#109 How To Boost NAD Levels To Fight Inflammation, Improve Recovery, and Slow Aging | Dr. Charles Brenner

0:00Today, my guest is Dr. Charles Brenner, who is a distinguished biochemist who made the groundbreaking discovery of nicotinamide riboside. This is a potent vitamin precursor to NAD. This is a molecule that is fundamental to cellular energy, DNA repair, gene regulation, and also immunity. Dr. Brenner is recognized globally as the leading expert on NAD biology, so it is a real treat to have him here today. This episode is an in-depth discussion on all things NAD. In this episode, Dr. Brenner and I discuss why nicotinamide riboside is uniquely

0:35positioned among NAD precursors for effectively boosting NAD levels. It has robust clinical evidence supporting anti-inflammatory benefits at doses between 500 to 1,000 milligrams a day. We discuss the significant role NAD plays in conditions driven by chronic inflammation, including obesity, insulin resistance, peripheral artery disease, and age-related cognitive decline. We also talk a little bit about the surprising implications of nicotinamide riboside and NAD

1:06for exercise recovery. We discuss how inflammation profoundly taxes the NAD system across a variety of different tissues. It's not merely just the blood, but also other organs as well, highlighting really the necessity of addressing all of these underlying lifestyle factors that affect inflammation. We also discuss practical guidance on supplement timing, particularly the rationale behind why taking nicotinamide riboside in the morning is important to align with the circadian biology.

1:37We discuss the emerging data indicating nicotinamide riboside's potential benefits for fertility, improved maternal lactation, and notably enhanced developmental outcomes in offspring. Everything from lean muscle mass to cognitive function. We also discuss the very critical evaluation of intravenous NAD therapies versus oral supplementation. We get through the myths, we talk about realities, we talk about evidence-based data, bioavailability, how these precursors and whether NAD can enter our cells, and we talk about clinical efficacy. We also discuss how

2:12our gut microbiome intricately influences NAD metabolism and can affect how we actually can benefit from supplementation. All this is to say, you're going to learn a lot about all things NAD and how to boost NAD levels in an evidence-based way in this episode. But before we dive in, I have a couple of quick announcements. First, as you might already know, the Found My Fitness podcast is 100% community supported by listeners like you. No ads, no supplements, no sponsorships. This really ensures

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4:20longevity and performance directly to your inbox. Go sign up today at foundmyfitness.com forward slash newsletter. Once again, foundmyfitness.com forward slash newsletter. And now on to the podcast on all things NAD with Dr. Charles Brenner. Welcome back to the podcast, everyone. I'm very excited to be here with Dr. Charles Brenner, who is a professor and chair in the Department of Diabetes

4:50and Cancer Metabolism at the City of Hope. But I think what Dr. Brenner is probably more well known for in not only in the scientific community, but in the broader health community in general, is his contribution to understanding NAD biology. He had discovered a precursor for NAD nicotinamide riboside, which has been made into a supplement. It's a NAD boosting supplement that a lot of you are familiar with. We're going to get into all that today. Dr. Brenner is very evidence-based. And so

5:24I'm very excited to have this conversation with you today on all things NAD. And we're going to talk about what that is and why it's important. So thank you for joining me on the show. I'm really happy to be here. Well, this is a perfect segue into what I am very, I think, excited to talk about with you, and that it really is, you know, NAD levels with age, right? So NAD levels do decline with age. Now, can you explain the leading theories why that happens in humans? So like, what do you think

5:56the strongest evidence is? Is it, you know, diseases, lifestyle that, you know, changes that happen as we get older? Why is it that, you know, can you just talk a little bit about what your thoughts on that? Well, I'm not super comfortable accepting every premise that you, you know, can pull from Instagram, right? And so... I didn't pull anything. Yeah, yeah, yeah. No, I know. But you're talking generally speaking. Right, generally speaking. So when people say NAD levels

6:31decline in age, I don't think that there's evidence that human blood NAD declines in age. I think that the likelihood that a number of human tissue NAD pools decline or are disturbed in age is incontrovertibly true. But I think that the idea that every human system's NAD declines in age is probably overstated. Because I've seen a lot of human blood NAD metabolomes. And essentially,

7:04there's three types of data that we get. We get normal people, male and female, who have 20 micromolar NAD plus calculated on a volumetric basis in their blood. You have people that supplement that are maybe twice that. And you have people with mitochondrial disease that are lower. So we discovered in collaboration with University of Helsinki a number of years ago,

7:40that people with mitochondrial disease, they were thought to primarily have muscle mitochondrial myopathy, right, are walking around with low blood NAD, right? Generally, we don't see people have low blood NAD. We don't see older people having low blood NAD. But when we've looked at alcoholics, we see disturbed NAD in their liver. When you have a population of people that have noise-induced

8:17hearing loss, I would bet a fair amount of money that their cochlear NAD is damaged. Okay. So we're talking about blood NAD versus tissue NAD. And I think the question I'm generally asking you is a more broader question, not blood NAD. I'm talking about, you know, as humans age, unfortunately, they become more sedentary. They become more overweight, more obese. They have things like diabetes and metabolic syndrome and all these disease states that do occur with age,

8:49right? So the question that I'm asking you is, you know, basically, like, is there evidence that some of these disease states, and I guess we'll get into this, do play a role in lowering NAD levels in the blood, in other organs? So the question- More broadly, yeah. But even in the blood, I'm curious, like, if someone, if you're saying I've got normal people and we looked at them, does that mean normal, like, they don't have any diseases? Or does it mean they don't have mitochondrial disease? Because, like, does someone who's obese have

9:21lower blood NAD levels than someone who is not? Well, you know, clinical trials always have our, you know, inclusion criterion, right? So the clinical trials that looked at people that were simply older and probably were not on, you know, 12 medications saw largely normal blood NAD. So it could be that if we look into people that have a lot of disease and conditions and have polypharmacy, we may see abnormally low blood NAD in aging people

9:57much more than I've seen. So that's a really good point. But I think that inflammatory processes are probably at work in many of the disease and conditions in which the NAD system is disturbed. In, in, in not just the blood, but in, but in every, in every. So, so one, one of the things that we found in 2020, um, you know, so remember, we all remember where we were in March 2020, right? So I was, uh, I was a

10:32department, um, head at University of Iowa and, you know, I got an email from either the, the dean of the College of Medicine or the president of the university saying, everybody needs to, to go home, tell the people in your department that, um, we're going to be teaching from home. We're going to be learning from home and we're not going to be going into the lab. The exception is if you're doing something related to coronaviruses, you can stay in the lab. So, um, turns out fourth floor of the BSB building

11:08where I was working was one flight above Stanley Pearlman's lab, who was probably one of the five most expert people on coronaviruses in the world. And, uh, he had been working on coronaviruses when no one cared about them and actually had given us samples of, um, coronavirus infected mice and, uh, we had done NAD metabolomics on it and we had kind of a shocking result. So we were actually

11:39able to stay in the lab and we published a paper in 2020 on the effect of coronavirus infection, not just on mouse liver, but on human lung samples that we're able to get from, from morgues, from morgues and from like databases where they had COVID infection. And just to, to, to come back to the PARP question, we found five different members of the PARP super family that were transcriptionally activated by, uh, coronavirus infection. Wow. Yeah. So they're, is that, were they consuming NAD?

12:16Yeah. You know what I think it is, is double-stranded RNA, right? Is seen as an invader by the innate immune system. So, um, just to bring everybody up to the same speed, um, your, your immune system has two parts. One is your innate immune system that can tell that double-stranded RNA is a problem because the human body just generally doesn't make double-stranded RNA, right? And the human body

12:47doesn't make endotoxin. So cells don't have to wait for antibodies to come along that are very specific for double-stranded RNA or endotoxin. They recognize double-stranded RNA and endotoxin as a foreign invader. And they do something immediate early to, um, to respond. And it turns out that one of the things that our cells are programmed to do is turn on five members of the PARP super family. So that infection, and turns out this is a common response, not just to COVID,

13:24but to a lot of things, is that we turn on these PARPs. So you think that, that may be something that happens with, you know, respiratory illness or... Yeah. Interesting. Um, that brings me back to this question, you know, and I do want to talk about, you know, some of the drivers of NAD loss. Maybe that's a better way to put it. Yeah. Um, you know, what we're talking, when you're talking about measuring NAD levels in the blood, like how much of that is really just reflective of your diet? Like, you know, like, let's say you're, you're getting a lot of, you know, B3 nicotinic acid, whatever, like you're getting a lot of tryptophan. Um, is there, is there somewhat of this like artifactual thing where NAD levels look

14:01normal or elevated because they're taking in the precursors and we're measuring it like blood? Yeah. Well, when people, you know, when people take substantive amounts of, um, NAD precursor vitamins into the 300 milligram plus, you can see a substantive change in people's, um, circulating NAD metabolome. Um, um, probably the foods that have the most NAD precursors are the same foods that

14:34have the most micronutrients of all kinds, right? People always talk about liver, spinach, right? Spinach source of iron and micronutrients, um, liver source of iron and micronutrients. That's because they're chock full of mitochondria, right? And chloroplasts in the case of, of plants that contain all of these coenzymes, right? And the coenzymes, you, you know, this, um, the coenzymes

