMN to NAD. I don't know. In theory, yes, you could have someone with this condition, but I haven't seen it identified yet. So under normal conditions were NMNs converted to NAD, I don't think that scenario can ever play out. It was an interesting lab trick, if you will. It's good to learn new things. Knowledge is power.

Dr. Mark Hyman: Yeah, so what you're saying basically is he created conditions that would never happen in the living organism in the test tube that actually could never be replicated. It might potentially cause cancer. So in a mouse. So we're so far away from this being actually a viable scenario for humans that you don't think it's an issue.

Dr. Andrew Salzman: No, not right now. No, I think we should continue to all do research. And that's a good thing, I'm in favor of research. I'll vote for that. But I'm not worried right now about that. No.

Dr. Mark Hyman: Now, what was really also interesting on the positive side was it was a really interesting clinical trial on NMN. It was in humans. 'Cause we've done a lot of research in animals and David Sinclair and those guys. Lenny Guarente did a lot of work on sirtuins and found [inaudible 00:46:15] could extend life by a third of rodents by taking this compound that stimulated sirtuins, which is what NAD does. But it turns out that humans are important to study, too. So need to study not just yeast and mice and so forth.
And there was a clinical trial and a man that I thought was pretty impressive that I thought would be talking about both the safety, the efficacy and what it did in people who were middle-aged was a double-blind, randomized, multi-center, placebo-controlled, dose-dependent clinical trial, which is highest level of research you can do. And can you tell us about that study? What it showed, what take homes were? And I thought it was pretty impressive, actually.

Dr. Andrew Salzman: Well, what they're looking at there is basically the energy capacity of people, and in particular, the ability to walk, to go distances. And they were able to show that there was a longer capacity to be functional, so you had more energy. And they looked at energy balance and they looked at insulin sensitivity and other things. And all of these things seemed to line up to tell a story that it was working. So although it's a small study, it's not a giant study, and we-

Dr. Mark Hyman: Sure. About 80 people. Right?

Dr. Andrew Salzman: That's right. Yeah. It wasn't 80 or 800 people and it was a small number. And therefore, the differences that are identified, you can question statistically about if they're there to really write home about. But I think being in the right direction is positive. There've been a number of small studies like this. And the six-minute walk test has been looked at and people can walk further, which is a holistic way of looking at the energy. Those are all positive.
But I would caution the audience that all of these studies are still somewhat small and I don't think we're there yet where we can conclusively say that NMN is has been proven to engender more energy. In animals, yes. It would appear in humans. We also have evidence in cardiac function in humans that the cardiac function is better, particularly in congestive heart failure.
So there have been some studies, but as I say, they're early and we shouldn't jump to conclusion that it's been proven. I think the pace of research will definitely increase. And the quality of research. One of the problems with NMN and NAD, in terms of research is that it has not been yet driven into the classic pharmaceutical space. And these [inaudible 00:48:56] are very expensive, especially if they're [inaudible 00:48:59]. And right now, the motivation to carry out a large randomized, double-blinded, placebo-controlled trial, which can cost millions of dollars.

Dr. Mark Hyman: Millions of dollars.

Dr. Andrew Salzman: Definitely. And it hasn't been there yet because the pharmaceutical companies don't own an NMN. So when you invest 5, 10, $50 million in the study, you better believe or you must believe that you've got something that you own. So that at the end of that, your evidence, your data leads to a financial outcome which means you can sell it exclusively. That won't happen with NMN, although there's one company in the US that's trying exactly to do that, to patent its exclusivity.

Dr. Mark Hyman: Yeah, I saw that.

Dr. Andrew Salzman: But this is the reason that NAD and NR and NMN have not enjoyed the large scale studies that you would need in order to exclusively... And it's a problem with all natural products.

Dr. Mark Hyman: And it was a promising study 'cause I thought that they reversed biological age, they improved six minute walking, they helped improve what we call SF-36, which is subjective quality of life. And these were people who were taking a, I didn't know whether they were taking a placebo or the compound. So it was really well-designed. But I think you're right, it was a small study and we need to now get more data.

