28: The Molecule That Could Slow Aging – NAD Breakthroughs with Dr. Joseph A. Baur

So this is part of a series on longevity and I have been fascinated with this topic lately of ways to influence my lifespan, my health span, to live longer, healthier, especially to be around to take care of my Rosie as long as I possibly can be. And I found so many of my patients are also curious about this topic. So I went deep guys and I found some of the top researchers in this space that you actually won't find interviewed anywhere else. And we pick their brain together. So this is the second of a series of three, maybe four if I can snag one more experts in this field. So be sure to tune into the other ones before and after this one. Today we have the absolute pleasure of interviewing Dr. Joseph Bauer. He is a professor in the Department of Physiology and the Institute for Diabetes, Obesity and Metabolism at the Perelman School of Medicine of the University of Pennsylvania. He has made key contributions to the understanding of how metabolism and dietary factors influence longevity. His laboratory at Penn is currently focused on the use of small molecules to understand and mimic the health promoting effects of of caloric restriction in rodents, with a particular focus on nicotinamide, adenine dinucleotide or what we all know as NAD metabolism. An emerging interest is in targeting anabolic pathways to offset muscle loss and maintain strength during calorie deficits. Dr. Bauer has co authored more than 100 peer reviewed publications as well as several books and numerous invited commentaries and reviews and served as a standing member and co chair of the NIH Study section on Cellular mechanisms of aging and development. I am so excited to have him here today and to share this conversation with you. Let's dig in. Welcome to Modern Thyroid and Wellness, the podcast that explores the intricate dance between health, wellness and thyroid, unraveling the threads that weave our vitality together. I'm your host, McCall McPherson and I'm so thrilled to guide you on this journey to optimal wellness. Well, Dr. Bauer, I am so happy that you are here and took the time to meet with me today. You are absolutely a leader in the space of NAD research. So welcome and thanks for coming.

Thank you. Happy to be here. Yeah.

So let's dig in a little bit before we talk about and go deep on the science. Tell me, in your opinion, why you think NAD is receiving so much attention lately.

I think the really attractive thing about it is it's something that people can dig in and do something practically about. Right now the supplements that people are talking about are over the counter and so there's, I think, a general resurgence in interest in aging as a field. But A lot of the things people hear about are things like eliminating senescent cells or putting Yamanaka factors in your cells to rejuvenate them and make them more like IBS stem cells or something like that. And these are things that probably for the best, people don't have a ready access to to do to themselves. So it's nice in a theoretical concept, you look forward to new therapies potentially being developed, but with NAD boosting, it's over the counter supplements. And so people are free to, to try it out themselves and see what they think.

I love it. And tell me too, how did you end up in this space of research? And was there a point in time where you thought, gosh, this could really be significant?

Yeah, I mean, so in terms of nad, I've always been interested in aging. I did some of my postdoc studies in David Sinclair's lab at Harvard working on sirtuin enzymes. And at that time, NAD was just this extra thing we had to squirt into the reactions to make them work. It's a necessary cofactor for sirtuin enzymes to have their activity. And I was really focused on the sirtuins and the NAD was in the background. When I started my own lab, I was starting to think a lot more about the idea that they really needed this CO factor and maybe its levels were going up and down and maybe this was the way to. Initially I thought about just as a way to regulate sirtuin enzymes. And that got me into developing mouse models and cell lines and things where we could change the level of nad. And as we did, we started to see all kinds of things, many of which were unrelated to sirtuins and really eventually led me to refocus the lab almost entirely on NAD with sirtuins just being one of many different downstream effects that we sometimes see in these different systems.

So cool. So cool. Tell me a little bit for the people who are unfamiliar with the specifics of all this, which is probably like most of my listeners, tell me the basics about NAD and also tell me the basics about sirtuins as well. Kind of lay that foundation for them.

Right. So I'll start with nad. So it is nicotinamide adenine dinucleotide. And so think about like nucleic acids like DNA or RNA that you might be familiar with. Those are blocks. Imagine like a chain of Legos sort of stuck together. And NAD is a dinucleotide. So it's taking two of those units and sticking them back to back kind of instead of long chain for DNA or rna. And the really unique thing about NAD is that on one end of it you've got adenosine, which is one of the normal bases that's used in DNA and rna, but at the other end you have nicotinamide. And that's sort of the business end of the molecule. That's a base that's not in DNA or rna. And it has this sort of unique ability to accept high energy electrons. So when you're doing chemical reactions and you're producing a molecule that needs to lose a couple of electrons compared to, to the, to the product you're trying to make, those electrons are often coming off of a lot of energy. And NAD captures them and gets itself converted into nadh, which is kind of a rearrangement on the nicotinamide ring that ends up adding two electrons and one proton. And so it's essentially a battery being charged, if you want to think of it that way, as chemicals are broken down. And so that really facilitates a lot of the biochemistry that's going on inside our cells being able to give those electrons and take them back when needed.

And that's sort of necessary for most chemical reactions. Right. Like, big picture, what would this, what systems of our physiology would this influence? Or is it basically everything?

