The New Darling Supplement Of The Anti-Aging Industry (& The Truth About Whether It Actually Works)

Hey, it's Ben Greenfield. I interviewed a really smart guy today. His name is Dr. Brenner, and he knows a whole bunch of stuff about how to make you live longer. So sit back and get ready to have your mind blown by this dude. Anyways, I had a lot of fun talking to him.

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Foreign.

Hey folks, it's Ben Greenfield. And you've probably heard me talk on other podcasts about how I've done injections with this so called anti aging molecule called nicotinamide adenine dinucleotide, or nad. As a matter of fact, you know, a few years ago I interviewed this guy who runs the NAD injection clinic in San Diego and since then have been doing IVs and injections and found it to be an incredible molecule, one that you'll actually learn more about on today's show. But these, these IVs and these injections, they're fringe, they're spendy, they're uncomfortable. You feel like your whole body is on fire and you're gonna have a heart attack. And some people will say that it's not necessary and that you can just get all the NAD that you need from supplementation. In particular supplementation with this other thing called nicotinamide riboside. Nicotinamide riboside, I don't know, it's a big word. NR is what that's abbreviated as. So I wanted to take a deeper dive into NR and whether it actually can increase NAD levels and why you'd want to use it and what it mixes and doesn't mix well with and what the actual research is on this stuff. So I actually am lucky enough to have the guy who discovered nicotinamide riboside. He discovered it as a vitamin. He's also one of the world's leading experts on NAD. So that's a handy 1, 2 combo for the questions that I have today. Anyways, his name is Dr. Charles Brenner. Dr. Charles Brenner. He worked in biotech for a while at the biochemistry department at Stanford University where He did his PhD research and he also moved on to Dartmouth College after that. And that's where he made the discovery of what's called the NR kinase pathway. The NR kinase pathway. And he now sits on the scientific advisory board of Chromadex, which is, from what I understand, a form of nr. And he's their chief scientific advisor and he researches basically NR and its effects on metabolism and diseases and metabolic stress. And so probably spends most of his time. I don't know, Charles, are you just like running lab rats through the maze with different forms of NR in their system or what's a typical day look like for you?

Typical day involves supervising human beings actually. But yeah, we've got a lot of mice and rats on nicotinamide riboside and we're always amazed at what this molecule can do. And it's been really kind of a thrill for me to have discovered the molecule as a vitamin back in 2004 and have it already commercialized and sold inside of 15 years. So we're super excited about NR Research and I'm happy to share that with your listeners. And I want to tell you this podcast thing, I mean, my hair and makeup is perfect.

Ben, I believe you.

I'm a little, I'm a little sorry that I can't share that with everybody.

I believe you. I personally have a face for radio and I often podcast in my underwear or less than that, sometimes not even any pants and so too much information. Yeah, yeah, sorry, I don't want to, I don't want to distract you with images of me prancing around my office pantless. So let's, let's get back to nr. Actually, I want to ask you this though, before we dive into NAD and NR in general and get a little bit more geeky and scientific. Obviously this is something that is quite popular right now in the longevity in the anti aging community. This concept of doing NAD injections or boosting NAD levels with supplements or certain foods or using things like NR supplements. Do you yourself do a lot of this anti aging and longevity enhancement via certain biohacking or food strategies or diets or supplements?

I'm not that radical in terms of my lifestyle, so I would say I'm a fitness nut. So I get regular sleep, I eat healthy, my energy intake is balanced with my energy expenditure, which is pretty intense. I do high intensity interval training, try to limit alcohol, don't do any drugs, I don't inject anything, and I do take daily or twice daily in fact, nicotinamide riboside as the true Niagen supplement that we've commercialized at Chromadex.

You take it twice a day?

Yeah, I take it twice a day.

I just started taking creatine twice a day because Tyler LeBaron, who's been on the show before, he and I were having lunch at a conference, and he was explaining me how the maximum amount of creatine you can absorb is about 2 grams. And I was just taking 5 grams every day. I love creatine as a way to stave off sarcopenia and muscle loss. It's a little bit of a nootropic. It' sit's a pretty well researched little molecule and has a lot going for it. And so I started doing it twice a day. So, you know, I split it up now so I get maximum absorption with something like nicotinamide riboside. We may be putting the cart before the horse by jumping into this. But I'm gonna ask the question anyways. Is that because you can only absorb so much at a time that you would take it a couple times a day?

Well, actually, it's the circadian rhythms of NAD itself. So, you know, when we've looked at it in a mouse and we've taken samples every four hours, we did this in collaboration with Paolo Sasoni Corsi's group at UC Irvine. And there's actually a diurnal cycle of nad. So there's essentially a daytime peak and a nighttime peak. And so you're boosting your daytime NAD by taking NR in the morning, and you're boosting your evening NAD by taking it in the evening. So the peak blood NAD is achieved at around eight hours after you dose. And our research shows that it is still up 24 hours after you take nicotinamide riboside. It's a dose dependent, of course, but when people go from a kind of typical recommended dose, which is 250mg of Nr chloride, Tru Niagen per day, to a higher dose, they tend to split it into a morning and evening.

Okay, interesting. Like a certain time of morning or certain time of eating.

It doesn't have to be that precise. So, you know, when you. When thou risest up. Right. Is a good time to take it and. And then 12 hours later. So for me, it's around 6am and then whenever I get home from work.

So 12 hours, that's how you separate it. Yeah. Okay, got it. So let's go back and talk a little bit about what NR actually is, or even if it's helpful, what NAD actually is what is nad? And then I'd love to hear kind of how you discovered NR and what it has to do with nad.

