How To Boost NAD Levels To Fight Inflammation, Improve Recovery, and Slow Aging

When most people hear the word NAD, they'll think anti-aging buzzword. So the question is why is NAD so important to biology? >> So converting fuel, building stuff, and repairing [music] stuff. Those are the buckets in which NAD co-enzymes are critical. >> So NAD levels do decline with age. There's a lot of people that are taking NAD [music] boosting supplements. It was initially my technology that turned into the nicotenoid ribocide and NAD [music] boosting industry and we published a paper in 2020. We had kind of a shocking result. >> How does NAD play a role in exercise recovery? >> Sports trainers and athletic programs [music] swear by this. It's well known that the Patriots took Niagen for many years. Can you please tell people 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? >> The the thing that your listeners need to know is that >> Welcome back to the podcast everyone. I'm very excited to be here with Dr. Charles Brener who is a professor and chair in the department of diabetes and cancer metabolism at the city of hope. But I think what Dr. Brener is probably more well known for in not only in the scientific community but in the comm broader health community in general is his contribution to understanding NAD biology. He had discovered a precursor for NAD nicotenomide ribocide which has been made into a supplement. It's a a NAD boosting supplement that a lot of you are familiar with. We're going to get into all that today. Um Dr. Brener is very evidence-based and so I'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 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 the strongest evidence is? Is it, you know, diseases, lifestyle that, you know, changes that happen as we get older? >> Why why is it that it, 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 from Instagram, right? And so, so, um, >> I didn't pull anything. >> Yeah. Yeah. No, I know. >> But you're talking generally speaking, >> right? Generally speaking, so when people say NAD levels decline in age, I don't think that there's evidence that human blood NAD declines in 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 systems NAD declines in age is probably overstated because I've seen a lot of human blood NAD metaboloms and essentially there's three types of data that we get. We get normal people male and female who have 20 microar NAD plus calculated on a volutric basis in their blood. You have people that supplement that are maybe twice that and you have people with mitochondrial disease that are lower. >> Okay. So we like we discovered in in in collaboration with University of of Helsinki a number of years ago that people with mitochondrial disease that were thought to primarily have muscle mitochondrial myopathy right are walking around with low blood NAD. >> Okay. >> 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 um you have a population of people that have noise induced hearing loss, I would bet a fair amount of money that their cocklear NAD is damaged. Okay. So, we're talking about blood NAD versus tissue NAD. Um, 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 they have things like diabetes and metabolic syndrome and all these disease states that do occur with age. Right. Right. So the question that I'm I'm asking you is you know basically like do is there evidence that some of these 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, so the question >> broad more broadly. Yeah. >> But even in the blood, I'm curious like if someone if 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 lower blood NAD levels than someone who does not? >> You know, clinical trials always have a, you know, inclusion criterion, right? So, um, 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. Um so it could be that if we look into people that have a lot of diseasing conditions and have polyfarm pharmacy we may see um abnormally low blood NAD in in aging people much more than than I than I than I've seen. So that's a really um good point. Um but um I think that um inflammatory processes are probably at work in many of the diseasing conditions in which the NAD system is disturbed >> in in in not just the blood but in >> but in every organ. So, so one of one of the things that that we found in 2020, um, you know, so remember we all remember where we were in March 2020, right? So I was a I was a department 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 corona viruses, you can stay in the lab. So, um, turns out fourth floor of the BSB building where I was working was one flight above Stanley Pearl Pearlman's lab who was probably one of the five most expert people on corona viruses in the world and uh he had been working on corona viruses when no one cared about them and actually had given us samples of um corona virus infected mice and uh we had done NAD metabolomics on it and we had kind of a shocking result. So we were actually able to stay in the lab and we published a paper in 2020 on the effect of corona virus infection not just on mouse liver but on human lung samples that we're able to get from from morgs from morgs 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 corona virus infection. >> Wow. Yeah. So they're that were they consuming the NAD? >> Yeah. You know what I think it is is doublestranded RNA, right, is seen as an invader by the innate immune system. So um just to bring everybody up to the the same speed um your your immune system has two parts. One is your innate immune system that can tell that doublestranded RNA is a problem because the human body just gen generally doesn't make doublestranded RNA right and the human body doesn't make endotoxin. So cells don't have to wait for antibodies to come along that are very specific for doublestranded RNA or endotoxin. They recognize doublest 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 but 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. 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 okay NAD levels look normal or elevated because they're taking in the precursors and we're measuring it like in blood >> well when people you know when people take substantive amounts of um NAD precursor vitamins into the 300 mgram plus you can see a substantive change in people's um circulating NAD metabolom um um probably the foods that have the most NAD precursors are the same foods that have the most micronutrients of all kinds. Right? People always talk about liver, spinach, right? Spinach source of iron and micronutrients. Um liver a source of iron and micronutrients. That's because they're chalk full of mitochondria, right? And chloroplast in the case of of plants that contain all of these co-enzymes, right? And the co-enzymes you you know this the co-enzymes break down to their soluble precursor form. So NAD breaks down to NR nicotenomide nicotenic acid goes back into cells. Cells rebuilds the NAD stores. Co-enzyme A breaks down to pantaththenate. Pantaththnate gets into cells. Cells make up their own pantaththenate. So, >> so then you know and this h how much do you do 