Basically everything. So at one level or another, I mean, not every individual reaction, but almost every chain of reactions that leads to a specific thing happening has some step that depends on nad. Or there's a phosphorylated form called NADP that is only made from NAD that does a distinct set of reactions. So having the extra phosphate on it allows it a distinct set of, of enzymes to use it as a cofactor. But it serves essentially the same purpose. And so the ones, I think the most, the most fundamental things that's involved in are the transformations that lead from food that you consume being turned into usable energy for the cell. So the typical cascades like glucose going through glycolysis just to pyruvate, which can then go in your mitochondria and be harvested to the Krebs cycle to make ATP, just cellular energy currency. Every viable path to make ATP for the cell requires NAD at least one step.

Yeah. So I kind of describe it similar to how I describe ATP to like regular humans, which is almost like a biological energy currency. Like we need these foundational components to do pretty much everything, correct?

Yeah, absolutely.

Okay.

And I mean, really I should make that argument and review articles that NAD is just as fundamental as ATP to cellular energy because. Because there is literally no sustainable path to generate ATP if you don't have.

Totally. And I know you touched a little bit on mitochondria and I know a lot of your more recent work is in mitochondria and how I, I'd love for you to explain a little bit about what mitochondria are and how they relate to nad, which I know ties into the description that you just gave too, but kind of spell it out a little bit for people and then I'll see if we can go a little deeper and make it as understandable as possible.

Sure. I mean, so there's the one phrase everyone remembers about mitochondria, Right. Is that they're the powerhouse of the cell.

Yeah.

They generate most of the ATP that we use. And so they're little membrane bound organelles inside our cells. They're thought to be derived long ago in evolution from bacteria, from sort of actually one bacterium invading another. And then the smaller one is the remnant mitochondria that we have. And then functions diverged. Mitochondria retain the responsibility for ATP generation and function for other, less famous processes. But certain, certain division of biochemical labor goes on inside the mitochondria. They also retain their own genome. So we have the famous nuclear genome, that's most of our genes, but there's a separate mitochondrial genome contained in the organelles that's a remnant of their bacterial genome. And so they perform all kinds of functions, but some of them are dependent on nad. And since they're inside a double membrane, the NAD has to be transported inside, which is what we've spent a lot of our work on lately, is identifying this transporter that allows NAD that's made in the rest of the cell to get placed inside of the mitochondria and then facilitate a bunch of these ATP generating reactions. Most famously the Krebs cycle, where Ayurveda comes in and goes around this little circle. You remember from your textbooks that it is spitting off NADH at various points, consuming NAD and making nadh. And that NADH is holding those high energy electrons that are the starting point for the electron transport chain, which generates an electrical gradient which fuels the pump that makes ATP.

Yeah. Which basically produces our biological energy, which is ATP, which is needed for what, like almost again every chemical reaction that happens in our body.

Yeah. At least anything that needs to, that is energetically unfavorable, that we need to force to go in the right direction. ATP is that force.

Yeah. And a couple cool things I know about mitochondria. Please correct me if I'm wrong because I love, I love to be corrected. But one is we inherit our mitochondrial DNA only from our mother and it does not blend with our father's DNA. Is that correct?

That is correct, yeah. Yeah. So there's actually, it's been used as an independent way to trace human evolution. There's a sort of the mitochondrial eve that you can trace everyone back to in Africa and you can look just at the mitochondrial DNA to find people along the lineages that spread around the world.

Did we originally, like, is it true that we can trace people back to eight women in terms of eight different original mitochondrial sources, essentially? Is that true?

I'm not positive if it was eight parallel, but there certainly are mitochondrial haplotypes. So that there are a set of mitochondrial genomes that do go very, very far back in evolution. Yeah, yeah, I'm not sure. Totally temporary. Yeah.

And so mitochondria paint a big picture, are responsible for energy production. Right. But that can manifest as like poor energy, poor cognition, poor metabolic function. Any other symptoms that people should think about when they think about maybe mitochondrial dysfunction?

Yeah, I mean, muscle weakness. I mean, mitochondrial diseases are actually famous for being really diverse and hard to diagnose. I mean, it's often the mystery patient in a hospital that nobody can figure out what's wrong when they discover it's some new mitochondrial disease that is manifested in a strange way. Or you'll have siblings in a family that have the same mutation causing mitochondrial diseases that have very different symptoms. And it just, it's, it's one of these things that's very frustrating clinically to try to pin down. But certainly high energy organs like sensory organs. So blindness and deafness are definitely very characteristic of mitochondrial dysfunction. Famous obvious ones that, that you might think of are like the mitochondrial or the like muscle mitochondrial dysfunction where you do get ragged red fibers and obvious weakness and loss of muscle mass. It can really manifest in a lot of different ways.

Yeah, absolutely. So in relation to mitochondria and NAD or the integration of both, I know that NAD declines as we age. Can you tell me maybe why? And then what the end result is, how it might manifest to a person in that case.