15:05break down to their soluble precursor form. So NAD breaks down to NR, nicotinamide, nicotinic acid, goes back into cells. The cells rebuild the NAD stores. Coenzyme A breaks down to pantothenate. Pantothenate gets into cells. Cells make up their own pantothenate. So. So then, you know, and this, how much do you, you think measuring blood levels of NAD really is indicative of what's going on in the whole system? And, you know, perhaps there is more of an age

15:40related decline in NAD in other tissues that we're not able to see in the blood. I think that there, I think there are very substantive age related declines in NAD in tissues and disease and condition driven declines in NAD tissues. And people are not, you know, there's no reason for you to volunteer a piece of your brain or your liver to, to measure that. What about animal studies? Do you think that animal studies, we, we have a lot of data on that in, in animals. Yeah. And, and what have those shown? I mean, are we seeing declines in

16:14the muscle and the liver and the brain? Is that something you think translates to humans? I think it, it probably translates to humans. I think in the liver, it's related to inflammation and the microbiome. It kind of varies from university to university in terms of where their mice are kept and what kind of, you know, microbiome there is in, in those facilities. But for sure in a lot of disease and conditions, the NAD system really comes under attack. So in heart failure,

16:49the NAD system comes under attack. In central and peripheral neurodegeneration comes under attack. Sun exposure comes under attack. Okay. So let's talk about some of this. I mean, if we're talking about three really common conditions in humans, obesity, insulin resistance at the top, right? We have chronic inflammation, which is the driver of heart disease, of Alzheimer's disease, right? Chronic sleep deprivation. Like of those three conditions, how, you kind of described a little bit of the illness, but like how do those, you know, conditions put stress on

17:26the NAD system? So like obesity, the chronic inflammation, and then we talked about, you talked about acute inflammation, I'm talking about chronic. Okay. And then also sleep deprivation. Yeah. Well, I would say we actually have data from our lab for, I think, those, those three. So from 2016, one of our first mouse experiments was overfeeding mice. We gave them a high fat diet and we pushed them all the way into type two diabetes. Their liver NAD system was disturbed. NADPH was the center of that. So their ability to detoxify reactive oxygen species

18:04was degraded by being fat and being insulin resistant. Sleep deprivation. So are they consuming more NAD? Is that like the driver? Probably. I think that they're facing a kind of raw storm that is consuming NADPH, is churning NADPH. So it's not like they can't make the NAD. It's that they're just, they can't get enough of it because of all the. And there could be more than one mechanism. Right. Okay. Yeah. Yeah. And then

18:35sleep disturbance. We know. Sorry, before you go to sleep, can I go back to the obesity? Because you mentioned the animal data. What do we know from humans in terms of like, has there, has there been any research looking at obesity and or metabolic syndrome? I'm kind of gathering them in the same group here. Do we know any, is there any human data that has looked at how that taxes the NAD system? There is, to my knowledge. And to some, I mean, fat is an accessible tissue. People remove fat,

19:13you know, from people that have more than they want. And so it is something that could be determined in the adipose tissue. We'd be very interested in knowing what's happening in the liver. liver. And I think I know of a resource in Europe where they have liver from people that were undergoing bariatric surgery. So I think it'll be a good thing that we can look into in the future. Okay, great. So you were going to mention sleep disturbance and chronic inflammation and how

19:44both of these sort of very common human conditions sort of tax the NAD system. Right. So chronobiology first. So sleep, I'm not sure a study has been done exactly on sleep, but for sure in mice, we've looked at, you know, young mice that have really good chronosynchrony and older mice that are kind of losing their synchrony and the NAD system becomes disturbed. There's a lot of time of day cues that go into NAD synthesis and NAD dependent metabolic

20:21processes. So I think that lack of sleep or time zone disruption is essentially assured to disturb the NAD system. Well, I'm going to circle back and go a little more in depth in that because I have some more questions on that. And then what about the chronic inflammation? I mean, and this is, to me, it makes sense knowing what I know about NAD biology. And here's where I can really claim some benefit in human, which is amazingly satisfying. That we've,

20:54not only have we shown that inflammatory stimuli like coronaviruses disturb the NAD system, but we've been able to show that in human beings and randomized control trials that nicotinamide riboside at like a gram a day type doses is anti-inflammatory. So that's now a proven fact. And it was initially, you know, a result that came out of trials where it was kind of like a top line

21:32failure in the sense that the first trial that reported that NR is anti-inflammatory set out to determine whether NR could improve old men's grip strength in like two or three weeks. Well, it's kind of a dumb trial, Rhonda. Okay. Because if you want to get stronger, you have to exercise, right? Not take a pill. So, so the, the premise of the trial was kind of unreasonable. It was the

22:05magical thing. There's no exercise involved in the trial. No, there's no exercise. There needs to be exercise plus the NAD. Yeah, you do exercise as standard of care and then you can see whether NR. Exactly. Yeah. And we even have a, you know, like a review article saying exercise should be the standard of care. And then you look for beneficial effects of NR and other things beyond that. But, um, what they did is they took older men and they did muscle biopsies and it was placebo controlled crossover design actually. So some had the NR first and then they got placebo.

22:39So I met placebo first and then they, they got NR and, um, nobody's grip strength got better. And then they went to the secondary outcomes and they found it was, NR was strongly anti-inflammatory, like greatly lowering IL-6, IL-10 and other markers of inflammation. In fact, it was so strong that the people that had the NR first followed by placebo still had lower anti-inflammatory results

23:15after three weeks on placebo. Yeah. But the effect was strongest right after NR, right? So then you worry a little bit, right? Because, and I had to learn about clinical research because I'm a bench guy, right? That started out with enzymes and now has mice and so forth and so on. And the thing that clinical researchers will tell you is that your pre-specified endpoint is the most valuable thing, right? Because, because their, their criticism of this anti-inflammatory result could be that,

23:52well, you set out to test whether NR would improve grip strength and then you measured anti-inflammation. But for every 20 things that you measure, you might find one thing that achieves this statistical significance at P.05. So if you measure a hundred things, you might find five positive results. It's maybe not that interesting, right? So you have to worry when you get a result as a, as a non-primary endpoint. But by this time, there are eight trials showing anti-inflammatory activity

24:26in, in human RCTs, including RCTs, one that I just read the other day in which that was the primary endpoint. The patient population all had COPD. So they're all very inflammatory. They're looking at inflammatory markers and sputum. So it's really disease relevant for this, you know, people with a respiratory condition. NR lowers those inflammatory markers, placebo doesn't. So we know it's for a fact. So, so what I think it's doing is it's rebuilding NAD in a system in which the NAD

25:02systems come under attack, rebuilding those supplies so that the free radical species can be detoxified and the anabolic processes and the repair processes can, can work better. Well, I think you kind of answered, you know, my question. I was kind of going to ask you, you know, with respect to these, these chronic conditions that are very common in the U.S. and also just a lot of developed countries, you know, what, if someone could change only one aspect

25:33of their, their lifestyle within the next two to three months, like what would have the biggest bang for their buck in terms of supporting their NAD? And it really sounds like the thing that's causing the inflammation, the chronic inflammation might be a big driver. So if it's obesity, you know, weight loss, right? If it's the, if it's the, the, you know, the sleep. So whether or not you're talking about, and like I said, we're going to dive into this, but like if you're, if your circadian rhythm's disrupted, I mean, trying to fix, fix that, or obviously supplementation, we're going to get

26:05into that as well. And for people wondering what NR is, again, nicotin, my riboside, we're going to get into all that very, very soon. Whether or not it's stress, stress causes inflammation, right? It could be drinking though. I mean, it could be drinking, it could be drug use. Right. A lot of things cause inflammation. Yeah. Yeah. And, and the thing is, the thing that's important, and I think that that's, that's good about, about your show is that, you know, there aren't one size fits all recommendations for people, right? So, you know, I don't understand why someone would tell large podcast audiences

26:43that everybody should be fasting or doing time-restricted feeding, because then you're going to get the people that have the most OCD, right? That have the most problematic relationship with their food to worry about time of day eating and counting calories, and they may be perfectly lean, right? So I don't think that everybody needs to be fasting, right? But people with overweight actually now have medical options that work, right? And including oral, you know, GLP-1 medications that

27:22in conjunction with resistance training can really improve people's health. So for people that have overweight and obesity, that's probably, you know, number one. There's a lot of options now to lose weight. People that, people that are, are drinking, GLP-1 actually helps some of those people. But, you know, people that are drinking or are, you know, sitting, you know, in front of a screen too many hours a day and are not moving their bodies, probably moving their bodies more is going

27:57to be, you know, important. Right, right. I want to get back to this, this idea of why, you know, the blood NAD isn't necessarily indicative of what's going on in your muscle and your brain. And specifically, I want to get into the, you know, let's say you're taking an NAD precursor supplement like a nicotinamide riboside. And you do see that, as you mentioned, that you'll see the NAD levels go up, like very high in the blood. What does that tell us about levels in the brain? Can we assume, I mean, I don't know that we

28:35can, or can we assume that the levels are going to go up in the brain or in the muscle? Yeah, there are, there are imaging experiments that show that oral NAD precursors increase brain NAD. There are small clinical studies that show that oral nicotinamide riboside improves cerebral blood flow in people with mild cognitive impairment. So, you know, that's a functional measurement. So, I feel pretty good about that.

