Understanding Human Metabolism | Dr. Charles Brenner

Darin: Before we get to this awesome conversation, I want to give a shout out to the sponsor for today’s episode, and that is Vivobarefoot. That’s right, Vivobarefoot. If you’re not familiar with them, they’re an awesome sustainable footwear company that are dedicated to designing quality footwear that not only feel great, literally feel great on your feet, your feet will be happy, I guarantee it. I’ve been absolutely loving these guys. And I’m stoked to be partnering with them because they’re offering you, the listeners, 20% off on your first order. So stick around to hear how you can try them out and let’s do this.

Darin: You are listening to the Darin Olien Show. I’m Darin. I spent the last 20 years devoted to improving health, protecting the environment, and finding ways to live a more sustainable life. In this podcast, I have honest conversations with people that inspire me. I hope that through their knowledge and unique perspectives they’ll inspire you too. We talk about all kinds of topics, from amping up your diets to improving your well-being to the mind-blowing stories behind the human experience and the people that are striving to save us and our incredible planet. We even investigate some of life’s fatal conveniences, those things that we are told might be good for us but totally aren’t. So here’s to making better choices in the small tweaks in your life that amount to big changes for you and the people around you and the planet. Let’s do this. This is my show, the Darin Olien Show.

Darin: Hey, everybody, welcome to the show. This is Darin Olien. This is The Darin Olien Show. Stoked to have you here. Thanks for your time for your commitment to yourself, for your life, and having a better one, receiving information, applying information, and using that to live a better life for yourself, for your family, for your children, for life itself. If we don’t like what we see in the world that is on us, if you see it, you can do something about it. How cool is that? That responsibility is on you. Then you can help create the future that you want, you can dream, you can journal, you can take action, you can call friends, you can see who resonates with your ideas and your thoughts and your concepts of the future that you see. I’ve always been willing to dream. I’ve always been willing to surround myself with people that support me and walk away from people that don’t. So, anyway, that’s a little bit of a tangent but it also is a perfect segue for my amazing guest, Dr. Charles Brenner. Listen, this guy has got more education than you can possibly imagine. He is a researcher, a PhD-er, a metabolism, cancer, diabetes, knows this stuff inside and out, knows what metabolism is on a level that blew me away that took every bit of education that I had and just amped it up by a thousand. But we were able to talk about it in a way that you will understand. Dr. Charles was such an amazing guest. I had literally one of the best times ever on my podcast and I was intimidated getting ready for this podcast because this dude is so smart but it just became this incredible epiphany. You’ll be able to tell in my voice when I got my mind blown. And I hope you get your mind blown as well. So he’s currently Alfred E Mann Family Foundation Chair in diabetes and cancer metabolism. His laboratory focuses on disturbances and nicotinamide-adenine dinucleotide, that’s NAD. Have you heard about it? It’s been the craze. We’ve been talking about it. It’s been a great discovery but this guy cuts through everything. We talked directly about NAD, the precursors, all of this stuff that will affect and does affect your metabolism, your cells, your brain, your central nervous system, every organ, every tissue. So ladies and gentlemen, boys and girls, this literally is an incredible conversation because you know what, he drops a big bomb into really understanding metabolism and really where it comes from and really the source of all energy of every bit that you’re trying to extract to use for your life. We talk about where it’s from and how it got there, and you will be able to follow along. He’s the chief scientific advisor of ChromaDex. Tru Niagen took the science of Dr. Brenner and his colleagues took all of that stuff, put it into capsules and supplementation that actually work to help your cell’s function pattern. So man, you can hear my excitement. I got blown away in this episode, so sit back or stand up, relax or get excited, whatever you want to do but enjoy my incredible conversation with Dr. Charles Brenner.

Darin: I am so stoked to have a conversation with you on so many different levels. So I guess to start, I mean, your background is so full and so down the rabbit hole of metabolism and cancer and diabetes and longevity, man, you are having some fun, I have no doubt and staying very busy. So tell me about your position and how you ended up at the City of Hope National Medical Center. Maybe let’s just start there and give the listeners and viewers a little context as the badass superhero that you are.

Dr. Charles: Oh gosh, now you’re embarrassing me. So, yeah, I’ve been at City of Hope since mid-August 2020. They created a new research department of diabetes and cancer metabolism of which I’m the inaugural chair, the Alfred E Mann Family Foundation Chair. Prior to that, I was the head of the biochemistry department at the University of Iowa.