So NAD is the central regulator of metabolism. And metabolism includes, but is not limited to, the ability of your body to convert food into energy, right? So the stuff that has calories, our macronutrients, our proteins, fat and carbohydrate, and we eat food in order to be able to move our bodies and have ideas and have all of our background functions like circulating blood and peripheral nerve function, so you can feel things and see and hear things. But in addition, metabolism includes repairing damage. So there is DNA metabolism that involves sensing DNA damage and repairing it. There's the ability to convert one set of molecules to another, so we can take those bulk foods and our adrenal glands can turn those into sex hormones. So we make our own androgens, we make our own own estrogens. Men and women make androgens, and women, for the most part, make estrogens. And that's a type of metabolism. And essentially any type of metabolic process that you can think of, including building up your muscles and restoring your muscle function after a workout, involves metabolism. And NAD is the central regulator. NAD, and then three other related compounds that are called nadh, nadp, and nadph, those are the central regulators of metabolism. Now, the thing about NAD is you think, okay, this is the ultimate family jewel, right? This is the thing that allows every single cell in my body, every single tissue to function. The brain to be a brain, the liver to be liver, the pancreas, the heart, you name it. You would think that this would be protected against damage by the homeostatic forces that we have operating in us. And just to clarify what that means, that means the ability of the body to maintain things in a regular state, like keeping our body temperature at 98.6. When we go up too high, we have ways to cool down. When we're too low, we have ways to heat up. So you'd think that your NAD would be protected, but it turns out that our NAD and our NADPH is under stress in a number of conditions, like alcohol. So when we drink alcohol, our NAD is converted to nadh, and then the food that we eat, where we want it to be converted to energy, can be converted to an alcoholic fatty liver.

That would be in a case of excess alcohol though, right?

In the case of excess alcohol, right.

Is that why a lot of anti aging docs will tell you that the worst possible thing you can do for your stem cells is to drink too.

Much Alcohol, it's not only your stem cells. The metabolism happens in hepatocytes, so in, you know, the functioning cells of the liver themselves. But then the liver becomes infiltrated by macrophages and all sorts of inflammatory cells. And, you know, it just, we generate acetaldehyde, which is toxic. And, you know, the biochemistry of alcohol is actually really well known. And it's really well known to depend on NAD in a particular redox form. And so our vitality becomes stressed when we are metabolizing too much alcohol. That's actually something that really, it requires some thinking about because most people think, oh, I drink alcohol in order to de stress. But if you talk to a biochemist, a biochemist will tell you, oh, alcohol is itself a metabolic stress. And it's a metabolic stress precisely because of what it does to our NAD system.

So this NAD system, in addition to getting damaged by, let's say, alcohol or excess stress, or having to engage in excessive redox reactions from just pushing food through and making ATP, is the damage like structural, Is that how the damage would occur? Or is the damage simply you get depleted of NAD because so much gets converted into nadh so that there's, there's enough reducing agents to donate electrons?

Good question. And I want to make sure I tell you the six other major conditions that, that attack nad. So, so let's run through them and then we'll talk about the consequences of what happens when your NAD or NADPH is under attack. So number one is alcohol. And I always bring that one up first. I bring alcohol up first because we know the most about it. And I bring aging up last because we know the least about it. But alcohol is number one. Number two is what I call overnutrition. So we set up an experiment in which we basically overfed mice and we made them fat with a high fat diet and we pushed some of them over the edge into type 2 diabetes. And we wanted to see what effect that was going to have on their liver NAD system. Well, it did depress their NAD somewhat, but what it really struck down was their liver nadph. And people don't talk enough about nadph, but NADPH is the metabolite and again, all of these things are restored by nr. So when NAD or NADPH is under attack, by boosting your NAD precursors with nicotinamide riboside, you can basically replete, you can fill up your tank and you can get back to the homeostatic condition. But NADPH is really important because it's the key metabolite for resisting Reactive oxygen species. Right. So when we generate reactive oxygen, that damages. And this addresses your question, that damages all sorts of molecules. Reactive oxygen can damage DNA, protein, carbonylation, it can damage lipids, and then lipid peroxides can spread through the body, damage nerves and damage your eye lens and all sorts of stuff. And so by depressing nadph, there is a systemic storm of reactive oxygen species. And we've shown that that is caused by overnutrition. So there's, as you know, there's a global epidemic of overweight and obesity in the United States. A third of us are overweight. Ballpark figures. A third of us are obese. Two thirds of us are above a BMI that is considered to be generally.

Optimum or skinny fat. Did you see that research article that came out earlier this week showing that skinny fat folks have. I believe it was increased mortality and increased risk of cardiovascular disease, even though they're at a relatively normal bmi. Right. Like people who are just kind of frail.

Absolutely. There's bodybuilders that have a BMI of 28 or 30 that are, you know, that have incredible, you know, muscle composition. So BMI itself is not the great greatest measure of adiposity. But yeah, it's really a combination that produces the metabolic syndrome in which there's not really high functioning skeletal muscle to dispose of glucose and there's inflammation. But all of these conditions basically lead to inflammation at a molecular level, which is production of reactive oxygen and tissue damage.

I like how you call it over nutrition, by the way. Instead of just like eating too much.

Damn food, you know, we can call it eating too much damn food. You know, you've got to ungeek me a little bit for your, for the listeners. But what I like to say is that, you know, overnutrition is the, you know, is the up and coming and leading, soon to be leading type of malnutrition that people are getting. Too many macronutrients, too much protein, fat and carbohydrate, certainly too much carbohydrate, but, you know, too much food in general. And that that's driving reactive oxygen species because the NAD system is under attack.

Got it? Okay. I promise I'll quit derailing you so you don't have to talk about the seven different factors for the next two hours. So go ahead and throw the next five at me.

Throw them in. Okay. So noise induced hearing loss. This was a study that. So alcohol is classic and too much food is something that we did. The noise induced hearing loss came out of A study at New York City in which I was not involved. And they subjected mice to a degree of noise that induced deafness. And when they measured NAD in the cochlea of these poor mice, the NAD was drastically reduced. And when they provided these mice with nr, they were able to protect mice against noise induced hearing loss. So that's a really interesting type of stress, because I would argue that mild stress, like a car horn, if I'm distracted and, you know, I start walking out into traffic, which, you know, I might do because I lived in California for 10 years where drivers are ridiculously aware of pedestrians. But if I'm, you know, back in my hometown of Boston and I step off the curb, you know, people are going to honk a horn. And that mild stress drives my, you know, corrective behavior. So, you know, the fact that I can hear that horn, I get out of the way of that car and I live to see, you know, another day. But the persistent stress of really loud noises, the persistent stress of a lot of the things I'm about to tell you. Number four is sun and oxygen damage. These kinds of persistent stresses will ultimately attack our NAD system.

