HS 398 - Your Metabolism & You with Dr. Charles Brenner

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My pleasure to welcome Dr. Charles Brenner. He is Roy J. Carver, head and chair of biochemistry at the University of Iowa and chief scientific advisor to Chromadex and Tru Niagen. Charles, welcome. How are you?

I am very well, thanks. Great to be on your show, Jason.

Good, good. It's good to have you today. So you are doing some very interesting research on metabolism and something called nad. And why don't you explain to the listeners what that is and what it's all about?

Gladly, I will give it a shot. So nad, it stands for something. Nicotinamide adenine dinucleotide, Jason. It's the central regulator of metabolism, the central catalyst. And you might ask, what is metabolism? Metabolism is the kind of the full set of reactions between everything that we eat and everything that we do, everything we think and really all that we experience and accomplish as animals and as human beings. So when we break down food and, and we generate energy in form of ATP, that's a kind of metabolism. When we convert the things that we eat into the things that our body needs, like making DNA and RNA and making heme, the iron carrier molecule, and detoxifying reactive oxygen species, all of that is metabolism. Repairing DNA is metabolism. And all of the biochemical steps in metabolism require catalysts. And the key coenzyme for all of these transformations is nad.

Interesting. So metabolism, you know, when most people say metabolism, they think of, oh, you know, this is why I'm overweight, because as I get older, my metabolism slowed down. But metabolism is really a lot broader than at least we commonly know it, right?

It is broader, Jason. But you know, that first point is maybe the most important one, right? Is that our ability to convert our food, which biochemists sometimes call fuel, meaning protein, fat and carbohydrates, the things that have calories in Our diet, our ability to convert our fuel into energy declines, and our ability to convert that fuel into body fat that decides to, does not seem to decline.

It's not a very fair equation, is it?

It's not fair. But the amazing thing is there are some amazing biochemical steps between sugar and fat, but they're actually very similar to the steps between taking sugar and turning it into cell membranes, which, you know, if you're building muscle and you're doing other anabolic things, you know, you need to build nucleotides and build precursors and cell membranes, you have to make your own estrogen and make your own androgens, and that can be made from fuel also. And all of those reactions depend upon NAD coenzymes as the central regulator of metabolism.

Okay, so why does this change over time as we age? Why is it that not all, but, you know, not me, thankfully. But you know, most people gain weight, right? You know, they say that people gain 10 pounds every 10 years, but I think it's way worse than that nowadays that I think that's a really old, old thing. Of course, the food supply is totally poison, we all know that. But, you know, some of this would happen naturally, even with good food, I guess, right? So what's, what's going on here? Why does that happen?

Well, let me give you a two word answer and then I'll give you a ten word answer and maybe a minute answer. The two word answer is stuff happens, right? And so there's damage, there's metabolic stresses and disruption. So the body, one of the most important principles of metabolism is what we call homeostasis, which is the body's attempt, right, to keep everything in balance. Like we're trying to maintain our body temperature and we're trying to maintain our ghrelin and our leptin cycles and a gazillion other things, but they get disrupted. And so there's a number of metabolic stresses that, that include overeating, alcohol consumption, believe it or not, noise induced hearing loss, time zone disruption, DNA damage, reactive oxygen species, all of these things depress our metabolism and they do so by attacking nad. So the central regulator of metabolism, nad, is under attack by conditions of metabolic stress and also disease conditions like we showed that heart failure and neurodegeneration and central brain injury can depress the level of nad. And then again, you have the experience of a depressed level of metabolism. Time zone disruption is a really interesting one, Jason, because if you've ever seen a nurse or a police officer go on a night shift, you tend to see weight gain and, you know, a metabolic stress if we do a time zone disruption. So if we fly, you know, from North America to Europe or Asia, we're changing time zones and we have this grogginess and this metabolic imbalance for a few days. All of these things actually upset NAD coenzymes. And. And when NAD coenzymes can't do their job, our metabolism is slower, our ability to repair our DNA is worse, and basically all of our bodily functions are depressed.

Yeah, yeah. So this is why it's just like a very simple view of things is just try and be as much as possible, in harmony with nature. You know, don't be a night owl. Go to sleep when it's dark and be awake when it's light. And, you know, when you travel, it does cause issues, Right, absolutely.

