How Nitric Oxide Controls Oxygen & Nutrient Delivery, Aging & Quality of Life – #1041

You're listening to the Human Upgrade with Dave Asprey. Today is a special Upgrade Spotlight edition where I go deep with an innovator or an inventor on something that they actually make. The reason for these episodes, they're short. But I want you to understand the people and the things that are out there that make biohacking happen. And this episode is about something that's really important. So important there was a Nobel Prize for it in the last. When was that?

1998.

1998. So about 25 years ago. And we're talking about nitric oxide. If you're into bodybuilding, you probably see like in o Pump Extreme 2000. This is not that. In fact, that stuff doesn't do anything. And we're gonna learn why it doesn't do anything. And I'm in just the spirit of full disclosure. I've known about nitric oxide for a long time, and I've tried strategies to raise it. And universally, it gave me a bad headache because, as you're going to learn in this interview, there's three different types of nitric oxide in the body. And I tended to always get the one that would give you a headache because of something called peroxy nitrite. So when I found something that actually just gave me massive veins. That's my bodybuilder voice, by the way. And something that really works for the other things that nitric oxide does. And we're going to get into that later without any sort of scandalous details. I'll just say, wow, this stuff works. And then I found out why it worked. And our guest today is Dr. Nathan Bryan from a company called N101. And he's the preeminent expert in nitric oxide. You'll find out there, innovator in the field, working on it, both for pharmaceutical applications as well as stuff that you can put topically, which I've never seen before, as well as lozenges. Dr. Nathan, welcome to the show.

Thanks, Dave. It's great to be with you.

I never asked you, should I call you Nathan? Dr. Nathan? I just call you Nathan when I met your answer. All right, Just Nathan. All right, good deal. So he's also here in Austin, which by definition makes him really, really cool. Just, you know, there you go. Right, we're done.

Okay.

And of course, you're like the type of doctor with all sorts of doctor credentials. I'm just looking at all this stuff. Dozens of patents. You studied biochemistry and you did postdoctoral training at the Whitaker Cardiovascular Institute and a bunch of other stuff. And you're the faculty of the University of Texas Health Science Center. So credentialed medical doctor with a ton of training. Okay, give me the elevator pitch on nitric oxide. What is it and why do we care about it?

Well, it's now recognized as one of the most important molecules produced in the body of humans. It's a vasodilator. So it controls the regulation of blood flow. It's what's responsible for oxygen and nutrient delivery to every organ, tissue and cell in the body.

Well, hold on. Is that's what your blood cells did? That's what your blood cells do?

Well, it's nitric oxide that controls the delivery of oxygen by the blood cells, so you can't divorce the two. So the red blood cells deliver oxygen, but that oxygen delivery is dependent upon nitric oxide being bound to hemoglobin in the red cell.

Okay, cool. So it's very short lived though, right? It doesn't last a long time.

That's been the challenge in really development and innovations over the past 30 years. How do you make a solid dose form of a bioactive gas that's gone in less than a second? And that's the riddle that I solved more than 20 years ago. So we were the first people to ever develop a technology that you could make a bioactive gas in a solid dose form.

And for listeners, I've talked about hydrogen gas in the past, and there's uses for that. Again, similar problem. There's also carbon dioxide, which you can breathe. In fact, that one's easy though. You can just drink carbonated water. And I've talked about how you do that on airplanes. It increases blood oxygenation, at least for me. But nitric oxide was a really tough one. But here's what everyone says.

Eat beets. So we've tested every beet product on the market. I have some very sophisticated analytical equipment. We can detect nano gas coming off of it. We can determine if it contains the right amount of substrates or precursors that would even generate nitric oxide.

And none of it raises nitric oxide at all.

I would say 99% of the nitric oxide products on the market. And there are hundreds of them, if not thousands. Don't do anything in terms of raising nitric oxide levels. So it's beets. And most of the beets are just what we call dead beet products. You know, they don't. The only thing they do is turn your pee and your poop pink and cause a lot of anxiety. But there's no nitric oxide. Activity.

Where's the anxiety from beets coming from? Because of the red color.

Because of the red color, they think they have a bleed. Right. Either a urinary bleed or a colonic bleed.

And you say that they're dead. Why do they not have activity? Beets are supposed to raise nitrogen.