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 related 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 conditiondriven 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. Right. >> What about animal studies? Do you think >> 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 the muscle and the liver and the brain? Is that something you think translates to humans? >> Um, 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, um, microbiome there is in in those facilities. But um for sure in a lot of disease and conditions the NAD system really comes under attack. So in heart failure the NAD system comes under attack in central and peripheral neurodeeneration comes under attack. Sun exposure it comes under attack. >> Okay. So let's talk about some of this. I mean, um, 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? >> Um, 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 the NAD system? So like obesity, >> the inflam chronic inflammation and then so we talked about you talked about acute inflammation. I'm talking about chronic >> and then also sleep deprivation. >> Yeah. Well, I would say um we actually have data from our lab for I think those those three. So um from 2016, one of our first mouse experiments was overfeeding mice. We gave them a highfat diet. We pushed them all the way into type 2 diabetes. their liver NAD system was disturbed and the pH was the center of that. So their ability to detoxify uh reactive oxygen species was degraded by being fat and being insulin uh resistant. Um sleep deprivation. >> So are they consuming more NAD? Is that like the driver? >> 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 um sleep disturbance. Um, we know, >> sorry, before you go to sleep, can I go back to the obesity because you mentioned the animal data? Yeah. >> What do we know from humans in terms of like has there has there been any research looking at obesity andor metabolic syndrome? I'm kind of glum gathering them in the same group here. Um, do we know any is there any human data that has looked at how that taxes the NAD system? >> There is to my knowledge. Um, and to some I mean fat is an accessible tissue um people remove fat you know from people that have more than they want and so it is something that could be determined in the atapost tissue. um we'd be very interested in knowing what's happening in the liver and I think I know of a resource in Europe where they have um liver from people that were undergoing beriatric surgery. So I think it'll be a good thing that we can look into in the future. >> Okay, great. So um you you were going to mention sleep disturbance and chronic inflammation and how both 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 um for sure in mice um we've looked at, you know, young mice that have really good um chrono synchrony 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 processes. So I think that lack of sleep or time zone disruption is um essentially assured to disturb the NAD system. >> Well, I'm going to circle back and go a little more in depth than that because I have some more questions on that. >> Um and then what about the chronic inflammation? I mean, and this is to me it makes sense knowing what I know about biology. And here's where I can really claim some benefit in human which is which is amazingly satisfying that um we've not only have we shown that inflammatory stimuli like corona viruses disturb the NAD system but we've been able to show that in human beings and randomized control trials that nicotenomide ribos side at like a gram a day type type doses is anti-inflammatory. So that's now a that's now a proven fact. And um it was initially um you know a result that came out of trials where it was kind of like a topline failure 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 2 or 3 weeks. Well, it's kind of a dumb trial, Rhonda. Okay. Because if you want to get stronger, you have to exercise. Yeah. >> Right. Not take a pill. >> So, so the the premise of the trial was kind of unreasonable. It was the magical thing. >> There's no exercise involved in the >> No, there's no exercise. >> There needs to be exercise plus the NA. >> Yeah. Yeah. You do exercise as standard of care and then you can see whether and Exactly. >> Yeah. And we even have a um 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 placeboc controlled crossover design actually. So some had the NR first and then they got placebo. Some had 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 IL6 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 after 3 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 well 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 100 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 in 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 in sputum. So it's really disease re relevant for this, you know, people with a respiratory condition. NR lowers those inflammatory markers. Placebo doesn't. So we know as for a fact. So, so what what I think it's doing is it's rebuilding NAD in a system in which the NAD systems come under attack, rebuilding those supplies so that uh 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. And I was kind of going to ask you, you know, with respect to these these chronic conditions that are very common in, you know, US and also just a lot of developed countries, you know, what if someone could change only one aspect of their their lifestyle within the next 2 to 3 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, um, might be a big driver. So if it's obesity, you know, weight loss, right? If it's the if it's the the >> [snorts] >> um you know, the sleep. So whether or not you're we're talking about, like I said, we're going to dive into this, but like if you're if your circadian rhythms disrupted, I mean, trying to fix fix that or obviously supplementation, we're going to get into that as well. And for people wondering what NR is, again, nicotine, my ribboside, we're going to get into all that very very soon. Um whether or not it's stress, stress causes inflammation, right? >> It could be drinking though. I mean, it could be drinking, could be drug use, >> right? A lot of things cause inflammation. >> Yeah. Yeah. Um, 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 oneizefits all recommendations for people, right? So, you know, I don't understand why someone would tell large podcast audiences that everybody should be fasting or doing timerestricted feeding because then you're going to get the people that have the most OCD, right? Um 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 um including oral, you know, GLP-1 medications that in 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, JLP1 actually helps some of those people. But um you know, people that are drinking or are, you know, sitting, you know, in front of of a screen too many hours a day and are not moving their bodies. probably moving their bodies more is is gonna be, you know, important. >> Right. Right. Um, I want to get back to this this idea of why, you know, the blood NAD isn't necessarily indicative of your what's going