And when you think about the types of metabolic stresses that I just named, so overeating, alcohol, noise, time zone disruption, and then sun, which can damage DNA. Well, all of us would love to hop on a plane and party in Ibiza, right? And there we would experience the opportunity for overnutrition, drinking and loud music and time zone disruption in the sun. And so there are some of the inevitable stresses of life actually disturb our nad. And then, in addition, it's been shown recently that in aging that some of our tissues experience a declining NAD level, which also may explain diminishing function of our liver and our muscle and our brain as we age. So, you know, the thing is, you know, my lab since the early 2000s has been working on the synthesis of NAD. And, you know, it was thought that you could make NAD from. It was known actually that you could make NAD from tryptophan, the amino acid, as well as two molecules that we call vitamin B3, niacin, or nicotinic acid and nicotinamide. And, you know, nicotinic acid and nicotinamide were discovered in 1938 as vitamin precursors of NAD. But we found in 2004 that there's an additional vitamin precursor of NAD called NR, nicotinamide riboside. And it's a wonderful molecule because you get more NAD per unit of this particular vitamin, it costs less ATP for cells to produce NAD from this form. And in many of the types of metabolic stress that I told you about, including heart failure and neurodegeneration, the gene and enzyme pathway to convert NR to NAD is actually turned on. So a stress cell is looking for NR in order to fill up its NAD stores and the ability to convert some of the other Compounds like nicotinamide into NAD actually declines conditions like aging and obesity.

So you're the first person, interestingly, that I've had on the show that talks about loud noise or loud music. I'm curious, and we don't have to go take a long time on this, but I really am curious. Definitely loud noise is a stressor. There's no question that feels stressful. But when it's harmonious or when I like the music, you know, I guess not all music is harmonious and people still like it, but I like harmonious stuff. Does that stress you as well? I'm kind of curious about that, yeah.

Okay, well, let's take a step back and talk about stress. I would say that mild stress is a good thing. Mild stress kind of. I mean, exercise is a stress, right? And mild stresses, you know, can drive corrective and adaptive behavior. So, for example, you know, if a car honks its horn at you and you jump back, you don't get run over by a car. And if there's a hot surface and you touch it with your finger, you're going to withdraw your finger so that you don't get burned. And so, you know, little bit of loud noise is, you know, isn't is a necessary alarm. But working with a jackhammer all day or being exposed to, you know, persistently really loud sounds that definitely, you know, will cause noise induced hearing loss. I don't that anyone has kind of measured the difference between loud cacophony and loud harmony. But persistent loud noise will take a toll on, you know, the cochlea. And it actually, the cochlea is just a part of the ear.

Oh, okay. You got it. Yeah, Very interesting. So this suppresses levels of nad, right? Along with all the other things you mentioned. So can we, how do we fix this? Can we supplement NAD or what do we do exactly?

You don't supplement NAD because so there's NAD in the food that we eat, but it breaks down into these vitamins. So NAD has, you know, in the structure of the molecule, which there's two phosphates and phosphorylated compounds don't get into cells. And so NAD is a coenzyme. It has these phosphates on it. And so basically it gets trimmed back to the vitamin precursors, which are either nr, nicotinamide or nicotinic acid. And then those are the compounds that go into our cells to replenish our nad. What I told you earlier is that NR is better than the other compounds at replenishing nad. And pretty remarkably, it's Already been commercialized. So I just found that it was a vitamin for systems from yeast to humans back in 2004. And we filed for some intellectual property protection and we got issued pat Dartmouth College, which was my employer at the time, my lab was at Dartmouth Medical School, you know, applied and filed and was issued patents for use of nicotinamide riboside as a supplement and basically as a drug. And that's already been commercialized. So around 2011, 2012, this company in Irvine, California, ChromaDex, negotiated for licensing agreements and they figured out how to make it at a high level, at a high degree of purity. And Chromadex has taken it through toxicology in my lab, did the first clinical trial. Nicotinamide riboside is sold commercially as niagen is what the ingredient is called. And our direct to consumer brand is called Truniagen. T R U Niagen N I A G E N truenigen.com is where the sales site is. And so, you know, individuals in the us, Canada, I think Hong Kong, Singapore and Macau can buy nicotinamide riboside as true niagen and can basically supplement and keep their NAD at a high level. So we think that this is a way for aging better. I don't really talk too much about aging. I don't use the word anti aging. I feel like we are all aging and we want to have the wisdom and mastery that can come with aging, but we want to avoid the, you know, the damage and the loss of function. And you need NAD for resiliency, you need NAD for DNA repair and to detoxify free radical species. So by maintaining NAD through these episodes of metabolic stress, we think that we can improve our health and wellness.

Sure, sure. By the way, the product has great reviews on Amazon. Is everybody low in nad? Does everybody need to supplement nad? Or if you're eating a great diet, do you not need to?

Yeah.

And then the second part of that question is, when you fix the NAD deficit, do you notice anything or is it, is it not really noticeable?