So don't go to a hot concert in the summer in the sunshine and eat too much food and drink a few beers, basically.

Well, so isn't that hilarious, right, Ben? Because when I go and I give public lectures and I say, okay, let's get a show of hands. Who would love to jump on a jet? Because time zone disruption is one of these things. Who would like to jump on a jet to Ibiza and be outside in the sun and oxygen, listening to, you know, loud music while we eat lots of food and drink alcohol, and everybody.

Raises their hand, it turns out that.

Alcohol overnutrition, noise, sun, oxygen, changing time zones, those are the almost the inevitable, you know, conditions of life, you know, those are a lot of the enjoyable things.

Yeah, it's really interesting because I suspect a lot of these things, like when I fly, like, I went to this event called a fest in Sardinia, Italy, recently. It stands for awesomeness fest. It was a great time, but I'm traveling multiple time zones. Every single meal is like this Italian buffet. You're dancing till like 1 or 2am you're drinking. And just based on what I know, you know, I do have a master's degree in physiology and try to study some of these metabolic reactions a little bit. I was popping NR like candy while I was there, just. Just because I know it's one of the ways to clean up some of that Cellular damage. But it's inter. You know, you and I hadn't talked, we. You and I haven't ever talked really before this podcast. But it's interesting to hear your seven reasons and know that pretty much anything that seems mildly hedonistic seems to damage nad.

Well, you know, sex and vigorous activity probably doesn't.

But yeah, I guess you're right.

So. But I don't know if I qualify.

Vigorous physical activity though, as hedonistic. I would classify that more as like stoic.

Okay. But you know, dancing. So yeah, probably the evidence based way to approach time zone disruption would be as, you know, would be, you know, you set your watch to where you're going to be. Right. And you try to sleep on their time even. It means skipping all of the food and drink on the plane. Right. And so, you know, it may involve some melatonin in order to try to, you know, skip ahead or, or hold back. You get to your destination and then you want to get sunlight at 6 or 7am to try to reset. And then you potentially would take a higher dose of nicotinamide riboside in the morning when you're trying to reinforce your morning in a new time zone.

Really? So. So it works on circadian rhythm like that too?

Yes, it does.

That's. I did not know that. That's very interesting. You know, it kind of, it kind of doesn't fly Too well with Dr. Sachin Panda's book and his teachings on how he says, you know, any supplement, even a cup of coffee, could disrupt your circadian rhythm. I'm, I'm kind of on board with the concept of if you're trying to get your circadian biology to catch up with traveling across multiple time zones, you may want to take a few of those supplements that actually assist with adapting to that time zone. I mean, for me personally, I've found that breakfast in whatever zone that I happen to be at, or waiting till whatever the next formal meal is, breakfast, lunch or dinner, because food is a circadian cue and then movement is a circadian cue and then light is a circadian cue. So I, so I move, I expose myself to proper light and I eat a meal. But it sounds like I could throw NR into that equation too, huh?

Right. So, and where does NR come from? This might even be skipping ahead into something you're going to ask me later. The natural source of NR that we've seen is basically milk. People ask me, how much milk do I drink? None. I'm lactose intolerant, so milk is pretty dairy is fairly special in that NR is quite stable in milk. And so commercial milk in North America is sitting somewhere for weeks or months and still has 5 micromolar nicotinamide riboside in it. You'd have to drink liters to get appreciable amounts. But really, in the wild, where we would get NR and other NAD precursor vitamins is by eating whole foods with a small W and a small fat, by eating non processed stuff, because plant or animal, all of those cells have NAD and NADPH in them. And when the digestive process, we're going to digest down the nad, NADPH into vitamins. Vitamins are precursor molecules of coenzymes. And so NR is the largest piece of NAD that can go into a cell and replenish your nad. The NR could further break down to nicotinamide or nicotinic acid, which were discovered in 1938. They're not quite as valuable as NR is as an NAD precursor vitamin, which is kind of why there's so much research on NR right now.

Interesting.

So we covered the five that we encounter without disease, Alcohol overnutrition, noise, sun and oxygen damage, and changing time zones, and then the two or three others that we've basically discovered by we and others by doing research with animals. Neurodegeneration. So in neurodegeneration, NAD is under attack both in peripheral nerves and in central brain injury. In heart disease, NAD is under attack. And in aging, there's a decline in tissue NAD in the liver and in some other tissues. And so essentially, Ben, whether you're a consumer or you're an advanced research scientist, if you come up to me with a question and you say, hey, I wonder if my favorite disease or condition, whether it's chronic fatigue syndrome or some immune activation phenomenon or something with stem cells, I wonder if condition X, Y, or Z affects the NAD system. There's a very simple way that we can figure that out right now, which is you give my lab a tissue sample, and if we see that these metabolites NAD or nadph, and some of these other metabolites are dysregulated, then we know that the NAD system is under attack. That's the first technology. And then the second, since my lab kind of finished and a few other labs finished discovering the hidden genes in the NAD gene set, we can now look at the gene activities in these tissues. And for example, heart disease was amazing. So in heart failure, NAD is down. And the nicotinamide riboside kinase 2 gene that we discovered in 2004, that gene is up. So what does that mean? It means that the failing heart is losing NAD and it's spiking up the NR pathway. So the failing heart wants NR in order to get its NAD back up to normal. And if we give those mice oral nr, we can make their heart disease much less severe, even though they're bred to be genetically predisposed to this particular type of heart failure. Seeing the same thing in neurodegeneration, Central Brain Injury, NAD goes down, the NR kinase pathway, NRK1 and NRK2, in that case, both go up and then you can protect the brain with nr.

That's fascinating. Do you think that in non diseased populations or people who don't have brain or heart damage, it could just be used to improve cardiovascular health or to improve cognitive performance?

