EFR 891: Nitric Oxide Explained - Dr. Nathan Bryan on Aging, Alzheimer’s, and Performance

00:00 - Chase (Host)

The following is an Operation Podcast production. 

00:03 - Nathan (Guest)

Our body are designed in such an intricate way where there's always reactions and we signal, we turn things on, we turn things off, and our body is always adapting to a new environment. But nitric oxide, once it's produced, it signals right. So it activates second messenger systems and the second messengers are a little bit longer lasting. And then you got endocrine function, where it binds to molecules. It's transported throughout the cardiovascular system. So I always say nitric oxide is like if you've got a string of dominoes and that last domino is kind of like optimal life, optimal performance, and nitric oxide is that first domino, right? So to get to that end, all you have to do is tip over that first domino and then everything else takes care of itself. 

00:44 - Chase (Host)

And we're going to learn how to do that in a really efficient way today. 

00:47 - Nathan (Guest)

Hey everyone, Dr Nathan Bryan here, international leader in molecular medicine, nitric oxide biochemistry this is Ever Forward Radio. 

01:00 - Chase (Host)

Guys, welcome back to Ever Forward Radio. I have, by popular demand, the other man myth and legend. Apparently there are a few keys in the nitric oxide world. By popular demand you all just raved about Dr Nathan Bryan from my last few episodes covering nitric oxide two with Dr Lou Ignaro that are now well into the millions of views, and any other time I have a guest where we highlight nitric oxide it just takes off and the more and more I learn about nitric oxide and I sit across from learned scholars such as yourself it just continues to blow my mind as to how woven in this molecule, this gas, is to really essential daily living. But more than that, just thriving, beating disease, performance, recovery, longevity and so much more With that. 

01:53 - Nathan (Guest)

Dr Nathan Bryan. Welcome to the show. That's great news. Thanks, chase, for having me. It's great to be with you. 

01:57 - Chase (Host)

Yeah, my pleasure, my pleasure, and so, out of the gate, I want to ask what might seem a typical standard question. I'm sure you get a lot, but just for maybe my audience members that are new what is nitric oxide? Why is it so important for our health and, more specifically, why is it so important to you? 

02:16 - Nathan (Guest)

Yeah Well, to answer the first question, it's a naturally produced molecule. It's a gas, it's a very simple molecule. It's one nitrogen, one oxygen, and when it's produced in the body it's gone in less than a second. So it's what we call a signaling molecule. In fact, the Nobel Prize was awarded for the discovery of nitric oxide as a signaling molecule. But it does so many things in the human body. It regulates blood flow, it oxygenates the blood and cells, it turns on mitochondria, it mobilizes stem cells and it's actually a foundational molecule in longevity and human performance. 

02:51 - Chase (Host)

Pretty great answer. We're going to dive into the weeds of a lot of that stuff, but I think my audience should really pick up on the fact of how short-lived nitric oxide is in our body. I think, if memory serves, it has a half-life of like half a second, something like that, yeah, like that. 

03:05 - Nathan (Guest)

So if you look inside the blood vessels, so intravascular half-life is about two milliseconds, so one fifth of a second. 

03:11 - Chase (Host)

One fifth of a second. 

03:12 - Nathan (Guest)

If it's outside the blood supply, what we call extravascular, like any other cell. It's about two seconds, two to maybe five seconds. 

03:20 - Chase (Host)

So something that is so short-lived in the human body yet is so instrumental in making sure the body stays alive and, like I said earlier, thriving, just continues to blow my mind. So it must be that powerful. Imagine if it lived any longer we could. 

03:36 - Nathan (Guest)

We even survive nitric oxide living any longer than a couple milliseconds I mean our body are designed in such an intricate way where there's always reactions and we signal, we turn things on, we turn things off, and our body is always adapting to a new environment. But nitric oxide, once it's produced, it signals, right. So it activates second messenger systems and the second messengers are a little bit longer lasting. And then you got endocrine function, where it binds to molecules. It's transported throughout the cardiovascular system. So I always say nitric oxide is like if you've got a string of dominoes and that last domino is kind of like optimal life, optimal performance, and nitric oxide is that first domino, right? So to get to that end, all you have to do is tip over that first domino and then everything else takes care of itself and we're going to learn how to do that in a really efficient way today. 

04:26 - Chase (Host)

So with that, can you break down for us please? How does nitric oxide work in the human body? If you find yourself chasing better sleep, want more energy and striving for a longer, healthier life, then listen up, because this might be the simplest upgrade you could ever make. Meet C15. This is the essential fatty acid your body probably has been missing. I get mine from Fatty15, today's sponsor, and see, it's not just another fish oil. This is science-backed cell-deep nourishment that's been shown to support longevity, improve brain function and help us get deeper, more importantly, restorative sleep. So if you're ready to think clearer, sleep better, live longer, go check them out. See the science, see why I love taking daily Fatty 15, this teeny tiny, one little vegan capsule. And they got a special deal as listeners of the show. You can actually get 15% off of your entire first purchase, in fact, 15% off the already discounted 90-day starter kit. Just head to fatty15.com slash everforward to learn more. That's F-A-T-T-Y 1-5 dot com slash everforward. Your brain, body and future self will thank you. 

05:34 - Nathan (Guest)

Well, it works in most cells in the body. So I'll go back historically. The first pathway to be discovered or the first role of nitric oxide was what has a vasodilator right. So that means it dilates the blood vessels. So when nitric oxide is produced by the endothelial cells these are the cells that line all blood vessels throughout the body that gas diffuses into that smooth muscle, relaxes the smooth muscle and that leads to the blood vessel dilation. So that normalizes blood flow. It regulates things like sexual function. So if we want to have sex or be intimate, we've got to dilate the blood vessels of the sex organs and that's done through nitric oxide. 

06:12

For males and females Males and females, if we want to, you know, have an engaging conversation. We've got to increase blood flow to the brain. So right now we've got to turn on the blood supply to our brain so you and I can have a deep conversation. We can recall memory, we can think, we can you know, perform cognitively an executive, a high executive level. 

06:33 - Chase (Host)

So the same molecule responsible for sexual arousal is the one I'm relying on right now to be as present and cognitive as possible with you. 

06:43 - Nathan (Guest)

That's right. So it's the control and regulation of blood supply, right? We can't dilate all the blood vessels in the body or else we'd lose perfusion pressure. So we have to perfuse organs at different times, right? Like when we eat, we activate blood flow to the gastrointestinal tract to absorb nutrients. If we're in the gym and we're working out, we've got to increase blood flow to the skeletal muscles. If we're in the gym and we're working out, we've got to increase blood flow to the skeletal muscles. If we're running, we've got to increase blood flow to the coronary arteries. If we're thinking, we've got to increase blood flow to the brain to oxygenate, activate the mitochondria so you can make energy and the cells can do their job. If we're about to have sex, we've got to dilate the blood vessels of the sex organs so we can get an erection and perform sexually. So, but get an erection and perform sexually, but we don't all run around with an erection. 

07:26 - Chase (Host)

Well, maybe some do, I don't know, but it's the loss of regulation of blood flow the inability to dilate blood vessels upon demand, which leads to cognitive decline. 

07:36 - Nathan (Guest)

Alzheimer's dementia leads to kidney disease, liver disease, coronary disease. When we lose the ability to dilate and perfuse organs on demand, then those cells and tissues become dysfunctional. 

07:49 - Chase (Host)

It's again just wild. I mean, you're already hitting on so many bodily functions and things that we want to do and also bodily functions that we don't want to have happen, like disease and breakdown of organs, and it's all coming back to this one teeny, tiny little. 

08:03 - Nathan (Guest)

Well, that's just one action, that's. We covered a lot, but that's just the vasodilatory actions of nitric oxide. But it's a neurotransmitter in the central nervous system. It's how nerves communicate with one another, but it's also critically important in our immune defense and our immune system. 

08:18 - Chase (Host)

How so. 

08:19 - Nathan (Guest)

Well, when nitric oxide we're exposed to a bacterium or virus or any pathogen right, Our body recognizes that, so we mobilize an immune response. Let's just say we have a cut on our arm and we get a bacterial infection, and you know what happens after that? It turns red, it turns warm and it swells up. 

08:35 - Chase (Host)

It's good inflammation, that's a good, so we're mobilizing an immune response. 

08:38 - Nathan (Guest)

We're turning on our monocytes and neutrophils and macrophages and those are generating a lot of nitric oxide. So nitric oxide binds to the iron sulfur centers of bacteria and shuts down their respiration. And if we get a viral infection so if we're exposed to seasonal flu or coronavirus which we all survived then the body has to mobilize an immune response and then when nitric oxide is produced, it prevents the virus from replicating. So we're exposed to viruses every day. Some people get sick, some people don't. I haven't been sick from a viral infection in more than 25 years. It's not that I live in a sterile environment, it's just I've never had COVID. I don't get the flu. It's just my body knows when it's attacked, mobilize an immune response, generate nitric oxide and shuts down virus replication. 