Dr. Andrew Salzman: Spent a lot of time in my life at the FDA, and we have all these fancy tests that people do and the audience may be aware of that. But at the end of the day, and the FDA... It's fascinating. I was sitting there at the FDA and I was telling them all about these biochemical advantages of this and that. And the guy looks at me and says, "I just have just a simple question. Can Mrs. Jones carry a bag of groceries up the stairs better or not? That's it. Because if she can't, all of this [inaudible 00:50:45] count for much." And the six-minute walk is a test where they take a person and they're on a treadmill and they say, "Walk and walk as much as you can for six minutes and we're going to keep track of how far you went." So if you could walk 200 feet in six minutes, you're hurting. But if you can walk a mile, this means your health is great. Right? Because everything is integrated. Your cardiac function, your respiratory function, your metabolic status, your NAD.

Dr. Mark Hyman: Well, that would be a run, a six-minute mile would be a run and not a walk.

Dr. Andrew Salzman: Be able to do that when I was very young. But that's the point, that six minute walk is really critical to understanding the overall promise of a drug like NAD or NMN, that can create and boost up the intracellular NAD levels. And that's why in that study, of all the things that I was impressed with more than the others, was the fact that they could-

Dr. Mark Hyman: Was the walk.

Dr. Andrew Salzman: You can't hide it, you can't fake it.

Dr. Mark Hyman: That's great. All right. Well, now let's talk about the practical application because there are people who recommend NR and there's companies that produce nr. There's companies that are making NMN. You can get NAD sublingually through liposomal forms. You can get subcutaneous NAD, intravenous NAD. And I'd love to have you take us through what's the pros and cons of each.
'Cause one of the things I sort of wanted to bring up was triggered by what you said earlier, is that NAD given as a compound can't get in the cells very well. And I had one experience with a patient, I read this in other studies who had Parkinson's and we gave her IV NAD and her tremor went away, not permanently, but for the short time she had more energy and she perked up, was able to walk better. And I was like, "Holy cow, this is impressive." But that would lead me to think that actually giving intravenous NAD can get it in the cell. So can you talk about these different forms and the pros and cons and whether I'm just making this up about this woman or if there's actually something to that?

Dr. Andrew Salzman: It's not black and white. I don't want to say that giving NAD cannot enter cells, period. That's not correct. But it is impeded it. It's not efficiently taken up. Now, having said that, there are hundreds of different cell types and it might be that certain cells have such a quenching thirst for NAD that maybe they've evolved shuttle mechanisms for NAD. You're talking about Parkinson's disease, and that's a disease which ultimately is regulated by a very tiny but very important tissue.

Dr. Mark Hyman: Mitochondria.

Dr. Andrew Salzman: And who knows, maybe those cells in the basal ganglia have a better ability to suck in NAD than other cells. So I don't know, that's never been studied.

Dr. Mark Hyman: But it is a mitochondrial disease. Parkinson's is a mitochondrial disease. That's why I think it may be effective.

Dr. Andrew Salzman: Well, Parkinson's is a mitochondrial disease, and it's also probably a disease in which the oxidant stress within certain select cells, these basal ganglia cells, it has been increased. And why it's been increased is anybody's guessed. The most recent research of Parkinson's that I've seen is really implicating tangles and what do you call it? Precipitates from proteins from misfolding, very analogous to Alzheimer's, which is some new work that's come out with alpha synuclein. And it's thought that these aggregates might impact the amount or way that oxidants are developed in the cells. The whole cell starts to become a factory of oxidants and it injuries itself. There are also Parkinson's patients who have fundamental deficits in handling oxidants.
And so to get NAD into the cells of a Parkinson's patient might be, it might be a very interesting way to look at that. We know that the model of Parkinson's disease that are used today, the most important one being the Rotenone Model, which is from Emory University in Georgia, that is created by actually blocking the first protein, the first enzyme in the mitochondria, in the term transport chain.
So definitely Parkinson's is somehow related as an example of NAD failure because the cells are not generating. There's a deficit in the mitochondria. And what your observation, if it's correct, suggests that maybe in that particular disease, NAD might be good. But the advantages of NMN are that it is known, at least in the intestine, that there is a specific shuttle or that a shuttle is a protein that's present in the membrane of the intestinal cells and it literally carries the molecule from the outside to the inside of the cell in a way that did not happen if it weren't for that. The NAD or any NMN without that shuttle, they can't-

Dr. Mark Hyman: Yeah, can't get in, can't get in.

Dr. Andrew Salzman: And that shuttle is like a smooth pathway that helps it across. So that's a reason from an oral perspective to suggest that NMN might be good. And those shuttles are present within the body as well. It's not just on the intestine.