So there's clinical testing to answer that exact question. So I'm not somebody that goes out there and advocates injections and you know, of anything, but I will address NR versus nad because we've done a brain injury experiment that directly addressed that.

Okay, I actually want to hear more about that. But before we delve into that, first of all, you mentioned that for somebody, if they wanted to test how much NAD they had, that they could, for example, send your lab a sample of their tissue. Is that something that's commercially available?

Well, right after this podcast interview, I've got a conversation with some folks at Chromadex and a potential partner to do that for a kind of early adopting community. And we got to work out the regulatory pieces of this. They're volunteers and I'm not giving them back health advice, but the technology is there and it's not particularly expensive to measure NAD in a blood sample.

Keep me posted on that. By the way, folks, if you're listening in, I'm going to keep track of all the shownotes over@BenGreenfieldFitness.com NR that's BenGreenfieldFitness.com NR. But if Dr. Brenner ever makes that commercially available, I'll just, I'll post a link over there so that anybody wants to test their NAD could go and do so. Okay, so we know the seven ways that NAD can get damaged. We know what NAD actually is. We know how we could potentially test or monitor our levels of nad. We've touched on a couple of the conditions that could benefit from nad, but I want to get more into that. But before we touch on the diseases or the conditions or the reasons that someone would want to boost NAD in the first place, tell me about how you discovered this NR thing, like whatever eureka moment that happened when you actually found NR.

So, basically, 2003, 4. I'm minding my own business, working on an enzyme. That's what a biochemist is supposed to do. And I was really interested in a particular enzyme that makes NAD in yeast cells. Same enzyme also makes NAD in human beings. And it had some peculiar things about it. It had what are called two active sites. A lot of enzymes only have one active site. And I wanted to figure out how they coordinate with each other. And it was right around the time that people started getting really infatuated with a class of enzymes called sirtuins. So they're related to the yeast sir2 gene. And, you know, the yeast sir2 gene is pretty important in longevity in a yeast cell. You know, I wouldn't say it's necessarily the central regulator of longevity in people. I think that's been very much an overplayed hand. But, you know, SIR2 is an interesting metabolic regulator, and SIR2 uses NAD. And when I looked at the received wisdom that people were operating with in 2003, they basically had a diagram of how a yeast cell or a human being can make NAD from tryptophan, the amino acid. And that's a very inefficient process. It requires eight biochemical transformations. And, you know, it's like, literally hard to draw how to get from tryptophan to nad, even for a professional biochemist. It's a lot of biochemical gymnastics. And then they had a diagram from nicotinic acid, niacin to nad. And then they had a way that a yeast or a human could use nicotinamide to regenerate nad.

What about aspartic acid? That's another one that I've heard of.

Oh, you know what? That's a really good question, because in a lot of bacteria, bacteria can use aspartic acid. So our own cells cannot use aspartic acid to make nad. But in our microbiome, we have bacteria inside of us that can use aspartic acid to make nad.

Okay, got it.

So you get bonus points for that, Ben.

Oh, thank you. I did my research prior to this show. No, I actually, before I started, you know, shoving over money and traveling around to try and, you know, get my own NAD levels up, I definitely looked into ways that it could be elevated, you know, and I found some of these tryptophan and aspartic acid and niacin pathways that you're referring to, but none of them seem to be incredibly significant, especially in Vivo and humans to actually get NAD levels that elevated?

Well, you know, I wouldn't, I wouldn't really dismiss nicotinic acid because it's a pretty important, it's actually used as a drug. So 15 milligrams of either nicotinamide or nicotinic acid prevents pellagra. Okay, so even though the people with the worst diet in North America today don't get pellagra, because 100 years ago, someone from the Public Health Service named Joseph Goldberger discovered that people that are eating corn rations and lard get pellagra because they don't have fresh food in their diet. And turns out their terrible diet was deficient in NAD precursors. And so in 1938, the, what we call vitamin B3, nicotinamide and nicotinic acid were discovered. They turn out to be NAD precursor vitamins and they're super important to human health. And then at much higher doses, like at a gram or more of niacin per day, you can improve your blood lipid. So you can actually increase your hdl, your good cholesterol and lower your low density protein cholesterol, your bad cholesterol, and your free fatty acids. So that's a pretty good thing. But the problem is that high dose niacin causes flushing. And so there's not a lot of people that really enjoy taking that.

Yeah, that's, that's something that of course is super uncomfortable. And you know, the niacin, though this might be confusing to some people for two reasons. First of all, nicotinic acid is not. Nicotine has nothing to do with like the smoke or the nicotine that you would find in tobacco, just so that people know you can't go smoke a cigarette, or as I have been known to do, chew on a nicotine infused toothpick, as pleasant and as cognitively stimulating as that can be. Different thing. And then as far as niacin goes, like I've taken niacin, you know, it flushes you. It's like good before a sauna for the detoxification effect. But this is what kind of confuses me right now. Niacin is commonly known as vitamin B3 or is nicotinic acid. How is that any different than, than what you discovered?