29:06Does it improve cognition or was it not looked at? People have tried, you know, to see, so there's a long COVID study in which all of the people that are enrolled have long COVID. So, they have complaints about their executive function, depression, their sleep quality, their mood. And there was a recent study, I think in the last month or two, it's Wu et al. And I think it's Lancet eMet Clinical Medicine or something like that.

29:43I'm a co-author on the paper that shows that there's within group improvements. So again, this is not quite the gold standard of placebo-controlled NR group is superior to the placebo group at the end of the study. But it's within group meaning when people compared their baseline level of executive function to their executive function when they were on NR, there's an improvement that

30:16was not seen in the placebo group. Did anyone look at whether or not that improvement correlated with inflammatory status? So, baseline inflammatory status being higher and that being reduced? No, but that's a beautiful hypothesis that Dr. Guzman should look at. So, if you're listening to this, Dr. Guzman, make sure each of you look at the inflammatory status. And then, you know, because I would think, you know, there's lots of evidence now that you can even, there's even, you know, human trials where people are injected with lipopolysaccharide, which induces inflammation or a saline control, and you can affect mood.

30:52You can depress the mood. You can depress cognitive function because inflammation affects brain function. So, I mean, I feel like it's a pretty, I would say, I would feel comfortable speculating that if you have, yeah, if you have someone with a, you know, high inflammatory status, baseline, for whatever reason, alcoholism, obesity, chronic sleep deprivation, whatever it is, there's many, many things that can get you there, right? That if you can, you know, either reduce that inflammation, obviously through lifestyle and diet, that would be ideal. And, or if you take the

31:26nicotinamide riboside, you know, to help replenish some of that NAD to help with the inflammation, that you would affect, you know, some of the functional outputs as well. So, how would, you know, and that kind of gets to this thing, you know, and a lot of people are taking, there's a lot of people that are taking NAD boosting supplements. And what do you think for them? Like, should they go get their NAD blood levels measured? Is there any sort of, you know, functional tests that they can do to really know if it's working? Or is it just kind of like a,

31:57like, like the fitness improvements, right? Let's say they are working out and they take the NAD, like, should they be measuring their grip strength or their, you know, via two months? Okay. So, let me, let me cover my COI right here, right? Yes, let's do that. This is perfect. So, so, so, so it was initially my technology that turned into the nicotinamide riboside and NAD boosting industry. So, I'm chief scientific advisor of Niagen, which makes this Niagen pill, right? I'm also chief scientific advisor of NADMed, which is an NAD testing company. Do I think

32:31there's a use case for Niagen in people in healthy aging? Yes. On the basis of eight randomized clinical trials showing anti-inflammatory benefits in people, positive trial and peripheral artery disease, and some of these suggestively positive trials like long COVID, which, which we talked about. Do I think that there is a value of NAD testing in people? Definitely in clinical trials, right? So, this company, NADMed, provides, you know, kits and reagents for clinical trial observations.

33:09People, some individual people buy the kits. Do I think that there's a use case for it? No, I don't. Okay. I'm kind of, I'm kind of with you on that. I feel like it's probably known that they're increasing it. So, they're, they're, if they're, if they're buying, you know, a nicotinamide riboside from Niagen, it's going to boost their NAD. It's like six to eight hours after ingestion, their NAD is higher. Like, do you, do you go to, if you take an aspirin, do you need to do a mass

33:43spec to see whether you ingest an aspirin? I don't, I don't see the use case for that.

33:49And there's probably some individual variability, right? Right. So, so, but again, in the context of a clinical trial, right, if we've enrolled 50 people and we're trying to figure out, you know, we had some responders and some non-responders, right, which is kind of getting into the questions that you're, you're asking, did it correlate with blah, blah, blah. So now you, in the context of a clinical trial, you want to, did it correlate with inflammatory markers? Did it correlate with the way their blood responded? Is there anything

34:20unusual about the way their blood responded? But I think that there's kind of a lot of over-worrying and over-testing and of the worried well. And I don't think that that's very helpful. I agree. You have to choose your battles. Otherwise you're going to drive yourself nuts. And like I said, we're going to get a little bit more into the NAD precursors. I kind of want to wrap up this lifestyle, diet lifestyle, you know, factors that are supporting NAD. We talked about that are consuming, but I want to talk a little bit about the supporting systems for NAD. And for me,

34:53exercise is always at the top of everything. So I'd love to start there. How, how does exercise affect NAD and what type of exercise would be better for increasing NAD? Would it be aerobic? Would it be, you know, strength training, resistance training, both? I can come up with rationales for why I think both would be either or. But you know that the exercise that you do is infinitely better than the exercise that you plan to do or wish you did. Yeah. Right? Totally. So anything's better than nothing.

35:24Yeah. And, and we do have some clinical evidence showing that exercise leads to an increase in the gene expression of NAD biosynthetic enzymes. So I recently published that with a group in Germany and I can't remember what kind of exercise that they did, but yeah, there's, there's evidence that people that exercise, you're boosting a lot of transcription pathways and gene expression pathways that are, you know, I hate the word rejuvenating, but it's, that are associated

36:00with youth and. I mean, mitochondrial biogenesis goes up when you exercise, that's a rejuvenating. I mean, you have to kind of, there are buzzwords that can, you, you kind of get, you know, they're overplayed, but, but when it's true, it's true, right? It's true, it's true. Does, does mitochondrial biogenesis play a role in some of the NAD increases as well? If you're making more mitochondria, is it like an adaptation where the body's like, we need more of this, you know, NAD around? Yeah. Yeah. Yeah. Yeah. So it's like this like response. Yeah. There's a key transcription factor that responds to the NAD system. And then, you know,

36:34you make more mitochondria, you have better beta oxidation. How does NAD play a role in exercise recovery? Like recovering from, and now, I mean, like that, that's part of the repair, right? Right. You would imagine it helps, but. So, yeah, the, the, the, um, the sports trainers and the heads of, you know, professional football clubs and, and college, um, athletic programs that buy, you know, Niagen by the tub swear by this. So

37:09there's not a lot of rigorous placebo control data on it, but there's training. Yeah. And, and, and, and, and, and Dr. Rudolph Tanzi, who's a professor at Harvard, um, you know, with Bill Belichick when he was the coach of the New Women Patriots and, and the coach of, of a 40-year-old

37:45Tom Brady. So it's well known that the Patriots, um, took Niagen for, for many years. I don't actually know whether they're still taking it post Belichick, but, um, it's in a lot of, um, training rooms for the reason of recovery. Have any of the exercise physiology scientists become interested in, in looking at this? Um, yeah, I think that it's something that really needs to be studied in, you know, laboratory exercise physiology science, because you can do those kinds of trials, right? Um, you can,

38:21you can work people really hard on a bicycle and, you know, see whether you can work them as hard the following day, right? Yeah. And all, and not just recovery, but in performance. I mean, you'd think if you're taxing the NADs that you're consuming more NAD, your muscles are working harder. And like you said, your adaptation is that you're increasing transcription. You're going to, you know, whatever these genes or enzymes are important for making more NAD are going to be increased. So you're going to make more NAD because your body, because your body knows I'm using more. I need

38:54to like respond to that. Um, it, it would be interesting to know if you supplemented with the precursor, if that also was beneficial, I would assume it would be, but it would be nice. Right. It sounds synergistic, right? Yeah, it would be exactly. It would be nice for someone to actually prove that. Um, we talked a little bit about circadian biology and being out of sync with your circadian rhythm. I want to kind of get to that, but before getting there, I think something that

39:24even more people are familiar with is like acute sleep loss. Like you have, let's say you have one night you're out socializing later than usual. You get to bed later. You have to wake up at the same time. You miss sleep. Right. How does that affect the NAD system? Is it now? I'm not sure that we have hard data on it because I don't, I mean, that there probably are accessible mouse experiments. I don't know how much you would value them because you can do things, um, you know,

39:58with mice where you, um, change the lighting around in the room or give them food and weird times per day. And you could potentially measure changes in the NAD system, but, um, it would be hard to enroll human trials like that. Yeah. I guess there's no, it's not, there's not a lot of empirical data on that. If I were to speculate on this and I'm sure you would agree, like at least in this, certainly with acute, you do get an increase in inflammatory cells, but I would say more so with chronic sleep

40:30deprivation. Let's say you have a new mom or, you know, like who's just getting constant fragmented sleep. Like we do know that inflammatory, you know, the inflammatory status is increased. Like people have more inflammatory biomarkers that are elevated with chronic sleep loss. Yeah. Well, I do want to tell you about a new mom though, because I can tell you about, um, new mother mice and, and rats. Um, we published this, I think in 2019. Um, so, um, we had this idea

41:02that if we had really, um, overweight female mice, that, um, they'd be conferring like a metabolic syndrome to their offspring, but it was our first time trying to get fat mice to be pregnant. Okay. And, um, um, so we had mice that were on control diets plus or minus nicotinamide riboside. And we had

41:33mice that were on high fat diets plus or minus nicotinamide riboside. And we simply didn't get enough fat mice to be pregnant and go to term with their baby mice in the fat group. But in the control group, something interesting happened, which is we had perfect fertility. We had mice that were whose, whose moms were either supplemented with an NR or not. And we were able to follow their offspring.