Prior to that, I was a professor of genetics and biochemistry at Dartmouth College, Dartmouth Medical School. Prior to that, I was at Thomas Jefferson University in Philly. And before that, I was a Postdoc at Brandeis. And before that, I got my PhD at Stanford. So kind of full circle back to California. But basically what I do, as you know, Darin, is I study metabolism. But the last 20 years, I’ve been investigating the central regulators of metabolism, the central catalysts, which are called NAD coenzymes. And when City of Hope, to circle back, why am I at City of Hope directing a unit called Diabetes and Cancer Metabolism is that about 65% of the research at City of Hope is cancer. It’s a comprehensive cancer center, right? The other 35% of research at City of Hope is diabetes and metabolism. And they wanted to create a new unit that would kind of bring together those two superfamilies of diseases. And they thought that I was one of the people that could do that. And the reason why it makes sense to me is that the NAD system, the central catalyst of metabolism, is disturbed in many types of cancer. And they’re always disturbed in metabolic diseases. And our research interests are very broad, so we try to figure out ways to protect healthy metabolism. And we try to figure out ways to target cancer when it gets dysregulated.

Darin: Well, to bridge that, it seems to me makes so much sense because I’m sure from your extensive background, reductionism can lead down a road of cutting off other inputs of information, and the fact that you’re bridging these gaps between diabetes, cancer metabolism. And so that’s the beauty, just in that minute that you described, I was like, oh, that’s beautiful because I often get fired up about reductionism losing the understanding of the whole. It’s actually quite perfect, your understanding of metabolism in cancer, as it relates to also longevity, and you’re bridging those gaps.

Dr. Charles: I mean, both of these constellations of diseases, I mean, cancer is not one thing, and common obesity is not one thing, type two diabetes is not one thing. And type two diabetes is quite distinct from type one diabetes, of course, but all of these diseases are disturbances in resource allocation in some sense. And so we try to understand that. And one of the things that has kind of been a problem is a kind of static picture of the cell. There is no “the cell,” even in the liver. So like a biochemist’s favorite cell is a hepatocyte. So I used to think of the liver as a collection of hepatocytes. And I can draw 10 enzymes that are taking glucose to pyruvate in glycolysis. And I can draw the pentose phosphate pathway. And then I can draw the mitochondria. And I can draw the TCA cycle and then I could draw various things going back. But it turns out that cartoon is good. So that’s useful information, but it turns out in overnutrition, which is a fancy $4-word for eating too much or having energy imbalance, so the cell composition of the liver changes a lot. And there’s a lot of inflammatory cells that start proliferating and then famously, the NAD system becomes disturbed in conditions of metabolic stress in aging and obesity and type two diabetes. But it’s really not necessarily even the hepatocyte that’s changing that much. It’s all these other cells that are doing other things with the NAD system. So we’re trying to understand all that in order to kind of, you’re not going to have really well-behaved hepatocytes if there’s a lot of inflammation happening.

Darin: So you described like this one aspect of like, if you’re overeating, that can really excite, even that alone, we’re not you’re talking about the adding up of overtime, let’s just kind of park that for a second. But overeating can literally create an acute inflammatory state, which is then–

Dr. Charles: It’s chronic inflammatory is probably the more relevant.

So here’s an interesting thing about inflammation. So inflammation is trying to help us. So the thing is that we have all of these inflammatory mediators. And really, the idea of inflammation is to fight infection and fight metabolic disturbances. Like if there’s a virus, or if there’s a bacterium, or there’s too much of this or that, there are responses. These responses that are attempting to be homeostatic. Homeostatic means that there’s a signal that’s coming in to try to keep the body moving and functioning the way it’s been moving. And inflammation basically kind of generates heat. And I’m sure that in traditional Chinese medicine, they have all kinds of interesting terms for it because you’re literally generating heat. And there are cells that generate reactive oxygen species to try to kill stuff, and it works. It actually works. When you cut yourself, you used to get pus and things that will kill bacteria, but it’s chronic inflammation that occurs where you start to end up with dysfunction, tissue damage, and tissue dysfunction.

Darin: So when that inflammation, which again, that inflammatory response is there to protect the body to do everything it can to keep the body in a balance to keep it moving and evolving and moving you forward in life. But when it shifts to that chronic storm always happening, it’s now gobbling up resources, and then it’s compromising other systems. And in this case, it’s gobbling up more and more and more of the NAD. So let’s back up a second, and I want to layout. So everyone gets to– some people may or may not even have heard of this kind of really one of those powerful compounds we have on the planet. We always hear about mitochondria, I always hear about ATP. We throw these terms out. But really, I want to hear from you like, from my perspective, it seems like NAD is kind of this symphony orchestrator of the cells. So let’s unpack NAD, and then let’s pick out those precursors and see how we can get that information out to people to be able to serve them? 