on your muscle and your brain. Um and and specifically I want to get into the you know let's say you're taking a an NAD precursor supplement like a nicotenomide ribocide >> 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 can 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 um experiments that show that oral NAD precursors in increase brain NAD. Um there are small clinical studies that show that oral nicotenomide riocide improves cerebral blood flow in people with mild cognitive impairment. So, you know, that's a functional um measurement. So, I feel pretty good about that. Does it improve cognition or was not not looked at? um people have tried you know to see so there is a longco study um in which um all of the people that are enrolled have long co so they have complaints about their executive function depression their sleep quality um their mood and um there was a recent study I think in the last month or two it's woo at all and I think it's Lancet e clinical medicine or something like that. I'm a co-author on the paper um that shows that there's within group improvements. So again, this is not quite the gold standard of placeboc controlled NR group is superior to the placebo group at the end of the study. But it's a um 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 was 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 >> No, but that's a beautiful hypothesis that um Dr. Guzman uh should should look at. If you're listening to this, Dr. Gooseman, make sure each of you look at the the inflammatory status. Um, 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 lipopolyaccharide, which induces inflammation or or a saline control, and you can affect mood, you can depress the mood, you can depress cognitive function because inflammation affects brain function. Mhm. >> So I mean I I feel like it's a pretty I would say I 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 nicotenomide riv side, 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 I'm, you know, I 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 test that they can do to really know if it's working or is it just kind of like a like 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 okay so let me let me cover my COI right here right >> yes let's do that yeah so um so it was initially my technology that turned into the nicotoni ribocide and NAD boosting industry so I'm chief scientific ific adviser of Niogen which makes this Niogen pill right I'm also chief scientific adviser of NadMed which is an ND testing company do I think there's a use case for Niogen 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 co which which we talked about um 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 um people some individual people buy the kit 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 they're they're um if they're if they're buying um you know nicotenocide um from niogen it's going to boost their NAD like 6 to 8 hours after ingestion their NAD is higher like do you do you go to when if you take an aspirin do you need to do a mass spec to see whether you ingested an aspirin I I don't I don't see the use case for that >> um And there's probably some individual variability right right there. >> 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 unusual about the way their blood responded? But I think that there's kind of a lot of overw worrying and over testing in of the worried well and I don't think that that's very helpful. >> Um, I agree. You have to choose your battles otherwise you're going to drive yourself nuts. Um, 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, exercise is always at the top of everything. So, I'd love to start there. >> Um, 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 rationale 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. >> Yeah. 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 um yeah there's there's evidence that people that um exercise you're boosting a lot of transcription pathways and gene expression p pathways that are you know I I hate the word rejuvenating but it's that are associated with youth and >> I mean mitochondrial biogenesis goes up when you exercise that's a rejuvenating I you you have to kind of there are buzzwords that can you you kind of get you know they're overplayed but >> but it when it's true it's true right >> it's true true >> um 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 so like this like key transcription factor that responds to the NAD system and then you know you 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? you would imagine it helps. But >> so yeah, 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, Niogen by the tub swear by this. So there's not a lot of rigorous placebo control data on it, but there's train Yeah. >> An anecdot. >> Yes. Um there's um you know, and there's there's like photos of um two advisors of NIA and myself and and Dr. Rudolph Tanzy who's a professor at Harvard um you know with Bill Bich when he was the coach of the New England Patriots and and the coach of of a 40-year-old Tom 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 postbell check 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? >> 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 you 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 al and not just recovery but in performance. I mean you'd think if you're taxing the NAD that you're consuming more NAD, your muscles are working harder and like you said your ad the adaptation is that you're increasing transcription. you're going to, you know, whatever these genes or enzymes important for making more NAD are going to be increased. So, you're going to make more NAD because your b because your body knows I'm using more. I need to 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 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 even 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 known? I'm not sure that we have hard data on it because I don't I mean the there probably are accessible mouse experiments. I don't know how much you would value them because you can do things um you know with mice where you um change the lighting around in the room or give them food in 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 real 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 SAS but I would say more so with chronic sleep deprivation. Let's say you have a new mom [snorts] 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 >> cuz 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 that 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 so we had mice that were on control diets plus or minus nicotenomide ribocide and we had mice that were on highfat diets plus or minus nicotenomide ribocide. 