Well, beets. So it's. It's not just something that's unique to beets. Right. It's any vegetable that's grown in the soil. Celery. So we assimilate nitrogen in the form of vegetables, provided there's enough nitrate in the soil. But the problem is when you take. So you have to consider from the seed that's planted to the soil conditions to the time of harvest, and then how you actually make that raw ingredient into a powder. And most of the time, people use high pressure, high heat drying processes that basically deplete that product of all the minerals. You get a red powder that has basically depleted of all nutrients, especially water soluble nutrients.

Interesting. Well, does boiling beets cause the same problem? Because it's heat, there's no pressure.

Yeah. So any vegetable that you boil or cook in water, you're basically leaching out all the water soluble nutrients. So if you're boiling your vegetables, you should probably drink the water in which the vegetables are boiled in as well as eat the vegetables.

And of course, then you'll get all the oxalate from that as well. So, like, did I want nitric oxide and kidney stones from oxalic acid from drinking the beet water? It sounds like maybe beets aren't the best way to raise nitric oxide.

Beets are not the best way to raise nitric oxide. And that's one of the.

What about bacon?

Bacon? No, you don't get enough. There's really.

Because they put nitrates in it, there's.

Very little residual nitrite in cured and processed meats. And I think that's also been the misinformation for the past 50 years on increased incidence of certain cancers due to cured and processed meats being due to the nitrate and nitrite.

So that myth we just built, burning meat, it's not from.

Yeah. There's other compounds like heterocyclic amines and other processes that are independent of the nitrate or nitrite. So the beauty of what we've done over the past 20 years is we've basically figured out the best ways to deliver nitric oxide gas. And we can use certain carriers or certain delivery systems.

This is the N101 stuff. And when you say ways to deliver gas. It just looks like this. It's a wafer, right?

Well, it's a lozenge. And so we put core technology in there. So as that lozenge is dissolving, this matrix falls apart and we actually generate nitric oxide gas. So this is. We can detect, we can quantify, we can verify nitric oxide coming off of that lozenge. So you can't put nitric oxide in the liquid. You can't put it in a capsule that you swallow, and you damn sure can't put it any type of gummy.

Wow. So actually how that guy just grew. How quickly does this head. Placebo.

Yes. So nitric oxide is one of the. So when we deliver it, it's very potent, it's very vasoactive. So meaning when you put that lozenge in your mouth, and if we had an ultrasound here, we could measure your carotid artery and we could see that blood vessel dilating. The other process is if you're using food or beets or kale or vegetables, if you will, that process takes 90 minutes. And that whole process is dependent upon the right oral bacteria. It's dependent upon stomach acid production. So most people aren't getting the benefits of eating certain foods or nutrients because number one, 200 million Americans wake up every day and use mouthwash, killing the oral microbiome. There's another 200 million prescriptions written for antacids every year. That's not even counting the over the counter, the Prevacid, the Prilosec, otc, the Nexium. All of that. Shuts down stomach acid production. Shuts down nitric oxide production.

You need stomach acid to make nitric oxide.

That's part of the process? That's correct.

Okay. Interesting.

Our philosophy is if you give the body what it needs, the body heals itself. We just have to figure out what's missing or what's being shut down so that the body can do what it's designed.

I typically have low blood pressure, and when I do n 1:01, I don't experience a drop in blood pressure. There's some things, if I vasodilate, I'll get dizzy because I just don't have enough blood.

That's one of the beauties of this technology. So nitric oxide is self regulating. So if you have high blood pressure, you take the lozenge, we can normalize your blood pressure. If you have normal or low blood pressure, it doesn't further reduce the pressure. And that's a very important safety consideration that we basically rolled out, I guess, 15 years ago. But we don't want to drop blood pressure in people with low blood pressure.

No, it's not a good thing. Something else I want to demonstrate, because it's really cool, is do you have one of the, what do you call it, serum?

So it's the N101 serum. So this is a dual chamber nitric oxide generating serum. So it's very simple. You just take one pump from one side, one pump from the other. I didn't get a full. And so when you mix this together, the chemistry starts. So similar to that lozenge falling apart, you mix these components together. So you'll see three things here. Maybe you can see it, but you'll see some micro bubbles. That's the nitric oxide gas being produced. It diffuses into the dermis, it'll dilate these blood vessels and it recruits capillaries. So now we're basically enhancing blood flow wherever you apply this. And when you enhance blood flow, you know, the skin is an organ, like one of our largest organs. And so you can see these veins here that are more prominent.