Dr. Charles: Well, Darin, you’re kind of referring to a bunch of things that the body is doing. So you said the homeostatic systems are trying to keep us functioning and keep us evolving and everything like that. You didn’t just say we’re burning fuel. So metabolism involves obviously taking our macronutrients, our protein, fat, and carbohydrate, and turning it into ATP, which is biological energy. And people understand that much about metabolism fairly well that we’re eating a certain number of calories, and we’re burning a certain number of calories. And that’s a key part of metabolism, but it’s probably about, I don’t know, 20% or something of metabolism. Metabolism is everything that we are and everything that we do. All of our ideas require metabolism. All of our repair processes require a metabolism. Everything that I’m looking at, at you, except your clothes, and your glasses, and your earbuds were made by you. You made all your own skin, you made all your own cells, you made and you maintain your eyeballs, you make your own blood, that’s all biosynthetic processes. A lot of that is in the bucket of anabolism, building things up. Whether you’re building a muscle, making blood cells, it’s anabolic, and we do it all the time. Resting metabolic rate is from making stuff and repairing stuff. Circulating our blood, maintaining the electrical energy in our body, maintaining your body temperature, that’s all resting metabolic rate. And there are four NAD coenzymes that are responsible for all of these metabolic processes. They all contain this thing called nicotinamide adenine dinucleotide. So there’s NAD, NADH, NAP, NAPH, and these are catalysts. So if people have internal combustion cars, there’s gasoline, and then you’re trying to turn the drive train, and you’re not trying to have a hot explosion, right? You’re trying to have controlled combustion. And you’re trying to convert the power of braking carbon-carbon bonds into moving a drive train, or you’re trying to take stored electricity in your electric vehicle. So there are catalysts involved in all of these things. And every cell has catalysts. And so NAD coenzymes are the critical, they’re the most important catalysts. You want to know what they actually do? They actually move electrons, believe it or not, they actually move electrons. It just occurred to me now, the idea of using analogies from an electric vehicle are not that bad because literally, NAD coenzymes move electrons.

Darin: Wow, what you just said is so important in that we’re moving an energy, we’re moving an electron. And in that, there are phase changes, there are catalysts that is happening. And the NADs got all these subcategories to it. So as it’s in itself, what is it doing? Because it’s moving these electrons and then–

Dr. Charles: So the electrons, you know, where the electrons come from? So you really want the cosmic version of it.

Darin: Absolutely.

Dr. Charles: Okay. Is there sunlight in the top of your building?

Darin: Yes.

Dr. Charles: Okay. So the thing starts with the sun. This whole thing starts with the sun. If you really want to get the really, really big picture here, let’s do it.

Sunlight. So now my background is the Japanese friendship garden at City of Hope where I work. But I used to teach biochemistry in Iowa. And so I had a classroom of students tonight, and some of them worked on cornfields, or you can certainly drive through cornfields to get to class, right?

Darin: I’m in Minnesota, so I absolutely–

Dr. Charles: The same thing. So the cornfield, it’s like a field of carbohydrate because I mean, corn is delicious and everything, but then a lot of it, the commodity corn gets basically turned into carb. It’s starch and then it gets refined and turns into saccharides. And so the energy from that came from the sun, their photons, and plants use that to do an anabolic program to make the corn. And there’s a ton of starch there, and then it can be refined into ethanol, or it could be refined into sugars. Then either we eat the corn or we eat the animals that ate the corn. It doesn’t really matter. We’re basically getting energy from the sun.

Darin: I love that because I’m a vegan. So I just cut out the middleman of the animal.

Dr. Charles: Yeah. You cut out the cow. And I can’t remember what the pig population is in Iowa. But it’s a lot more than– there’s like 3 million people and I remember the year that the chickens were being slaughtered. There were like 30 million chickens or something. It’s crazy. But they’re animals that basically eat the macronutrients that came from the sun. Those animals are either livestock or us. So there was metabolism that converted the photons from the sun into food, that’s what plants can do. And then we eat the plants directly, or we eat the animals that ate the plants. Now we have protein, fat, and carbohydrate coming into our bodies. And whether it’s protein, fat, or carbohydrate, there’s carbon-carbon bonds. And the food is going to be oxidized. And there are high energy electrons, high energy man, high energy electrons in the food that basically get captured on NAD+. And when they get captured on NAD+, you have the second form of NAD, which is called NADH. And then a lot of the NADH is associated with a mitochondrial membrane, and then transfers the electrons in a process that generates ATP. It’s like the most mind-blowing thing. So they’re through all of these steps. The energy from the sun got converted into food, that literally the high-energy electrons in the food got transferred onto NAD. And then in further biochemical reactions, ATP is made, and that ATP is literally transducing the ideas in your brain that are capturing my memory of all of these things, and forming new connections right now. All of that is metabolism. I wanted to teach the kind of higher-level stuff to the biochem majors.