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 NR or not. And we were able to follow their offspring. And 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 uh 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 can test such things in in mice. Um so they did better on a Morris water maze and they even had better adult hippocample neurogenesis if the mom had been supplemented. >> This is very interesting. I mean I think for me in my brain two things are going on here. One, we're talking about fertility. I'm thinking mitochondrial health. I'm thinking all this. And two, I'm thinking if these if these pregnant mice were taking nicotine ribbocide throughout pregnancy, then I'm shifting to gene regulation. So, did you guys look at any of the >> So, so 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. >> The 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 it could be right. But it was also more bulk calories. So >> interesting. Yeah. um histone deacetylases epigenetics. I'm thinking are we is that like a possibility as well in terms of >> 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 mammorary system for the mammorary biosynthetic lactation yeah biosynthetic program >> it's also distributing NAD precursors so the mammory NAD >> in NR our supplemented mothers was greatly increased. >> Interesting. >> And actually the liver NAD system declines in a non-supplemented mother. The blood NAD metabolism increases and it basically accumulates in the memory in order to support the mammorary biosynthetic program. >> I we are going to talk about safety and stuff. We're I'm jumping ahead of myself but since we're on this topic. >> Yeah. Do you I mean with pregnancy it's always like it's always my you [snorts] know rule that I like to sort of get off all the like dozens of supplements I'm taking and go down to the essentials right that we know is safe important >> um is there any reason to believe that taking nicenide ribocide during pregnancy would not be safe or is that something that >> there's there's no data um and >> aside from the animal study human data >> there's no human data 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 model system lactation. So um Dr. Garman 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 preeie moms of preeis don't generally produce enough milk because you know this very very well is that you're the the things that are happening in the new mom's body are kind of in sync with baby development, right? And so if baby for some reason comes out really early, mom's mammorary 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 preeis and I think that there are some other studies 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 nicotenomide ribocide. I do actually know some fertility doctors that do recommend true niogen by the way. >> Yeah. for fertility. >> We know that it's being done. Um, you know, this is an 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 that 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 millig? >> The clinical doses are generally around a gram a day. >> A gram. So that would be like two true ngen. >> There's different >> different. Okay. But yeah. >> Okay. Um fascinating. And I would like to kind of just circle back to the the sleep because um you do have some at least pre-clinical evidence on disrupted circadian rhythms. Yeah. There are many many people in the United States who are shift workers. 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 and there's a ton of other shift workers, right? They're doing a lot of really important work to help our society out >> at the cost of their own health. >> And um >> you mentioned 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 strategies 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, right? >> Like melatonin, getting bright light exposure, trying to timerestricted 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 that they set their w 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 6 or 7 a.m. their time. Um if you I think this this is a potential use case for for niogen. So um you know bright sunlight um and you know potentially nicotenoid ribocide 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 to get through and then you you try to re 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 nicotenomide ribbide 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. That's one. the timing does the timing matter because 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 is 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 would presume it would you would feel lower energy like cognitively and 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. Um [laughter] >> like I I try to be evidence-based here. Um what I can tell you is that um NR is doesn't feel like a stimulant. No. >> Right. Yeah. >> 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 and 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? the micronutrients are going into your cells to rebuild co-enzymes and the macronutrients are going into your your liver and intestine and breaking down and depending upon co-enzymes for their conversion to ATP. So to me waking up in the morning and I'm on team breakfast. I'm not a timerestricted guy. Um you know I take niggen 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 11:00 p.m. and they wake up at 9:30 p.m. then they're presumably having breakfast at 1000 a.m. And I would >> 10 p.m. >> think or sorry 1000 p.m. So I think that that person would probably have coffee and naggen at that beginning of their work cycle. To me that's >> 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. They're convinced it's important at the very least for energy, right? If not more repair, regulating genes. Um I 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 nicotenomide ribocide? So maybe you could talk about >> why that is and also maybe just touch on nicotenomide ribocide versus nicotenomide monucleotide. 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 nicotenocide. Um it gets into cells nicoten ribocide kinase then phosphorolates it puts a phosphate group on it. Then there's another enzyme that comes along that adds what's called an AM group to it. And then it's a ducleotide that has two phosphates on it. Um, nicotinic acid does not have phosphates. Nicotenomide 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 enough nicotinic acid to boost NAD, you're probably going to feel kind of an uncomfortable hot flash type experience. Um, that said, um, there's some cardiologists that recommend it for lipid regulation and so it has a long, you know, human experience. Nicotinomide has been in the food supply for a long time, usually pretty low dose. It's in pro 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 incidence of skin cancer, right? so high that you can do a prospective um preventative clinical trial to see whether nicotinomide supplementation lowers the risk of skin cancer and it does. Right. So nicotenomide is really safe. >> Do you think that has to do with DNA damage repair? >> Yeah. Yeah. Yeah. And um so so nicotenoid ribocide is probably the kind of premium um NAD precursor in the sense that the NR kinace pathway gets upregulated in a lot of conditions of metabolic stress. So in the failing heart in a um damaged neuron nicotenomide ribocide kynise one and two genes get upregulated and so that's why NR you know works in a lot of mouse models in which nicotenomide doesn't work like in the heart failure experiments nicotenomide can't actually boost the NAD in the failing heart because in the failing heart it's overexpressing a gene called NMRK2 nicotenomide ribosite kynes 2. So the failing heart is sort of looking for the whole nucleus >> in order to boost its NAD system. >> Um so it's not that it's necessarily easier for nicotine 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. There'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 it? 