Oh, wow, look at that little one that just popped out. Like, this is direct biohacking, signaling molecule manipulation.

And it turns pink. So we're recruiting capillaries and forcing blood flow directly where you apply that. So in terms of esthetics and beauty, when you restore blood flow to the skin, you improve collagen deposition, you improve hydration, the cells turn over more quickly. So we're mobilizing stem cells and fine lines and wrinkles disappear.

So I do this before I, before I go to bed on my face. But I'm just going to rub it in so people can see it. So you see how there's like a big red patch, that's where the tiny little blood vessels that never otherwise would see this much oxygen and blood, where they actually got woken up. So you can do this. And for wound healing especially, like I had a 3 1/2 inch incision all the way down to the joints on my big toe three days ago. And I am putting N101 on it as part of how I'm making it heal faster.

Well, that just goes, I mean, to the principles and kind of the benchmarks we set for nitric oxide products in anything we bring to market, you can quantify, you can verify, and exactly see that product working right before your eyes.

Okay, let me ask about this, though. So what about nitric oxide precursors? There's L arginine and there's citrulline. And they're amino acids. Talk me through, are those real? What do they do? What do they not do?

The first pathway to be discovered in the nitric oxide signaling cascade was an enzyme that converts arginine to nitric oxide. Citrulline is actually a byproduct of nitric oxide. So citrulline is an end product of nitric oxide production. So it's not a precursor at all.

Why do people take citrulline to increase nitric oxide?

You know, there was some evidence, and we published this in 2011, that part of the urea cycle, and it's very complex. Biochemistry recycles citrulline and forms arginine and then arginine kind of shuttles through that, but you're at least three steps away, like seven electrons away from nitric oxide, from citrulline. So it's very ineffective. So the problem, and we make enough of these amino acids through normal metabolism. So these are semi essential amino acids, meaning that our body produces them and we get it from the breakdown of protein.

Eat a steak and eat.

And in fact, there's 20 times more, even in the sickest of sick people that are needed to saturate the enzyme to make nitric oxide.

Yeah. So citrulline doesn't limit the production. So citrulline is. Is there any reason to take citrulline?

None. There's no reason to take arginine because the body makes enough of it to saturate the enzyme. And in fact, there's studies out there showing that if you take high dose arginine, you can actually divert the metabolism away from nitric oxide production. You get an increased expression of arginase and you basically excrete it as urea. And then the other problem is if you have what's called endothelial dysfunction. So if you've had a heart attack or you have peripheral artery disease and you take high dose arginine, it actually makes things worse. So it's contraindicated. So we're never limited in the amount of arginine or citrulline. The problem is the body's lost the ability to convert it to nitric oxide. So I tell people it's like putting gas in a car with a blown up engine. Right. You're not out of fuel, your engine's broken. So there's no reason to take arginine or citrulline. In fact, it can make things worse if you have endothelial dysfunctions.

I've seen the studies that say arginine is Good for you. And there's some anti aging ones say a couple grams might be good, but there's others that say it's actually harmful.

Well, look, the biochemistry is completely different in a healthy person versus a person with endothelial dysfunction or somebody who has vascular disease. And the biochemistry complete is basically opposite. So there is evidence and I don't dispute that. But in young, healthy, well trained individuals, if you take L arginine, you can get a little bit more. It's called the arginine paradox because the body already has enough arginine to fully saturate the enzyme. So the paradox is why when you give more, do you see any nitric oxide being produced? But again, there's a just like everything.

So that's only in young healthy people.

There's a U shaped curve. So too little is bad, Too little is bad, too much is bad. But there's a sweet spot.

How many, what percentage of young people are healthy enough to qualify for that.

To work these days in today's world?

Yeah.

Very little.

Okay. So the case for arginine isn't very strong.

Not at all.

The case for citrulline is non existent, not existent. Okay. I've seen some bodybuilders seem like they're getting good results with citrulline.

So there's very few products out there that are just arginine or citrulline. They're throwing a lot of minerals and B vitamins and caffeine. I'd take the caffeine out. Caffeine's a vasoconstrictor.