Superb questions. So in the blood, you can't see that much of a change, except in some rare individuals that have, you know, genetic diseases. But tissue NAD in the skin, in the looks like in the brain and some other tissues does decline in aging. You get NAD precursors from diet. And so, you know, this is not a substitute for all the other good advice that we got from, you know, grandmother and our parents, which is to, you know, eat well and you already said sleep regularly and maintain a high level of Physical activity, stay mentally challenged, have social engagement, and, you know, all of those things are really good for healthy living. I think that with metabolic stresses, many of which are inevitable, and with aging, our tissue NAD is going to decline. And so probably the most people that supplement with Tru Niagen are 35 to 40 and above. Although there's some pro athletes that are, you know, in their 20s that are. They're kind of boosting their NAD with this product. What do you notice? So some people say that they feel more energy, you know, from the first day that they take it. I wouldn't say that. That was my experience. I would say that in the first week or two, I felt my digestion get better. And quite a lot of people talk about stamina, but if you don't really have a health complaint, then you may not feel that much. It's sort of like a boost to your intrinsic operating system. It's sort of like antivirus software for a computer. It's supposed to prevent things from going wrong and virus disruptions. And if it's working, then you notice nothing because you haven't been disrupted by things. But you might go through a winter and see your friends and family suffering from flus and colds, and you might be on a plane with a business partner who is terribly jet lagged, and you just sort of skip through these types of metabolic stresses much easier than other people. I've seen my run times improve and, you know, I wasn't really watching my weight, but, you know, after a few months I noticed that I was, you know, at a newly kind of constricted belt loop. And so it tends to be associated with a higher level of, you know, physical activity and, you know, and wellness. But it doesn't feel like a stimulant, like it doesn't feel like a cup of coffee. One thing that's really interesting, though, Jason, was just published yesterday in Nature Communication. So not sure when folks are going to be listening to this podcast, but today is March 30, and on March 29, Nature Communications published a study from University of Colorado Boulder in which they gave pretty high doses of NR to healthy older adults. And the really interesting finding was that it was a placebo controlled trial. And with six weeks on a gram of NR per day, there was a reduction in systolic blood pressure. And when they did a subgroup analysis, it turned out about half of the people in the study had moderately elevated blood pressure. So, like systolic between 120 and 139.9, where 140 would have been medicated. Turns out those are the people. The people with a moderately elevated blood pressure were the ones that got a benefit of about 10 millimeters of mercury, about 10 points. The people that had normal blood pressure didn't become hypotensive. You know, it didn't press their blood pressure down to a low level. But the people that were moderately elevated had their blood pressure regularized. So we think that's a super exciting thing. And going forward, there's going to be additional clinical studies not only in, you know, healthy adults, but with people in diseases and conditions including heart failure and neuropathy and fatty liver, that we've been able to help in animals.

Yeah, yeah. Very interesting. Good stuff. Well, I think you already gave out the website. Is there anything else you want to share where people can find you and find out more about the work and then kind of wrap it up with tell us where this is going. If, if you have any thoughts on.

The future of this, I'd be delighted. So truniagen.com, t r u n I a g e n.com is a sales site. Aboutnad.com is a good educational site. Aboutnad.com and then my lab is Brenner Lab UIowa edu and you know, we have, I don't know, 125 publications and you can read about the research we're doing. So I just started giving a brand new seminar on what I call the maternal and neonatal effects of nicotinamide riboside. You know, I'm really interested in females and, you know, unfortunately in the laboratory research community, there's a lot of things that were only done with male animals. And we started to look at females and we're looking at post gestational biology. So what happens for a mom after she's given birth? And we're seeing some really exciting effects of nicotinamide riboside for maternal health and things that are going to have strong implications for neonatal health and development. So very, very interesting.

I gotta ask you one thing about that and I'll let you continue. But so is there sexual discrimination in lab animals too? This is just, I mean, it's just everywhere. You know, you hear this stuff.

It's unbelievable.

What do you mean? Come on.

No, I'm absolutely serious.

Okay.

So the general, you know, feeling in the animal, and I haven't historically been an animal researcher, I was a guy that basically worked on enzymes. And I, when I want to do my experimental system, I would do a thing with yeast with baker's yeast, you know, that you used to bake bread or brew beer. I say this on the eve of Passover where I'm not going to have bread or beer for a week. But, you know, when I entered, when I started doing animal experiments, you know, in order to, you know, see what is going to be the effect of NR in, you know, vertebrate systems, one of the things I learned is that a lot of labs only want to do things with males and they think that females are too complicated because of the estrous cycle. Like there are different times of the month, the animals are going to react differently, which they might. But there have been some terrible cases where, like drug candidate compounds have gone all the way through the preclinical pipeline only doing experiments in males. And then we don't even know what the dosing and the side effects are going to be in females. So I very proactively wanted to look at the effect of NR in male and female animals and male and female people. And we're getting a really pretty exciting story out of it.

Yeah. Yeah. Well, those poor males, they have to endure all the lab experiments. So, yeah, that's not very fair.

I don't know. They live in hotels. These mice in the laboratory get to live two years where out in the wild there's predation and they have very short lifespan. So we use animals very sparingly just so that we can learn really important things about human health. And I was very fortunate that I was able to discover NR from experiments with yeast. And the same sets of genes are all the way from yeast to human beings. But we certainly have learned some things about fatty liver and neuropathy and diabetes and heart failure from doing judicious animal experiments. So I hope that people understand that part of the scientific process.

Right. Well, Dr. Charles Brenner, thank you so much for joining us. This been a fascinating conversation and nad it's definitely something to look at. So check out the website and go from there. Charles, thank you.

Thank you so much.

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