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. Neither can NMN get into cells. So these compounds break down into NR or something smaller, right? So NAD is breaking down into probably breaks down into Nammen first and then to NR and then NR can get into cells nicotenomide can get into cells nicotinic acid. >> So this is the mechanism for the NI NAD drips that we're talking about. Right. >> Yeah. Yeah. Right. There's actually now a niogen plus which is like a uh drip grade nicotenoid ribocide which 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 niogen 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 pharmaccoinetics. >> You can get higher levels. 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 introvenous 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, you 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 to 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 and deliver presumably deliver some small fraction of the total molecular weight as an NAD booster. >> Okay. So it's not >> 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, >> I thought NR got broken down to NN. >> Well, no, NR gets um phosphorolated 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 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 well NMN is one step closer to producing NAD. That's >> in the cell. >> Yes, in the 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. Yeah. >> 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 developing nucleotides and bases as anti-cancer and antiviral drugs. In fact three of them got a Nobel Prize. Gertrude Dion 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 nucleotide that it can go into cells and be converted into a toxic nucleotide and it can do things like block viral replication. Like you've heard of ACT, >> right? HIV drug. So act is a nucleioide right. So it's the you make nucleioide it gets taken up into cells and then inside the cell act gets converted into a triphosphate act triphosphate and then that is an inhibitor reverse transcriptase. Right? So nicotenomide ribocide is not toxic. Um it's an NAD 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 but 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. So, >> well, this is good. At least people have an idea now. So, I think um I want to get to some 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 seem to possibly play a role in NAD levels in different tissues perhaps. >> Yeah. Um, how is that do they is the gut bacteria in our guts playing a role in the conversion of NR and amen into >> brand new paper out of um Nestle in Switzerland says that um the gut microbiome plays a role 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 stuff that um you can see like gravitational effects of of matter in cases where you can't see the matter itself. So there's um once someone takes or a mouse takes nicotenide riocide 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, you're extracellularizing, to use a technical term, you're releasing enzymes that break down the NR artifactually. So there are things that are difficult to observe in clinical testing. 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 that 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 nicotenomide ribocide NR is 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 the tried andrue function of at least something that we can mostly expect if someone's going to supplement with the right dose being 500 milligrams to 1,000 milligs of nicotine riide >> 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 immune system is a major consumer of energy right I mean it's a major consu if you're act 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 >> do you think that supplementing with NR are could help um with any other immune related benefits like fighting off infections, autoimmune disease like having someone that's chronically having an activated immune system. You mentioned long co 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 yeah on that. So there are some human data showing that um NR could be active in conditions in which the inflammosome is activated. Um there for sure there's randomized control trials in in that space. Um my idea after seeing the innate immune response to corona virus infection of these parts getting transcribed is that it was going to inhibit infection. So, I wanted to see a clinical trial with 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 and nurses to see whether in a placebo control 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 2 three trials that showed NR in a cocktail of three other over-the-counter supplements lowered um time to um recovery from from CO. 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 >> Yeah. >> you know, pathogens, then you would imagine they would fight them better. Yeah. >> Or it wouldn't take as 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 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 be 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? >> 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 of clinical trial at at at six months, they might walk, you know, 8 m fewer than they did at the beginning of the trial. So, they're really in decline. And in uh Mcdermach, McDermott at all, and I believe that she's the top peripheral artery disease clinical trialist in the country. She's at Northwestern did a threearm clinical trial placebo versus nicotenomide ribocide 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 resveratrol 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. So yeah that reserverrol 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 McDermad is doing a much larger trial. So um this might be one of the first real medical indications for niagen 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. >> Yeah, neurogenerative disease comes to my mind as well, right? Right. I mean this is something we know that neuroinflammation is now known to be 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 there first of all if there's any biomarker I mean obviously inflammation would be something to look at but yeah you know cognition improvements in people. It's always harder when you have someone that has Alzheimer's disease, right? You know, so the the question is, you know, it it always becomes, well, they're already so broken, it's hard to fix them. Like you if you and it goes with anything like omega-3 supplements, anything, right? 