I wash my N101 down with danger coffee. I don't think I'm going to stop.

Well, I wouldn't recommend you stop because look, there's certain benefits, but if you're trying to achieve a certain threshold, like enhanced performance, for example.

Yeah.

Caffeine is a very well established ergogenic aid. Perceived exertion improves, athletic performance improves. What we have to do is basically balance these vasoactive substances. Right. And when you take nitric oxide, you preserve that balance of vasoactivity.

I actually think that's real. I notice a difference. I don't like how I feel if I don't have coffee, even if I go for two weeks, there's no physiological. Coffee's actually something that makes life better. I agree.

I can't go without my morning coffee.

Okay, got it. And if I was going to go do some extreme exercise thing, which I'm not because I'm into anti aging, would I want to do A cup of coffee and an N101 or would I skip the coffee or skip the N101?

No, I think it's. Look, there's different mechanisms that are very well established for both. And I think I'm not a fan of any extreme. Right. I think we have to do we have to recapitulate physiology. So there's bonafide benefits of caffeine in terms of performance and perceived exertion and ergonomic aid or ergogenic aid. And then there's well established benefits of nitric oxide. So it's not just improving blood flow and oxygen delivery, but it's improving mitochondrial function. And so the mitochondria are what's producing the cellular energy that allows you to go for a hike or go for a walk.

So N101 is improving not just the lining of the arteries, the endothelium, it's improving mitochondrial function as well because of the signaling. Okay.

And it's mobilizing stem cells, it's reducing inflammation. So every aspect that we know about aging and quality of life all are controlled by nitric oxide. So there's three main ones, right? There's stem cell function. Nitric oxide is what controls and regulates stem cell function. There's the telomeres, the end of the chromosomes. The shorter the telomeres, the shorter the lifespan. Nitric oxide is what controls telomerase activity and prevents the shortening of telomeres. And then the other is mitochondrial function. Every single age related chronic disease is characterized by mitochondrial dysfunction, lower numbers and lower activity. So nitric oxide has been shown to improve mitochondrial biogenesis as well as mitochondrial ATP production. We improve the efficiency of mitochondria.

Okay, so there's a pretty strong anti aging case. There's a pretty strong performance enhancing case. What about nootropic functions making your brain work better?

Well, if we followed the work of Dr. Daniel Amen.

Absolutely. I'm on his board of directors.

Neurological function is controlled by cerebral blood flow. So what he's been able to show through SPECT scans is every neurological disease is characterized by decreased blood flow to a certain region of the brain cerebral. So if you can dilate the blood vessels of the brain, improve oxygen nutrient delivery to certain ischemic or hypoxic regions of the brain, you can recover neurological function. It's foundational for anything we do. And in the world of biohacking, which obviously you're the pioneer and father in this, is that what are we trying to accomplish through biohacking? It's basically to optimize our systems. Well, nitric oxide is foundational for optimizing everything we're doing. Why do you eat certain diets? Why do you exercise? Why do you take certain things? Well, at least biochemically for me, we're trying to improve nitric oxide. But if your body's lost the ability to make nitric oxide, then you're not going to get the benefits and the so called biohack. So if your body can't make nitric oxide, we do it for you. And that's the basis.

All right, can we get a little bit nerdy about nitric oxide types? Okay. I became, I would say, really interested in nitric oxide maybe 15 years ago. And I went really deep on it. I tried all the different things available at the time to increase my levels. And what I determined was that there's these three different genes, there's Nos1, Nos2 and Nos3. So these determine like your likely nitric oxide production. But what I found was that I was getting levels of peroxy nitrite. So when you take nitric oxide products, whether it was a gut bacteria thing, I don't know why it was, I was getting really unpleasant, like pro oxidative symptoms. So can you talk to me about what happens with neural nos versus endothelial nos versus inducible nos? Because I think people need to know.

No, it's. Look, it's very important, but it's also a very complex science. So these are called isoforms. There's three different isoforms of the nitric oxide synthase enzyme. So years ago, probably 25 years ago, we referred to them as NASA inducible, nos and Enos. Now they're called nos 1 for NAS, nos 2 for INOS, and nos 3 for ENOS. Because now you can find ENOS expressed in places other than endothelial cells.

They first noticed it in the endothelium. Okay.