Yeah. So it's been a pretty consistent observation that the is less NAD in older individuals, humans, and in the mice that we study, it's not every tissue. So we'll see the muscle usually in brain we see a little bit of a decrease definitely in fat tissue. And in some of the intestinal tissues we pretty consistently see decreases. In other tissues we don't necessarily. So it's a little bit debated exactly what the cause of that is and how much it is a fundamental consequence of aging versus a reflection of different disease processes taking place potentially in the animals and in the humans. So there are different enzymes, particularly one called CD38, that's induced by inflammation that degrades NAD. There's another one called PARP1, that's induced by DNA damage and degrades NAD. And so we know those things increase with age. And so one thought is that it's the upregulation of these enzymes in response to these other things, pathological processes that are already happening, leads to the NAD getting broken down over time. At the same time, we know your capacity for NAD synthesis decreases with age, some of the key enzymes that make it. And so one of the studies we did recently was to really try to pin down whether it was decreased synthesis, at least in mice, or increased turnover. And based on heavy isotope tracing. So we're putting in labeled NAD precursors and we can tell how fast they're contributing to the NAD pool in tissues. When we do that, it does look like in our hands, it's the consumption that's increasing. So we want to blame the enzymes, either the DNA damage responsive one, PARP1, or the inflammatory one, CD38, potentially, as culprits. The method we used is really agnostic to who it is doing. It just shows that more NAD is getting degraded and that synthesis rate was really unaffected in our mice, even though NAD levels had fallen. Wow. We think the capacity for synthesis is decreasing with age. So if you had some massive depletion of nad, you'd be maybe less able to recover if you're older. But in our hands, it looks like the rate of synthesis is still really maintained. Even though you have a little bit less of some of those enzymes, they're maintaining the production that you would normally have. And that the fall in our hands seems to be consumers getting more active.

Wow, that is fascinating. And I have never heard that before. So if that's the case, are there things that we can do in our lifestyle to theoretically mitigate this over consumption of nad?

Yeah, I mean, a lot of the same things that we would always recommend, right? Eat the right foods, exercise, so we know we can actually boost consumption through exercise. So that may offset it, I guess, in terms of increasing consumption to offset the. The. Or, sorry, increasing production to offset the increased consumption. But certainly eating fruits and vegetables that are rich in antioxidants and things that we know are kind of associated with having less DNA damage also would potentially lead to less activity of some of these pathways that are degrading things. And just in general we know that healthy lifestyles associated with being less inflamed in general there would just be less CD38 activity that it probably is really associated with some of this chronic background inflammation that we see in eight.

How fascinating. And I know there's so I'm like in the world of sort of progressive medicine and there's medicines that people take to sort of reduce inflammation, things like low dose naltrexone or what's called LDN. LPs are really potently powerful and they're honestly the most powerful thing I've seen in terms of inflammatory reduction. So I'm so curious if in the future we'll see research come out tying these types of things into our ability to break down our NAD less and less as we age and be able to maintain that access that we need to thrive. This is super fascinating.

Yeah. So, so there have been a couple of studies in calorie restricted animals, so pre GLPs, but just doing actually feeding list where they've seen at least that that offsets the loss of NAD and adipose tissue. It really seems to be keeping it a little bit higher and had a milder but present effect in muscle as well. So I think there's a lot of hope for that. And actually I've got a colleague who has sort of dragged me into the GLP1 field recently and that is one of the things that's on our agenda is to really see NAD system in the animals on that drug.

Can you update me when that is like looking like you're finding some information? Because I am fascinated. I mean the weight loss piece is great. Like it's amazing. It's life changing for so many people. But all these other pathways that these medications are influencing that I think create quite significant shifts and in healthspan lifespan, longevity potentially are so interesting. So yeah, I cannot wait for that to come out. You really will. You'll have to bump me when the study comes out or when you guys get more and more information and as it evolves.

Happy to do that.

Yeah. So I know you've done some studies on NAD in mice. What benefits have you found when you're actually giving mice NAD and you're supplementing with it? And do you think that we could extrapolate those findings to humans?

Well, so I think the, the answer in terms of extrapolation is has been mixed. So there's a lot of Benefits in mice, we found it does things like, like promote liver regeneration. That was one of the first systems we started studying. Studying it in just because it had been known for a long time that, that NAD levels fall as the liver is regenerating. Probably because you're in this competition between having to make more DNA and RNA with some of the same building blocks and needing more NAD for the regenerating tissue. And so we were able to show that if we supplement NAD in that situation that the liver can regenerate much faster and better. So but I think the field in general is everybody's gotten their hands on these precursor vitamins and tested their own favorite systems. And in mice it's been pretty uniformly positive results. So things like diabetes have gotten much, much better. You can promote weight loss in mice. There've been a bunch of studies on cognitive disorders of different models of Alzheimer's disease where they might get cognitively better when supplemented. A lot of different models of heart failure where they again always seem to, you always seem to get about half the contractility of the heart back if they're on NAD precursors.

Wow.

Breaking. So we've moved into heart failure now a little bit too. And I'm just kind of laughing at how much we've recapitulated exactly what's in the literature. It's just weird that it's always about a 50% recovery. And that's exactly what we saw too. So.

Wow.

Not sure why.

Right. And it seems like we could safely do that study in humans.

Right?

Like so easily.