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, right? >> 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 nicotenoid ribocide is beginning to show some you know important 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. Right. I mean, you're getting energy, you're getting glucose, you're getting all the goodies to your brain, right? Oxygen. >> Yeah. So, I mean, one would think that would that would also play a role. I'm al I'm also interested in asking you about the liver >> because I mean, the liver is obviously the first >> one of like one of the first places that you know is going to see this these NAD precursors like nicotenomide ribocide. Um do you is there any evidence that taking nicotenomide ribocide would have a positive benefit on some liver diseases? >> There 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 trial. >> 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. 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 2 diabetes in a in a mouse in a couple of months and I can treat it in a couple months, right? But um you can't then go to um 60 or 70year-old Danish men who are overw weightight and type 2 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-1 medication then you could see the uh NR on top of that right so there was a trial was done I think it was dollar up at all 2018 and I'm a co-author 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 K. Okay. And um that's a moonshot. So So yeah, it's really a moonshot, right? Because they last played hockey, you know, four or five decades ago. Um they smoke, they're >> um they don't have a lot of physical activity. And so in terms of the topline 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 NR and there was quite a big effect on hypatic fat. >> Mhm. >> Okay. like a difference of um something like 21% down to 11% fat fat in the liver like 10 absolute percent points. >> Was this a subgroup analysis like did or 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.05 >> when you do the way that the the math works out. But the reason is >> don't get me started on I I feel like there's a lot Yeah. There's there's a lot of arbitrary stuff going on there too. Right. Anyway, 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 10fold better than placebo, it didn't reach um statistical significance on the liver fat. So I think if we randomize people that all had fatty liver disease and then also we did some exercise plus minus NR could be positive in >> did you did you guys look within that group um of 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 fat liver but like if they also had that high inflammatory status >> yeah no one had done the inflammatory everything in 2018. It wasn't until around 2019 >> that Alhassan and at all in another, you know, topline failure trial showed, wow, the inflammation is is much lower. So now, you know, we can design better trials. They should be randomized for liver fat, right? probably they should be on either GLP1 or exercise or something to try to mobilize fat and then see the beneficial effect of NR on top 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 the 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 give expecting someone to take nicotine ribicide 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 status 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 nicotine ribocide 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 synergizes so well, you know, with exercise that and exercise makes everything else work better. >> Amazing. Okay. >> And I think it's worth with a worth a try. Well, full disclosure here. I have been taking Triogen for about I mean since August and I too a lot of other things but um >> my recovery is great. >> That's why and I work out a lot. >> Great. >> 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 but 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 sort of touched on it a little bit. You talked about some of the clinical trials out there >> typically using 500 milligrams to 1,000 milligs. >> 1,000. Yeah. >> 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 2,000 milligram study out there for nictimide rigide. So I'd love to know 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 2,000 milligram a day what the end points were but if if there's someone like myself you know so I'm taking 1,000 milligrams a day of true ngen nicotine my ribbocide does that seem like a reasonable dose in your opinion I know this >> well so I'm not your doctor and I based on the evidence of mice Um, and um, I I think that um, you know, for for for most people, you know, 500 milligrams to 1,000 milligrams 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 3 g 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 your 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 a little bit. When it comes to taking nicotenomide ribocide, these NAD precursors, you mentioned stacking it with rveratrol, which is a type of polyphenol that um it sort of negated some of the bene benefits at least in peripheral artery disease, right? [snorts] >> Um there are you can find some of these NAD boosters with other combinations. Teroselbean being one. I think the rationale behind that was that it increased the bioavailability or something like that. 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 terrace still 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 huge amount. But I'd love to know your thoughts on um can they be mixed like should they be >> there's there's no use case for resveratrol or terrace still in in in my view um both of those compounds were thought to be cert one activators um I don't think that there's a evidence basis for saying that cert one is a longevity gene um terrace still and resveratrol don't actually increase the activity of certain one anyway and and as you said terrace 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 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 you 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 something like that and then you go on Amazon and you buy NN, 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 neutrauticals 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 the shelf at any store that most people shop at or off the shelf of Amazon warehouse shelf. Um oftent times 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 thirdparty 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 it's really a big problem in the entire industry. So I think that is definitely a a good thing to point out. >> Yeah. 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. Biosyn synthesis 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. Right? 