And now you can see the NOS isoform expressed outside of neurons. But the difference is the Enos and ENOS are what's called constitutively expressed. So they're very well controlled, they're calcium regulated, and those generate nitric oxide upon demand.

Those are the good ones.

Those are the good ones. So for neurotransmission, for phasodilation, the INOS is what's called inducible. So when we get an injury or we get an infection, and this was very apparent for the past three years in Covid, it's called the cytokine storm. Four hours after you start this inflammatory cascade and upregulation of cytokines, you get induction of the INOS enzyme. So it's not constitutively expressed, it's only upregulated and expressed upon activation.

And this is what makes you feel like crap, because peroxynitrite is not a good thing. But what turns off peroxynitrite?

Well, peroxyanitride is a byproduct of no reacting with superoxide. And so if you're. And the best example is taking high dose arginine when you have an upregulation of Ionos. So now if that enzyme is uncoupled, you're generating a lot of superoxide instead of nitric oxide. So you're getting a lot of oxidative stress and a lot of nitrogen stress, which in an acute environment is actually beneficial because that's what kills the bacteria, it prevents virus from replicating. The problem is when it's upregulated and you have chronic inflammation, and then you're priming this enzyme and priming this superoxide nitric oxide interaction and causing a lot of undue damage. So you get tyrosine nitration, you get a lot of oxidative stress, nitrosated stress. So the problem is, or really the solution is, how do we control and regulate nitric oxide production while suppressing this chronic overexpression of INOs? And I believe we were the first to publish on that, I believe in 2004, where we showed that if you have chronic INOS overexpression, it shuts down the constitutive isoforms.

Oh, so then it causes damage to.

Your arteries, it shuts down in mass, and it shuts down enos. So chronically inflamed people, although they have overexpression of nitric oxide, for instance, in ulcerative colitis or inflammatory bowel disease, they're producing a lot of nitric oxide in the lining of the gut, but yet the blood vessel, nitric oxide and the neuronal loss is completely shut down. There's a feedback inhibition that's leading to the suppression of that.

So if I was one of those people who's chronically inflamed and I take N101, I'm increasing nitric oxide, is that going to be a good thing?

No, that's. That's a very good question. So what we do is completely different. We do two things. If your body can't make nitric oxide through ENOS or nmos, then we provide it for you, but it's also dose dependent. So we did this 20 years ago, through radio labeled isotopes, we know exactly how much nitric oxide a healthy person would make in 24 hours. So what we do in any technology that we bring to market, we want to recapitulate what normally occurs. So we want to deliver the same amount of nitric oxide that our body would normally see, not the whopping doses through Inos. So and then number two, we recouple that. So there's, there's, and that's what's complicated in the science is there's a particular, what's called a redox potential, an electron oxid reduction oxidation potential. So it's the voltage at which is necessary to extract an electron from a biomolecule. And the rate limiting step in nitric oxide production is the oxidation of BH4. So we preserve the reduction of BH4.

What is BH4?

It's tetrahydrobopterin. It's an important CO factor for nitric oxide production. If you've got an uncoupled nose and you have endothelial dysfunction, then that lozenge is recoupling the nos. So you're suppressing superoxide production, you're enhancing nitric oxide production and you're bypassing that entire peroxy nitrite.

Interesting. So is there a case for, if you're chronically ill, you take your N1O1 and then you'd huff on some hydrogen gas and that, that might help you to balance even more quickly?

Well, I think, look, nitric oxide is foundational, right? It's critically important, but it's not the end all, be all, cure all. Right? You have to restore the production. And basically my whole philosophy is people get sick for two reasons, two reasons only. The body's missing something that it needs or it's exposed to something that it doesn't need. So if you remove yourself from exposure to toxins, you take good nutrition and replete nutrients, then the body is regenerative by nature and it's self healing. So hydrogen is one of these interesting molecules that goes into a cell unmodified and comes out. There's still some question in science of what's the mechanism, right. How is hydrogen modulating all these biochemical reactions? When it goes in as H2, comes out as H2, what's it doing? But the benefits, the therapeutic benefits of hydrogen are pretty well established. And similar with hydrogen sulfide, you know, another important biological gas.

That's the stuff that smells like rotten eggs.

It does, yeah.

That stuff is poisonous. Like it shuts down Mitochondria, the same.

