Dr. Louis Ignarro:
Antioxidants can increase nitric oxide. Why? Because the antioxidants destroy the free radicals that go after nitric oxide to destroy the nitric oxide. So antioxidants will boost nitric oxide simply by stabilizing the molecule.
Dr. Mark Hyman:
Welcome to the Doctor’s Farmacy. I’m Dr. Mark Hyman. That’s Farmacy with an F, F-A-R-M-A-C-Y, a place for conversations that matter. You may not know why this conversation is going to matter to you, but it will because it’s about everything that matters about your health, in terms of longevity, your cardiovascular health, your sexual health, your blood vessel health, and lots more.
Dr. Mark Hyman:
So we’re going to be talking with an extraordinary man, our first Nobel Prize Winner on the Doctor’s Farmacy, Dr. Louis Ignarro, who’s discovered nitric oxide, otherwise known as NO. He won the Nobel Prize in Medicine for this. He discovered how this impacts our health and longevity. So you want to listen up. You might not really know about this molecule, but you probably do even though you don’t know you do because if you’ve heard of Viagra, it’s how Viagra works.
Dr. Mark Hyman:
So you better listen up because getting your nitric oxide up is important to getting everything working. So he’s a Professor Emeritus in Molecular Medical Pharmacology at UCLA. He’s got a PhD in pharmacology. He’s just an extraordinary guy who has been teaching. He’s even one of the first speakers at one of the Institute for Functional Medicine’s Annual Conferences. He started a biotech company that focused on using nutritional supplements to boost the body’s nitric oxide production. We’re going to hear all about that. So welcome to Doctor’s Farmacy.
Dr. Louis Ignarro:
Thank you. Thank you, Dr. Hyman. It’s really great to be here. I look forward to this.
Dr. Mark Hyman:
Well, I really am so in awe of scientists who spend their life digging into questions that seem so obscure and irrelevant, but end up solving some of our biggest problems. We were chatting a little before this about your tenacity and persistence. You were very humble and said you weren’t that smart, but you worked hard. I think there’s probably a combo of working hard and high intelligence because nobody gets a Nobel Prize by accident. You discovered this amazing molecule, nitric oxide, which is key in the cardiovascular system and helps your blood pressure and your blood vessels stay healthy. So tell us about, for those uninitiated medical people, what is it? How did you first how did you first get into even thinking about it that led to the Nobel Prize?
Dr. Louis Ignarro:
Yes, Well, I’m happy to talk about it. It actually started way back when I was in high school, when I noted that so many people got heart attacks and strokes, whereas an equal number of people were perfectly healthy. What I was able to see and figure out was that the people who had the cardiovascular disease were obese and also led a sedentary lifestyle. I was thinking about it, I had not really taken too many science courses. I came up with a hypothesis that maybe, just maybe our bodies produce a molecule that protects us against high blood pressure, heart attack and stroke. Some people make this molecule, some people don’t.
Dr. Louis Ignarro:
Well, 15 years went by, until I finished graduate school, medical school and started researching in the laboratory. It was a roller coaster ride, up and down, up and down. Eventually, in the 1980s, I did make that discovery that our arteries actually produce a molecule that lowers the blood pressure and prevents inflammation of the arteries, which means it has the potential, right, of preventing stroke and myocardial infarction.
Dr. Louis Ignarro:
So after a couple of years of study, very difficult studies, we were able to identify and isolate this molecule, and it turned out to be nitric oxide. That was very difficult because you see, nitric oxide is a gas just like oxygen or CO2.
Dr. Mark Hyman:
Is that like laughing gas? Is that what it is?
Dr. Louis Ignarro:
No, no, no laughing gas. nitrous oxide.
Dr. Mark Hyman:
Okay. All right.
Dr. Louis Ignarro:
Which is in N2O and nitric oxide is NO. Believe it or not, even though the chemistry sounds similar, they’re remarkably different. So nitric oxide is not laughing gas. It’s no laughing matter for sure.
Dr. Mark Hyman:
Was that a pun? It’s no laughing matter, NO? Is that pun?