09:22 - Chase (Host)

I'm sure you have some kind of maybe nitric oxide optimization protocol that is supporting that which actually I want to get into a little bit later on, but before we do, I'm really curious. Before we get into really understanding how to maximize and become more efficient with utilization and creation of nitric oxide, let's talk about symptoms of low nitric oxide. What does it look like? What does it feel like? What can maybe someone you know drop into their? 

09:50 - Nathan (Guest)

body that's listening, watching right now and go oh, that's kind of me. Well, we have to rely on symptoms and we have to listen to our body, because our body is always talking to us Right, and if we don't listen and don't respond and take action, then we get sick. But in terms of nitric oxide, the first sign and symptom and we call this the canary in the coal mine is sexual dysfunction. 

10:07 - Chase (Host)

Really. 

10:08 - Nathan (Guest)

Because if you can't make nitric oxide in the blood vessels that supply the sex organs, then it's not isolated to the pelvic region. You have that same dysfunction in your coronary arteries. You have the same dysfunction in your cerebral arteries. It just manifests first in the sex organs. Because if you can't make nitric oxide, you can't dilate the blood vessels. If you can't dilate the blood vessels, you don't get engorgement. If you don't get engorgement you don't get an erection. And it's the same in men and women. The anatomy is a little bit different, but the physiology is exactly the same. 

10:36 - Chase (Host)

Yeah, I feel like understanding that for a man is pretty obvious. Is it as obvious in terms of sensation and physical manipulation, in a woman? 

10:46 - Nathan (Guest)

So for women to have an orgasm that is triggered by an increase in intralabial and interclitoral pressure. So it's an increase in pressure that really manifests and climaxes as an orgasm. So where does that pressure come from? The pressure comes from an increase in volume. Increase in volume comes from dilation of the blood vessels. To get engorgement, that dilation is dependent upon nitric oxide production. So even in the female, if you're not generating nitric oxide in the pelvic region, in the sex organs, you don't get clitoral engorgement, you don't get labial engorgement, you don't get an increase in pressure and women become anorgasmic and you don't get to the secretions. So women develop dryness, painful intercourse. So it's the same thing. For men it's just a blood flow problem, but for women it's secretions, it's sensitivity, it's lubrication and it's orgasms. 

11:37 - Chase (Host)

So the number one sign that we are deficient in nitric oxide is always going to be that sexual function. 

11:45 - Nathan (Guest)

It's usually manifest as sexual dysfunction. And then you know, because nitric oxide is the primary vasodilator. If we lose the ability to dilate blood vessels, then we get an elevation in blood pressure, because you have a finite amount of blood pumping through your body right now and if you can't make nitric oxide, you constrict the blood vessels. Now you've got that same volume going through smaller pipes. 

12:06

And simple physics says pressure goes up. So you know, two out of three Americans have an unsafe elevation in blood pressure. 50% of the men over the age of 40 self-report ED. I think the numbers are much higher because most 40-year-olds, I know aren't going to self-report and admit ED. 

12:22

It's a prideful thing, so I? I mean we have an epidemic of nitric oxide deficiency, so it's sexual dysfunction, it's high blood pressure. Then you start to develop metabolic disease. Nine out of ten americans are metabolically unfit. Because we my group, was the first to publish I think in 2010 that nitric oxide is part of the insulin signaling really so insulin resistance is a symptom of nitric oxide deficiency. 

12:46 - Chase (Host)

I've never heard this before. 

12:47 - Nathan (Guest)

Yeah, and it was a very important paper in 2011. We published that in Journal of Free Radical Biology and Medicine. 

12:53 - Chase (Host)

So are you saying, then, that pre-diabetes and diabetes type 1, type 2, all the above is actually traced all the way back to a nitric oxide deficiency? 

13:02 - Nathan (Guest)

Type 2, specifically, specifically, because it's insulin resistance. So you're not in type 1, your body's not making it. 

13:08

Type 2, insulin loses its ability to bring glucose into the cell, and so in this paper we published, we know that insulin binds to the insulin receptor in a cell primarily it's a muscle cell, liver cell or a fat cell and then intracellularly that turns on nitric oxide production and then that activates GLUT4, which is an intracellular protein to go to the membrane and bring glucose into the cell. But without nitric oxide production GLUT4 doesn't get the signal and you don't get glucose uptake. So it's insulin resistance. So you can develop hyperglycemia, hyperinsulinemia, and that's what we call type 2 diabetes. 

13:42 - Chase (Host)

Wow, I feel like I could go down a rabbit hole there of so many people when they hear pre-diabetes and getting a diagnosis of type 2 diabetes. It all comes down to majority speaking for, like, movement, nutrition, exercise you know your overconsumption. 

13:54

Diabetes is completely preventable, curable, treatable, right Well it makes me think, you know, are we not to say that maybe someone in the pre-diabetic or type 2 diabetes boat probably has room for modification in their diet and physical activity? But maybe if we just focus first, or maybe more, on things to support nitric oxide production, getting it back up, there might not need to be as many changes. That's exactly right. 

14:21 - Nathan (Guest)

We have to understand at the molecular level what's going on in the disease production. How does the human body make it? What goes wrong in people that can't make it? And then, only when you can answer those two questions can you develop rational therapies. Because if you don't know how the body makes it and you don't know what go wrong in people that can't make it, then who the hell are you to develop rational therapies? You can't do it. 

15:00 - Chase (Host)

Is there ever a situation where the human body, for whatever reason you know, becomes deficient in nitric oxide? It slows down, or can we even stop making nitric oxide? And if so, how do we ramp it back up? 

15:11 - Nathan (Guest)

The answer is yes, and the way to do that is to be American. What do you mean? It's the American lifestyle. 

15:17 - Chase (Host)

The standard American diet, the sad diet. 

15:19 - Nathan (Guest)

It's a sedentary lifestyle it's not sweating. 

15:26 - Chase (Host)

It's exposure to fluoride, mouthwash antibiotics, antacids. I learned which we're going to get into. 

15:28 - Nathan (Guest)

Yeah, now, most things that people are doing Americans are doing, and to me it's no reason why Americans are some of the sickest people on the planet. It's like everything they're doing their diet, their lifestyle, their oral hygienic practices, their medical practices and drugs they're taking all lead to shutdown of nitric oxide production. Wow, and then what happens? You get high blood pressure, you get ED, you get inflammation, oxidative stress and immune dysfunction. 

15:52 - Chase (Host)

And it's just a myriad, a cascade, of other. 

15:55 - Nathan (Guest)

It's the domino effect. It's a downfall right there. 

15:56 - Chase (Host)

Yeah, it's the bad domino effect, that's right. 

15:59 - Nathan (Guest)

That's the reverse domino effect you, I'm going to reverse it. 

16:02 - Chase (Host)

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17:16

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18:00 - Nathan (Guest)

I think it's primarily due to diet. You know we eat too much sugar, too many simple carbs. You know, if we followed the experts and the government pyramid chart on how the government thinks that we should all eat, we get sick. I mean it should be inverted. Don't follow that chart. No, don't follow that chart. I mean it's an experiment gone horribly wrong. No, but look, it's a high glycemic index food. Uh, diet, because when you get an increase in blood sugar, glucose right, glucose is glue glucose, it's sticky, it sticks to everything. Right, if you spill a soda water on the counter, you come back the next day it's sticky, it's sugar and so that's what happens in your body. 

18:44

It sticks to protein, it sticks tooglobin and that's hemoglobin A1C it's the quantifiable amount of sugar stuck to hemoglobin. And hemoglobin is a molecule, is a protein that has to undergo changes. Right, it goes to an allosteric structural change. When it goes from the arteries to the veins, it has to go change its conformation structural change. When it goes from the arteries to the veins, it has to go change its conformation. Take, deliver oxygen, pick up carbon dioxide. If glucose is stuck to it, it's glued together. You can't deliver oxygen, you can't pick up CO2, you become hypoxic, acidotic, you can't heal wounds, and that's why diabetics develop macular degeneration, poor wounds, neuropathy. 

19:25

It's because you can't deliver oxygen, just a walking inflammation, yeah and then it sticks to the nitric oxide synthase enzyme, and any enzyme has to undergo a conformational change to transfer electrons for a biochemical reaction. If it's glued together, it doesn't make nitric oxide, god. 

19:42 - Chase (Host)

Jeez man. Nitric oxide. It's everywhere. It's so important If you drink too. 

19:45 - Nathan (Guest)

If you consume too much sugar, you completely change the microbiome in the mouth and the gut need to develop dysbiosis and it's a slippery slide from there on. 