Right. Well and that's true for a lot of these. And so I mean things like Alzheimer's disease, the trials have started in humans. We don't, we don't have great data yet. We have to wait and see. That takes a bigger study and longer time point. But things like the diabetic effects were very low hanging fruit to move into humans. That's, that's been done at least in smaller studies. And that's one of the areas where not everything is reproduced, unfortunately. So the improvements in insulin sensitivity were in one study mild and relatively restricted to muscle in humans. And a couple of other studies really were non existent, not detectable. Where in the mice you're almost curing the diabetes. And then it's very frustrating to see in the humans. It's certainly not, not going to compete with our anti diabetes drugs that we have on the market right now. So probably not the most useful place for these precursors. But there's other things like, like the mitochondrial myopathy model where you get a kind of mitochondrial dysfunction that is specifically associated with mitochondrial myopathy. So muscle wasting and some of the NAD precursors of mice were therapeutic in that model as well. And so it led to one group going out and finding humans with mitochondrial myopathy and treating them with niacin as an NAD precursor. And that was effective. I mean, functionally. So things like the six minute walk test and stuff improved in these people and you could actually measure NAD deficiency in their muscle and measure it getting rescued. So it's been a bit of a mixed bag. I think some things that looked really promising in mice have not panned out at all so far, and others have translated pretty well. And I think there are, we are going to find uses for NAD supplementation in some of these disease conditions. And we really are in a bit of a race to figure out who, who needs it and when it's useful.

Yeah. And again, like in medicine, so much is always about risk versus benefit. Right. And the benefits are pretty, pretty profound. I know. We'll touch on one risk too, in a few minutes that I, I always get asked about, so. Fascinating. And when you say an NAD precursor, is it an injection, is it an oral formulation? How is it administered in the mice?

So in mice, it's depending on the study. It's usually either oral or intraperitoneal, which is a little bit less relevant to humans, but very convenient for the mice, where you basically inject it into the belly and try not to poke an organ.

Yeah. And what are some of the precursors? So is it like nicotinic riboside? Is it niacin? Tell me, you tell me what they generally are.

It's. So the traditional ones are nicotinamide or niacin, nicotinic acid. I mean, those are the traditional forms of vitamin B3, and some labs are still using those. The new ones that have become popular as supplements and generated a lot of interest are nicotinamide riboside or nicotinamide mononucleotide.

Yes.

So those both come in a little farther down the synthesis pathway towards NAD. So nicotinamide riboside was recognized in 2004 to have its own enzyme to get it into the pathway. Before that, it was known that that could contribute to nad, but the thought was you digested it down to nicotinamide to the conventional B3, and then it went through the synthesis pathway. 2004. This is what kind of kicked off the supplement craze. It was discovered that there are kinases specifically for nicotinamide riboside. And so you actually skip the bottom part of the pathway and it gets converted directly to nicotinamide mononucleotide inside the cell and then goes straight to NAD in the next step. So you can bypass some, especially an enzyme called nampt, which is the one that goes from nicotinamide to nicotinamide mononucleotide. That one seems to be the most, it is the most energetically costly reaction and it is the one that's subject to feedback inhibition and usually is rate limiting. And so that became the exciting point that in cells you could show really clearly with nicotinamide riboside, you can actually skip that step, get higher levels of NAD more efficiently in terms of energy. And shortly after that it was realized you could give nicotinamide mononucleotide directly to the cells and they would use that as well. So you didn't have to start with the nicotinamide riboside. So either one of those can theoretically get you more efficient NAD production and higher NAD production.

Very cool, Very cool. Tell me too about. So obviously there's a lot of talk and we touched on earlier about nad, their relation to sirtuins. Can you in DNA repair energy metabolism, can you help us unpack that interrelationship in sort of a reasonably understandable way?

Sure. So two ones are one of several families of enzymes that use NAD as a cofactor and they became famous for extending lifespan in yeast. Some screens were done in yeast to find things that initially things that would make them more stress resistant under the hope that would make them live longer. And sirtuins were the major hit from that screen that made the most stress resistant yeast and those yeast turn out to live longer. And since then it's been a little bit more debatable in worms and flies and other laboratory model organisms, but in some labs finding lifespan extension there as well, and some not so much, but definitely finding some changes in stress resistance and in different signaling pathways, and the same has been true in humans or in mammals so far, is that the sirtuins seem to be integrated into things like circadian rhythms and to play important roles in biology. It's a little more debated again whether they're likely to really be related to lifespan or not in humans. I think that's certainly been challenged a little bit more, but they're integrated into a lot of different systems and they require NAD as a substrate. And so they're sort of provide a way to potentially sense NAD levels. And we see that with circadian rhythms, especially where the SIRT2 and SIRT1 as well, as the synthesis machinery for NAD are both tied into the circadian clock. And so at the same points, when you wanna have high one activity, you actually make more NAD to fuel it. And so it does seem like this is something that a subset of enzymes are really looking for in the cell is what's going on with the NAD system to decide what level of activity they're going to be at. And so that.

Oh, sorry, go ahead.

I was going to move on to parts. So if you have a certain question, go ahead.

Yeah, I'm wondering if the interrelation between those and the loss of sleep is that. This is an elementary question, but are, is, is those, is the loss of those two things or the shift of them as we age related to age related sleep difficulties? Like as we age we just sleep less, we have more problems. All the things. Is that interconnected at all or completely? You have no idea. And I'm asking the most random question right now.