Dr. Louis Ignarro:
Right, exactly. So that’s how we initially discovered it. Of course, it’s more complicated than that. But the point I want to make is that I had an idea before I took my first course in science. I had an idea, and I shared that some of my friends, some of my teachers who said, “Okay, you should be a scientist and see if that’s true later on.” That’s what I did. So I had an idea, I went after it. When I got my doctorate degree, I did not go after a simple problem to solve in science. I wanted to use something that nobody else had done. I wanted to develop or follow a path that no one else had followed. That’s what I had in mind. So I worked hard, did the necessary experiments, most of which failed. But certain ones were successful. That’s what led me to the initial discovery of nitric oxide.
Dr. Mark Hyman:
That’s an unbelievable story, because you basically hypothesize the theoretical existence of some unknown molecule that no one had ever discovered and had this crazy idea and went after it. How do you even begin to go, “Gee, I’m going to go try to find a molecule that no one’s discovered?”
Dr. Louis Ignarro:
Well, that’s why it took 30 years to find, I had no idea where to start. But I remember when I gave my Nobel lecture in 1998 in December, in Stockholm, and no one had heard that story before. It’s just my own story. But when I was done, in the next three days, the members of the Nobel Foundation were intrigued that I had an idea so many years before. To me, it was a natural idea. People who are obese and lead a sedentary lifestyle are the ones who get the heart attacks and stroke, and everyone else didn’t. Those people within an exercising all the time and ate a healthy diet. I mean, I was aware of this way before, as you know-
Dr. Mark Hyman:
That’s amazing.
Dr. Louis Ignarro:
I mean, way before the rest of us became aware of healthy lifestyle.
Dr. Mark Hyman:
I want to get into the exact reasons why nitric oxide is so important in our biology and all the different things it does, everything from heart health to sexual health.
Dr. Louis Ignarro:
Yes.
Dr. Mark Hyman:
But what’s what’s fascinating to me is that nitric oxide is this very quickly formed and eliminated molecule, but it’s so important. Well, what really struck me was when I started to research about the effect of statin drugs, which is the number one selling drugs in the world, they’re for lowering cholesterol. I began looking at the research on cholesterol, it didn’t really seem that the cholesterol lowering effect of the statins was the real reason that it had all the benefit. That you could look at people who had high LDL, but if they didn’t have inflammation, and they had these others issues, they’d be fine.
Dr. Mark Hyman:
One of the mechanisms of action of statins is it increases something called nitric oxide synthase, which is a enzyme that makes nitric oxide. So I’m wondering what you think about that theory that maybe it’s the effect of nitric oxide and not the cholesterol lowering issue around heart attacks. So to me, it just seems like a no brainer.
Dr. Louis Ignarro:
Well, I’m so happy that you understand that because a lot of people don’t, most physicians don’t.
Dr. Mark Hyman:
Well, I’m a little weird. So …
Dr. Louis Ignarro:
All this time, I thought that the statins work by altering cholesterol, metabolism and on and on. But then there were a couple of abstracts I remember, a couple of papers that came out, publications. I heard somebody speak at a meeting showing exactly what you said. That some of these statins can upregulate the enzyme, that is create more enzyme, NO synthase. That’s the enzyme that makes nitric oxide. So if you have more NO synthase, you have more NO. People reproduce that work. I remember that I met Joe Goldstein at a meeting. He was one of the guys who shared the Nobel Prize for discovering cholesterol metabolism, and their work led to the statins. I said, “You realize that, of course, the bottom line is really nitric oxide.”
Dr. Mark Hyman:
What’d he say?
Dr. Louis Ignarro:
He laughed and said, “Get out of here,” and he walked away. But I think that one of the major effects of the statin drugs is to boost nitric oxide because nitric oxide prevents inflammation of the arterial wall that will prevent certain blood cells from coming in to deposit cholesterol plaque and develop atherosclerosis. That is why our arteries make nitric oxide. We make nitric oxide in order to protect us against hypertension and protect our arteries against inflammation and then prevent unwanted blood clotting. Nitric oxide, very potent that way. So if you prevent unwanted blood clotting, you can prevent a stroke. If you prevent inflammation of the arteries, that certainly will go a long way to preventing the development of coronary artery disease, right? Which causes myocardial infarction or heart attack.