42:06And what we found is that the offspring of supplemented mothers had better lean mass, um, at the time of weaning that they were able to maintain for their whole lives. They had, um, faster, um, mechanical physical development. So their performance on like a balance beam type thing was better if the mom was supplemented. Um, they had lower fear and anxiety to the degree to which you

42:42can test such things in, in mice. Um, so they did better on a Morris water maze and they even had better adult hippocampal neurogenesis if the mom had been supplemented. This is very interesting. I mean, I think for me and my brain, two things are going on here. One, we're talking about fertility. I'm thinking mitochondrial health and thinking all this. Yeah. Yeah. And two, I'm thinking if these, if these pregnant mice were taking nicotinamide riboside throughout pregnancy, then I'm shifting to gene regulation. So did you guys look at any of the, well, so,

43:15so the, the weight at weaning of a mouse is really important because the more, um, you do calorie transfer from the mom from lactation, right. Then the more, um, you know, muscle and fat the baby has and the kind of the better life course it has. So it turns out that the NR supplemented new moms also had better weight management, right? And it was simply calorie transfer. They produced more milk.

43:50The NR supplemented moms produced more milk than the non-supplemented moms. And potentially it was higher in bioactives as well. We don't actually know, um, we don't have a full characterization of the milk from the supplemented moms versus the non-supplemented moms. So there may have been very specialized fatty acids or altered microbiome. There's a whole bunch of different things that it could be. Right. But it was also more bulk calories. So yeah. Um, histone deacetylase is

44:29epigenetics. I'm thinking, are we, is that like a possibility as well in terms? Um, yeah, there could be a lot of different things going on, but one of the things that we found is that a new mother's liver, not only is it distributing protein, fat, and carbohydrate to the mammary system for the mammary biosynthetic lactation biosynthetic program, it's also distributing NAD precursors. So the mammary NAD in NR supplemented mothers was greatly increased. And actually the liver

45:06NAD system declines in a non-supplemented mother. The blood NAD metabolome increases and it basically accumulates in the mammary in order to support the mammary biosynthetic program. I, we are going to talk about safety and stuff as we're, I'm jumping ahead of myself, but since we're on this topic, do you, I mean, with pregnancy, it's always like, it's always my, you know, rule that I like to sort of get off all the like dozens of supplements I'm taking and go

45:38down to the essentials, right? That we know is safe, important. Um, is there any reason to believe that taking nicotinamide riboside during pregnancy would not be safe? Or is that something that- There's, there's no data. Um, Aside from the animal study, no human data. There's no human data, right? Um, however, you know, as soon as, um, our group published this work, we got calls from UC Davis and, um, the whole group in Sacramento that works on human lactation and

46:11model system lactation. So, um, Dr. Gehrman and a number of other folks at, at UC Davis are some of the biggest experts in lactation in the world. And they started, um, planning some large animal trials as well as human trials. So one of their ideas was that preemie moms of preemies don't generally produce enough milk because you know, this very, very well is that you're the, the things that are happening

46:46in the new mom's body are kind of in sync with the baby development, right? And so if baby for some reason comes out really early, mom's mammary system is not generally ready to produce a lot of milk and you have a, a new, very small baby that has major nutritional needs. So I believe that they have planned a human lactation study with moms of preemies. And I think that there are some other

47:19studies that are being done or being planned at UC Davis. Well, at least with the, with the lactation. That's interesting. I always, I mean, it sounds like for, like fertility wise, it's always, you know, it might not be a bad idea to try the nicotinamide riboside. I do actually know some fertility doctors that do recommend truniogen by the way. Yeah. Yeah. So for fertility, we know that it's being done. Um, you know, this isn't, this is an area where, you know, it's a little bit like the sports trainers being out, um, ahead of randomized trials. Um, the animal results are so strong and

47:57that generally the safety data are so, you know, uh, comforting that, um, there are a lot of women that are, you know, presumably taking 500 milligrams or a gram of niogen, you know, per day during pregnancy or to get pregnant. Would that be the, the human equivalent dose from, from your animal study? Would it be something like 500? Yeah. Clinical doses are generally around a gram a day. A gram. So that would be like two true niogen. There's different, different regulations. Yeah. Okay.

48:32Okay. Um, fascinating. And I would like to kind of just circle back to the, the sleep because, um, you do have some, at least preclinical evidence on disrupted circadian rhythms. Yeah. There are many, many people in the United States who are shift workers. Yeah. We rely upon them. Thank you for all the work you do. We've got nurses, doctors, firemen, policemen. I mean, there's just, and there's a ton of other shift workers, right? They're doing a lot of really important work to

49:02help our society out at the cost of their own health. And, um, you mentioned that, that, that being out of sync with your circadian rhythm, so that could be shift work. It could be traveling to another time zone, right? Jet lag, as we call it for those individuals that are, you know, either under chronic, you know, circadian misalignment with their, their work, or if they're just experiencing it because they're traveling in a different time zone. Um, what do you think would be some good

49:35strategies to help them mitigate the effects on NAD system? I mean, would supplementation come in there or would it be, you know, bright light exposure? The things that we've heard of from, you know, the chronobiologists, like melatonin, getting bright light exposure, trying to time restricted eating, if you're a shift worker, trying to not eat all throughout the day, like things like that. Yeah. So, I mean, this is something that, you know, clinical and human experience is very valuable, right? So people that do it a lot, that have figured out a way to do it, will tell you

50:10that they set their what, if they're going to be taking an international trip, which I'm taking on Monday. Um, set your, um, calendar to where you're going to be. Think about trying to sleep when they're sleeping. Um, get bright sunlight at, you know, six or 7am their time. Um, if you, I think

50:40this is a potential use case for, for Niagen. So, um, you know, bright sunlight, um, and, you know, potentially nicotinamide riboside at that morning time. Um, so, and in particularly if you've been taking Niagen in, in the morning, um, you might have a weird day that is only 14 hours or 40 hours, depending on which direction you're going. And so you're going to have a weird day that you have

51:13to get through and then you, you try to reset with sunlight and activity. You just brought up a really interesting question in my brain and that is, and the next thing we're getting into is the NAD supplementation and all of that. But before we get there, um, you said you were talking about taking nicotinamide riboside perhaps in the morning. Does the timing of when you take it actually matter? So let's say you, you're, you know, you're okay. I have two questions.

51:44That's one, the timing, does the timing matter? Cause you did mention that, that you get this boost in your, in your circulation. I don't know how many hours after taking the supplement, but also let's say like, let's say you are, you know, a shift worker or you are changing time zones and your NAD system's disrupted. Lots of things are disrupted, but that's one of many things, you know, is that, is that really going to, is that going to affect your energy levels? Like the NAD being down, one way to presume it would, you would feel lower energy, like cognitively.

52:15And is that something that you think could be replenished through supplementation? I know I'm asking you to speculate, which is hard for you. I know. Like I try to be evidence-based here. Um, what I can tell you is that, um, NR is, doesn't feel like a stimulant, right? Um, most people take it in the morning. Um, there's not a, to me, it's logical to take it in the morning because, um, the way your body gets micronutrients

52:46and macronutrients is the same, right? Is that we, if, if, if you were eating, you know, a plate of, of, of liver, you'd be getting protein, fat, um, a little bit of carbohydrate and micronutrient in the same meal, right? And the micronutrients are going into your cells to rebuild coenzymes and the macronutrients are going into your, your liver and intestine and breaking down and depending upon coenzymes for their conversion to ATP. So to me, waking up in the morning and I'm

53:21on team breakfast, I'm not a time restricted guy. Um, you know, I take Niagin in the morning, I have coffee and I, and I, and I work. Um, so it could well be valuable for shift workers. Um, presumably if somebody has night shifts and let's say they start work at 11 PM,

53:51and they wake up at 9 30 PM, then they're presumably having breakfast at 10 AM. And I would think, or sorry, 10 PM. So I think that that person would probably have coffee and Niagin at that beginning of their work cycle. To me, that's their morning, the most logical way of doing it. Okay. Um, let's get into this. I mean, hopefully by now everyone's convinced they know what NAD is.