No, I mean, it's not a random question. It's a good question, I think, but I don't think we really know the answer to that yet. I mean, certainly if you disrupt some of the other players in the circadian clock, if you make genetic models in mice where you knocked out things like BMAL or clock, these core components of the circadian clock, you do lose, completely lose regulation of sleep and activity and feeding behavior. So it's certainly plausible or probable based on that that the NAD levels and certain levels are having an effect on that as well. But that not been studied as carefully. And it's been studied mostly in peripheral tissues where it doesn't control the behavior of the animal so much, you know, so for instance, you can think, take things out of sync just in the liver and show that that's, that's bad for metabolism to have your circadian rhythms drifting off course a little bit there. But at least I'm not aware if it's been done in the scn, which is the brain region that can, that really controls the overall behavior in response to light. I'm not sure if the system has been perturbed there.

Interesting. Okay, carry on. Sorry for the interruption.

Right, so this is the, another family of enzymes like the sirtuins that use NAD as a cofactor is PolyADP, ribosomes, polymerases, okay, polymerases, PARPs. And so PARP1 is the one I mentioned before, that's one of the famous responders to DNA damage. And what it does in response to DNA damage is flag the area with adp Ribose, which is part of the NAD molecule that it's taking. So it's throwing the nicotinamide away and taking the rest of the. And sticking it on to areas of DNA or proteins around DNA damage. And that brings in many of the other repair factors. And so it's good from a signaling sense, like to actually repair the DNA and get things back in order that the PARP's active. But if you get too much of that, you can actually deplete the NAD levels.

So that's kind of because of over signaling. Basically. They're just rushing there. Okay.

Yeah. I mean, you're basically consuming one molecule of NAD for every unit you add to this chain that is flagging the DNA damage. Mm.

It also is probably. Sorry. Sorry. It's also probably why I'm putting all these pieces together in real time, why the breakdown of our DNA can deplete NAD more and more quicker over time. Is that right?

I mean, yeah, that is. That is the thought that that's happening is with age, as we know, we have more standing DNA damage, there's a little bit more activity of this PARP enzyme, and that's one of the things probably contributing to the. The NAD levels going down. And maybe one of the reasons why it would be good to have more NAD there for DNA repair. Right. You're allowing those PARP enzymes to have access to a full complement of NAD molecules again so they can signal properly. And you're also helping avoid the depletion that they were causing. And so that's actually played out in some models, like Cockayne syndrome, where there's a primary DNA repair defect that causes that disease. But if you look at the DNA damage, there's all kinds of DNA damage happening that goes beyond the enzyme that was actually defective. Other types of DNA damage are also accumulating. And at least in the mouse models of that disease, it's now been shown that that goes in concert with NAD levels falling. And if you put the NAD levels back, you repair a lot of that other type of DNA damage. So you help restrict it more to. There is a primary defect that you're not fixing. It can't fix a certain type of DNA damage, but you're stopping it from cascading. And that cascade may be in large part because you're causing NAD depletion with the. The initial DNA damage, and then it leads to more.

That is fascinating. Like, it really, really is. Wow. Yeah. No, I've learned so much already about this that I never, never knew. Tell me, are researchers seeing Potential in NAD for slowing or reversing age related diseases like cognitive decline. You talked about heart failure. I know, in. In mice. Right. And then a little bit about the cognitive decline piece. Right. Alzheimer's dementia. Is that what you mentioned?

Yeah. I mean, so I think that in mouse models, it's already pretty clear that you do see some improvements in cognition in humans. Most of the studies that are the larger studies, longer term ones, have not reported yet. So it's really, I think.

Oh, that's right.

Needs to be answered. I'm actually involved in one at the University of Oklahoma that is still blinded. So we've had quite a few people come through that now, but I still don't know what the result is.

I love it. I'll have to check back in with you. I'm so. It's fascinating stuff. Shifting gears slightly. The most common question that I get in discussion that I have with my patients about NAD is there are some studies that link NAD and cancer. The one that comes to my mind is one for breast cancer. Patients have an increased or suspected increased risk of brain metastasis of their breast cancer. I'd love for you to give me your input and thoughts on those studies.