Dr. Mark Hyman: Yeah, but it's hard to get NAD 'cause you have to either take it intravenously or subcutaneously. And the beautiful thing about NMN and NR, is that you can take them as supplements. So what's in NR and NMN and why should we be more focused on NMN, which seems to be winning out the horse race?

Dr. Andrew Salzman: The shuttle is specific for NMN. So even though NR is closer to NAD and it's easier to get into the cell, it doesn't have the advantage of a built-in shuttle that God designed to move that material from the outside to the inside. First of all, NMN is a natural molecule, by the way. It's not just something [inaudible 00:57:04], we make NMN. And so this shuttle is there for a reason. It's to facilitate entry and we're just leveraging that when we give it therapeutically. But that pathway, that shuttle is a fundamental issue. It changes the whole question about how do you get this stuff into the cells that here to fore, NAD just doesn't cut it.
Now, I [inaudible 00:57:27] do research with NAD and NR because there may be certain cells that function differently that we haven't examined, so we should continue that. And if you look at the literature, there's far more studies of NAD than NMN by many fold. So that was [inaudible 00:57:44] began and it made sense. They knew NAD is important, let's give it and see what happens. But I think the tide has changed and you'll see a lot more loading studies now, where NMN loads the cell with NAD, and that's going to be a bevy of studies like that, clinical, animal, and even cellular, you'll start to see a lot of that.

Dr. Mark Hyman: So what you're saying is that the NR doesn't have the same shuttle to get the medicine or the supplement or the ingredient into the cell as NMN, which has a specifically designed shuttle?

Dr. Andrew Salzman: Yes.

Dr. Mark Hyman: Right?

Dr. Andrew Salzman: Yes.

Dr. Mark Hyman: Okay. Well, I wanted to talk about specifics then, in dosing and how we take it. There's a product called Wonderfeel Youngr NMN or Youngr NMN, which includes not just NMN but a bunch of other stuff. So I'd love to talk about that product. I know you're involved with the company. I've been talking to them as well, advising them. Tell me why you think this is unique and different and what's important to know about this?

Dr. Andrew Salzman: We began with the premise that NMN is important. NMN by itself is probably not the whole story because there are mechanisms within the cell that are very active as you age, as you have disease, and these are going to interfere with the benefits of NAD [inaudible 00:58:58] we talked about, that already oxidant stress being the most important. So when you add NMN to a cell and you get NAD in there, it's good. It's going to increase the glutathione levels, it's going to [inaudible 00:59:12] all of the mechanisms, the defense I talked about. But you have a lot of offense, particularly as you get older. There's a lot going on in the [inaudible 00:59:21], a lot of injury, a lot of oxygen stress.
So we said to ourselves, "Well, let's build a frontline defensive line that's more than just one guy. Let's build a whole defensive line with backups so that it's a team effort to suppress the damage of the aging cell." So we were not castigating or denigrating NMN in any way. It is the basis, as I said, it's the basis we're starting with, but we have supplemented that now with additional team players, each of which has their unique role. And together as a team, in working in concert with each other, we think we will have a much more effective result. So we chose supplements to fill in the gaps, if you will, to make that frontline that defensive line.
The first one was ergothioneine, again, a natural molecule, as something that we ingest in our foodstuffs. And that has very powerful and quite specialized antioxidant features that have effects on inflammation and on cell survival, on anti [inaudible 01:00:36] specifically. And so we put it, and it is very well tolerated. Another principle [inaudible 01:00:41] in this concoction was, do no harm. So we did not want to create a model system where we had some good things in there, but carrying some toxicity risk. We wanted this to be very, very safe, based on natural products. And that's something that could rear its ugly head with some toxicity. We hadn't thought about.

Dr. Mark Hyman: Ergothioneine is in oyster mushrooms and black beans and liver and stuff. So it's found naturally in plants and animals.

Dr. Andrew Salzman: Yes, we don't produce it. You don't make ergothioneine, you obtain that from your environment by eating various foodstuffs. So that's a good thing.

Dr. Mark Hyman: It's almost like a longevity vitamin basically. Right?