54:25They're convinced it's important at the very least for energy, right? If not more repair, regulating genes, um, I mean, a lot of things, right. But I think energy stands out to a lot of people. Uh, can you please tell people and explain to them the question I know that's in their minds, which is why can't I just supplement with NAD? Why do I have to take this precursor like nicotinamide riboside? So maybe you could talk about why that is, and also maybe just touch on nicotinamide

54:55riboside versus nicotinamide mononucleotide. That's another precursor. Yeah. Yeah. So basically the, the issue is phosphates. So, um, you know, compounds with phosphates don't get into cells. Um, so the biggest piece of NAD that can get into a cell is nicotinamide riboside. Um, it gets into cells, nicotinamide riboside kinase, then phosphorylates it, puts a phosphate group on it. Then there's another enzyme that comes along that adds what's called an AMP group to it. And then

55:31it's a dinucleotide that has two phosphates on it. Um, nicotinic acid does not have phosphates. Nicotinamide does not have phosphates. Both of them are considered NAD precursor vitamins. Um, problem with nicotinic acid is high doses of it cause flushing. So if you're trying to take it, enough nicotinic acid to boost NAD, you're probably going to feel kind of an uncomfortable, hot flash type, type experience. Um, that said, um, there's some cardiologists that recommend it for

56:09lipid regulation. And so it has a long, you know, human experience. Nicotinamide has been in the food supply for a long time, usually pretty low dose. It's in probably every multivitamin. Um, we know it's really safe. We know that it's cancer preventative, which is a very good thing about this class of molecules is that they were tested in Australia, you know, where there's a very high

56:39incidence of skin cancer, right? So high that you can do a prospective, um, preventative clinical trial to see whether nicotinamide supplementation lowers the risk of skin cancer. And it does, right? So nicotinamide is really safe. Do you think that has to do with DNA damage repair? Yeah. Yeah. Yeah. And, um, so, so nicotinamide riboside is probably the kind of premium, um,

57:11NAD precursor in the sense that the NR kinase pathway gets upregulated in a lot of conditions of metabolic stress. So in the failing heart in a, um, damaged neuron, nicotinamide riboside kinase one and two genes get upregulated. And so that's why NR, you know, works in a lot of mouse models in which nicotinamide doesn't work. Like in the heart failure experiments, nicotinamide can't actually

57:47boost the NAD in the failing heart because in the failing heart, it's overexpressing a gene called NMRK2, nicotinamide riboside kinase two. So the failing heart is sort of looking for the whole nucleus side in order to boost its NAD system. Um, so it's not that it's necessarily easier for nicotinamide riboside to get there. Oh, well you asked about NAD and NMN, right? Well, yeah. NAD. So NAD is not even getting in inside of cells essentially. You're taking it orally.

58:19There's a, there's a funny thing where people started, um, injecting, right? Yeah. Let's get to that. NAD, NAD IV drips. Yeah. So, so, and then, um, have you ever talked to anybody that has done that? Yes. Did they tell you how painful it is? No, they talked about how great they felt and how they had energy. Yeah. But it's a, it's delivered over a several hour period in which the people experience an innate immune response because the NAD can't get into cells and neither can NMN get into cells.

58:52So these compounds break down into NR or something smaller. Right. So NAD is breaking down into, probably breaks down into NMN first and then to NR and then NR can get into cells. Nicotinamide can get into cells. Nicotinic acid. So this is the mechanism for the NAD drips that we're talking about, right? Yeah. Yeah. Yeah. Right. There's actually now a Niagen Plus, which is like a, a drip grade nicotinamide riboside,

59:22which is not painful. But that you can do in a drip, that you can do that in a drip. Um, again, the clinical data behind oral Niagen is much more extensive than IV. That said, that said, there are some, you know, mouse experiments where intravenous NR goes further into different tissues than oral NR. Why is that? So the whole biodistribution, you know, thing is that's pharmacokinetics.

59:58You can get higher levels. You potentially can deliver more NR to the heart or to other tissues through IV. So I think that in the future, we're going to have more, you know, disease relevant data from IV delivery. So I'm happy that there is, you know, clinical grade intravenous NR, but there's much more data today in January of 2026 on oral NR. We know it's safe. We know it boosts NAD. IV is something that is kind of a,

1:00:37you know, developing product. And, um, but it's now available to the clinical research community as well. Okay. Well, just for people that are listening here, just summarize, because I know that you can actually go online and buy an NAD oral supplement. Um, that is not going to work, right? Well, it's going to break down. I mean, half of the molecular weight or 40 or some percent of the molecular weight of NAD is NR. So it's going to break down into, um, you know, so it'll be digested

1:01:15and deliver, presumably deliver some small fraction of the total molecular weight as an NAD booster. Okay. So it's not- But NAD itself, you know, I, technically, uh, NMN is, you can argue whether it's a precursor. It's sort of a precursor of NR, which is a precursor to cellular NAD. But again, NMN breaks down to NR and then that gets into cells and becomes NMN and NAD again.

1:01:46I thought NR got broken down to NMN. Well, no, NR gets, um, phosphorylated, gets converted up to NMN. Okay. NMN has a phosphate on it, but that, so it's a, it's a funny thing. Like why as a chemist would you put a phosphate on to NR to produce NMN when NMN has to be degraded down to NR in order to get into cells? But it's popular, right? It was popularized by a number of researchers and, um,

1:02:18um, the question with NMN is whether you can get, um, pure safety tested material. There are some reports that 17 out of 20 products labeled as NMN don't have NMN in it or don't meet, meet the label claims. Some people, so some people that are listening are familiar with both NR and NMN. Some people, this is the first time they're like hearing about all this, but they do know about NAD. Um, you know, when the, I, I know, I know a lot of people, the way they think about it is they think,

1:02:50well, NMN is one step closer to producing NAD. That's, that's a cell. Yes. In this cell. That's a general like idea that's, that's kind of in a lot of people's minds. So why wouldn't I just supplement with the closer part of this process? Yeah. It doesn't work that way though. Why doesn't it work that way? Well, it doesn't work because the NMN has a phosphate group that precludes its transport into the cell. So in the 1980s, there were people that were

1:03:21developing nucleosides and bases as anti-cancer and antiviral drugs. In fact, three of them got a Nobel prize. Gertrude DeLyon and Hitchens and someone else got a Nobel prize. They worked at, um, research park in North Carolina. And, um, what they, the idea is that if you make something that resembles a nucleoside, that it can go into cells and be converted into a toxic nucleotide,

1:04:00and it can do things like block viral replication, like you've heard of AZT, right? HIV drug. So AZT is a nucleoside, right? So it's the, you make a nucleoside, it gets taken up into cells and then inside the cell, AZT gets converted into a triphosphate, AZT triphosphate. And then that is an inhibitor of reverse transcriptase, right? So nicotinamide riboside is not toxic. Um, it's an

1:04:38NAD booster. So it's a direct precursor of NAD. The NR can get into cells. It can get decorated with the phosphates and converted into its final nucleotide form. NMN can't because NMN already has a phosphate. That phosphate has to be put on inside of cells. So if someone takes, if someone is able to find a safe, pure form of NMN, um, which you're, if you're at a drug company that is making and testing NMN, you could have access to that. Most of us wouldn't have access to that.

1:05:13But if you could find a safe, um, form of NMN and take it orally, that NMN is being converted back to NR before it gets into cells. Right. That was the long-winded way of answering the question, which is essentially that you actually, it's being converted back into NR. Yeah. So then why not just take the NR? Well, um, NR is the most, you know, safety tested NAD booster on, on the market. Well, this is good. At least people have an idea now. So I think, um, I want to get to

1:05:47some of these health outcomes. But before we do that, you mentioned something interesting when you were talking about some of these animal studies that kind of piqued my curiosity here, which was, you said gut microbiome. And you were talking about different strains of animals and how the gut microbiome seemed to possibly play a role in NAD levels in different tissues, perhaps. Um, how is that, do they, is the gut bacteria in our guts playing a role in the conversion of NR and NMN into? Brand new paper out of, um, Nestle in Switzerland says that, um, the gut microbiome plays a

1:06:29role in human conversion of NR and NMN into NAD in our tissues. I think that they got part of the story right. I don't think that they got all of it right because it's very difficult to see NR in human blood. Um, we know that, um, it sort of behaves like dark matter, you know, so dark matter is,

1:06:59stuff that, um, you can see like gravitational effects of matter in cases where you can't see the matter itself. So there's, um, once someone takes or a mouse takes nicotinamide riboside orally, you can see effects in the cardiac tissue. You're going to see effects in the muscle. You can't always see how it got there because when you draw blood, you're breaking half of 1% of the blood cells and you're releasing,

1:07:38you're extracellularizing to use a technical term, you're releasing enzymes that break down that NR artifactually. So there are things that are difficult to observe in clinical testing. Um, so it's hard to see the effect of NR getting into various tissues, but this group, um, at Nestle showed that the, um, microbiome is altered in a very useful, positive way by supplementing with NR. And they suggested

1:08:09that there's some conversion of NR into things like nicotinic acid that could be beneficial as well. For the gut bacteria. Interesting. So, so this was a human study. Yeah, that was a human study. Okay. I'll have to look at that. So talking now, getting into some of these, you know, conditions and, and supplementation, right? Now we're talking NAD, you know, precursors, mostly, and nicotinamide riboside, NR, is a major one that's used in animal studies, as you mentioned, in clinical studies as well. I think the, you've made a pretty strong statement with respect to

1:08:46the tried and true function of at least something that we can mostly expect if someone's going to supplement with the right dose being 500 milligrams to a thousand milligrams of nicotinamide riboside, lowering inflammation, particularly if you have a higher inflammatory status, presumably to like start with. Um, do you think there's any other, first of all, is there any data? And if there's not any data, I would love to hear your hypothesis and speculation on this, which is, um, I know the

1:09:21immune system is a major consumer of energy, right? I mean, it's a major consumer. If you're active, if you're, if you're, if you're, if you're sick, like that is a huge, you know, obviously sink for, for NAD. Yeah. Do you think that supplementing with NR could help, um, with any other immune related benefits, like fighting off infections, autoimmune disease, like you're having someone that's chronically having an activated immune system. You mentioned long COVID. I don't know how much of an autoimmune component there is to that, perhaps some, but I'd love to know your thoughts on, um, on that.