19:56 - Chase (Host)

Let's get into um, talking about nitric oxide and performance, recovery and longevity a little bit. You know, at my core, everford radio really is a health and fitness show. I started I was a clinical health coach and wellness director for a concierge medical practice for several years and my audience has grown with me a lot. But we definitely come back to what? What can we do to properly move as well and long as possible? Not saying everyone out there is just like the Olympic athlete. But you know we're trying to just feel good, look good for our own individual wellness goals. So let's talk individual performance and endurance and recovery. How does nitric oxide affect athletic performance and endurance specifically? 

20:31 - Nathan (Guest)

Well, I think it's an important subject because our health is our greatest asset, right? I mean, we've got to take care of our body if we're going to, you know, live up to the expectations of what we're here to do on earth. But there's kind of there's an acute effect of nitric oxide on performance and there's an adaptive effect. So, for instance, when you start to exercise and you're what, let's say, a well-trained athlete, olympic athlete, a professional athlete when we start to exercise, there's it causes sheer stress in the lining of the blood vessel. That says tells the blood vessels I need nitric oxide because I need more oxygen downstream. So that body produces nitric oxide. You dilate the blood vessels. Now you're going to get better oxygen, nutrient delivery to the heart, to the skeletal muscles, whatever muscle group you're working. So that's number one. Number two it improves the efficiency of mitochondrial ATP production. So it's directly affecting the efficiency of ATP production. So you're producing more energy with less oxygen. 

21:28 - Chase (Host)

Let me pause you real quick right there, nick. Are we good? Good, okay, more energy with less. More efficiency, less energy. 

21:39 - Nathan (Guest)

More efficiency, more energy, more efficiently with less oxygen. So now what does that mean? If you push the anaerobic threshold back, you get less lactic acid buildup, because you're more efficient, and so that means your recovery is going to be improved. 

21:52 - Chase (Host)

So is that saying, when we get the classic DOMS right, the delayed onset, muscle soreness and that quote, lactic acid buildup? Is that really because of a lack of sufficient nitric oxide, or did we just go too hard in the gym? 

22:04 - Nathan (Guest)

Well, you just switch, you run out of oxygen and then you start this anaerobic metabolism to get lactic acid as a byproduct and that causes muscle soreness. 

22:12 - Chase (Host)

Okay. 

22:13 - Nathan (Guest)

So if you can improve the efficiency of oxygen delivery and the efficiency of oxygen conversion into ATP in the mitochondria, then you maintain this aerobic cycle and metabolism. You get less lactic acid buildup. 

22:28 - Chase (Host)

Okay. 

22:28 - Nathan (Guest)

So that's the acute effects. Number two, the adaptive effects, are if your body's continuously making sufficient nitric oxide, there's a signaling pathway that tells the cell to make more mitochondria. So nitric oxide induces mitochondrial biogenesis no way. So now the net effect of that is now these cells have more mitochondria, generating more energy more efficiently, so now you're a well-oiled machine. 

22:51 - Chase (Host)

I've heard so much over the last few years come up around mitochondrial revitalization and, just you know, metabolic health. Mitochondrial health has been, at least in my world, a big topic and I, up until honestly sitting down with Dr Ignaro last year, haven't heard anybody talk about, as hey do this to help support healthy mitochondrial function. Quantity, quality why are we talking about, why are we talking more about, nitric oxide and its direct impact on our mitochondrial health? 

23:21 - Nathan (Guest)

You know, I don't know. We've appreciated this in the scientific and medical literature for the past 20 years. I mean I think this was. These were discovered in the 90s, so this isn't new information in terms of nitric oxide-inducing mitochondrial biogenesis and improving mitochondrial function. But you know there's a lot I mean for me. You know, every age-related chronic disease has lower numbers of mitochondria per cell and the mitochondria aren't functioning. So if nitric oxide can create more mitochondria that are working more efficiently, then that leads to the root cause of most age-related chronic disease. 

24:01 - Chase (Host)

Does nitric oxide improve cardiovascular health and longevity directly? 

24:06 - Nathan (Guest)

absolutely and mechanistically. We can explain this. So number one with cardiovascular disease, you know, is a broad category of symptoms. It's it's hypertension, it's obstructive coronary disease, ischemic heart disease, it's alzheimer's, it's it's a it's cardiovascular disease. What that means is that the blood vessels are no longer reactive so, which means you can no longer dilate the blood vessels. Or there's what's called obstructive coronary disease or obstructive cardiovascular disease, where you start to get plaque deposition in the lining of the blood vessel. There's like a physical obstruction in the lumen of the blood vessel, so you've got less blood flow getting to that organ. 

24:46

So what nitric oxide does? When you lose the ability to produce nitric oxide we call that the functional loss of nitric oxide in the endothelium then that's what sets the stage for the onset and progression of cardiovascular disease. So it's doing this through dilating blood vessels. If you can't make nitric oxide, you don't dilate blood vessels. Nitric oxide suppresses the expression of adhesion molecules. So when you lose nitric oxide you start expressing these adhesion molecules. Now your blood vessels are like Velcro. All the immune cells stick, you know, fat stick and everything. Then you lose the barrier function of the endothelial cells. You start to get smooth muscle hyperplasia, you get foam cells, atherosclerosis and then, at the end of the day, the plaque ruptures and that's heart attack and stroke. So everything we know about the onset and progression of cardiovascular disease can be traced back to the functional loss of nitric oxide and it's affecting platelet function and blood clotting, and everything we know about heart disease, heart attack, stroke, cardiovascular disease. 

25:44 - Chase (Host)

Forgive me if you already touched on this, but can we trace it back even further? Like what is the origin of nitric oxide? Is it a chemical reaction, chemical byproduct? Does it need other molecules in place and functioning properly in order for it to like exist? Like how does nitric oxide even come into the play? 

26:03 - Nathan (Guest)

Well, it's a molecule that's produced. It's produced by several pathways. So there's an enzyme found in our endothelial cells and there's the same isoform that's found in our neurons. There's a different isoform found in our immune cells, but this enzyme, its job is to make nitric oxide and it's a very complex, complicated reaction. It's what we call in biochemistry. It's a five electron oxidation, multi-step oxidation reaction. So you have to be able to count electrons and figure out where you got to have electron donors. 

26:32 - Chase (Host)

That's above my pay grade for sure, but it's important to know. 

26:35 - Nathan (Guest)

Thank you this enzyme takes L-arginine and you're listening to probably with L-arginine and through that five electron oxidation, arginine is converted to nitric oxide gas and then the byproduct of that reaction is l-citrulline. 

26:49 - Chase (Host)

So citrulline is a byproduct of nitric oxide production, it's not a precursor these terms are probably pretty familiar for a lot of my audience members, myself included. 

26:59 - Nathan (Guest)

These are two very common ingredients amino acids workouts and amino acids you have bcas, things like that, yeah, interesting but our body is never deficient in these amino acids, so it makes no sense to supplement with them it makes no sense to supplement with l-citrulline with arginine or l-citrulline really there's no. 

27:16 - Chase (Host)

We already had like a max threshold. Like by taking any more we're not getting any extra benefit no, in fact, by taking you could actually do more harm. What. 

27:24 - Nathan (Guest)

Yeah. 

27:27 - Chase (Host)

My workout this morning I took I take a stimulant free pre-workout. Caffeine free has arginine, l-citrulline in it. So are you telling me I'm thinking I'm getting a better workout but I might be causing mitochondrial? 

27:40 - Nathan (Guest)

damage. There's a couple of things. You're a young, healthy guy. The clinical data tell us that if you take a patient and these were done in post-infarct patients, so people who just suffered a heart attack these studies were published in the 1990s but they wanted to and the design, the intent of the study was good. Right, you want to increase nitric oxide production in people who just had a heart attack to see if you could improve recovery of the heart right, and so they give them high dose L-arginine, and this was in a double-blind, placebo-controlled clinical trial. 

28:13

They gave a placebo and they gave L-arginine. And they stopped the clinical trial halfway through because the patients who were getting the L-arginine suffered higher death, higher morbidity, higher mortality. Why am I not? 

28:26 - Chase (Host)

dying by taking this in a pre-workout, then Well, because you have good enthylal function. 

28:30 - Nathan (Guest)

So mechanistically we know that if you push arginine through a patient that has an uncoupled NOS enzyme, that enzyme produces superoxide, which is an oxygen radical, instead of making nitric oxide. So you're exacerbating the condition you're trying to fix. And then several years later the same thing happened in patients with peripheral heart disease High dose arginine the patients got worse. 

28:52 - Chase (Host)

Wow. 

28:53 - Nathan (Guest)

They don't get better. 

28:55 - Chase (Host)

I can understand from what kind of that acute clinical model, but I just want to bring it back to you know myself and kind of you know, my typical listener audience member here. I think most people are still taking pre-workouts that have this ingredient in it and I just want to kind of like revisit this again with you. Are we doing damage or is it just more unnecessary? 