But there was one year where I gave the first four lectures to the biochem students that had just come across the river from the chemistry department. The kids that want to become doctors. They’re just going to get one semester of biochemistry like 44 lectures, and I gave them like the first four lectures. And I told them, there’s nothing that isn’t biochemistry. I told them, tell me anything, love? There’s nothing that you do, there’s nothing, I don’t know, I defy anyone to come up with something that doesn’t have a biochemical component to it. And if it has a biochemical component to it, it’s powered by metabolism. And if it’s powered by metabolism, then high energy electrons were captured on to NAD or NADP in order to make things happen, not directly in one step, but in multiple steps.

Darin: That was the greatest explanation of metabolism that if unless you’re already dead, how do you not get excited about this miracle that we have going on? Because I can tell already, like, just by your response of like, we eat these plants, and we get energy from the frickin sun. Like, I was like, I’m gonna love this guy. Because that, to me, is an unbelievable miracle that’s happening every time we look at a plant, every time we open our mouth, every time we chew food, and we swallow it. In some form or fashion, we’re utilizing the energy that was a photon. What the heck.

Dr. Charles: Isn’t that amazing? There are very few exceptions. There are thermal events. There are deep water microorganisms that get energy in a couple of different ways. And there are a couple of exceptions to that. But pretty much everything around you that you’re looking at, all the energy came from the sun in your body.

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Darin: That’s incredible. So let’s unpack because now, I was already a fan of NAD but now I’m like, you’re a superhero taking electrons and transferring it into the cell, that should be a cartoon. So I want to be the NAD superhero or you should be because that’s crazy. So it’s literally transferring electrons. How did you come into that? And then what are the mechanisms? Because I want to unpack this so people don’t glaze over because obviously, there are lifestyle factors here and there’s what you can do and eat and everything else. But the crazy thing is you’re involved in, there are compounds that are literally standing up to research that are showing this stuff.

Dr. Charles: Yeah, so now our metabolism works. And not only is it happening in all of our cells, it’s happening in all of the plant cells. It’s happening in all bacterial cells. Viruses don’t make their own NAD, but viral synthesis and antiviral things involve the NAD system also. So metabolism is just kind of happening. But in the course of my career, we found, I would say two big pillars of things that are interesting and important. One is the thing that most people know that we did and then another thing that is I think equally important. The thing that people know that we did is that we discovered nicotinamide riboside as an unanticipated vitamin precursor of NAD. So NAD is very important. Coenzyme, they are 100 years ago, in the American South, there was actually a pandemic, Darin, called pellagra.

Darin: Wow, what year was that?

Dr. Charles: Second half of the 19-teens and into the early 1920s. So literally 100 years ago. There was an epidemic called pellagra that a lot of people initially thought was an infectious disease because you go into towns and you will see a lot of pellagras, people that had diarrhea, dermatitis, and dementia, and ultimately death. There were hospitals that had all these pellagra patients and they founded the US public health service, which is the forerunner of the National Institutes of Health, the NIH. The very first public health service grant was given to someone named Joseph Goldberger, who went down to the American South. And he went into hospitals and prisons where there was a lot of pellagra. And the first thing that he saw were the prisoners have pellagra, and the jailers dumped hospitals. Patients have pellagra, doctors and nurses don’t. So we thought it might be dietary and not a communicable disease. And he basically gave some fresh food to people that had pellagra and cleared it up, and the diet was horrific. Okay, so a really good way to get pellagra is corn rations and molasses, or lard and molasses or something like that. With lard and molasses, it’s almost like you’re eating all of your food from the aisles and in the supermarket as opposed to around the perimeter where the fresh food is, except the food in the aisles now is enriched with nice wipes and rich in niacin because all you do is you eat these kinds of processed things like fat and sugar. There’s no NAD precursors in it. So it turns out that pellagra is a disease in which the people have very low levels of NAD precursors. Now, here’s another interesting fact. The Mizo Americans used corn as a staple, never had a problem with pellagra. They pounded their corn like pozole, like kernels of corn, right, dried kernel. They pounded that with limestone. And the alkali in limestone basically extracts the cornmeal in a way that liberates NAD precursors and can keep you healthy. It was a sustainable agriculture and food management practice that was thought to be primitive, and of course, it was brilliant, whereas the commercial corn grinding equipment that was being distributed in the American South made cornmeal that was very deficient in NAD precursors. So basically, pellagra was discovered to be a nutritional deficiency. In 1938, someone named Conrad Elvehjem at University of Wisconsin basically discovered anti-pellagragenic vitamins. And those things today are called nicotinic acid, or niacin, and nicotinamide. They’re collectively B3 vitamins. And they have chemical structures that are related to NAD. They can be taken up into cells. They’re small molecules, even smaller than NAD. They can be taken up in cells, and our cells will convert those to NAD precursors into the fork, NAD coenzymes. 2004, I came along and found that nicotinamide riboside is a third vitamin precursor of NAD. So a third chemical entity that sells from yeast all the way up to human cells can convert into the NAD precursors. And our nicotinamide riboside is the biggest piece of NAD that can get into a cell. The thing that happens right after NR goes into a cell is a phosphate gets put on it. It’s then called NMN and then it’s just one more step away from being NAD.