1:09:55So there are some human data showing that, um, NR could be active in conditions in which the inflammasome is activated. Um, there for sure there's randomized controlled trials and, and that space. Um, my idea after seeing the innate immune response to coronavirus infection of these PARPs getting transcribed is that it was going to inhibit infection. So I wanted to see a clinical trial

1:10:31with people that were still going into work during, um, COVID, you know, work restrictions, like, um, nurses and people that are roommates with delivery drivers and nurses to see whether in a placebo controlled trial NR was lowering infection, right? Those trials to my knowledge were not done when they could have been done. Um, there were trials including successful phase two, three trials

1:11:04that showed NR in a cocktail of three other over-the-counter supplements lowered, um, time to, um, recovery from, from COVID. So it, it does look like it has use cases in infectious diseases and, and inflammation. Which makes, I mean, it makes sense. I can logically understand why that would be if you're giving your cells the precursors they need to have energy to fight off, you know, pathogens, then you would

1:11:35imagine they would fight them better. Or it wouldn't take as long, you'd lower the, the severity and or duration of the illness. But the thing I'm, I'm even more excited about is peripheral artery, artery disease, because let's talk about that. 10 or 15 Americans probably have peripheral artery disease. Can you describe what that is? So a lot of times they're former smokers. Um, they have very limited ability to do exercise. Um, they get tired easily. Stuff is painful for them. Um, in extreme cases, they could, um,

1:12:11be told that something has to be amputated, right? So this is a serious, you know, condition, age-related condition. Wow. So is it like a, like a pain sensation, like that they feel like it's peripheral? They're fatigued. Um, they can't, um, walk fast. You do a clinical trial of these people, a six month clinical trial. And, you know, the end of the, uh, of a clinical trial at, at, at six months, they might walk, you know, eight meters fewer than they did at the beginning of the trial. So they're

1:12:45really in decline. And in, uh, McDermott, McDermott et al., and I believe that she's the top peripheral artery disease clinical trialist in the country. She's at Northwestern did a three-arm clinical trial, placebo versus nicotinamide riboside versus NR plus resveratrol, and found that the NR arm improved their six minute walk test. And the placebo arm, as well as the NR plus

1:13:20resveratrol arm degraded their six minute walk test. So the resveratrol not only was not helpful, but it actually blocked some of the benefit of supplementing with NR. So yeah, that resveratrol thing, as you, as you know, well, is just kind of science fiction. But, um, but the NR result was really quite striking. And I believe it was N of 40 or 75 people per arm. It was like not a super small trial. And on the basis of the positive results, McDermott is doing a much larger trial. So,

1:13:56this might be one of the first real medical indications for niogen in an age-related disease population. That said, um, if you want to consider inflammaging, you know, to be an underlying condition in a lot of people's aging, then you could say that eight randomized clinical trials showing beneficial effects of NR in lowering inflammation could be broadly useful for, for human aging.

1:14:30Yeah. Neurodegender of disease comes to my mind as well, right? I mean, this is something we know that neuroinflammation is now known to play a very early causal role in Alzheimer's disease. I mean, the brain, you know, having chronic inflammation in the brain is, is, is not good. No. So it would be interesting to know, you know, whether or not they're, first of all, if there's any biomarker, I mean, obviously inflammation would be something to look at, but you know, cognition improvements in people, it's always harder when you have someone that has Alzheimer's disease, you know? So the,

1:15:04the question is, you know, it, it always becomes, well, they're already so broken. It's hard to fix them. Like if you, and it goes with anything like omega-3 supplements, anything, right? Like, like, like it's always easier to help prevent, like, like you don't want all the inflammation to, to get to the point where you're like already in the disease state. Yeah. Yeah. So mild cognitive impairment might be the disease population, right? And so that's, I think I'm, I'm on at least one paper on mild cognitive impairment where nicotin or riboside is beginning to show some, you know,

1:15:37important signs like improving cerebral blood flow, you know, in this population, but you will like ultimately to have, you know, functional metrics of like keeping your stuff together. Yeah. Right. Yeah. I mean, improving blood flow. Most of the time, if you have an increase in blood flow, you're going to see a correlation with improved cognition, right? I mean, you're getting energy, you're getting glucose, you're getting all the goodies to your brain, right? Oxygen. Yeah. Yeah. So, I mean, one would think that would, that would also play a role. I'm also, I'm also interested in asking you about the liver because I mean, the liver is obviously the first

1:16:09one, like one of the first places that, you know, is going to see these, these NAD precursors like nicotinamide riboside. Do you, is there any evidence that taking nicotinamide riboside would have a positive benefit on some liver diseases? There is, there is in fact, there is in fact human data on this. Okay. Let's hear about it. Well, so again, it's one of these things that's a little bit frustrating for me because, um, the primary endpoint was an unreasonable endpoint in, in this

1:16:41trial. This is a story. This is, this is like the story of every clinical trial like ever. And look, the way I see it is like, this is how you often find things too. Well, you know, right. So some, the first trial can maybe teach you how to do the trial, but the problem is that NR is so remarkable in mice that, you know, I can induce obesity and type two diabetes in a, in a mouse in a couple of months and I can treat it in a couple of months. Right. But, um, you can't then go to, um, 60 or 70

1:17:18year old Danish men who are overweight and type two diabetic and insulin resistant and expect to see weight loss and insulin sensitization in 13 weeks without, uh, you know, because it's not, it's not itself a weight loss drug, right? It's a supplement. So if you had, you know, imposed caloric restriction, or if you had GLP one medication, then you could see the, uh, NR on top of that. Right. So there was

1:17:55a trial was done. I think it was dollar up at all 2018. And I'm a coauthor on, on the first paper in which the hypothesis to be tested was that NR was going to improve weight loss and insulin, insulin sensitivity in 13 weeks as a monotherapy in 70 year old, 70 year old Danish guy. Okay. And, um, so yeah, it's really a moonshot, right? Because they last played hockey, you know,

1:18:28four or five decades ago. Um, they smoke there, um, they don't have a lot of physical activity. And so in terms of the top line results, it failed, but then we went in and we looked at everything else. Right. And so we found that, um, it was about an N of 20, I think in placebo and, and R and there was quite a big effect on hepatic fat. Okay. Like a difference of, um, something like

1:19:0421% down to 11% fat, fat in the liver, like 10 absolute percent points. Was this a subgroup analysis? Like, did you know, was this, this was, No, that's, that's the NR group. Now the problem, and it, it, when you calculate a P value, it was P.13, which means it probably worked. Yeah. Right. P.13 is actually pretty darn close to P.75 when you do the way that the math works out. But the reason is... Don't get me started on,

1:19:37I feel like there's a lot of, yeah, there's a, there's a lot of arbitrary stuff going on there too, but anyway. Right. But, but the problem is they weren't randomized for their liver fat. And so there was a lot of variability in the liver fat, which is why even though, um, on an absolute basis, it was like tenfold better than placebo, it didn't reach, um, statistical significance on the liver fat. So I think if we randomized people that all had fatty liver disease, and then also

1:20:09we did some exercise, plus minus NR could be positive in fatty liver. Did you, did you guys look within that group, um, within the NR group, it all, just going back to this inflammation thing, because it seems like that's such a powerful lever that NR is affecting that like within the people that, you know, obviously there's a lot of them that have fatty liver, but like if they also had that high inflammatory status. Yeah. No one had done the inflammatory thing in 2018. It wasn't until around 2019 that Al-Hassan and, and at all in another, you know, top line failed trial showed, wow,

1:20:44the inflammation is, is much lower. So now, you know, we can design better trials. They should be randomized for liver fat, right? Right. Probably they should be on either GLP-1 or exercise or something to try to mobilize fat and then see the beneficial effect of NR and talk of that. Well, I mean, it's encouraging. It sounds like there's a, there's a nice signal there to continue to study. Um, I think to me it become, it's a little bit, for me it's, it's becoming clear,

1:21:16the pattern, which is, you know, there's, there is room for improvement, particularly in people that are unhealthy, whether that's because they don't exercise a lot or they're obese or, um, if you're making the lifestyle changes, that's the most important thing, right? If you can add this on in addition to that, like you said, like weight loss, giving, expecting someone to take nicotinamide riboside and lose weight in 13 weeks is, I mean, you have to do something in, you know, in addition to that, right? If that's, especially if that's helping with the energy and inflammation

1:21:49status and things. So, um, if there's a healthy individual out there, right? Someone who's not overweight or obese, someone that is physically active, um, it, and they do want to add a, what would you, what would you say is the best argument for adding? I think I already know your answer, but I'm going to ask you anyways, the best argument for adding a NAD precursor, like nicotinamide riboside to their routine and the best argument why they don't need to do that. Yeah. I think the best argument is probably, um, workout recovery, right? Because that it