29:17 - Nathan (Guest)

I think it's in young, healthy people. I think it's just unnecessary because we're never deficient in arginine. Okay, the binding constant, the amount of arginine you need to bind to theoretically saturate the enzyme nitric oxide synthase, is only five micromolar. That's nothing. There's 100 to 200 micromolar inside the cell. So you already have 20 to 40 times more than what's necessary. The problem is you can run into problems if you take too much arginine. You increase the expression of an enzyme called arginase 2. And arginase diverts arginine away from nitric oxide and through ornithine and urea disposal. So theoretically and biochemically you could divert arginine away from nitric oxide and toward urea, because it's the body's response to too much nitrogen. If you take too much nitrogen you get into problems and your body has to dispose of it through urea in the urine. 

30:09 - Chase (Host)

And I want to actually, while I have you here, I'm like live fact-checking something I want to look at this like ingredient profile of a very common pre-workout to see exactly the levels, to get your feedback on it. Oh, excuse me, it's L-centitrulline. I'm not seeing actually any arginine, but I do know it is a fairly common ingredient. It can be found in a lot of products like a pre-workout. How do you feel about L-Citrulline being in there? 

30:39 - Nathan (Guest)

Again, all these amino acids. These are semi-essential amino acids. We get it from the breakdown of proteins. Whether you eat animal protein or plant protein, these are common constituent amino acids of proteins. The other thing is every cell in the body has what's called the partial urea cycle, and so this partial urea cycle is continuously producing arginine and citrulline. And because citrulline is a byproduct of nitric oxide production, any time you give a byproduct of a biochemical reaction, sometimes there's feedback inhibition so it can shut down nitric oxide production. But citrulline is so far away from nitric oxide. Citrulline has to go through an enzyme called argininosuccinate synthase. It has to go through an enzyme called argininosuccinate lys to make arginine. Then arginine's got to go through nitric oxide synthase to make nitric oxide and citrulline. So you're so far away, wow, from nitric oxide. Again. 

31:31

Probably it's not going to cause any harm, it's just unnecessary, unnecessary and these, these companies who do this, just don't understand the enzymology and the biochemistry I doubt it um some maybe, but I doubt it. 

31:42 - Chase (Host)

what about, excuse me, kind of staying on track with the supplements and lifestyle here? Looking at beetroot powder, I know that's becoming, I think, more common for replacement for a pre-workout because of its supposed nitric oxide-inducing benefits. 

32:00 - Nathan (Guest)

Supposed is probably a good word. 

32:02 - Chase (Host)

Really. 

32:03 - Nathan (Guest)

Look beets. There was some pretty good data coming out of the UK in 2010, 2011. So by the time the 2012 Olympic Games came around in London, you found that most of these Olympic athletes were drinking liters and liters of beetroot juice and causing a lot of gastric discomfort, but they were getting some benefits out of it, and the published data showed that if you took beet juice with a standardized amount of inorganic nitrate, then if you had the right oral bacteria and you had sufficient stomach acid production and the circuit was in place, then you could produce nitric oxide and it could talk about all the performance-enhancing effects that we talked about earlier. So then the market was flooded with beetroot products right, Beetroot juice, beetroot powders and so I began to test these products because clearly, the mechanism of action of the performance-enhancing effects of beetroot was due to the nitrate content, and then the person had to have the right oral bacteria and the person couldn't take antacids or else you completely bypass this effect. 

33:04 - Chase (Host)

So it has to be this perfect storm of the person taking it. 

33:07 - Nathan (Guest)

So number one I tested almost all the products and probably 95% of the products out there. There was no detectable nitrate or nitrite in the beetroot products, so they were dead beets. They're dead beet products. So, in fact, and we were doing clinical trials at the time and we used these commercial beet products as placebos in our clinical trials because they're the perfect placebo. They're beets but they don't produce nitric oxide. What, wow? So the market is now flooded with these products and really the only thing they do is turn your pee and your poop pink and cause a lot of anxiety. Pretty wild colors. 

33:40 - Chase (Host)

So you know again, to kind of cap up this you know recovery performance section. So you know again, to kind of cap up this you know recovery performance section, what can we really do? That is, one safe and two going to actually move the needle to get the results we want. 

34:04 - Nathan (Guest)

but sometimes a solution is pretty simple. You only have to do two things to enhance nitric oxide production. Number one you've got to stop doing the things that inhibit it. And number two, you've got to start doing the things that promote it. So what is that? The first thing you've got to do is stop doing the things that we know shut down nitric oxide production, like what Aniseptic mouthwash, anything that's going to destroy the microbiome. Fluoride in your water supply, fluoride in your toothpaste these are antiseptics that kill all bacteria. Antacids we talked about antacids, the proton pump inhibitors completely shut down. 

34:42 - Chase (Host)

We're going to get into that a little bit deeper. Hold on everybody. 

34:44 - Nathan (Guest)

And then it's a high sugar, high carbohydrate diet. Again it causes you know, shuts down nitric oxide production, causes a lot of oxidative stress. So if you get rid of fluoride, if you get rid of mouthwash, if you stop using antacids and you eliminate simple carbohydrates and sugar, anything that leads to an increase in blood sugar, now you've released the brakes on the body to produce nitric oxide and then to activate it and stimulate it, you can moderate physical exercise. 

35:14 - Chase (Host)

Define moderate for us. What do you? 

35:16 - Nathan (Guest)

mean by that. We used to say 20 to 30 minutes of moderate physical exercise was sufficient. You know, get your heart rate up, get your breath rate up. Now we know that just four to five minutes of high-intensity interval training is enough to stimulate nitric oxide production Daily or a couple days a week. 

35:33 - Chase (Host)

What's that sweet spot there? 

35:34 - Nathan (Guest)

I mean, I think it's important that we have to do this daily. I mean, probably each time you do it, you're going to get a cumulative effect. So that's a more ideal scenario More ideal scenario Number two is nasal breathing, so there's a high concentration of this enzyme in the upper airway sinuses. 

35:51 - Chase (Host)

Yeah, please go there more for us. This is actually another question I had around what's the science behind nitroxide nasal breathing techniques and why is nasal breathing so important for nitroxide efficiency in production? 

36:03 - Nathan (Guest)

Well, that same enzyme that's in our endothelial cells is also in our epithelial cells. So the endothelial cells are inside the body, right Endo. The epithelial cells are outside the body, in our gut, in our sinuses, but this enzyme is found there. So when we do nasal breathing, there's mechanoreceptors on these epithelial cells and when they're activated they go. I need nitric oxide. You got to make nitric oxide. So now, when you're making nitric oxide, you're doing nasal breathing, You're delivering that NO into the lower airways and it's not just a vasodilator, it's a bronchodilator. No-transcript. You're supersaturating the red cell and you're lowering blood pressure. And there's clinical data showing nasal breathing, deep breathing, meditation, can lower blood pressure and it's a nitric oxide-related phenomenon. But here's the big but that enzyme has to be functional. So if you have all these risk factors, if you have ED, if you have high blood pressure, if you eat a high-sugar diet, you can nasal breathe until the cows come home. 

37:07 - Chase (Host)

But you're not producing any nitric oxide. You're not even like, let's say, someone has ED, has cardiovascular disease, and they're going to start with one thing today and it's nasal breathing. Is there ever a point where it's going to help them, or is the damage already done? 

37:16 - Nathan (Guest)

No, you can reverse this function of that enzyme so we can recouple it and maintain its normal function. So now we can do this through a gas phase analyzer that I have. I've used in the research lab and I have one at home. But you can measure the nitric oxide coming out of the nasal sinuses either when you're humming or when you're doing nasal breathing talk to us about humming. 

37:35 - Chase (Host)

This was something that I did a clip with dr gnago on this and it took off Like millions of views. People were just floored as to how humming actually has any kind of net positive health effect. Why humming? What does it do? What's going on there? 

37:49 - Nathan (Guest)

Well, there's certain frequency. When we think about biochemistry, everything is transfer of electrons In humming. There's certain frequencies of sound that'll activate this and either release nitric oxide from certain carrier molecules or stimulate nitric oxide production. 

38:03 - Chase (Host)

So do we have to hum in tune. 

38:06 - Nathan (Guest)

Well, the challenge is it's different for everybody because the resonance frequency is dependent upon the volume of the sinuses and the oral cavity, but you just got to figure it out and figure out what's comfortable. But this resonance frequency is what stimulates nitric oxide production. 

38:21 - Chase (Host)

So how do we know if we want to start nasal humming right now? How do we know it's in the right tune, the right resonance? 

38:28 - Nathan (Guest)

There's a certain frequency and I can't recall the literature now. It's searchable, I just don't recall what it is. 

38:34 - Chase (Host)

Do you feel confident that most people just their standard, whatever just hum comes out of their nose? Are we close or is this just a waste of time? 