Dr. Mark Hyman:
Yeah, absolutely. I think what’s striking is statens have what we call pleiotropic effects. They have multiple effects, they lower cholesterol, they increase nitric oxide, they decrease inflammation through other mechanisms, and lower C-reactive protein. That may be the real way they work. But what’s really fascinating to me is, is this link between nitric oxide and inflammation because anybody who’s listened to my podcast or understands my work around the role of food as medicine is that inflammation is the driver of almost all the major chronic diseases we see today. Heart disease, cancer, diabetes, Alzheimer’s, autoimmune disease, all these diseases are driven by inflammation. So it seems like nitric oxide could play a big role in in modulating these diseases or influencing diseases.
Dr. Louis Ignarro:
That’s exactly correct. Nitric oxide has pretty powerful anti inflammatory effects. The reason is that nitric oxide is a free radical, believe it or not, it is a free radical, but it’s a fairly safe free radical. What free radicals like to do is to interact and find other free radicals so that they can react covalently and take them out. That’s what nitric oxide does. It is a an anti inflammatory because it goes after other radicals, whether it’s oxygen radicals, like superoxide, or fatty acid radicals, for example, that hang around in membranes.
Dr. Mark Hyman:
By rancid fat in your arteries. Right?
Dr. Louis Ignarro:
Exactly, exactly. By neutralizing those free radicals, then by definition, nitric oxide is anti inflammatory. Actually, we can say that NO is anti oxidant. Many cases, believe me, after all the years of research I’ve been involved with, antioxidant and anti inflammatory are very similar phrases. It’s almost the same thing.
Dr. Mark Hyman:
Absolutely. It’s incredible. So let’s talk about some of the mechanisms because what was going on with Viagra was fascinating, because it was designed to be a blood pressure drug. It didn’t really work that great, but it had the side effect that people complained about or maybe they were celebrating, I don’t know. That’s what happened in this blockbuster category of drugs, which are these are drugs that actually increase nitric oxide. Tell us about this relationship between blood vessel health, blood pressure, blood organ flow, because really where blood goes is where health goes, right?
Dr. Louis Ignarro:
Of course, of course, well, I can tell you a little bit more about Viagra and the development, if you like.
Dr. Mark Hyman:
Yeah.
Dr. Louis Ignarro:
I mean, as you said, so when Viagra was first being developed, it was actually tested to see if we could lower the blood pressure in humans. They found that if they raised the concentration high enough, it was still very safe and could lower the blood pressure. But unfortunately or fortunately, depending upon how you look at it, a side effect was produced. That is all the male volunteers who were in this study developed an erection, whether they wanted to or not. Appropriately this was noticed by the nurses who were running the study.
Dr. Mark Hyman:
I don’t want to hear about that.
Dr. Louis Ignarro:
Yeah, yeah. I was on the Scientific Advisory Board of Pfizer for a long time before, a while back. So what happened was that Pfizer did not want to deal with this. They had no concept then that this could be a useful drug to treat erectile dysfunction, but because of the side effect, they said, “Listen, we’re not going to mess with this.” So they stopped developing the drug, they put the drug on the shelf.
Dr. Louis Ignarro:
Then I published my work in 1992, in the New England Journal of Medicine, that nitric oxide, because we had shown for the first time the neurotransmitter released from the nerves that causes penile erection was not known. That’s why no drugs could be developed to treat ED. You didn’t know what the neurotransmitter was. How can you develop a drug? So we discovered that the neurotransmitter was our good friend, nitric oxide, which makes good sense, right? It’s vasodilator.
Dr. Louis Ignarro:
So they read my work. They realized, “Oh my goodness, our drug works by increasing nitric oxide.” So they filed a new drug application. They took the drug off the shelf, they developed it, the FDA fast tracked it. In six years, it was marketed as sildenafil or the trade name, Viagra. What’s interesting is that Pfizer invited me six months later, because it was just after the Nobel Prize, invited me to their pharmaceutical company in England, where the work was done, and showed me the laboratory where this was done. You could see all my reprints pasted on a wall. In the laboratory notebooks it was really great to see this. From that point on, I’m not sure if you’re aware of this. But from that point on, I was given the acronym of the Father of Viagra.