It's the genes, basically. So niacin cannot be used by a neuron. Right. And so if we're interested in cognitive health, we need an NAD precursor that is available to neurons. And so the tryptophan pathway gets turned off by a whole bunch of important tissues. The niacin pathway Gets turned. Niacin is mainly made in our gut by bacteria. So nicotinamide can be used in every cell type and tissue of which I'm aware. But the problem is that at high dose nicotinamide, you're inhibiting these sirtuins. So you're raising your NAD with high dose nicotinamide, but you're also inhibiting this class of enzymes that we're trying to stimulate. Right? So nicotinic acid basically not available to all tissues. Tryptophan is inefficient, not available to all tissues. Nicotinamide available to all tissues, but inhibits sirtuins. And NR is just in this really nice sweet spot, so it does not cause flushing. It is available to all cells and tissues. It doesn't inhibit sirtuins. And in fact, the NR pathway, the genes for NR utilization, the NRK1 and NRK2 genes, are turned up in conditions of metabolic stress, whereas in inflammation and obesity, the ability to use nicotinamide goes down. So in our heart failure paper in the mouse, and we actually, in the paper's very cool paper, it was in Circulation, which is a very high profile journal for cardiovascular biology, we found the same thing happens in human heart failure. So in mouse heart failure, NAD goes down, the NRK2 gene goes up, the gene for nicotinamide usage goes down. And when we looked at, it's hard to get tissue samples from failing human hearts, right? That's not easy to come by. But we got some and we looked at them and the gene expression pattern was the same. So the NRK2 gene is going up and the nicotinamide usage gene is going down. And when we tested in a mouse, nicotinamide will not restore that mouse's NAD in its failing heart, but NR will. And nr, you know, improves the heart function. So the advantages of NR are that it doesn't cause flushing, it doesn't inhibit sirtuins, and cells and tissues that are under metabolic stress are actually calling for nr. If some of your listeners know about AMP kinase, AMP kinase is a stress sensor. And in this same paper in Circulation, we showed that in the failing heart, there's a bioenergetic crisis. So the heart, you take creatine, so you're, your heart is making as much ATP as possible and then it's converting creatine into phosphocreatine in order to do mechanical pumping. When there's low ATP, there's going to be something produced called amp. AMP is like bad news. It's a bioenergetic warning. It's like the car horn that kept me out of traffic in Boston. And what the AMP signal does, among other things, is it turns on expression of the NRK2 gene so that if there's nicotinamide riboside around that the NAD can come back and restore function to that failing heart.

I've seen some evidence that nicotinamide and niacin, not NR, but nicotinamide and niacin. So you talked about how the reason you wouldn't want to just take niacin is first of all, you get this annoying flush. You can, you can inhibit sirtuins, which are associated with a host of positive benefits, including, of course, longevity. At least longevity. And anti aging is one of the reasons that those have been championed of late.

Right. And that's certainly shown in some model systems.

Right.

It's not really been demonstrated in people.

Mostly. Mostly yeast. Right.

Well, it goes a little beyond yeast.

Yeah.

Okay, we'll talk about it.

Okay, got it. And then the other thing is that there are some cells and some tissues that can actually use NR niacin to boost nad. So there's reasons you wouldn't necessarily just wanna use niacin. But I've also seen some evidence, like I mentioned, that nicotinamide and niacin could cause some blood glucose issues like insulin insensitivity. Is that something that you would need to be concerned about as well with nicotinamide or ibicide?

So we've just published a human clinical study in obese men in Denmark. So most of the authors are from Aarhus University, Aarhus, and the first author is Dalarup, and it just came out in American Journal of Clinical Nutrition. So these were obese Danish men and the dollar et al group, they had read our papers in the mouse literature where NR was incredibly powerful in obese and type 2 diabetic mice. It was clearing their fatty liver, it was improving their blood glucose, and then it was also protecting them against diabetic neuropathy. And so we needed to address this human population. The first question is really Ben safety. So you go from a mouse to a human, the first thing that you want to make sure that you're doing is that you're not going to make anybody sick. We figured that we would need a pretty high dose. And so these guys were on 2 grams of NR per day. And then, you know, it was a fairly exploratory study. So they were on a placebo or high dose nr for 12 weeks.

Can I ask you a quick question? You said high dose nr. I take four of these NR capsules each Day, am I anywhere near high dose?

That's getting, you know, so that's 500 milligrams. So if you're taking four capsules of Tru Niagen, that's 500 milligrams. And there was a really interesting study at University of Colorado that addressed pre hypertension, so moderately elevated blood pressure, where people were taking 500 milligrams twice a day and these guys in Denmark were actually taking a gram, effectively, they were taking eight of these 125mg capsules in the morning and evening. You know, the therapeutic trials, meaning trials, clinical trials that are placebo control, that are really addressing diseases and conditions are probably going to be done at a higher dose than, you know, than people are taking just to improve their wellness.

Okay, I don't want to derail you too much. So that just came across my head. But so you gave these mice high dose nr.

So mice get high dose nr. But the thing is, you can induce their obesity and diabetes in 12 weeks, right? And you can induce their obesity and diabetes in 12 weeks, you treat them in four or five weeks and you get these remarkable effects. Whereas a human being, a typical obese man in his 60s, has had three or four decades to add all of that body fat and the insulin insensitivity and the inflammation and everything. And you know, this is just a trial of 12 weeks. Right. So the question is, what are we going to move the needle on? Are they going to lose any weight? Are they going to get more insulin sensitive? God forbid they're going to become insulin insensitive, which is your concern, that there's some of the niacin literature. They might have become insulin insensitive, Right. Or is it going to have some effect on fatty liver or what? So I'm excited to tell you that the safety data were perfect. So when you look at incidents like any given day, somebody might have a headache or a bellyache or a sneeze. Right? But if you look at the adverse events that were reported to the nurses and docs on placebo, compared to the adverse events that were reported when people are on 2 grams of NR, there's basically no serious adverse events. And there's nothing in the group taking NR that was not observed in placebo. So it's really, really safe.

Okay, so there's a host of reasons then that you would use NR as opposed to, to, to niacin or, or nicotinic acid per se.

Well, for one thing, Ben, if they took 2 grams of niacin every Single one of them would have flushed.

Yeah, it'd suck. I don't, I don't, I don't like the flush. Like I've used the non flushing form. I think Thorn has some non flushing form. A NIA safe they call that one. But you know, let me put it this way. If you want to do like a full on intense sauna detox session, there's nothing like walking in there with a floor flush. I'd still rather exercise before to get my flush and get my heat up, but ultimately, yeah, it's, it's not pleasant.

I'm not sure if every single one of them would, would have flushed, but a vast majority of them would have flushed.

And for a day of work, it's just, it's, it's annoying. It's distracting, right? To, to feel like your body's on, feel like your body's on fire while you're trying to work. So, so I think we've established, just, just to make sure that we're able to squeeze in everything, I want to ask you in the, in the, in the limited amount of time that we have, we've established that NR is a, is a, is a better alternative to some of these other things that might potentially boost nad. You discovered this, you discovered this pathway. I want toto veer off into the actual benefits though. Like why would somebody want to boost their NAD levels? And remember, a lot of the people listening in right now, they're not obese, they don't have a chronic disease. I don't want to discount everybody, but in terms of a guy like me, what's it going to do for. Selfish question. What's it going to do for me.