38:42 - Nathan (Guest)

No, I think it's probably close. I think whatever occurs naturally is typically by reason. But again, we've got to focus on recoupling that enzyme and making it functional. So when we start to hum and we start to do nasal breathing, we're actually producing nitric oxide and get the benefits of it. Where we can oxygenate tissue, we can mobilize stem cells and lower blood pressure. 

39:01 - Chase (Host)

Okay, it makes me think about nasal breathing. It's become very popular uh for mouth taping. Yeah, I've been mouth taping for a couple years now and uh, walk us through the benefits. Is there any of mouth taping to stimulate nasal breathing while we sleep to help nitric oxide production? 

39:17 - Nathan (Guest)

I think there's benefits to mouth breathing, provided you've seen an airway physician to make sure that you've got an open airway, because if you don't, if you've got obstructive airway disease and you tape your mouth, I mean you could become severely anoxic and certainly hypoxic are you talking more of a true sleep apnea? 

39:35

yeah, so it'd be, and it's an anatomical obstruction, either the jaws push back and it's obstructing the airway, so that sometimes you have to do some manipulation or some some appliances. But in a person that has a normal airway and they're just mouth breathers, yeah, you tape the mouth closed because here's what happens the mouth breathers at night are not only bypassing this normal nitric oxide production, they're inhibiting the nitric oxide production by the oral bacteria because you're fully oxygenating and changing the ecology of the bacteria and it's leading to a low ph in the saliva, it leads to tooth decay, it completely changes the microbiome, it completely shuts down nitric oxide production. So, close your mouth, tape your mouth and you're going to change the ecology in the microbiome. But I think, just as importantly, now you're going to start the ecology in the microbiome. But I think, just as importantly, now you're going to start to activate nitric oxide production. 

40:25

And people with sleep apnea they don't oxygenate at night, right, and so in order for that enzyme to make nitric oxide, it requires oxygen. So when we sleep, that's our time to repair right, and nitric oxide is the signal that tells our own stem cells to mobilize and differentiate. So at night, when we sleep, we're mobilizing stem cells, we're repairing dysfunctional cells and we're repairing the body. We're regenerative by nature. But if you're hypoxic because you have sleep apnea, you don't have enough oxygen to make nitric oxide, so you develop hypoxia, you don't mobilize stem cells, you wake up tired, your mitochondria become dysfunctional and you feel awful the next day. 

41:05 - Chase (Host)

And this could be or could not be really the needle could be moved or not, by mouth taping, the needle can be moved. 

41:13 - Nathan (Guest)

Number one it's going to change the ecology of the microbiome and once we concentrate on focusing, recoupling the function of the NOS enzyme, now you're going to get nitric oxide production, you're not going to develop hypoxia, You're going to oxygenate at night, you're going to mobilize stem cells and, you know, wake up feeling much better. 

41:30 - Chase (Host)

Okay, I've heard you mentioned a couple of things that seem to be the crucial kind of steps, process pathways, if you will, of nitric oxide production, where we can stimulate it and where we're maybe prohibiting it. And besides the nose, you brought up the mouth biome a few times. Why is the? 

41:52 - Nathan (Guest)

mouth so important to nitric oxide production. Or you know, squashing it Back in the probably 70s or 80s. Well, the late 70s, it was discovered that our salivary glands concentrate inorganic nitrate from the diet. So nitrate is this molecule that's found in green leafy vegetables, beets, for example. And then in the 70s these cancer biologists thought nitrate would form nitrosamines, which would then intercalate dna, cause mutations and cause cancer. Right, it's the whole cured meat, bacon hot dog cancer hypothesis. 

42:21 - Chase (Host)

Yeah, okay, yeah, that's why you see no nitrates, no nitrites. Is that all because of this? 

42:26 - Nathan (Guest)

That's right. That's deceptive marketing, by the way, wow. 

42:29

So in the 70s it was realized that the body number one, the kidneys, reabsorb nitrate and then concentrate it in our salivary glands. So the question was, why is the body intentionally concentrating nitrate on our salivary glands? And then in the 90s it was recognized that they're nitrate-reducing bacteria that take that nitrate. They're faculty of anaerobes, so if you don't have oxygen they respire on nitrogen. And now they're converting that nitrate into nitrite. Now our saliva is enriched in nitrite. We swallow our saliva and the intention is to produce stomach acid. So now that nitrite becomes nitric oxide in the lumen of the stomach. So now the health benefits of a diet, a plant-based diet, are you eat these nitrate-rich foods. The bacteria convert it into a usable form because humans don't have a nitrate reductase gene. And now if we make stomach acid, we get a burst of nitric oxide in the lumen of the stomach and it's like a reservoir of nitric oxide and it can dilate blood vessels. It kills H pylori, it kills E coli, it kills salmonella, it kills botulism, anything, any foodborne pathogen it kills. 

43:33 - Chase (Host)

Okay, so that poses the question right there for me of you know are vegetarians and vegans. Are they naturally more rich with nitric oxide because they hypothetically are consuming more of these vegetables? Deep leafy green vegetables. 

43:46 - Nathan (Guest)

Well, it depends. It depends upon their oral microbiome and if they're taking antacids. Okay, but here's what we know from the work of Caldwell Esselstyn, joel Kahn, a lot of these vegetarian vegan cardiologists. The data are very clear. If you've got a patient with advanced coronary artery disease and obstructive coronary disease, you put them on a plant-based diet. You can see plaque regression. It happened with Bill Clinton. It's happened to a lot of high-profile people. 

44:12

But in having conversations with Dr Leslie, he goes. You know, some people respond, some people don't, and I go. Well, here's the question. You have to ask how many of those people you switch to plant-based diet use fluoride toothpaste? How many of those people are using mouthwash? How many of those people are on antacids? And he goes oh shit, he goes, that's it then. Wow. So now if you're going to eat a plant-based diet, you've got to make sure you have the right microbiome. You can't have fluoride. 

44:46 - Chase (Host)

You can't use antiseptic mouthwash and you damn sure can't take antacids, or else the diet won't work for you. Okay, take us to the antacid point. Um, I heard you talk about this on a few other episodes, few other shows, and the whole like proton pump inhibitor thing just blows my mind as well, one how people are just popping them like for months and years when that was never supposed to be the case. 

44:59

Um, so there's a whole nother issue there, just like why are we taking medication for so long when it was never approved or proven safe? But on top of that we're solving one problem you know, supposedly but really causing potential detrimental damage to nitroxide production. 

45:16 - Nathan (Guest)

Yeah, so these drugs? I mean there are different classes of antacids. Right, there's the H2 blockers, there's the buffersers, the sodium bicarb, then there's the dangerous ones called proton pump inhibitors, and these are the. The original prescription drugs were the mopazol and the pantoprazole. 

45:31 - Chase (Host)

Those are prescription forms of this I used to be on those, yeah yeah, no, and look it's so. 

45:36 - Nathan (Guest)

The clinical trials when you do a clinical trial through the fda, you go through kind of a protocol and you look for a specific endpoint, a dosing regimen, and the purpose was to treat acute gastroesophageal reflux disease. 

45:50 - Chase (Host)

Really bad heartburn. Really bad heartburn For the layman. Yeah, right, yeah. 

45:53 - Nathan (Guest)

And so these drugs were used for three to five days and never after that right Acute esophageal reflux disease. But then at some point some regulatory or probably some lobbyist had this idea well, let's make these over the counter, where you don't even need a prescription for them. Now you can go get your Prilosec, prevacid, your Nexium. And people take these every day, and some people have been taking them for 15, 20, 30 years. And now if you look at the outcome data that people have been on PPIs for three to five years, there's three independent reports 40% higher incidence of Alzheimer's, 35% incidence higher incidence of heart attacks and strokes Come on. 

46:34 - Chase (Host)

It's not increased risk. 

46:36 - Nathan (Guest)

It's increased incidence. It's actual incidence. 

46:38 - Chase (Host)

Just for taking heartburn medication. 

46:40 - Nathan (Guest)

Just taking the PPIs. 

46:41 - Chase (Host)

Come on. 

46:43 - Nathan (Guest)

That's horrible when you take that clinical observation. And then what we try to do is take that observation. Let's work backwards, figure out, okay, what's causing this, because it's indisputable. I mean highly significant P-value of like 0.001. So, mechanistically, what's causing Alzheimer's, heart attack and stroke? And a group out of Houston determined that these drugs are completely inhibiting nitric oxide production from the enzyme in the lining of the blood vessel and from the nitric oxide that's being produced from the diet, from swallowing our own saliva. So you want to know what happens when you inhibit nitric oxide production you get heart attack, you get stroke, you get Alzheimer's. So these and I've argued this for the past 10 years, because this data is more than 10 years old the drug companies and the regulators have to take these drugs off the market. These are worse than the COX-2 inhibitors back in 25 years ago. 