1:22:22synergizes so well, you know, with exercise that an exercise makes everything else work better. Amazing. Okay. And I think it's worth, worth a try. Well, full disclosure here. I have been taking Triniogen for about, I mean, since August. And I do a lot of other things, but, um, my recovery is great. That's why, and I work out a lot. So great recovery. And then, um, I was going to say inflammation as well, but because even a healthy individual, there's always, you know, maybe a little bit of room for, for recovery,

1:22:54but I like that. I like that answer. I I'd love to talk a little bit about, you know, dosing a little deeper. I know we, we sort of touched on it a little bit. You talked about some of the clinical trials out there, typically using 500 milligrams to a thousand milligrams. A thousand. Right. Or a thousand. Is there an upper limit? I say this because there's a lot of people that like to go the extreme. And so it's really important to talk about, like, I think I've seen even a 2000 milligram study out there for nicotinamide riboside. So I'd love to

1:23:25know your thoughts, like in terms of, you know, obviously there, there's the evidence and we can talk, you know, you can mention, I don't know the 2000 milligram a day, what the end points were, but if, if there's someone like myself, you know, so I'm taking a thousand milligrams a day of true niagen nicotinamide riboside. Does that seem like a reasonable dose in your opinion? I know this. Well, so I'm not your doctor. No. Right. And I, based on the evidence. I take care of mice. Um, and, um, I think that, um, you know, for, for, for most people, you know, 500 milligrams to a thousand

1:24:04milligrams is a, is a substantive amount of, of NR to take the safety and the source of the NR is very important. Um, this material has been safety tested up to, um, three grams per day in certain populations. Um, I don't think that people should really, um, go beyond that. You know, I don't think, and, and also, you know, in certain, you know, diseases and conditions, we always say, ask

1:24:37your doctor. Um, your doctor may or may not have a background and, and be able to, um, address it, but if somebody has some weird condition, you know, they could potentially get a weird result, right? Yeah, for sure. And I do want to get into some more safety, um, precautions in, in, in a little bit. When it comes to taking nicotinamide riboside, these NAD precursors, you mentioned stacking it with resveratrol, which is a type of polyphenol that, um, it's sort of negated some of

1:25:13the benefits, at least in peripheral artery disease, right? Um, there are, you can find some of these NAD boosters with other combinations, terostilbene being one. I think the rationale behind that was that it increased the bioavailability or something like that. I remember reading, maybe you can, maybe you can correct me on that, but, um, it also perhaps could potentially raise LDL. I think terostilbene, at least to some degree, I don't know that that matters unless you're already someone that has high LDL cholesterol because it wasn't like a huge,

1:25:44huge amount, but I'd love to know your thoughts on, um, can they be mixed? Like, should they be mixed? There's, there's no use case for resveratrol or terostilbene in, in, in my view. Um, both of those compounds were thought to be SIRT1 activators. Um, I don't think that there's a evidence basis for saying that SIRT1 is a longevity gene. Um, terostilbene and resveratrol don't actually increase

1:26:15the activity of SIRT1 anyway. And, and as you said, terostilbene shows a dose dependent increase in LDL cholesterol, which is generally not a good thing for people. So for people that are interested in just boosting their NAD, this is not necessary. No, not necessary. Okay. Um, good. So the safety issues that I, I kind of wanted to touch on, um, have to do with a reason I stopped taking NAD precursors many years ago when I had started taking them. So for, let's start with the top safety questions. Like what do

1:26:49you think are the most safe, important safety questions right now when it comes to taking an NAD precursor? Well, sourcing is probably the biggest safety issue, right? Because if the material is the same material that has been clinically tested, then you have some, you know, basis for feeling that you can take it as a, as a human, right? Um, if it just has the same chemical name, like if it's, you read some study about NMN being done in a hospital in Boston or Tokyo or

1:27:28something like that, and then you go on Amazon and you buy NMN, you're probably not using the same material that was tested in that hospital, right? And there's really no telling what's in it. So I think that, um, the source is really, really important in terms of what people are taking. And just for people listening, I mean, this is not specific to NAD precursors. This is a systemic problem in nutraceuticals in the supplement industry. There have now been many, many published studies showing that quite a large, large range of a variety of supplements that you can pull off

1:28:05the shelf at any store that most people shop at or off the shelf of Amazon warehouse shelf, um, oftentimes don't contain much of the active ingredient. And even more concerning, often contain contaminants that could be harmful to ingest as well, particularly if you're ingesting large doses. And so my recommendation always is to get third-party tested, uh, supplement brands that have been third-party tested that you can look at the data, NSF certification, which also is very rigorous, and they're testing for potential contaminants as well, um, with any supplement because it's,

1:28:40it's really a big problem in the entire industry. So I think that is definitely a, a good thing to point out. Um, let me ask you specifically about a concern that I have had over the years, and this has to do with cancer risk. So obviously NAD is important for all of our cells. Our cells need to make energy. There's a variety of, you know, other processes that you described that are very important biosynthesis of molecules. These are also things that cells that are mutated and potentially are cancerous also like. They need energy. They need to build more cancer cells,

1:29:13right? Right. The tumor wants to grow. And so I'd love to know your thoughts on the role of taking an NAD precursor with respect to cancer risk. Obviously someone already has cancer currently or had previously had cancer in those contexts as well. Yeah. So, um, there's a hierarchy of evidence, right. In which, um, large randomized placebo control trials are the, the top of the, of the hierarchy.

1:29:46Right. And so we know from the Australian nicotinamide trials that supplementing with, you know, the classic NAD booster nicotinamide, um, lowers cancer risk at the population level. So it's not like if, if there was a signal that said that higher NAD status would, um, cause more, you know, small tumors to appear, you would have seen that in, you know, the clinical data. So that's,

1:30:22we can be grounded with that as kind of, um, you know, foundational information. It's clearly not causing cancer. Yeah. Not causing cancer. Right. Um, now, um, there are things that you can do with cell lines and in mice, um, where, um, you know, it looks like some tumors could potentially be limited by NAD supply. Um, NAD is not really a fuel. Like I said, it's more the wiring

1:30:55of, um, um, between the fuel and ATP production. So I think at the population level, it's not really, you know, a risk that said, um, we do say, you know, ask your doctor. And if you have a disease or condition, you know, if there's some type of cancer chemotherapy, a person is undergoing, um, you know, it could be contraindicated potentially. And so I don't have the knowledge to, you know, to reassure every possible situation. Um, but overall the clinical data say that NAD

1:31:34boosting is preventative for cancer and that Niagin is safe. Did you see this study, the animal study that gave mice that had, I believe it was pancreatic cancer. They already had, they had pancreatic cancer and they gave them nicotinamide mononucleotide and it accelerated tumor growth. Is that ringing a bell? Um, no, but you know, there are, there are a lot of trials that you can do things that you can do in,

1:32:06in mice that are very prone to, to cancer or where you're injecting them with, you know, literally 10 to the sixth, you know, MCF seven cells or something like that, where they're all going to get tumors. And I just don't know how important those are for the human condition. That's not the way, you know, human cancers develop. We don't get injected with a million MCF seven cells. Good. So it sounds, I think that, that evidence with the nicotinamide that was given to people in

1:32:39Australia and it actually not only didn't increase cancer risk, it lowers the risk of melanoma. Yep. Yeah. Of, uh, I think it might've been non-melanoma skin cancer. Non-melanoma. Like the most common. Okay. Got it. Um, that's very reassuring, um, particularly for me because I had seen this, this Japanese, I don't know if it was Japanese study, it might've been out of Japan. Um, but it was definitely NMN given orally. No, no, actually it was given by, it might've been injected to mice with pancreatic cancer and it accelerated cancer growth, which isn't too surprising. I mean,

1:33:13if you already have a bunch of tumors and then you're giving, you know, a bunch of, whether it's folate or NAD or something, you might expect, um, rapid cancer growth, but who knows? So I think, I think that's kind of what shut me down for a little bit on, on taking the NAD precursor back to taking them. But, um, I guess it's always a concern if you already, if you actually have cancer, you probably, probably not going to want to take a bunch of supplements in general. Um, anyway. So, um, I do want to ask you, is that something that you kind of agree on? Is that what

1:33:46you're kind of getting at? Yeah. I think that, you know, for the, the general public, you know, we're, we're, we think NR is safe. Um, there's a registry at FDA. So as you know, the F in FDA stands for food and, um, nutritional supplements are in under the F in FDA. And so because Niagen went through the process of being a, uh, compound that is generally regarded as safe and as a new

1:34:17dietary ingredient, if there are any complaints or observations or clinical trial observations that are linked to NR, there's a file on them, you know, that we're aware of. And so far the safety data look really good. So if there were, I'm going to ask you this like final question. If a listener does come up to you and say, Dr. Brenner, I mean, do you think that it'd be worthwhile, worth my, my time to start supplementing with nicotinamide riboside? Um, in addition to the other healthy

1:34:53lifestyle factors and diet and lifestyle factors that I'm adopting to improve my health, like what would be the most honest answer you would tell them? Yeah, I think that there's, there's use cases for people. And I don't, I don't think that it's strictly age related, right? Because, you know, 20 year old football players that are in a, you know, collision sport on Sunday and have to be back on practice field on Tuesday, have a, have a benefit from, from Niagen supplementation. Um, people that are

1:35:25busy and people are doing, you know, intense workout schedules, um, people that, um, go into crowded rooms where 5% of the people might have the flu or 2% of the people might have a COVID infection. There's probably a use case in not getting sick all the time. So I think it's, you know, I'm happy, I'm kind of proud that we developed something that is useful to, to people and is safe and that with

1:35:57future trials of peripheral artery disease and potentially the fatty liver trial that, that we talked about, um, fertility, you know, there could be really multiple use cases for this compound. Wonderful. Wonderful. Well, thank you so much, Dr. Brenner for joining me on this podcast. I know that you're very active on X. You want to tell people your, your... Yeah. So it's Charles M. Brenner. Um, people can ask me questions there. I do my best to, um, to respond and reply.