What it did for the guys in Denmark? It looked like it was starting to move the needle on their fatty liver. They were not actually randomized for their liver fat. The guys that took NR turned out to have a starting liver fat that was not as bad as, as the people that were on placebo. But they got a 2% drop in their liver fat and placebo got a 0.2% drop. So that was at. It achieved a p value of 0.13. So not a 0.05 where you plant your flag and you say it definitively cleared fatty liver. But it looks like it started to move the needle on fatty liver and so that's exciting for future clinical testing.

Would that mean if I have had more than a couple of drinks at night? I don't drink that much. I have a glass of wine at the end of most Days or a Moscow Mule or something like that. But could you add this into a party stack, for example, or is that extending the results of that study a little bit too far?

Well, it's not directly addressed by that study because it wasn't really an alcohol study. A party stack concept, if I understand it correctly, is like an acute thing.

Yeah. Like how could I protect my liver, basically.

Yeah. So it's not illogical. I'll put it this way, it's not an illogical idea. It would have to be clinically tested in order to, you know, if we want to measure the amount of acetaldehyde toxicity that you have, that could be done in a short term study. It wouldn't be terribly expensive to. It would be easy to enroll. I'll tell you, I live and work in Iowa City, which is typically a top five party school in the United States. So it'd be easy to enroll people in that study. It's not specifically been tested, but it's not an illogical thought.

But long story short is this study, it just came out, this was a few days ago, if I'm not mistaken, in the American journal Clinical News Nutrition.

Right.

The long story short is that you took these obese men and you found that it not only produced profound improvements in their ability to be able to regulate blood glucose and insulin sensitivity and kind of.

No, I didn't say that address. So it did not improve their, it didn't improve their insulin?

Oh, it didn't.

The question is, what's it go in 12 weeks? In 12 weeks, is it going to change their body weight? Is it going to improve their insulin sensitivity? Is it going to make that worse? Is it going to do something about their blood pressure, their fatty liver or anything else that we can measure? And the thing that it looked like it was affecting as a primary, it looks like the first thing that we should have measured would be fatty liver.

Okay, so reduction in fatty liver. I gotcha. I misunderstood.

But if you do it for six months. Right. You do it for six months, we probably would have achieved, we potentially would have achieved significance on fatty liver. And then at that point they're gonna start losing body weight.

Get those fat men with, with the, with the healthier livers back in your lab for six months, man. Do it. Call them back.

We would love to. So. But, but first, you know, first you needed 12 weeks to assess safety. So, you know, you got. People have to remember, people get frustrated sometimes at the pace of, you know, clinical research and sometimes how long it takes people to complete you know, enroll. Accrue the people and, and then, you know, analyze the data and get the thing published. And people are frustrated how long it takes and how much money it costs to do this kind of research. But my God, I was in doing yeast experiments, you know, until into the 2010 decade and into this decade, in fact. And, you know, we're suddenly in human beings, so it's really early innings. But in terms of wellness and like human performance and what's it going to do for Ben Greenfield? You know, the question is, how good is, you know, are your records. So do you have a sleep journal? Do you have, you know, performance logs of Your, of your 500 meter split on a, on a rower, you know, or something like that?

I pay, I pay more attention to things like my blood glucose regulation, my telomere length, which I know, you know, there's a lot of eyebrows raised on how accurate that measurement is right now that, like the telo years telomere test, I pay attention to. You know, four times a year, I do a full blood panel once a year, I do a gut panel every day, though the main things I pay attention to are my sleep, my hrv, or the health of my nervous system. And of late, with increasing frequency, I've been slapping on these, these continuous, continuous blood glucose monitors and monitoring that and, and cognitive performance, that's a little bit more subjective. I have this new thing I've been messing around with called a brain gauge that I have it on my desk right now. It tracks like your reaction time and your, your processing speed, things along those lines. And I'll hopefully, for those of you listening in who haven't heard of that, I'll write an article on it soon or do a podcast on it soon once I'm done testing it. But ultimately, those are some of the things I measure. I'm. I mean, 10 years ago I would have been more interested in my 40k time trial time, but now I'm looking more at longevity and cognitive performance.

Okay, so what you would have to. For an n of 1, if you're interested, what you'd have to do is you'd actually have to cycle off. Right? So if you're taking 500 milligrams of NR now, if you're willing to cycle off for three weeks or something and keep on, you know, logging your. I mean, you could also do like a donut challenge every once in a while or something if you, if you wanted to, because, you know, your diet may be so good that you don't really have A lot of glucose excursions. But, you know, if you wanted to see whether you're, you know, you're getting benefit from, you know, nicotinamide riboside, given the things that you're monitoring, you basically have to cycle off and see, did my sleep get worse? Did my awareness and all of the other things that you're measuring get worse? I don't think that you're going to see your telomeres shorten over any short or long term basis. But what a lot of people notice when they go on nicotinamide riboside is actually one of the things that people notice is that fingernails and hair grow faster. And that's actually an anabolic function that's due to nadph. So that's not nad. Plus that's supporting nadph, which is allowing us to, to make, you know, macromolecules like, like hair and, and, and fingernails.

Okay, what about the aging thing? Because that's what, you know, there, there are a lot of companies that I've seen talk about NR for anti aging and for longevity. You seem pretty reasonable. Like so far, all the responses to the questions that I've asked you, you, you, you seem like you're pretty much basing things on the research and not on subjective reports. But what is the deal with the whole aging thing when it comes to NR or when it comes to boosting NAD levels?