47:33 - Chase (Host)

I will. You know, the Vioxx, the Celebrex, those were causing heart attack and stroke and they took them off the market. That was a responsible thing. I hope people would choose to live with heartburn than not live at all. 

47:42 - Nathan (Guest)

No, that's right. These are deadly drugs, they're dangerous and they should not be over the counter. And I tell people all the time you got to wean off of these, no matter how bad the heartburn is. You got to slowly wean off of these drugs, titrate off of them, and else you're going to get a heart attack, stroke or Alzheimer's and you're going to die from it. 

47:58 - Chase (Host)

Is there anything you can walk us through to further support oral microbiome health beyond not using antiseptic mouthwash, not using fluoride? Are there any particular foods or liquids? Or, you know, I think the nasal breathing technique can definitely support that, like we talked about. But what else can we do to support a healthy oral microbiome, therefore supporting healthy nitric oxide function? 

48:23 - Nathan (Guest)

Well, it's dependent upon diet, the foods you eat. So the bacteria that we've investigated and cultured and published on these are faculty of anaerobes, so they live on the dorsal part of the tongue, near the gag reflex, deep in the crypts of the tongue. So if there's oxygen around, they can respire on oxygen. If there's no oxygen, they reduce nitrate into nitrite and they use that as their energy source. So, yeah, more green leafy vegetables. So nitrate can act as a prebiotic. You've got to close your mouth. You can't be, because that changes the pH. You've got to have an optimal salivary pH and then just eliminate things that destroy the microbiome Antibiotics, antiseptic, mouthwash, fluoride those are the big ones. And sugar, sugar, completely changes the ecology of the microbiome. 

49:10 - Chase (Host)

Well, I'm very happy to share with you. Before we sat down, my lunch was a large sweet green salad full of deep green leafy vegetables. Hopefully you didn't use fluoride toothpaste. Nope, nope, nope. I haven't used that for years. I I swap out the spring mix salad and my guacamole greens for kale. So, uh, you know what? Besides kale? Maybe you know what other? Maybe it's actual if you're familiar other dark, deep green leafy vegetables that we can well typically the darker, the green, the more nitrogen okay and so just any green vegetable any, any green vegetable. 

49:40 - Nathan (Guest)

But you know, in 2015, we published this paper. That's got a lot of attention because we wanted to make recommendations Like if you wanted to enhance your nitric oxide production, the question was, how many stalks of celery or how many grams of spinach or lettuce or kale would you need to eat in a single serving to fuel and prime this nitric oxide pathway? That's a very important question. So we went to Dallas here in Los Angeles, raleigh, north Carolina, new York and Chicago Kind of five cities around all US and then we brought those back to my lab, we analyzed them, we extracted the nitrate and we analyzed it and we reported it. What we found was that the nitrate in vegetables grown in Dallas and Los Angeles were 30, 40, 50 times different than what was grown in Chicago or New York. 

50:32

Why? Well, it's the soil conditions, it's the growing season, it's whether you add nitrogen-based fertilizers to the soil or not. It's the time of harvest. It's the time of harvest. It's the amount of lightning storms that happen in that area, because lightning fixes nitrogen in the air. The air we breathe is 78% nitrogen. 

50:50

God, the level to which everything is connected to nitric oxide Lightning fixes that nitrogen and puts it in the soil. 

50:54 - Chase (Host)

Mother nature could be why you have low nitric oxide. You live in a high lightning environment, no move, that's right. You live in a high lightning environment, no move, that's right, oh my God, geez. Well, I mean, this is a whole other conversation as well. Yeah, that's a whole field of agronomy, of just like the dip in agriculture and the poor soil levels and just being depleted and not being turned over properly. 

51:14 - Nathan (Guest)

So I mean this is just so there's no way we can predict or make recommendations on which vegetable, because even across from vegetable, from celery to lettuce- to spinach, I mean, there's as much as a 30 or 40 fold difference. And even that same vegetable from celery in Dallas to New York, it's a, you know, 80 fold difference. 

51:34 - Chase (Host)

It makes me think, just like and not to get bogged down in the details, but just whatever diet you abide by, right, let's say you're traveling and you know, and you go to Dallas, you go to LA, you go to Chicago, you go to Raleigh, north Carolina, and you might be staying true to the same diet. Maybe you eat the same foods or same quantity or types of food, maybe 90% of your diet, like myself, is pretty regimented, pretty much the same. But depending on where you are, you could actually really be way far off from maximizing these goals, especially when it comes to nitric oxide. 

52:05 - Nathan (Guest)

Well, I just spent 10 days in Italy and I can tell you, the food that I ate there made me feel incredibly better and different than eating the same foods here in the US. Isn't that the best? Yeah, I'm trying to convince my wife to move all the time to go over there. 

52:21 - Chase (Host)

I mean, we love a pasta and stuff in Italian food anyway, but it's just like why is that? And now we know why you go over there. You eat pasta all day, every day, and over here it's kind of demonized like no carbs, no pasta, none of this stuff. 

52:33 - Nathan (Guest)

But it's like I can eat my body weight in pasta over there and I feel better than I do over here. 

52:37 - Chase (Host)

It's crazy, so it's crazy. So we've been talking a lot about different ways to really influence nitric oxide production and maximize quality and efficiency. 

52:52 - Nathan (Guest)

Are there any risks to boosting nitric oxide through these practices? Yeah, there's risk in everything. I mean what we know about the toxicology of nitric oxide. There's only two things we worry about. The toxicity of nitric oxide is defined by an unsafe drop in blood pressure and a condition called methemoglobinemia. So you'll see an unsafe drop in blood pressure long before you start to see any methemoglobin formation. So methemoglobin is when you take too much nitric oxide. It oxidizes the iron of hemoglobin and changes it to an iron three or what we call methemoglobin. So people become cyanotic. Their blood looks like it's really chocolatey. So it loses the oxygen-carrying capacity of the red blood cell. But you don't see that. And so if you take too much nitric oxide or you administer too much nitric oxide, it could lead to systemic vasodilation, you could lose perfusion pressure, unsafe drop-in blood pressure, you could syncope and maybe pass out. 

53:42 - Chase (Host)

Would this be something someone would be able to tell pretty quickly that this is happening? I'm just thinking they're listening. I'm eating all the dark, deep green, leafy vegetables possible. 

53:52 - Nathan (Guest)

You cannot overdose on food, okay. 

53:54 - Chase (Host)

I'm like, am I going to get too nitric oxide-y? 

53:56 - Nathan (Guest)

No, but I think there's an inherent inefficiency and I think it's by design. There's an inherent inefficiency and I think it's by design. So the amount of nitrate that we consume in the diet, under absolute best scenario you're only going to metabolize about five percent of that wow. So the kidneys reabsorb about 25 of it. It's concentrated in our salivary glands and then the bacteria that live in the mouth are only going to convert about 20 of what's in the saliva. So 20 of 25 is five percent. Wow, of what's in the saliva. So 20% of 25 is 5%. And that's under the absolute best optimal conditions. 

54:28 - Chase (Host)

Can you take us back to that point you made about the creative marketing around nitrates and nitrites and like certain foods and deli meats and even wines and things like that, and why does that matter? 

54:40 - Nathan (Guest)

So again back probably this started in the 50s. We'll go back, because I always try to. Why are we doing things? Why are things done today? And they have to have a reason. So I have to go back historically and go what started this whole field? And in the 1950s there was a paper showing that nitrite-cured salmon or fish they could detect low molecular weight nitrosamines in nitride cured meat. So then low molecular weight nitrosamines are known carcinogens, mainly liver carcinogens. There it is okay. So it's thought okay, nitride added to meat forms nitrosamines. Nitrosamines cause cancer. So if A equals B and B equals C, then A equals C. 

55:16 - Chase (Host)

A equals C yeah. 

55:17 - Nathan (Guest)

And so the nutritional epidemiologists started down this road and they started doing studies of people who eat a disproportionate amount of cured meat right Hot dogs, bacon, sausages and they found they have a slightly higher increased risk of gastrointestinal disease, mainly stomach cancer. So then they thought, okay, well, it's the cured and processed meats that have nitrite and nitrate, that form nitrosamines, that are causing the cancer. 

55:43 - Chase (Host)

And probably taking antacids too. 

55:45 - Nathan (Guest)

There's so many confounding factors In nutritional epidemiology. If you don't have a relative risk of greater than two, it's probably noise, so it's not a real effect. But then if that were the case and I started publishing on this in the early 2000s if this were the case, if nitrite and nitrate cause cancer 2000s, if this were the case, if nitrite and nitrate cause cancer, then vegetarians would have a 10-time higher rate of cancers than meat eaters, because 85% of the burden from nitrate comes from green leafy vegetables. 