Yeah, I mean, so first of all, I do think it's an understudied area. I've been a little bit frustrated by the real hardcore cancer labs haven't really jumped on this question. There's been a lot of smaller studies done by labs that don't even traditionally work on cancer. Like often in NAD lab. And even in my lab, we did a few experiments in this. And not really being cancer biologists in our hands, we never really saw a shift one way or the other. What really caused the alarm was a study done by a group that was actually developing chemical methods to track nicotinamide riboside through the body, but did an experiment at the end where they injected cancer cells into the heart and then looked for spread to other parts of the body. And they saw a statistically significant increase in movement of those cells to the brain and sort of raised the alarm that maybe there could be some problem here for metastasis. Now, again, that was a lab that doesn't really focus on cancer. That wasn't really the type of model we used to study metastasis. And there have been other studies with other tumor models where they've actually shown improvements with NAD precursors. So I would say, I guess one fear that I think is pretty legitimate still is that there could be a subtype of cancer, a specific tumor type In a specific location where actually I hope not, but we might find that in one of those cases it's a really bad idea to take NAD supplements. I would say. The reasons I feel pretty good about that so far are if we do lifespan studies in mice, first of all with NAD supplements, there's not that much evidence that they live much longer. We think that they're healthier longer, but living about the same. But almost all those mice die of cancer and they're not dying a lot shorter, they're not living shorter and we're not finding more tumors in those studies. And those are very cancer prone organisms. Just flooded with this stuff, taking up a lot more than humans would take. Right. I think the other thing is niacin, nicotinic acid, even though it's not as fashionable anymore with some riboside of the mononucleotide around it, also boosts NAD levels and that's been used since the 60s at high doses for long times and people. There's been follow up. In fact, there was one study where they did a six year intervention to look for cardiovascular mortality and showed basically nothing with that treatment or several others and then did a nine year follow up after that and showed decreased mortality overall in the people who had spent six years on intensive niacin therapy. And so in my mind, I think there's, it's certainly not like it's a brand new drug that nobody's ever seen the long term consequences of. I think we've got quite a bit of evidence that boosting NAD levels overall appears to be safe. There's actually been a phase three trial done for nicotinamide for skin cancer where it improved, decreased the amount of skin cancer. So I think overall the evidence is in favor of the idea that it's going to be protective against cancer. I don't think we've done as many studies as we should to be confident that different subtypes of cancer aren't going to have different risk profiles.

Sure, right. I mean, I feel like that's an endless rabbit hole to do research on. It could never end. And just a follow up question. Do you think that we don't really use niacin as much anymore for this purpose because there's just more fashionable things that have come out with great marketing or is it that people have difficulty tolerating higher doses of niacin from a flush or both?

So I mean, I think the, the primary reason is the flush, right? I mean people just want to avoid that and that certainly does lead to some, some people just can't tolerate that at all and end up discontinuing because of it. Now, I think at the cell culture level I kind of described it, my riboside or mononucleotide can bypass nampt. Right. And sort of potentially boost nucleophiles higher and more efficiently in vivo. We haven't found that to be as true as we hoped. So a lot of those molecules, this is based on heavy isotope tracing now, so we're actually putting atoms with an extra neutron in them in the dose that's given now to animals, so we can extract that through the body. And figuring out where these administered molecules go. And what we've actually found is, to our surprise, when you give them orally, most of it gets broken down in the gut. So the gut microgram gets a hold of it and they release a lot of nicotinic acid. So as much as we were trying to avoid nicotinic acid in the first place, a lot of the administered dose actually gets converted into that. And in that sense, it's almost like a big part of the dose of nicotinamide riboside or mononucleotide is acting as a slow release niacin because you're waiting for the gut metabolism and it's stewing down there, but it comes into the bloodstream, a lot of it as nicotinic acid.

Okay. And so is, is a realistic way to increase our NAD levels with oral supplements or not really.

So it does increase NAD levels. Yeah, I think that's important to sort of note as we're complaining about the, the metabolism being maybe advertised incorrectly, in many cases, it still ends up boosting NAD levels and a lot of the niacin. But a lot of tissues can use niacin in the first place directly to make their own nad. A lot of what's left gets scooped up by the liver and converted to nad. And then when that turns over in the liver, it releases nicotinamide, which is the major NAD currency for the, for the body. And so even the cells that need nicotinamide eventually get a boost in nicotinamide from supplementing. And so certainly no matter which form you're giving these NAD precursors in, we do eventually see tissue levels of NAD going up. Cool.

And then talk to me too about like, compare and contrast oral nmn, NR versus NAD infusions, NAD injections. What are your thoughts on all of these methods? Like, I'm so curious too, to know your thoughts on these IVs, because I know they're heavy duty doses given over hours at a time. Yeah. So tell me what you think.

Yeah, I mean, I've never seen a coherent argument articulated for why you need the intact NAD molecule. And these fields have kind of developed separately almost. There's been this. People working on sirtuins, parbs and things, and getting into the NAD field that I've been in and working on these precursors like riboside or mononucleotide, and publishing papers. The people that are doing the NAD infusions intravenously are sort of the students of a. A line of doctors that started doing this stuff for schizophrenia and for addiction in the 60s. And in most cases, they weren't controlled studies, they weren't large studies. People were having trouble reproducing each other's findings and going back and forth writing opinion papers about why the other one didn't make sense. And that's sort of come up all the way in parallel with these worlds never really talking to each other until.

Till right now, Dr. Bauer. Till right now. That's why you're here today.

I'm trying to remember what year. What year it was when there was a fast. There was an NAD conference in New Orleans maybe eight years ago, where a bunch of people from a nearby clinic that did NAD IV infusions came and started talking to everyone. And it was really like worlds colliding, like they unaware of most of the research that was going on. And most people there were completely unaware that people were being infused with IV NAD at that point. And so, I mean, my strong suspicion is that it's still breaking down, that it's not getting into the cells as intact nad, and that it's cleave to nicotinamide or to nicotinamide mononucleotide, and that's what's taken up. And I think the part of the risk with using intact NAD is that the adenosine side can signal. Right. Cells. See that? So there's purinergic receptors that do all kinds of things on different cell types that are probably getting activated as an unintended consequence of infusing intact NAD instead of just the precursors. Interesting.