Right? So essentially, you know, whereas, you know, aging can bring, you know, mastery and the ability to advise and provide for others, and, you know, stress can, mild stress can give us, you know, derived corrective and adaptive behaviors, stress and aging also bring challenges, right? So with persistent stress and with aging, you get injuries and accumulated damage, cognitive decline, hormone changes generally, loss of critical hormones, loss of muscle imbalance, food is converted to fat rather than energy, and ultimately we're a potential burden to our children rather than providing to our children and our peer group. And so what you're doing by trying to maintain NAD through the stresses of life and through the damage and injuries that occur through life, and these things happen at a molecular level, is you're basically trying to maintain all of your NAD dependent processes. So we think that potentially people can age better by, you know, maintaining their metabolism and their ability to repair DNA and repair muscle and detoxify reactive oxygen species over time.

Now, what about things you could do to boost your own NAD levels? You know, let's say I were taking NR and shoving aside all considerations of whether or not someone's doing, like injections or IVs of actual NAD and I am going to ask you about that. By the way, I warn you, are there foods that you could take to just increase your own availability of NAD or improve your NAD to NADH ratio?

Okay, so food, all cellular stuff that we eat, whether it's animal or vegetable, has NAD precursors in it. If you think about, you know, if you think about poultry, you know, sort of like the dark meat versus the light meat, the darker stuff is darker because it's richer in mitochondria and it has a higher density of. In addition to heme iron, which is what you're, you know, literally seeing, it also has a higher density of nad. When you're eating food, NAD is going to be broken down into these vitamin forms. And so the more food that you eat, the more NAD precursor vitamins that you're going to get. But you don't really get ahead by eating more food. Right, because the overnutrition can depress your NADPH in your liver. So we think that because of the inevitable stresses of life and aging, that supplementing with nicotinamide riboside makes sense. It is orally available, does not need to be taken by injection. And when you're taking nr, you're getting your NAD precursor through the NR pathway, which costs cells and tissues less ATP to make, and as we discussed earlier, is available in all cells and tissues.

Well, I can tell you this, too. I mean, you mentioned. I was already aware of that as one way that one could boost available nicotinamide. Yeast and beer are two others that I'm familiar with. And I'll be honest with you, dude, I don't really like milk, yeast, or beer. Those aren't staples in my diet.

The beer is an urban myth.

Oh, really?

Yeah. So someone misread one of my patents. So I have a patent with two of my former students, Balenki and Bogan, where we figured out a way that we could engineer a yeast strain that would. We could feed the yeast strain nicotinamide or nicotinic acid and have it spit out nr. So it's kind of a cute little thing. Chromadex licensed this patent. I don't think it's really been developed yet. NR is made in a chemical process rather than in a yeast fermentation. But we have a technology in which you could use an engineered yeast strain to make NR that does not. If you were to make, you know, a beer or wine with that engineered yeast strain, then it would have NR in it. But, sorry, Ben, you know, normal beer doesn't have NR in it. Yeast Extract does.

Right. Like, like the nutritional yeast you would get, that you would like sprinkle on a salad or something like that.

Yeah, that, that, like any other, you know, cellular stuff or formerly cellular stuff, has a high concentration of micronutrients.

Am I getting anything close to that? I think. What'd you say, about 500 milligrams?

Well, the way I think about it is that if you sit down and have a 4 to 6 ounce portion of salmon or red meat or something around the amount of NR or what I call niacin equivalents that you get in that meal, that's approachable by taking NR supplement. But of course you're not getting all the calories. So basically the common sense advice is to have a good diet, clean water, avoid smoking, have good physical mental activity, sleep, regular hours, and, you know, potentially boost your NR by taking a supplement.

Okay, got it. Now, this NR you've mentioned, Chromadex before, which is the company that you worked with to basically patent this form of NR that you found. But there's other forms of NR out there. I mean, and the one that, that I use is this true Niagen stuff, which uses the Chromadex form that you discovered. What about all the other forms of NR that you find out there? Because you can, I mean, you can find this stuff on Amazon.

So the patent is actually, you know, owned by Dartmouth College. That was my employer when we discovered NR and the NR pathway and it was licensed by Chromadex. And they did a lot of great work. Right, because when we started, nobody could even make substantial amounts of nr. So they developed a clean, scalable synthesis of NR and they did toxicology. And then the important thing about Chromadex is the exclusive license holder. And we did the toxicology and we did the human clinical, initial human clinical testing and submitted all of the data to the US Food and Drug Administration and got two notifications from the fda. One as a new dietary ingredient and the other as a generally regarded as safe. And so the only nicotinamide riboside that has gone through that level of review is either called Niagen as an ingredient in. You know, somebody can sell NR with Niagen as an ingredient or the direct to consumer product that's called Tru. Niagen. I won't, you know, name any names, but there is no other, you know, commercial entity that has a license to develop this technology and there is no other entity that has gotten notifications from the US Food and Drug Administration. So if somebody is buying NR from Another source. It doesn't really have a safety pedigree. And buyer beware.

Okay, so basically, you guys have researched Tru Niagen, and that's the one that you've used in these studies. That's the form you're using when you're testing it on these obese men, for example.

That's the stuff that is nicotinamide riboside chloride. And I. No one can vouch. The FDA cannot vouch for what is in something that is not called Niagen or true Niagen.

Okay, got it. So that's what you want to look for is N, I, a G, E, N if you're looking at the label of an NR supplement.

Right.

Okay, got it. All right, so elephant in the room, I mentioned I was using injections, NAD injections, and I've even done NAD push IVs. I've taken intranasal NAD via intranasal spray. And of course, I interviewed a guy for like an hour and a half about NAD injections and the profound improvements people are reporting on things like addiction. I'll link to that podcast, by the way, if you guys go to BenGreenToPfitness.com NR you can listen into it. What is your opinion on injecting NAD either in between supplementation of NR or just injecting it in general?