56:12 - Chase (Host)

And that's not happening. 

56:13 - Nathan (Guest)

That's not. It's protective and in fact, in 2009, I published a paper showing that nitrite and cancer in animal models of cancer prevented the cancer, prevented metastatic disease and protected many certain types of cancer. 

56:28 - Chase (Host)

So this whole nitrate nitrite-free is just clever marketing. It has no actual immediate impact on our health. 

56:35 - Nathan (Guest)

No, in fact, I think meat companies should be advertising this, because think about what they do. They're saying no nitrite added, but what they're doing can't by definition, you can't have a cured meat product without nitrite. So what they do is that they're not adding potassium nitrite or sodium nitrite salt. They're adding cultured celery extract, so celery salt, which is high in nitrate, and then they put a starter culture of bacterial in there, usually staph aureus and oraph carnosus, and that reduces the nitrate to the nitrite. So the nitrite is still curing the meat, but because they're adding cultured celery salt, they can put that on the label. It's still nitrite at the end of the day. Oh my goodness. 

57:13 - Chase (Host)

Okay, all right. So then we have celery salt in our pantry as like a seasoning. Is this something we should consider not using anymore? 

57:22 - Nathan (Guest)

You have to have bacteria on that surface of that for that celery salt to. I mean, nitrate is the curing agent. Nitrite is the curing agent and so in our 2010 paper, we published that nitrite cured bacon has about three to four times higher levels of nitrite than the nitrite cured. The no nitrite added bacon has three to four times higher nitrite, residual nitrite, than nitrite cured bacon. How are companies getting away with this? It's pushed by consumer demand. The consumers are so misinformed that they're demanding this from the meat supplier. I went and I consulted for Kraft, oscar Mayer and I go. You guys should be advertising. This is nitrite added meat and this is a health benefit. This is an indispensable nutrient and they go well. The consumers won't buy it, so they got to put no nitrate on it. So let's actually deceptive marketing. You should be advertising this. 

58:13 - Chase (Host)

That is a whole nother mess. Oh, my goodness, jeez. Uh well, while we're kind of talking about um, you know, consumer awareness, we can't have more consumer awareness without proper research happening first. So this is the world that you live in. What are the latest breakthroughs, if any, in nitric oxide research today, here at 2025? 

58:34 - Nathan (Guest)

Well, you know I've been doing this for more than 25 years now and really you know folks like Lou Ignaro and Fred Murad and Bob Furch got started this whole field with the Nobel Prize and their discoveries that you know 10, 20 years before the Nobel Prize was awarded. So these guys discovered that nitric oxide is produced in the human body and it signals. And then the next frontier was how do we safely and effectively deliver nitric oxide in product technology and drug therapy? And that's really been my focus for the past 20 years. Because I've solved the riddle of how to deliver nitric oxide in product technology and drug therapy. And that's really been my focus for the past 20 years. Because I've solved the riddle of how to deliver nitric oxide gas. 

59:08

We've made the solid dose form of nitric oxide gas. We can deliver it in an outpatient setting through an orally disintegrating tablet. We've had these products on the market for a number of years. But really what I'm focused on now is developing drug therapies around nitric oxide, because I think that will be the cure for cardiovascular disease. It will be the cure for Alzheimer's. We're developing a topical drug for diabetic ulcers and non-healing wounds. Nitric oxide completely heals wounds, diabetic ulcers, non-healing wounds. It kills the infection inside the wound, creates blood flow to an ischemic wound bed and the wound heals. 

59:44 - Chase (Host)

By you know, taking this kind of drug therapy by like an oral form of it. 

59:49 - Nathan (Guest)

We have OTC products. We have so-called dietary supplements on the market now that produce nitric oxide gas. So our whole thought process, my thought process when I started making these discoveries and following patents, was if you're If you have ED and you have high blood pressure and you have diabetes, I can't give you arginine or beet because you have dysbiosis. Your body can't make nitric oxide from it. That's your problem. So all these products that have been on the market giving you amino acids, precursors, substrates, beets they may work in a young, healthy individual, but people who are sick, who need nitric oxide, that's not a nitric oxide source for them. So I had to think a little bit differently. Best example is hormone replacement therapy, and nitric oxide is a hormone. We published on that in 2007. 

01:00:35 - Chase (Host)

Nitric oxide is a, hormone Is a hormone. 

01:00:36 - Nathan (Guest)

I was the first person to demonstrate that nitric oxide is a hormone. It's a 2007 paper. 

01:00:41 - Chase (Host)

I can't handle any more mind-blowing facts today. It's very simple now If any more mind-blowing facts today. 

01:00:46 - Nathan (Guest)

It's very simple now If you're low in testosterone, we give you testosterone, right? If women are low in estrogen, we give you estrogen. We don't give you DHEA or pregnenolone and hope your body can make these hormones out of it, we give it to you. Same thing with nitric oxide If you can't make nitric oxide, then I got to give it to you. So how do you deliver this fleeting gas? It to you? So how do you deliver this fleeting gas? And so how to develop a solid dose form of nitric oxide gas. And this is a lozenge you put in your mouth that dissolves over five to six minutes and we release therapeutic amounts of nitric oxide. 

01:01:15 - Chase (Host)

Okay, All right, this is fascinating. Is there only a net positive benefit for someone taking that, if they have these other chronic illnesses and diseases and are truly deficient, versus someone like I? Kind of go like you know the optimization biohacker route here of oh, if there's a way that I can just ingest it and get a little bit more, can I. Is that safe? Is that even realistic? 

01:01:38 - Nathan (Guest)

No, I think it. I say there's only two people in the world who need nitric oxide. There's the people who are sick and want to get well. There's the people, like us, who are well and don't want to get sick, and want to optimize and want to function every day to the best of our ability. 

01:01:51 - Chase (Host)

You would think everyone would fall into one of those categories. No, we either are sick or don't want to get sick, that's right. Hopefully that's you watching. 

01:01:58 - Nathan (Guest)

No, but I've been taking early forms of this. I had this epiphany back in probably 2002. Where I go? I back in probably 2002, where I go, I can make nitric oxide and I can go, and I did early experiments. I'd go to the gym and I'd do pull-ups and I'd take my nitric oxide. It was an early nasty tasting powder. Then I'd go back and I could do probably 20%, 40% more pull-ups. 

01:02:17 - Chase (Host)

No way. Immediately, immediately, it's not dependent on, like letting ATP regenerate or you know, really so. 

01:02:23 - Nathan (Guest)

I've been taking forms of my nitric oxide now for almost 20 years and I I take it not because I need it, because I don't want to need it right, because I want to make sure that my nitric oxide is optimized every day, when I wake up and throughout the day and so I'm very cognizant I watch my diet. 

01:02:43

I do an 18 hour fast every day. I work out first thing when I wake up in the morning, do 100, 100 push-ups, 100 squats, high-intensity interval training, and I pop a lozenge. I take my beets and beet powder in the morning, take my lozenge in the afternoon and it gets me through the day. I'm going to ask you to revisit that because I did have a question specifically around. 

01:03:08 - Chase (Host)

I have to know we have to know what is your nitric oxide optimization protocol. It's a number of things. It's hard work you personally. 

01:03:11 - Nathan (Guest)

No, me personally. I'm, as you, very regimented, so I try to get at least six and a half seven hours of sleep. My optimal sleep is seven to nine hours, and if I don't look, nobody can perform if they're not getting good sleep. 

01:03:24 - Chase (Host)

I'm a new dad here. Don't even talk to me about sleep right now. Going through a four-month regression, it's the worst. Yeah, yeah, no. 

01:03:31 - Nathan (Guest)

But my day starts out with an 18-hour fast. I eat my last meal at 6. I usually don't eat until noon the next day. But I wake up. I usually put on a pot of coffee, I take my what's called no beats, put it in two ounces of water, take it as a shot and then I do um 25 push-ups, 25 squats. 

01:03:52 - Chase (Host)

I do four sets sorry can we go back to the coffee and beats thing? I'm curious, uh, is that because you take it with coffee? Is that because it's, uh, works better? No, it's just, I like to have a cup of coffee in the morning, so I, I brew the cup, cup of coffee I'm just trying to extract all the secrets here. 

01:04:06 - Nathan (Guest)

So I take the beets so that immediately, as soon as it hits water, the solution just generates nitric oxide gas. Okay, so I take that first thing in the morning and it just dilates my blood vessels, gets my blood going. Then that's when I do my early morning workout. Okay, I do 100 push-ups, 100 squats, squats. I do it in usually less than four minutes can I ask your age sir? 

01:04:25 - Chase (Host)

51 you guys got to watch the video. This guy does not look. 

01:04:27 - Nathan (Guest)

51 well, I have the vascular age of a 36 year old. 