And what would that manifest as? Like, what would people experience or consequences that. Or is it just completely unknown at this point?

Yeah, I think it's unknown depending on which subset of cells they're hitting those receptors on. I mean, they signal all kinds of things for inflammation or different neurotransmitters, and things can be affected by the signaling through that pathway. But I do know that there's a limit to how fast you can infuse IV nad. And I suspect that's not, I would suspect that's not related to the NAD side of it. That's maybe this signaling aspect of the other end of the molecule that's causing those issues.

Interesting.

So, but I think, I guess the end, at the end of the day, there's almost no literature still on the effects of IV nad. I mean, this has almost all been done clinically and you reported sort of anecdotally between people doing that kind of treatment. There's shockingly little. If you go to pubmed where we look for scientific research right now, there's one paper that I'm aware of that shows up there for IV nad, and it just does the pharmacokinetics just documents where some of the molecules are going to.

Interesting. Yeah. I'm not necessarily a big fan myself of nadivs. I, I just don't. One, there's not a lot of data. Two, they're wildly uncomfortable and overpriced. And three, I'm just not sure they justify risk, benefit, cost. Yeah. Anyway, it's fascinating though.

Yeah, no, I mean, I'm really, really curious to see if there is some evidence that comes out that, that, that you get any effects that are really different from supplementation. Yeah, there's some other way.

Yeah, no, I agree. Tell me, are there other things we can do to support our nad? I know you mentioned caloric restriction. Right. And did you say exercise can promote the production.

Yes, at least in muscle, but probably to some degree in other tissues as well. But definitely it induces expression of the key enzyme NA bt. That, that's, that's rate limited, rate limiting for NAD production. So definitely you can boost your NAD levels in muscle by exercise. And definitely in older people there is a strong correlation between function and activity level and NAD level in the muscle.

Got it. So it's another reason why we don't want muscle wasting as we age. We want to keep up our muscle mass. Yeah. That impacts longevity and health span in so many ways. It's cool that NAD correlates with all that other data. What about hot cold therapy? Any other lifestyle things that we can do to influence our nad? Getting creative over here.

Yeah, I know. I mean a lot of them people have speculated about and things like sleep. I mean, I don't, I don't know anything specifically for hot cold therapy other than it the, in adipose tissue and you're fat. The cold therapy obviously has some potential to cause it to turn a little more brown, which is, you know, forming these adipocytes that are better at spending energy than to generate heat instead of storing energy. And those certainly come with more mitochondria and require more NAD because of that. So you will. You would get a boost in that sense from cold therapy, potentially. Sleep is one of the things where there's a little bit of clinical evidence suggesting some improvements in sleep quality. It's very common to hear that. Anecdotally, if you talk to people who are taking supplements long term, that's one of the things they almost always say. I've personally started to stop supplements quite often just trying to see if I can detect myself. And I find when I go on them, at least in the short term, I don't sleep as well, which is really frustrating because all these people are telling me how much better they sleep on them. They disrupt my sleep a little, but maybe I just need to get a few months in and then see.

I love that you experiment on yourself while doing the scientific experiments. Like, I think that's the. I kind of live my life in a similar way, minus the scientific experiment part. But always in my clinical experience experiments, I like to be the mouse myself before I take it to patients. Is there a way that we can test our NAD levels or track them? Like do a baseline, make an intervention, retest, see if we've been able to influence it, et cetera?

There's a couple of different companies that will do that at the level of whole blood. So it's in the cells in your blood, not in the plasma or serum, or a little bit in your plasma or serum, but that's at a much lower level. And the significance of that is debated, whether it means anything at all, or whether it's maybe just related to cell death or something that you pick up a little bit in the plasma serum. But you can detect a decent amount of it in whole blood if you keep all the cells. And there's a few different companies that will test that. And that does respond to supplementation in humans. So you can certainly. You can push it about double a lot of the time if you're taking these supplements long term. What we don't have a good way to do in humans is to know if it's getting into the target tissues that we care most about. Right. So we know that the blood cells circulating have more. We don't know unless you do a muscle biopsy, if you have any more there. And a few of the studies that have done muscle biopsies haven't shown very convincingly that there is any more there from the Sub despite the blood level being up. And so I think this is the big question in humans is sort of how predictive is that blood level of NAD levels in other places?

How interesting that you can increase the circulating amount but not necessarily show that it's getting where it needs to go and absorbed where it needs to be absorbed.

Yeah, I mean, we've seen that there's a bit of a different tendency from tissue to tissue to increase nad. So in the mice, for instance, the kidney and liver levels will go through the roof if you supplement them. Muscle levels only go up a little in the mice and in humans, not so much at all. But we have made, for instance, genetic models where we deplete NAD in the mice, like block this enzyme or knock out the enzyme NA ampt. And so the muscle NAD levels fall and the mice are doing really badly. And those mice, if we supplement, at least if we give it intravenously, the muscles will just vacuum up the NAD precursor and refill the pool really quickly, at least from an IV dose, where IV dose wild type mice, they barely take any into muscle. So it does seem like they have a bit of a set point in some sense where they don't really want to vary too much from that.