Well, I have seen the data. They're not really clinical data. They're more like observations of people that either were drug addicts or alcohol abusers or in other cases, kind of performance nuts like yourself that. That wanted to try injectable nad. And, you know, the personal accounts are very impressive. The thing is, NAD is a class of. It's an intracellular acting coenzyme. It has two phosphates on it, and compounds with phosphates don't get into cells. NAD is not a drug. And. And, you know, NAD has profound effects inside of cells, but it cannot get inside of cells because it has the two phosphates. And pretty much any biochemist or pharmacologist knows this. There's antiviral drugs of the same class of molecule. They're called nucleotides. There's antiviral drugs like azt, that is an. That's a nucleoside. And people take it as a nucleoside. It has to be converted into a nucleotide inside of cells. AZT phosphate doesn't work. Right. And so when people are taking injections of nad, it's almost certainly being degraded to nicotinamide riboside and to nr, which are then going into Cells. And we have a paper, and I presented it in San Diego at The so called NAD 2018 summit that was organized by a group that kind of runs a clinic, an NAD injection clinic. And I show data that we did a direct trial of NAD vs NR on a brain lesion in a mouse. So we induced excitotoxic brain injury. I'm sorry, to the mice, but this is a scientific process to figure out whether things work. And so we induced excitotoxic brain injury to these mice and directly compared infusion of NR versus infusion of NAD. And NAD protected, but it took 15 times as much NAD to protect against the lesion compared to the efficacy of the nr. Why? Because NR goes right into those neurons and NAD has to be degraded back to NR before it can be used by the intracellular nicotinamide riboside kinases. So injecting NAD doesn't really make a whole lot of sense to me. It may work, but I don't think it's necessary.

Have you ever injected or done an NAD iv?

No, but what I have done is I've suggested to this group a clinical trial design, crossover trial where they think that NAD is so efficacious for drug addiction that they think it's not ethical to do a placebo arm. And I said, okay, well, but you need that caliber of data if you want to change health care, if you want to change clinical practice and get people to be able to benefit from the profound effects of NAD that you say you're, your patients are observing. You have to do an accepted type of clinical trial in which you have to compare it to something. And so we suggested that, I suggested that they have an NAD injection arm and those people switch over to oral nr and then they have oral NR and those people switch over to injected nad. And you know, if high dose oral NR does what injected NAD does, then you know you're going to get that result. And if you really need the injected nad, you're going to get that result. And everybody will get the injected nad, either first or second, but they won't know which.

Well, I'll tell you what, I'll tell you this because I know we're, I know we're running up on time here. Pretty soon, I'm going to take what you said about these two phosphates causing NAD to not be able to, to get absorbed by the cell. I'm gonna ask a couple of these folks. One guy who actually sends me my nad IV's obviously biased, and the other guy runs the NAD Injection clinic. I'm gonna see what they say about this. And for those of you listening in, if they get back to me, I'll post their responses on the post.

Yeah, I mean, it's not a matter of opinion. Right, Right.

It's a matter of research. I get it.

So it's like it's five or six peer reviewed papers that show that the ability of both NAD and nmn. NMN has one phosphate, NAD has two phosphates. The ability of NAD or NMN to elevate cellular NAD depends upon loss of the phosphates outside of the cell and putting the phosphates and an adenine nucleoside on inside of the cell. And you know, it's. Everybody can have their opinion, but that doesn't mean that's, you know, the way it works. So I get it. So it's possible that, you know, we'll in the future be able to formulate, you know, forms of NR that are, you know, have different stability, better stability maybe, and get to different tissues even better than oral nr. But we know from our animal work that oral NR is active in peripheral nerves. We know that oral NR is active in the failing heart. And it's difficult to quantify circulating NR in the blood for technical reasons. But we know that oral NR is available to many, many tissues.

I get it, man. I respect your reply too. I love how you keep everything based in research. And by the way, I shouldn't necessarily discount or minimize the thing that you mentioned about neuronal cell death because some of this new published research showing NR to be an effective NAD precursor in slowing or stopping neuronal cell death is really interesting too, especially when you consider the neuronal cell death was associated with, with NAD depletion. So there's the whole cognitive aspect of it too. But there was a fantastic article because we got to wrap things up soon. There's a fantastic article while I was stalking you to prepare for today's show on, on the website seeking alpha or as a response to the claim that Niagen is just as expensive as vitamin or is just expensive vitamin B3. And actually that article went into a lot of like the politics and the research behind the scenes when it comes to nr. And I'll link to that in the show notes if people want to take a look. But it's, it's fascinating how much interest there is in NR right now. And I'd say if you listen to this whole podcast and you kind of wrapped your head around it, you understood it, you follow a few of the resources and the studies that we talked about that I'll link to over@BenGreenfieldFitness.com NR I'm hoping now you're, you're positioned to not only understand a little bit better, but I mean, like I mentioned, I'm taking four of these, these true Niagen capsules a day right now, which is the, the Niagen form, the nr, obviously, duh, as the name implies. And based on what Dr. Brenner just told me, I'm probably going to split that into like two morning and two evening. Ultimately, though, I'm impressed with it. I like it as a supplement. I know a lot of people think, oh, just another supplement or yet another supplement to take, but this is one you can't get from food unless you're just a total milk and beer junkie. And it is something that I am very impressed with, intrigued by. And I want to thank you, Dr. Brenner, for coming on the show and sharing all this stuff with us.

Well, you know, I'm really happy to be here. I'm really happy to do my best to explain NR to the general public. And I feel like your listeners are very wise consumers of health advice. The general take home is that we know that NAD is under attack and a lot of inevitable conditions of stress, some disease and aging. And that by boosting our NAD with nicotinamide riboside, you kind of generated kind of like an antivirus software for your operating system. So you may experience fewer disruptions in your life. Your work colleagues and friends and family may be suffering from more colds in the winter and have a hard, harder time functioning when they're just off of a jet plane or something like that. So people should definitely keep a journal and see how they feel. And they can also get in touch with me by contacting the folks at Tru Niagen or about NAD.com cool.

Got it. I'll link to all that stuff over@BenGreenfieldFitness.com NR I'll link to Tru Niagen only to these studies. And Dr. Brenner, thanks so much for coming on, man.

My pleasure. Thanks.

All right, folks, I'm Ben Greenfield with Dr. Charles Brenner signing out from BenGreenfieldFitness.com have an amazing week.

You've been listening to the Ben Greenfield Fitness podcast. Go to BenGreenfieldFitness.com for even more cutting edge fitness and performance advice.