01:04:30

We do functional measurements um but then I do once I finish my workout, I go set in the sauna, 170 degrees for 30 minutes, an infrared sauna. So now I'm, but before I get in the sauna I take binders like corella spirulina. Sometimes I've activated charcoal Activated charcoal, yeah. And then, usually a couple days a week, I'll do a cold plunge three minutes at 37 degrees and then, when I'm home about that time the sun's coming up, so I'll go sit in my front yard naked looking at the sun for 15, 20 minutes, the beautiful Texas sunrise that's right, and then I eat a high-protein, low-carb lunch, and then I eat a dinner mainly protein. 

01:05:13

I live on 800 acres. I grow my own food and raise my own beef 800? 

01:05:17 - Chase (Host)

That's incredible. 

01:05:19 - Nathan (Guest)

So we know what I'm putting in my body and it's nothing like it. 

01:05:24 - Chase (Host)

There is nothing like it. I grew up on almost 200 acres in southwest virginia and, um, we ate most of the food that we grew and just ran amok in the woods and played in the creek and yeah, I, I feel you on that and the older I get now I'll be 40 this year I just keep wanting to go back to that. I'm like I'm looking for another 200 acre plot somewhere to just have a garden in the creek. 

01:05:45 - Nathan (Guest)

It's incredible completely self-sufficient. Yeah, we grow a garden, certainly. We've got a garden now where we're harvesting them that's incredible. 

01:05:54 - Chase (Host)

I want to go back and nitpick a little bit, just because I mean you are a researcher, you're a biochemist, I mean there's probably nothing you don't do, especially to this level, that has some kind of quantitative and qualitative reasoning, you know. Let's go back to the sauna. Use the cold plunge, use I heard you say frequency, I heard you say degrees for both. Can you walk us through why in both Is there a certain, is there a certain research that you know shows otherwise? Or just you kind of found this to be your sweet spot? 

01:06:22 - Nathan (Guest)

I think I mean, everything I do is based on some, as you said, objective, quantifiable and really what's published in the clinical data. The clinical benefits of contrast therapy. Going from hot to cold is pretty convincing. I mean, you turn on longevity genes, you turn white fat, adipose fat into, or visceral fat into brown fat, which is more thermogenic, and you get more mitochondria. That's what makes them brown, um, and then you turn on all these longevity genes and it's, it's hormesis. But for me, I do the sauna for two reasons. Number one I want to sweat. I mean, I live in texas, so sweating is not a problem, um, but even in the winter you know we still have to sweat. 

01:07:02

So 170 degrees in an infrared sauna, I mean I completely, I completely. And it's detoxifying, right? We detoxify by breathing, by sweating, by pooping and by peeing and if we're not doing all of those on a consistent basis, we're building up toxins in our body. So I've always done I've been on that for probably 10 or 15 years Then, several years ago, this cold plunge and I hate cold water. I hate cold cold water. But when this started to become popular and I did it, I just it's awful for three minutes, oh yeah, but 10 minutes after I get out of that, I mean it's like a feeling of energy and just it's the best way to start my day. 

01:07:42 - Chase (Host)

I have one at home too. I know exactly what you're talking about. 

01:07:44 - Nathan (Guest)

Yeah, it's incredible but I don't, I hate't, I hate it, I hate it every time I get in it. 

01:07:47 - Chase (Host)

There's this whole other component of like you're building mental resilience to this as well. 

01:07:52 - Nathan (Guest)

No, that's exactly right, Because you have to mentally prepare yourself to get into an ice bath and you got to come into your breath. I think probably that's one of the benefits is you have to get into your breath hopefully nasal breathing nasal breathing and you've got to convince yourself. This is going to be offer for three minutes, but my philosophy is don't be a P, don't get in there. 

01:08:10 - Chase (Host)

I heard I forget where I heard this. It might've been like a Huberman clip or something. I actually have a buddy here. It was a big cold plunge guy actually coaches people through this like professional athletes and musicians and he was sharing with me that. The mechanism really of action. Here is the true benefits happen from cold water therapy, cold water exposure when we don't want to do it. Something happens when people flip that switch of like. Maybe they just are sadistic and they're like I want to do this and they actually really truly do. I'm not there yet. 

01:08:43

Yeah, there's not like the same downstream effects, it's not the same net positive effects of. You know I don't want to do it but I'm gonna do it anyway. It's something about this like mental resilience aspect then converts into the physical benefits. That's not as much when we actually want to enjoy it. 

01:08:57 - Nathan (Guest)

No people. People are conditioned to want to take the easy route. They don't want to do things that are hard. And things that are worth doing are typically hard. And you've got to get your mindset right. It's like JFK said we're going to go to the moon not because it's easy, because it's hard. And I think that's the mindset that people have to take, because taking the easy road is going to lead you to a miserable life, poor health, poor outcomes. You've got to do things that are hard. 

01:09:23 - Chase (Host)

Well, you're in good company here. I'm just going to get actually to my final question with you because I feel like this is a perfect segue. I could seriously just talk for another hour about this. It just, nitric oxide is at the root of everything. 

01:09:39

If you want to maximize health today, longevity tomorrow and you know, definitely we didn't get into it a whole whole lot here today, but you have so many podcasts and pieces of content and research out about really showing how this I think I've even heard you say will cure Alzheimer's so if you want to do better today and be around for as long as possible for a high quality of life as long as possible tomorrow, focus on things that support nitric oxide efficiency and production. But I'll wrap all the science stuff there and let's pick back up where you just left off about the mindset Ever forward. The whole point of the show is to bring people on like yourself that embody this philosophy, this mantra that I learned from my father growing up, and through your lens of what you do, you've really shined a light as to how we can move forward in a unique area of our well-being today. But those two words if I were to ask you, dr Brian, what does it mean to you to live a life ever forward? What would you say? 

01:10:38 - Nathan (Guest)

I think it was a great transition, because we were just talking about that. It's doing the tough things and you know, I'm convinced that what we've discovered through science is that these are fundamental truths of human physiology. And Schopenhauer, the German philosopher, said 400 years ago all truths go through three phases First, it's ridiculed. Second, it's violently opposed and then, third, it's accepted as being self-evident. So, for me, ever forward is seeing through those three stages. You gotta, you gotta endure the ridicule, ridicule, you gotta survive the violent opposition because it's it's, it's accepted as being self-evident. But if you're not ever forward, you'll never get to that third stage where it's self-evident. So that's my mission and that's what I'm here for there's never a right or wrong answer. 

01:11:24 - Chase (Host)

I appreciate everyone's interpretation and I lied. I have one little piggyback quick question I was sharing with you earlier. You know the origin story. This came from my father who passed away in 2005 from ALS. Have you come across anything in your research of nitric oxide supporting, preventing, reversing or just seeing hope for anything related to ALS? 

01:11:44 - Nathan (Guest)

I mean, certainly nitric oxide can mitigate the inflammatory components of ALS or any autoimmune disease. But I think until we figure out what causes it, there's a root cause for everything, just like there's a root cause for cancer, there's a root cause for ALS and you've got to remove from the body the source of exposure that's causing that neuromuscular dysfunction and then replete missing nutrients. Then the body heals itself. Nitric oxide can certainly support that and kind of mitigate the inflammation that occurs from that, but it would be supportive, not curative. 

01:12:15 - Chase (Host)

Well, it's good enough for me, it's definitely. You know I have a lot of habits in my life that support nitric oxide production and efficiency, and you know I've shared this with my audience before. You know a lot of what I do now in terms of content and my own personal wellness habits comes from fear. I mean being 19 years old and burying my father. You know who was my best friend and just you know, seeing this, just this rough, tough mountain of a man, this, this big, burly army guy just wither away to nothing. 

01:12:44

Fear drove. Fear was my catalyst for making all these changes in my life, and it's incredible where fear can take you when you learn how to really utilize it the proper way not living in a state of fear, but living because of what you know a fearful life can do to you. 

01:13:00 - Nathan (Guest)

Absolutely. It's a great motivator. 

01:13:02 - Chase (Host)

Well, you're welcome back anytime and, oddly enough, I'm going to be in quite literally your backyard. I fly to Houston tomorrow. Uh, I'm going to visit my brother. He's having a baby shower. He lives out in Missouri city, oh, yeah, yeah. So, uh, I'll wave when I'm flying over, but you're welcome back anytime. This was incredible. 

01:13:16 - Nathan (Guest)

Thank you so much I. 

01:13:18 - Chase (Host)

I, I. Every time we talk about nitric oxide, I don't realize how much I want to nerd out more about nitric oxide. It's in everything and just because of, and can influence so many things. It's crazy. Just please don't stop the work that you do. It's been incredible just watching. 

01:13:35 - Nathan (Guest)

We're just getting started. We got a lot of work to do. 

01:13:37 - Chase (Host)

Amazing. For more information on everything you just heard, make sure to check this episode's show notes or head to everforwardradiocom.