Dr. Andrew Salzman: Yes. And there are companies out there that are marketing, not many, but there're their marketing ergothioneine as a standalone and it makes sense that would have benefit and that it could help with aging and help diminish a lot of the oxidant stress that we're prey to.
Then we added resveratrol, which is a polyphenol, it's a simple molecule actually. It's present in grapes, present in red wine, for example, well known. And it is also sold on the market. You'll see lots of instances where people are out there advocating the use of resveratrol alone. It's a relatively weak antioxidant. It's not anywhere near as potent as a natural antioxidant mechanisms we have within the cell. But it is adjunctive and it's helpful. I wouldn't recommend it much as a standalone because it's not that potent, but in concert with [inaudible 01:02:18], it has specific types of antioxidant defense, particularly in the cell membrane and lipids and various places in the cell, and people who drink red wine a lot.

Dr. Mark Hyman: You'd have to drink a lot.

Dr. Andrew Salzman: It's known that the French, for example, are very enamored with red wine. And spite of the fact that they're eating pastries and they have a lot of things that they shouldn't be eating so much, their cardiac consequences are less than you would predict. And one of the hypothesis that they're also drinking every meal with a big glasses, plural-

Dr. Mark Hyman: May be true, but I wouldn't recommend drinking alcohol as a health strategy.

Dr. Andrew Salzman: That's what the French are doing. So they're drinking a lot of red wine. So that's resveratrol, a very interesting molecule, easy to purify and to add to the supplements and moderately effective. And then the last one I think is the most interesting one, which is hydroxytyrosol. And this came to me because I'm living in Israel right now and we're not too far from Greece. And we have [inaudible 01:03:21] climate here, and everywhere in Israel, in Greece, just covered with olive trees. Everywhere you look, that the Greek population that indulges in using special types of olive oil, which I'll come back to, has a lower incidence of, a host of different diseases, including Alzheimer's disease. And so there is quite a lot of research in Athens, especially, by some friends of mine there, some professors at the University of Athens. And they've identified the elements within the olive that are most effective in creating this antioxidant and anti-inflammatory effect. And there are different molecules, but most of these are polyphenols. And the most important one is this oleuropein And-

Dr. Mark Hyman: Yeah. Oleuropein. Yeah.

Dr. Andrew Salzman: And when you take people who are using a lot of olives in their diet, they tend to have the benefits from that. And what we now know, we know a couple things from this man's research there, all olive trees are the same, which I didn't know. So every orchard of olives is actually quite different-

Dr. Mark Hyman: They're the same?

Dr. Andrew Salzman: They're not the same. They're over 1000-

Dr. Mark Hyman: No, they're not the same. Right.

Dr. Andrew Salzman: Because he studied, and when you do an analysis in the olive from cultivar to cultivar, orchard to orchard, there are vast differences. And so his research has identified orchards in Greece that have incredibly high levels of these particular polyphenols. Second thing, is that how you treat the olive has a dramatic effect on the survivability, think an American factory that's processing millions of olives every day and all of that.
And olive oil, you go to the Stop & Shop and you buy olive oil. Unfortunately, the processes used there to get there have decimated the very most important molecules, these polyphenols, it's oxidized them and they're not active. So in order to receive this benefit, you have use virgin olive oil and from these special orchards and on and on and on. Now, most people can't find that olive oil in the store. But we know that the hydroxytyrosol is very special in creating this effect. So what we've done is take pure hydroxytyrosol, not olive oil, but the part of the olive oil that we care about. And that is what we've added together with the resveratrol, ergothioneine, and the NMN.

Dr. Mark Hyman: Yeah. Actually, I'm in Sardinia right now where I'm teaching a longevity retreat and there's olive trees everywhere. And it's interesting, they have wild olive. Sometimes they actually handpick them and don't let them drop to the ground. They press them right away to make sure that the... And I would this olive oil tasting and you can taste the different qualities of olive oil and can actually taste that kind of polyphenol content 'cause it's a little bit of acidic and bitter in the back of your tongue. So you're absolutely right. These are powerful molecules in olives and olive oil, and I think that combination's great. So any last thoughts?

Dr. Andrew Salzman: So we're looking now in models where we explore these combinations to better tease out how the juxtaposition of these different players has an effect on these outcome endpoints and to try to understand how they're interacting with each other and supporting each other. But it's definitely a team effort approach. That was the concept biologically to bring a team, an offensive line, sorry, defensive line, and then to put them together in the right fashion.