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 context 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 of the hierarchy right and so we know from the Australian nicotenomide trials that supplementing with you know the classic NAD booster nicotenomide 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 we 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 of 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 boosting is preventative for cancer and that niggen is safe. >> Did you see the 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 nicotenomide monucleotide 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 in mice that are very prone to to cancer or where you're injecting them with, you know, a literally 10 to the 6th, you know, MCF7 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. And that's not the way you know human cancers develop. We don't get injected with a million MCF7 cells. >> Good. So it sound I think that that evidence with the nicotenomide that was given to pe to people in Australia. Yeah. >> And it actually not only didn't increase cancer risk, it lowered >> lowers the risk risk of of melanoma. >> Yep. Yeah. >> Of uh I think it might have been non-melanoma skin cancer like the most common. >> Okay. Got it. Um that's very reassuring um particularly for me because I had seen this this Japan I don't if it was Japanese said it might have been out of Japan um but it was definitely en given orally no actually it was given by it might have been injected >> to mice with pancreatic cancer and it accelerated cancer growth which isn't too surprising I mean if 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 I think that's kind of what shut me down for a little bit on on taking the NAD precursors. I'm 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 you're kind of getting at? What? Yeah, I think that, you know, for the the general public, you know, we're we're we think an R 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 Nigen went through the process of being a uh compound that is generally regarded as safe and as a new dietary 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 [clears throat] to ask you this like final question. If a listener does come up to you and say, "Dr. Brener, I mean, do you think that it'd be worthwhile, worth my my time to start supplementing with nicotenomide ribocide? Um, in addition to the other healthy lifestyle 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 the practice field on Tuesday have a have a benefit from from Niogen supplementation. um people that are busy 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 COVID infection. There's probably a use case in not getting sick all the time. So, I think it's, you know, I'm I'm happy, I'm kind of proud that we developed something that is useful to to people and is safe and that with future 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, thanks. >> Thank you so much, Dr. Brener, 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. Brener. Um people can ask me questions there. I do my best to um to respond and reply. >> Is there anywhere else you want to direct people to that they can >> Yeah, my my lab website is brenerlab.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 a popular topic right now. >> Great. Thank you so much. >> Thank you for joining me today in this fascinating conversation with Dr. Charles Brener exploring the 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. Brunner shares the fascinating biochemical journey behind his discovery of nicotenomide ribocide, uncovering an NAD pathway that was previously unknown to science. 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 I can't get behind um downgrading the interest of biochemical metabolites because I'm that kind of nerd, right? So, I really grew up as an enzyologist and I did my posttock and discovered a super family 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 um essentially it was um found in yeast and it was found in human. and it clearly had a so-called NAD synthetase domain. This is not actually nicotenomide ribocide or nicotenomide ribocide. This is an enzyme that converts a a wacky metabolite called nicotinic acid adine ducleotide NAD. I didn't stutter. It's N A um converts N A into NAD. It has an piece on it that basically puts an amino group on nicotinic acid adding ducleide to form NAD, right? And the the interesting thing to me was that all of the ukareotic ones, the ones in yeast and human and flies, etc., etc., had what was what I could see was a glutaminase domain, an enzyme that will take an am a vitam amino acid glutamine and convert it to glutamate liberating an ammonia group, a nitrogen group. So that seems pretty obscure, but in 1958, I'm a 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 NADases needed or could use glutamine to provide that ammonia group. So I thought given the importance of NAD as the central catalyst in metabolism, I really need to work on this enzyme. And I loved that enzyme um 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 drawing diagrams of NAD synthetists. So folks at MIT, Harvard, um, Washington University and 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 uh 1938 and they had a pathway from nicotinomide and uh I realized that 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 nucleioide nicotenoid ribocide and I essentially set up the experiment to test whether there might be an NR pathway. So basically started working on 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 view. >> Wow. >> Yeah. >> Okay. Well, when most people hear the word NAD, they think of energy or they'll think anti-aging buzzword. So maybe you could explain to people in sort of you know more simple understandable terms like why is NAD >> okay >> so important to biology. >> 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 um Ford F-150 Lightning. They're they're not a sponsor of the podcast as far as I know, but um so two 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 um the the battery is storing uh high energy electrons and then copper wires are distributing those high energy electrons to all of the moving parts. The 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 co-enzymes. So NAD co-enzymes NAD+ captures high energy electrons from our food protein, fat and carbohydrate and it collects those high energy electrons as a hydide group. That's a proton with two high energy electrons forming NADH. you're being very patient that because you you learned this in first year of college, right? Um but um 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 electrons 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. Right? So, so when you say your your typical um listener thinks about NAD+ as energy, this is the way that that that transaction works is that NAD+ is taking um high energy electrons from food. Um, it's not. So, the 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 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, right? We can't we don't have a way to um 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. >> Well, so for everyone that was uh following that hopefully definitely important for energy. I think that you get anything out of this. >> But but do you want me to do a couple more? Um you can or maybe you could talk a little bit about you know what like let's talk about maybe like the two mo most important roles of NAD in the body. Okay. What would you say? >> But well first can I'd like to expand I I I just called out two NAD co-enzymes. Okay. NAD+ and NADH. Right. So let's call out the other two which are NADP++ and NADPH which is which are really really important for anabolism 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 and do, right? >> So, one of the really