Right. We have built in protective mechanisms to not overdo it, I guess, which are more complex beings. I wouldn't be surprised if kind of wrapping up. I want to think about if you could give someone one thing to do to improve their NAD and then their longevity, potentially by proxy, what would it be? Or maybe what's one thing you do to try to improve your NAD levels?

I mean. Well, I mean, obviously I'm playing around with the supplements and just making a difference. But the, I mean, the right answer is exercise, right? We know exercise, the unad level in, in your muscle and certainly to some degree the circulating nicotinamide that would be released from muscle going to other tissues. And so there's. That is unarguably good for your longevity and general health. And if you can get NAD out of it too, all the better. I think the other thing people should do depending on their diet is just pay attention to diet quality. So there's a lot of NAD precursors in meat, but vegetarians who then eat a poor quality vegetarian diet are much more at risk of developing NAD deficiency. So sort of famously, the NAD precursors that are present in corn are not really bioavailable. And so people who ate a really high corn diet were at risk of this disease, pellagra, which is the nutritional deficiency of All NAD precursors. And so that eventually becomes fatal. I mean, there's a, it's neurodegenerative and you get skin disorders and things and get sick, but then eventually, eventually it can become completely lethal. Even though there's a decent amount of NAD precursor in corn, you have to actually treat it with something like lye to release it from the proteins to be able to digest it and get it in. And so, I mean, I guess just showing that as one, one anecdote, meat basically will cure pellagra. And, you know, any, any sort of decent quality diet that involves meat and potentially milk will, will keep you fine. But vegetarians, I think, who, who don't fully embrace the healthy aspect of that lifestyle can be in trouble. I think you're, you're still fine if you eat a wide variety of fruits and vegetables and things and, and, and keep your diet pretty good. But for instance, my daughter, when she first decided to go vegetarian, decided ice cream was vegetarian and that was going.

To be the carbs and cheese.

Exactly. So then, then I think it's worth taking a step back once in a while and making sure you're getting adequate nutrition out of the diet you're selecting. And certainly with meat being such an important source of NAD precursors, it's important for vegetarians to think carefully about it.

Yeah, I had no idea that meat was such an important NAD precursor. That's really good to know.

Yeah. And partly in the in sense. I guess the third pathway we haven't really talked about is you can actually make NAD de novo from tryptophan. Right. So it's the, the protein in meat that is, can be enough to keep you going on, on producing NAD through the stenova pathway in your liver. Interesting. And you don't get any vitamin B3. Then you get the dizziness.

You know what? That's interesting. I'm going to write that down. My daughter has a rare genetic disorder and it involves tryptophan metabolism. And as we've been talking about this, I've just been thinking, gosh, I wonder if I should talk with her science team about finding a way to get nad. Yeah, I'm gonna have to look at that pathway and integrate those two together. It's interesting stuff. Tell me what you think we'll see on the horizon about NAD research or what, what are things that you're excited or working on in this field?

Yeah, well, I mean, I think a lot of clinical trials are in progress for a lot of the same questions we've been talking about. Just Getting larger numbers of people in. So I think we'll certainly get some more insight specific to nicotinamide riboside of mononucleotide and whether cancer's a risk, whether there's improvements in cognitive function in people with either mild cognitive impairment or full blown Alzheimer's disease. I think we're going to see some larger trials of heart failure in humans, and so we'll see if there's really a benefit there to back up all these mouse benefits that we've been seeing. So I think on that front, clinically, it's a really, really exciting time. All these trials are enrolling and, you know, it's frustrating to have to wait for the results, but I think in a couple of years, we're really going to see a lot of interesting things coming out. Personally, I'm really just excited about a lot of the basic science we're doing right now. Right. We found this transporter that gets the NAD into the mitochondria. We know there's other compartmentalized pools around the cells, and we're starting to really understand which cell types respond differently to NAD levels, which ones are at risk of being deficient within those cells, which processes really are sensitive to changing NAD levels? I think that's been one of the biggest frustrations in the field is that there's about 500 redox reactions that require NAD. There's about 40 of these NAD consuming ones that we know of. So well over 500 things changing when you move NAD levels, and we just don't know which ones are sensitive. Right. We have a lot of data from the cancer field where you wipe NAD out completely and everything stops. But we already knew Those reactions required NAD. We don't know in aging when you have a 30% decline in NAD in the overall tissue, which enzymes care about that and which subcellular compartments are really being affected. Is it that the nucleus is just fine and the Cytosol has a 50% decrease in NAD, or is it that spread evenly? So, personally, I mean, I guess that's kind of the geeky answer, but those are the things that my lab's really getting excited about, trying to tease out now and to understand which processes really care when this NAD change happens.

Yeah. Fascinating. Well, thank you so much for your work. And, I mean, this conversation was enlightening for me. I learned so much. I know the listeners will feel the same way. And I am so excited to stay up to date with everything you have going on. And please keep me posted as new things come out and new findings occur. But thank you again. This has been so, so insightful.

Thank you for having me. This has been fun.