As cyanide does, but our body makes it. So 30 years ago, people thought the same about nitric oxide.

Oh, that it was poisonous.

Because on my nitric oxide gas cylinder where I calibrate my machines, it's got a skull and crossbows on it and it says poison.

That's true.

If you breathe pure, it's dose dependent. So same thing with hydrogen sulfide. It's dose dependent. And probably the same thing with, well, anything. Right. If we drink too much water, we're going to oversaturate cells and people die from that. So there's a dose dependent effect of everything. And what we do with nitric oxide is we dial in what the human body would normally make.

What's the upper limit for how many N101s I can take?

We recommend one twice a day because it's very difficult, if not impossible, to ascribe a one size fits. All right. Your objectives are completely different from, you know, Susie Homemaker. So the metabolic demands on what your body needs are much different than somebody else.

When I take N101, it is improving blood flow in the brain, and I think my brain likes that.

Well, no, we can actually measure that. So we can do that through SPECT scans through Daniel. Amen. We can do it through functional mri. You can actually do it just measuring the blood vessel diameter with the ultrasound. You know, we have a number of different kind of techniques we use to measure the efficacy of these products. The serum is very simple. Right. You can actually see that product working on your skin, the lozenge, whether we use ultrasound, whether we use thermography, whether we're measuring blood pressure before and after SPECT scans, functional mri. This product works in every single modality that we use as an endpoint.

Wow.

So there's no questioning it's working.

Now, as a single guy, talk to me about the beneficial interaction of Viagra, Cialis and N101. And should you mix them? Should you not mix them? Walk me through that.

So these drugs like Viagra and Cialis and Levitra, these are called phosphodiesterase inhibitors. These compounds inhibit an enzyme that breaks down a second messenger that's activated by nitric oxide. Now, that was a mouthful, but the whole point of me saying that was these drugs are obviously very effective. They've been on the market for, I guess, probably 15 years now, but they only work in about 50% of the man in which they're prescribed.

Oh, really?

So the clinical data on treating men with erectile dysfunction or even symptoms of BPH, which is benign prostate hypertrophy. 50% of the men don't respond. And why is that? Because the function of these drugs are dependent upon nitric oxide production.

Oh, they can't produce it.

So if your body can't make nitric oxide, then you don't get a response from Cialis or Viagra.

So the 50% of people where it doesn't work, if they took one of those, like Viagra, let's say, and then they did an N101, they would have it.

Now we can take non responders and make them responders.

Holy crap.

And you can actually titrate down the drugs of these so you can get much better effect. So the safety profile is much better of 2 1/2 milligrams of Cialis, then 40 milligrams of Viagrate. You see the side effects from these commercials, the headaches, priapism, the four hour erection. We've had a number of physicians, urologists and cardiologists actually start to wean people off prescription medications because the whole concept of restorative physiology is if you can get biochemical systems working again, then there's really no need for pharmacotherapy.

So if you're listening and you've taken one of those medications and it wasn't working well, maybe this would make it work, which is actually really cool. So I think this is a breakthrough product. I have tried other ones, including well known ones, and I've never actually recommended one or liked it because I would get headaches and it didn't seem like either it didn't work or it didn't make me feel right. I reliably take this up, like especially when I fly, when I travel.

Well, you know, this is very important to What I spent 25 years in academic medicine and really drug discovery and trying to innovate because most people, most physicians and scientists agree that nitric oxide is the holy grail. The challenge has been how do we develop safe and effective nitric oxide technologies. So now we've done this in nutrition, we've done it in skin care, we're doing this through FDA drugs. Now we've got a number of drugs through going into phase three clinical trials. So nitric oxide is so potent and so important to the management and treatment of chronic disease that I think this is going to be a game changer.

It is and it's relatively recent. So we're just getting into this and there's probably another 70 years, although with AI, maybe it's just another five years of additional work on this before we figure it all out, but I really wanted to talk with you on the show because this stuff is very noticeable systemically. Nathan, thanks. I appreciate you coming out to my place here in Austin, and I'm really enjoying using this stuff. I've used it for about the last six months and I think it has really sped healing on lots of things. Thank you guys. N101.com it's just four characters. It's easy to do. As you know, Nathan just talked about his product on the show. Use code Dave. They'll give you 10% off. You're listening to the Human Upgrade with Dave Asprey.