Darin: So it’s NR, NMN–

Dr. Charles: NAD. Right. And then you can make from that, you can make any Dp and NADH and all that other stuff. So basically, the first contribution we made to NAD was finding the NR is an NAD precursor. And then we found the genes and the enzymes that allow NR to be made into NAD. Now the second big thing that my collaborators and I have discovered is from the analytical work that we do.

So we set up a way to do what’s called targeted NAD metabolomics, which means it’s like genome x, you can sequence an entire genome. You can sequence all the DNA in any cell. Transcriptomics, you can see all of the genes that are turned on. In proteomics, you can see all the proteins. And then something called metabolomics, you can see all of these small molecule metabolites. If you want to look at lipids, you can look at lipids. We decided to look at the NAD metabolites. And to our amazement, many, many conditions of metabolic stress disturb the NAD system. And so reactive oxygen species generation, which is one of these inflammatory processes, and it occurs in overnutrition. These inflammatory processes, they make cells churn their NADPH. So the NADPH becomes depressed. And that’s really important because you need NADPH to make testosterone, estrogen to detoxify free radicals, really important.

Darin: The overall thing is, hey, it just happens over time it goes down, but there are some real mechanisms that are being disrupted.

Dr. Charles: I don’t do the time axis very much because I’m an East Coast guy, and I want to get experiments done. So we typically look at things where animals are under acute conditions of metabolic stress, like heart failure, nerve degeneration, chemotherapy, overnutrition. It’s usually attacking NAD+. So NAD+ is becoming degraded or it’s getting used to mountain anti-inflammatory response or NADPH is used to try to detoxify your free radicals. And under these conditions, the NAD system is coming under attack. And then this fundamental energy generation, the ATP generation processes or the biosynthetic processes or the repair processes can’t work really well. And then, of course, we know that as we age, our metabolism and our repair processes are depressed. At that point, there’s actually kind of a use case for supplementing with an NAD precursor. So we’re not looking at people that have a frank pellagra, but look, all of us are working these long hours. And all of us are exposed to sunlight, which generates DNA damage, and oxygen, which generates reactive oxygen species. And so we’re all under conditions of metabolic stress in which the NAD system is basically being challenged.

Darin: Yeah, so all of these things that, I mean, hell, look at the frickin world going on. Of course, we’re stressed. It’s a crazy situation. And so just so for everyone understanding, this is so huge in terms of metabolism, in terms of its dysfunction on the body. Can you break it down a little bit? I mean, we’re talking every cell, every tissue, mitochondria dysfunction, cellular senescence, glucose metabolism, break it down. What’s the top 10 things that are being disrupted so people can grok the magnitude. If they don’t want this to happen, but it’s probably happened.

Dr. Charles: It’s happening. Back in the day, a couple of years ago, when I have a crowded room of people, I would ask for a show of hands and say, “Okay, how many people want to hop on a jet, fly to Ibiza, stay out late in a different timezone, be outside in the sun, drinking lovely red wine, eating lots of food, and listening to loud music?” And everybody says I want to do that. But every single one of those things, all of them enjoyable, disturbs the NAD system in one way or the other. Now, I’m talking about noise sufficient to produce hearing loss. So I don’t know that everyday sounds do this, but in animal models of noise-induced deafness, we definitely see the NAD system under attack in alcohol metabolism, the NAD system is under attack and overnutrition, it is. Almost certainly in timezone disruption. And then DNA damage and oxygen are just constant and enjoyable, inevitable parts of life. Then lots and lots of disease processes, heart failure, neurodegeneration. Coronavirus infection attacks the NAD system. Probably most types of viral and bacterial infections attack the NAD system.

Darin: So if you’re, like say, we’re living normally but yet we have stress and we’re not getting enough sleep, we’re not getting enough water and we’re working hard and we’re not eating as well, and so all of those factors and many more is depleting our NAD. So then as that’s depleting, it seems to me just by talking to you that if you have a cellular dysfunction that’s going on and NAD is being depleted, what disease, cancer, diabetes, heart disease is not literally being created in some form or fashion as a result of low NAD? I mean, it’s almost across the board.