Dr. Mark Hyman: Well, it's olive oil, red wine and mushrooms. And you kind of add that with NMN and you got this product is younger, it's younger NMN, which I love. And what's interesting about this product also is the dose is high. A lot of the doses of NMN or NR out there are low, they're 250. Or if you take two, it's 500. But actually, clinically, it seems like the dose needs to be much more like 900 or 1000 to get the most benefit. Right? And this is actually done at a lower cost. I'm sort of surprised because a lot of these products are really expensive, but this is actually a reasonable cost for that higher dose.

Dr. Andrew Salzman: Well, there are reasons for the dose selection. There are two reasons. First, let me begin by saying always do no harm. So that's the place you begin at where you do not want to use a dose of a material that has the potential to harm. But the safety profile has been so unremarkable with NMN to date from people's experience and in animals, although there haven't been large formal toxicology studies, but the data out there suggests that this is a well-tolerated ingredient. So therefore, it makes sense to use more of it if there's [inaudible 01:08:26]. Why would there be a benefit? Because we know that certain pathways, particularly on inflammation, are very tightly related to the amount of NAD that will be there. So a small amount of NAD doesn't cut it. To be specific, there's a very special pathway in the cell regulating inflammation. This is the pathway. It's a fancy name called NF kappa B, but it's basically a pathway in there which turns on all our inflammatory genes at once. Like a symphony.

Dr. Mark Hyman: Yeah, that's what I was talking about before. Yeah.

Dr. Andrew Salzman: Yes. The direct conductor lifting the baton and the whole orchestra plays at once, and so that's NF kappa B. That's the symphony conductor. And when you turn that on, you get what's known as a cytokine release, and an extreme example, you get a cytokine storm. And we now all know that word because of the last few years with COVID. That's why COVID patients die because this pathway has turned on incredibly all at once and you get this massive release. The problem [inaudible 01:09:36], NMN suppresses, sorry, NAD suppresses that pathway specifically, but you have to give enough of it to get there. So we specifically gave a high dose of NMN so we could suppress that pathway and so that we could be sure that the mitochondria was enjoying a full benefit. So there was a very careful decision about elevating the amount of NMN to do that.

Dr. Mark Hyman: That's great. Any other thoughts you have in conclusion about NMN, what should be doing? How much we should be taking? Basically the dose you're recommending is about 900 a day. Right?

Dr. Andrew Salzman: That's what's in there, yes, that's right. I recommend further research. I recommend research on how frequently to take it. We wanted to have a once a day if possible. People don't have time to take things. But we need to better understand the pharmacokinetics to understand how long these things last. Not just in blood, but actually in the cell, where they're going. That's the important thing. How much [inaudible 01:10:42], whether they go to all the right tissues, how long they're there, we need [inaudible 01:10:47] on specific inflammatory and oxidant-related conditions, like Parkinson's and diabetes and arthritis and colitis to elucidate which clinical problem might be best served. We need to do more studies on aging, which is a very long, long study, but we need to do that.

Dr. Mark Hyman: I know I've started to take it and I think I've committed to it as part of my longevity regiment. Well, Dr. Salzman, thank you so much for being on The Doctor's Farmacy podcast and teaching us all about NMN. I think it's a really important topic. I think people just don't understand it well enough. You've done a great job of getting in the weeds and helping us understand why it's important, how it's critical to our health and aging itself.
If anybody wants to learn more about it, you can read Dr. Salzman's work online. Also, you can learn about this product he was talking about by going to, that's G-E-T, wonderfeel, and learn more about it and research the science as well. It's a great product and I think your work is really important and I want to keep you going so we can learn more about how all this stuff works for us and actually advance treatment of aging itself, which is what we're talking about.
If all of you have enjoyed this podcast, please share with your friends and family on social media. We're sure they'd like it. I'm sure they'd love to hear about this and learn more. I've love this podcast, I've learned so much. Leave a comment. Maybe you tried to take NAD or NMN or NR, what's happened to you? How have you felt? I would love to hear from you, subscribe wherever you get your podcast and we'll see you next week on The Doctor's Farmacy.

Closing: Hi, everyone. I hope you enjoyed this week's episode. Just a reminder that this podcast is for educational purposes only. This podcast is not a substitute for professional care by a doctor or a other qualified medical professional. This podcast is provided on the understanding that it does not constitute medical or other professional advice or services.
If you're looking for help in your journey, seek out a qualified medical practitioner. If you're looking for a functional medicine practitioner, you can visit and search their Find a Practitioner database. It's important that you have someone in your corner who's trained, who's a licensed healthcare practitioner, and can help you make changes, especially when it comes to your health.