1:36:30Is there anywhere else you want to direct people to that they can... Yeah. My, my lab website is Brennerlab.net. And so you can see what we're up to in the laboratory. Amazing. All right. Well, thank you for, you know, this evidence-based discussion on NAD, boosting NAD. Um, I, it's, it's very, I think, informative and it's good to have this out there because it definitely is a popular topic right now. Great. Thank you so much. Thank you for joining me today in this fascinating conversation with Dr. Charles Brenner, exploring

1:37:02the science of NAD, aging and inflammation. For those who love to dive deeper, be sure to stay tuned for an exclusive bonus segment at the end of this episode. Dr. Brenner shares the fascinating biochemical journey behind his discovery of nicotinamide riboside, uncovering an NAD pathway that was previously unknown to science. And lastly, as a reminder, if you value these deep dives into science and appreciate content that remains free of sponsorship bias, consider supporting the podcast by becoming a Found My Fitness premium member. Your support

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1:38:44foundmyfitness.com forward slash N-E-W-S-L-E-T-T-E-R. Thanks so much for listening, and please stay tuned for this special bonus segment with Dr. Charles Brenner. You've obviously studied NAD for decades. So can you tell me, you know, what were some of the early observations in your career that convinced you, this is an important molecule? This isn't just some biochemistry, you know, metabolite. Like, this is like, this is something to pay attention to. Well, I can't get behind downgrading the interest of biochemical metabolites because

1:39:18I'm that kind of nerd, right? So I really grew up as an enzymologist, and I did my postdoc and discovered a superfamily of nucleotide-binding proteins. So I was just really interested in enzymes and proteins that bind and interact with nucleotides. And sometime around 2003, I ran across an amino acid sequence that really, really interested me. And essentially, it was

1:39:52found in yeast, and it was found in human, and it clearly had a so-called NAD synthetase domain. This is not actually nicotinamide riboside or nicotinamide riboside kinase. This is an enzyme that converts a wacky metabolite called nicotinic acid adenine dinucleotide, N-A-A-D. I didn't stutter. It's N-A-A-D. It converts N-A-A-D into N-A-D. It has a piece on it that basically puts an

1:40:29amino group on nicotinic acid adenine dinucleotide to form NAD, right? And the interesting thing to me was that all of the eukaryotic ones, the ones in yeast and human and flies, et cetera, et cetera, had what I could see was a glutaminase domain, an enzyme that will take an amino acid glutamine and convert it to glutamate, liberating an ammonia group, a nitrogen group. So that seems pretty

1:41:04obscure. But in 1958, I'm a kind of master of knowing literature. 1958, somebody named Jack Priest of Priest and Handler fame had purified this enzyme NAD synthetase from yeast. And he showed that it required glutamine. And no one had ever explained why the yeast and the human NAD synthetases needed or could use glutamine to provide that ammonia group. So I thought, given the importance of NAD

1:41:41as the central catalyst of metabolism, I really need to work on this enzyme. And I loved that enzyme because it had two active sites. It had the glutaminase active site that interacts with this amino acid. And then it's liberating an ammonia group. And somehow it's shuttling the ammonia group from one active site to the other active site where it's going to form NAD+. And so I decided I was going to work on that enzyme. And in the course of working on that enzyme, I realized how many people were

1:42:16drawing diagrams of NAD synthesis. So folks at MIT, Harvard, Washington University, and a lot of places were drawing these cartoon diagrams of how NAD is made. So they had a pathway that came from tryptophan that went through this NAD synthetase enzyme that I was working on. They had a pathway through nicotinic acid niacin that was discovered in 1938. And they had a pathway from nicotinamide. And I realized

1:42:52that if I knocked out the gene that I was working on in yeast, according to prediction, there's no other way to make NAD. And I thought there might be another way to make NAD through a nucleoside, nicotinamide riboside. And I essentially set up the experiment to test whether there might be an NR pathway. So basically started working on an enzyme and ended up working on the whole pathway, because at the end of the pathway is the central catalyst of metabolism. And I knew that.

1:43:25Wow. Okay. Well, when most people hear the word NAD, they think of energy, or they'll think anti-aging buzzwords. So maybe you could explain to people in sort of, you know, more simple, understandable terms. Like, why is NAD so important to biology? Okay. So my wife just dropped me off in an electric vehicle, right? There's a big battery in it. And the battery has copper wires going to the front drivetrain and the rear drivetrain. This is a big

1:44:02Ford F-150 Lightning. They're not a sponsor of the podcast, as far as I know. But so two drivetrains, front and back. There's windshield wipers that run on electricity. There's air conditioning and heating that runs on electricity. So there's a lot of copper wires going to a lot of different places, right? And the battery is storing high energy electrons, and then copper wires are distributing

1:44:33those high energy electrons to all of the moving parts. The thing that your listeners need to know, or watchers need to know, is that high energy electrons run us as well. They run living things as well. And the wiring for the high energy electrons are basically NAD coenzymes. So NAD coenzymes, NAD+, captures high energy electrons from our food, protein, fat, and carbohydrate. And it collects

1:45:06those high energy electrons as a hydride group. That's a proton with two higher energy electrons, forming NAD+. Forming NAD+. You're being very patient because you learned this in first year of college, right? But NAD+, collects the high energy electrons from food. It's now NADH. And then it passes on those electrons along things like the electron transfer chain. And every time the high energy

1:45:42electrons get passed on to a lower energy carrier, right? Because things flow downhill, water flows downhill, right? You don't see waterfalls that go up. You only see waterfalls that go down. So when electrons get passed to carriers at a lower energy state, work can be done, right? So we can do things like we can pump protons across membranes and you can use the return of those protons to drive ATP synthesis,

1:46:13right? So when you say your typical listener thinks about NAD+, as energy, this is the way that that transaction works is that NAD+, is taking high energy electrons from food.

1:46:36So the amazing thing about biological fuel oxidation that's different than if we were to, we could take my breakfast, right? And we could light it with a match and its calorie content would be essentially what its calorie content is for me in my body. But the problem is that when we light it on fire to generate heat, the high energy electrons go up in smoke, right? The water vapor goes up in smoke,

1:47:11right? We don't have a way to direct that energy into our muscle function, our memory formation, and our heart beating and pumping and all the other things that we want to do, right? So the way living things work is they couple all of the energy transfers to reactions that need to be run. And we don't let the high energy electrons go up in smoke.

1:47:44Well, so for everyone that was following that, hopefully, definitely important for energy. I think that if you get anything out of this, that's... But do you want me to do a couple more? You can, or maybe you could talk a little bit about, you know, what, like, let's talk about maybe like the two most important roles of NAD in the body. What would you say? Well, first, I'd like to expand. I just called out two NAD coenzymes, NAD+, and NADH, right? So let's call out the other two, which are NADP+, and NADPH, which are really, really important for

1:48:23anabolism, anabolism, right? Making stuff, right? So we like to say that metabolism is the set of processes by which we convert everything that we eat into everything that we are and everything that we do and the maintenance of all of the things that we are and do, right? So one of the really amazing things that NAD coenzymes can do is they can take the high energy electrons on NAD, which is

1:49:00NADH, and get those high energy electrons put onto NADP, forming NADPH. And then NADPH, NADPH can distribute those high energy or direct those high energy electrons to do things like form carbon-carbon bonds, convert ribonucleotides into deoxyribonucleotides, right? So then, because we have to make all of our own RNA and we have to make all our own DNA, we have to make all of

1:49:32our own lipids, we have to make all of our own proteins, right? We have to make everything in all of our cells and we have to repair all of those processes, right? So in the biggest buckets that I can describe to not get into the specificity initially, the biggest buckets are converting fuel into ATP, right? Building stuff and repairing stuff. Those are the three biggest buckets

1:50:04in which NAD coenzymes are critical. I think that's a pretty good explanation and hopefully that makes sense to people. I think, you know, we're about to get into the NAD biology and you've described it as this rechargeable molecule. Um, I think, I think that a lot of people have heard of energy production, mitochondrial energy production, DNA repair, gene regulation. So you talked a little bit about this mitochondrial energy