Dr. Charles: So we certainly know from animal models that animal models of heart failure have a very significant attack on cardiac NAD. But here’s the other interesting thing that takes those two pillars and kind of brings them together and bridges them. If I said that we discovered nicotinamide riboside and the genes and enzymes that convert NR into the NAD coenzymes. And then I told you, we developed this technology for targeted metabolomics. And we found that, I sometimes call them the crown jewels of metabolism, are not locked in a vault that are protected from the elements. They’re actually exposed to the elements of metabolic stress, and they’re disturbed. And then as it turns out, nicotinamide riboside kinase 1 and 2, the genes that Pawel Bieganowski and I described in 2004, those genes get upregulated when cells have their NAD under attack, it’s the NR pathway that actually gets jacked up. So it looks like a stressed cell is looking for NR in order to, another $4-word, replete in order to fill up its NAD stores. And there’s some biological logic for that. You need NAD to generate ATP, but you also need ATP to generate NAD, it’s the circle of life, right? So when NAD is under attack, ATP is under attack. And it turns out that because it takes less ATP to rebuild NAD stores with NR, the cells turn up the nicotinamide riboside pathway, so that the mouse that is getting NR in its diet is a very lucky mouse because it’s heart cells are turning up the NR pathway. And if we’ve provided an NR in its diet, then it can maintain its NAD level, and it can protect what’s called its ejection fraction, and it has a better heart function. So we think that the use case for NR is that it allows our bodies to sort of maintain their optimal NAD levels. And then going forward, there’s kind of a nutritional case for NR in wellness prevention. And then there may be a disease management case that can be made on the basis of placebo-controlled studies. And ours being tested in a lot of these placebo-controlled trials where people have a condition of metabolic stress where we know the NAD system is under attack, and we want to see whether NR supplementation can protect that.

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Darin: So you isolated this NR. It’s a precursor to the NAD. It’s the holy grail of metabolism. So now with Tru Niagen, you guys were able to isolate it, prove it in science, and now getting it out in the world. This could be a jump. But I think about one of my first supplements I sold out of lockers in the ’90s was creatine. And creatine monohydrate was something that, well, didn’t really do anything for you if you didn’t stress the muscle, and it didn’t create the need. It’s kind of like I thought about that in the sense of if your metabolism doesn’t, it’s got enough NR, then it kind of doesn’t need it, in a sense. But if you were under stress, which is the 3d world certainly now, then you need it. And the reserve of that is more and more essential. And so that literally helps you in the moment of acute use of metabolism and cellular health, then link that then to the longevity site because this NR, NAD is always linked to this longevity and link that for us.

Dr. Charles: Let’s do a disclosure there. So there’s an invention, and when I’m at Dartmouth, and then ChromaDex comes along and I’m the Chief Scientific adviser for ChromaDex. I’m an employee of City of Hope, but I advise ChromaDex, I won the stock, and they basically license the Dartmouth intellectual property and came up with a trade name of Niagen and a finished product called Tru Niagen that actually will sell you clean nicotinamide riboside chloride that has been safety tested and clinically tested and so forth and so on. And so that’s the stuff that’s available for sale.

Darin: So you’ve done all this work, you were able to isolate it, do the work, and then this company was able to let you guide them in that advisable–

Dr. Charles: And they’ve done a lot of work too because there’s a crystal form that was developed, and there’s a manufacturing process, and I advise them on safety and what kind of study should be done. Then you jump into the area of healthspan and lifespan. So when we started the Tru Niagen direct to consumer brand, I agreed that we could say age better. The idea is that by taking Niagen, nicotinamide riboside, we want to promote wellness, we want to promote healthy aging. So I tend to shy away from longevity claims because it’s not something you can prove. I sort of don’t want to be associated with thousands of years of grift, frankly, because every generation has had people that have claimed to have found a fountain of youth and are selling some kind of thing that basically doesn’t work, and also claiming to have the aging process understood, and as aging optional or reversible. And it turns out, it’s a lot more complicated than that. And I’m actually always going to bet against when someone makes those claims. Like, for example, in the heart failure trial, if I wanted to let the mice go their whole lives comparing NR supplemented with not, we probably could have seen months and months or a long time for a mouse, we probably could have seen something that could have been described as lifespan extension. But life-death, it’s such a kind of a dirty endpoint. And I wouldn’t have learned as much about the heart function. So frankly, when you do animal experiments, you have to sacrifice the mice. And if you sacrifice it during the intervention, you learn a lot more about it than if you just let it go and you report how many days they lived. So we generally don’t do that “lifespan” thing. So I’m a little uncomfortable in the topic.

Darin: I love the fact that you’re explaining it this way because number one, that’s integrity and number two, you were going back to the origin. The origin is, allow the cells to function better and give them the opportunity to do that.