amazing things that NAD co-enzymes can do is they can um take the high energy electrons on NAD, which is NADH, and get those high energy electrons put onto NADP forming NADPH. And then NADPH can distribute those high energy or direct those high energy electrons to do things like form carboncarbon bonds, convert riboucleotides into deoxy ribboucleotides, right? So then because we have to make all of our own RNA, we have to make all of our own DNA. We have to make all of our 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 in the biggest buckets that I can describe to to not get into the specificity initially, the biggest buckets are converting fuel into ATP, right? Um building stuff and repairing stuff. Those are the three biggest buckets in which NAD co-enzymes are critical. I think that's a pretty good explanation and hopefully um 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 production, >> right? How does NAD play a role in the repair process and also in the gene regulation process? These are like some other important aspects of NAD. >> Well, um, repair is a really big bucket, right? And so part of repair is reynthesis, right? So part of repair like if if if I were to cut myself then um or I I don't cut myself but if I were to but I constantly get into cuts and and and scrapes and um we all we all do and um so we have to make make more lipids. We have to make more nucleic acids and so that depends on NADPH. So that's an example where we take fuel oxidation and then we put the high energy electrons onto NADP forming NADPH and we can make more lipids. So you can make more cell membranes and you can make more nucleic acids and you can basically make more cells. Um but in addition because we live in an oxygen environment um there's always reactive oxygen species being made and the detoxification of react reactive oxygen species also depends on entity pH >> and what about so you know you're talking about oxidation oxidation's also formed as a byproduct of metabolism right as well >> and um you know a lot of these oxidation products can damage mitochondria, which have to be repaired, but they can also damage our DNA. Y and as people that have listened to this podcast before know, DNA damage can be a precursor to encogenic mutations that cause cancer, particularly if they're double stranded breaks, particularly if the double stranded breaks occur in parts of the genome that allow for an encogenic mutation to occur. >> So what about the role of NAD in repairing DNA damage? So I think about for example PARP. Yeah. So part one is incredibly important. It's a huge NAD consumer and this is the first time I word used the word consumer this morning. So in in in the N in the classic NAD co-enzyme function high energy electrons are being basically transferred onto NAD forming NADH. NADH can become can basically distribute those electrons again which reoxidizes it to NAD+. The same thing happens with NADP+ and NADPH. But when an enzyme, an NAD dependent enzyme called PARP one sees DNA damage, it basically gets excited if enzymes get excited and um it actually starts churning NAD and forming a polymer. It's kind of a weird ribboucleic acid polymer that consists of ADP ribos that is polymerized. It can form a polyadp ribos polymer um that is linked to protein. It can form a poly ADP ribos primer just in the nucleus. And that's a signal that assembles a bunch of DNA repair enzymes to localize at a particular point and get that DNA repaired. and and then there's a point at which DNA repair sort of can't be done and then some of these signaling processes can essentially induce cell death in order to eliminate the cell because in a big organism like like us with 37 trillion cells or however many we have um we can it's better for us to lose some cells than to try to repair everything, Right. So, you already described, you know, a a few very, very important, you know, biological processes in our bodies that I think people can kind of gravitate to. We're talking about energy production >> is essential for everything. >> Yeah. >> You're talking about repairing, you know, damage at the cellular level, being able to like make new cells, but also repairing damage to DNA and how these very important enzymes that do that consume NAD. we have other enzymes that are involved in regulating our genes, right? Making sure they're active or not active and you know, so that's another role of NAD. Do you want to touch on that for a minute and then I have another follow-up question? >> Yeah. Yeah. So, so in in this in this um area of NAD consuming enzymes, there's PARPs. PARP one was kind of the first one that was described, but there another 15 or 16 members of the PARP super family. Many of them don't polymerize ADP ribos, but they modify proteins with ADP ribos. So they they they cut NAD and they add an ADP ribos unit on something to do a signaling reaction. Um there's enzymes called certuins that use NAD. Um they very often remove a small modification on protein lysines. So acetil modifications on lysines, asil groups on lysines, suanil groups on lysines. That's usually something to do with enzyme regulation, gene regulation. As you said, classically, there's a lot of gene silencing that is done with with uh this this reaction. Um there's also things like ADP ribosyes. There's a there's enzymes that can take NAD and kick off the nicotenomide group and then cyize the ADP ribos. And usually what that is doing is releasing calcium from an intracellular store like the endopplasmic reticulum in order to do some kind of a signaling reaction. >> So the question is you know if all these really important functions are NAD is central to them. >> Yes. >> Right. What happens if there's a limiting amount of NAD? Like how does the body triage or does the body triage? Who gets the NAD pool? How do we know if we're able to make enough NAD? Like where where like what's the bottleneck here? So um you know the full systems analysis of it is not fully understood right and I'm not the type of person that is going to claim to know things that are that are not known. So what is generally understood which is easy to determine from gene expression patterns is that certain tissues like the liver can make NAD from tryptophan nicotenomide ribocide nicotenomide and nicotinic acid. So any precursor they can make NAD and they um there are processes in the aging liver that disturb that system. Alcoholism can disturb that system. Over nutrition can disturb that system. But it's actually a fairly robust system. And and that liver tends to be a very generous organ. it actually distributes things for other tissues. But um the more concerning thing is in cells like neurons right where if they don't have a pathway to make NAD from tryptophan and they generally don't have a pathway to make NAD from nicotinic acid then what happens in a neuron that has high bioenergetic requirements if it starts losing expression of one or the other pathways and you get a lot of, you know, cell and tissue dysfunction in those conditions. There's a lot of disease processes that disturb the NAD system. Well, this is