Dr. Charles: Put it this way, Darin, let’s say it was a type one diabetes model. Type one diabetes is an autoimmune disease in which a person or a mouse has gone to war against their pancreatic beta cells, they can’t make their own insulin any longer. So you could preserve a mouse’s glucose metabolism by giving it insulin. And then you could make a synthetic insulin analog. And you can see if it works as well. Well, in this heart failure model, we figured out the mechanism is the NAD system is under attack. And then we figured out that NR kinase chain is upregulated. And then we figured out that nicotinamide, an old form of vitamin B3 from 1938, nicotinamide won’t rescue the NAD. Why? Because a gene called NAMPT, which cells use to make NAD from nicotine amide, NAMPT expression is going down. Whereas our gene, nicotinamide riboside kinase 2 is going up. And NR will allow the mouse heart to maintain at NAD level. So we’ve figured out that NR is basically going to be medicine for these mice, right? Just like somebody that knows that Type One Diabetes is a lack of insulin synthesis is going to be dosing them with Type One Diabetes. Somebody doing a not very insightful experiment could have said, oh, insulin is a longevity drug. No, insulin is a medicine for a type one diabetic. What you need to be doing is dosing with some new form of insulin, and you can look at its half-life, and you can look at how well it’s binding to the insulin receptor, and you’re going to do a mechanistic experiment with that. So we did mechanistic experiments with NR. So it turns out human aging is way more complicated than mouse aging, and no one is going to do the clinical trial that is going to look at people’s lifespan over decades. It’s just not going to happen. So the best you can do is look at biomarkers. And you have to be very, very careful to look at biomarkers because like NAD, boosting is not actually that interesting. We know that NR does that. That doesn’t show that you’re going to live longer. That just shows that your blood NAD is higher. What you really want to be doing is you want to be affecting people’s NAD in tissues that are being challenged by their conditions. And so we’re designing experiments that are going to be insightful. We think that NR will promote wellness. People who report anecdotally a lot of benefits like workout recovery and sleep and hey, I didn’t get no colds, and back when people were traveling a lot, recovery from jet lag, and a bunch of things and athletic training, and so on and so on. But I personally, I’m not comfortable saying that NR is a longevity drug. I think it’s irresponsible for people to make those kinds of claims.

Darin: That’s the thing. It’s like, you know that heat of inflammation is at the core of every disease and every metabolic stress and all of that stuff. So it’s like, okay, well, you can deduce that this is a good thing to have. I mean, obviously, so I really appreciate that. Because listen, even though when the telomerase and all of that stuff started coming out, they’re like, oh, that’s it, we can definitely tell you what your age is. And now all these companies sprouted up and these miracle supplements. Like some of these supplements were charging $2,000 a month and all of this stuff. But again, I think what they did is they deduce this all down to something that’s infinitely more complex and took advantage of people.

Dr. Charles: I think they are taking advantage of people. And like I said, any number of our trials in mice could have been described as longevity trials and to get a longevity endpoint when you’re actually addressing a distinct pathology. We do think that those pathologies apply to human beings. And we think that NAD is so central to metabolism, and our supplementation has potential in fatty liver, has potential in mild cognitive impairment. It has potential in a lot of things. But those claims will be made in conjunction with clinical tests that measure those things. I’m not comfortable with the extrapolation. And moreover, I think that some of the kits that are being marketed now are kind of like tautological, like, somebody will take a supplement that they know moves a particular biomarker, and then they’ll say, well, because we move that biomarker, we reversed a bunch of people’s age. And no, you just basically came up with a kit to take people’s money. And I literally have had the technology to measure blood NAD since 2013. And I don’t think there’s a use case for healthy people. I can guarantee you that six to eight hours after you take an NAD precursor supplement, your blood NAD is higher. That’s not interesting. What’s interesting is how you feel. What’s interesting is your mile time. What is interesting is your repair capacity. Now, there are some people with human diseases. There are some people with rare mitochondrial diseases that are actually walking around with low blood NAD. We were the ones that measured them in collaboration with a group in Scandinavia. And so there are rare humans that have low blood NAD. And then there’s a lot of humans that have a depressed NAD system in their liver, in their adipose or in one tissue another that no one’s going to donate to me, no one’s going to give me their brain or their liver.

Darin: I love that. What’s the difference then between taking NAD, straight NAD I can find on Amazon and take that or get an NAD from a functional medicine doctor just right into my veins?

Darin: Talk about the supplement first because people again flood the market with all these NAD here and NAD here, so that number one. And number two, I want to just unpack the supplementation of NMN as well.

Dr. Charles: Great. So NADP has 3 phosphates, can’t get into cells. NAD has 2 phosphates, can’t get into cells. NMN has a phosphate, can’t get into cells. NR is the biggest piece of NAD that can get into cells. Just like in glucose metabolism, the first thing that cells do with glucose is they put a phosphate on it so that the glucose can be metabolized. The first thing that happens with any NAD precursor or vitamin is a phosphate gets put on it or a ribose phosphate gets put in nicotinamide gets a ribose phosphate, and nicotinic acid gets a ribose phosphate, and NR already has a ribose. So NR gets a phosphate put on it. If somebody thinks they’re clever and they say, oh, I want you to take NMN, they’re basically a chemist, went to the trouble of putting the phosphate on and then basically in your alimentary canal which means in your mouth and in your digestive system, the phosphate is coming off. So you’re basically getting NR. You’re paying for NMN and you’re getting NR. And you’re getting something for which there is not a safety dossier like there is for NR. Like NR, we’ve known how to make clean, pure NR for a long time. And the FDA has made a ruling on it that it’s generally regarded as safe. Just in the last week or 2, the FDA made a ruling that rejected the idea that NMN should be generally regarded as safe. They said there’s not sufficient evidence to say that. I don’t think that people really know what they’re getting if they’re buying NMN, but they’re certainly not getting something with the safety dossier.

Darin: So it’s a gamble. You don’t know what you’re getting and how much of the phosphate is off and how much–

Dr. Charles: Well, you know the phosphate’s got to be taken off because that’s just the way that the cell transfer works, then there’s NAD drip thing. So again, somebody is putting NAD into an IV bag, basically, and then it goes into cells and then that breaks down also into NR or nicotinamide which goes into cells. So the thing is, why shoot something into your veins? This is orally available. When you eat the plants or the animals, you’re getting the NAD coenzymes that are in those cells. Those NAD coenzymes are breaking down into the NAD precursor vitamins. So this actually intact NAD in food, in raw food. And as you process food, you get it broken down into the precursors, which is fine. And then the precursors go into cells so that your cells can rebuild it into the NAD coenzyme. So there’s really no use case per injection. Your digestive system knows how to take NAD or NAD precursors and deliver it to cells.

Darin: Well, then thank you for clearing that up because those are definitely something else. And then again, just on the lifestyle perspective, being able to eat fresh food has some of these precursors in there and then lowering stress just in general, all of these things can help save some of the use of the NR and also the NAD.

Dr. Charles: Yeah, but the kind of stress that I’m talking about is not just like I have a big deadline tomorrow. Every cell experiences stress of having to repair its DNA before the DNA gets replicated. There are cellular work to be done, put it that way. There is cellular work to be done in the phase of DNA damage, reactive oxygen damage, and then the inevitable encounters of life. So it’s not like you’re just gonna sit and do yoga and your NAD is gonna be more intact. I love strenuous exercise. And strenuous exercise requires repair as well. Some of the stresses are avoidable like alcohol is avoidable unless you’re alcohol addicted, then it’s harder to avoid. But there are dietary things that are in the choice, addiction spectrum, same goes for alcohol, but a lot of the repair processes are things that just accumulate over time. One of the things about that is that like we report in 2004 that there’s NR in milk. And then everybody immediately asked me, so how much milk do you drink and the answer is none. I’m lactose intolerant. But the thing it’s actually kind of a misinterpreted finding because really you get, again, remember the cycle of life, I said, you need NAD to generate ATP and then you need ATP to regenerate NAD. So you need NAD precursors to make NAD and then you need NAD to make NAP precursors. So vitamins and coenzymes are in the cycle of life. So when you’re eating whole foods with a small “w” and a small “f”, you’re actually getting intact coenzymes that break down into vitamins. So it’s really food is the source of all of our macronutrients and all of our micronutrients. And then there’s a use case for certain things like NAD precursors because we found the NAD system becomes a challenge by metabolic stress. So that’s where we are.

Darin: Amen to that. Eat your whole foods, marvel at the metabolism, and then when we get a chance to take something that upregulates your NAD, then, hell, let’s do it. Well, I got to tell you, Dr. Charles, this has been a mind-blower. I freaking love every second of this thing. I just want to applaud your work, your dedication, and your ability to understand. Again, I want to praise that your ability to understand the big picture all the way down to the small metabolizing mechanisms that you understand and I think just that on a personal note, I just want to say I’m just so stoked to get to know you here and know that you’re doing that work and the work that you’ve then been able to translate into Tru Niagen stuff with the NR products backed in some serious science. It’s just super exciting and a person that loves physical stress and charging in life, it’s just part of the arsenal now. So anyway, man, thank you for your time. I hope this is the start of many conversations but I’m stoked for the information you gave here today, and we’ll be in touch.

Dr. Charles: Thanks so much. People can ask me questions on Twitter, @charlesmbrenner, and on lab website is brennerlab.net. And I think there’s something called asknad.com and truniagen.com. I answer questions all the time on Twitter.

Darin: Oh, right on. We’ll put all of that in the show notes and make sure people will get access to you because you’re a wealth. So thanks, brother, I appreciate it.

Darin: What a fantastic episode. So tell me, what is one thing you got out of today’s conversation? If this episode struck a chord with you and you want to dive a little deeper into my other conversations with incredible guests, you can head over to my website, darinolien.com for more episodes and in-depth articles. Keep diving my friends. Keep diving.