Dr. Mark Hyman:
Yeah.
Dr. Louis Ignarro:
Which is an acronym I don’t mind at all, but my mother was alive at the time. She used to get very upset, whenever she heard that.
Dr. Mark Hyman:
Very embarrassed.
Dr. Louis Ignarro:
She would tell me, “Why don’t you tell them to stop that already?”
Dr. Mark Hyman:
I imagine they probably didn’t have trouble getting volunteers for that study, I bet.
Dr. Louis Ignarro:
Yeah.
Dr. Mark Hyman:
So that’s incredible. So you call it a neurotransmitter as well as an antioxidant, anti inflammatory. So it has all the different effects, right? It’s really amazing.
Dr. Louis Ignarro:
When it’s released from the nerves, it functions as a neurotransmitter in the erectile tissue of men and women, by the way. But it’s also a neurotransmitter in the brain, where it’s released in certain areas of the brain that promote memory, learning and information recall, many scientists believe that dementia, especially Alzheimer’s disease, may be attributed to a deficiency of nitric oxide neurotransmitter in the brain. What I tell all my young scientists, when I was teaching, I would tell my graduate students that remember this, the brain has 10 times more nitric oxide than does any other organ in the body. We don’t know why. So go after that problem. I mean that’s a good problem to go after.
Dr. Mark Hyman:
It’s amazing. So let’s just kind of review and then I want to get into the question everybody’s thinking about, which is, “How do I get more of this stuff in my system?” So let’s see, it dilates your blood vessels and lowers your blood pressure, improves blood flow in your organs.
Dr. Louis Ignarro:
Of course
Dr. Mark Hyman:
It prevents clotting, you mentioned. Then it prevents blockage in the arteries. It’s an anti inflammatory, so it helps keep the healthy arteries. It promotes learning, memory and information recall. It helps regulate erectile function in men and arousal in women, and other things including protecting your skin from the sun and skin cancer. You also mentioned in your work that it promotes digestion by helping the movement of digested foods and regulating digestive enzymes and hormones. So it’s an incredible molecule that is doing all these things that no one even knew about until you came on the planet.
Dr. Louis Ignarro:
Isn’t that something? I mean, it took somebody to discover that nitric oxide, which had long been known to be a pollutant in the Earth’s atmosphere, it took someone to show that our bodies could actually produce it. Once that was identified, everyone jumped on the bandwagon, and so many different people discovered so many different effects of anti-
Dr. Mark Hyman:
Effects.
Dr. Louis Ignarro:
But what’s miraculous is that one single molecule can exist ubiquitously throughout the body and produce all of these effects. We’ve mentioned only half of them. To me, a scientist, I find that remarkable. But if you have a chemistry background, which I do, and you look at NO, it’s perfectly suited for its job. Why? Why have 25 different chemical molecules in the body each doing something when you can have one? Nitric oxide, but it has to be regulated because you don’t want to increase blood flow to your legs at the same time that you’re creating penile erection. I mean, in one place, it works. In other place, it doesn’t. So it’s highly regulated, so that it’s not working everywhere at the same time.
Dr. Mark Hyman:
It’s incredible. So how do you know if you’re low in nitric oxide as a person walking around the street?
Dr. Louis Ignarro:
Well, let me tell you something, sir. If I did not retire, and I still had my laboratory, I would invite you to my laboratory to try to work out that problem. Because it’s such a difficult problem. It’s impossible to measure nitric oxide in realtime because it’s an unstable gas. It has a half life of about two or three seconds. That’s it.
Dr. Mark Hyman:
Wow.
Dr. Louis Ignarro:
As it’s made in the body, it works within a second or two, and then it’s gone. That’s what you want from a signaling molecule. You don’t want the molecule to hang around forever. You just want it to hang around just for a little bit. But luckily, we’re continuously making nitric oxide. If we have healthy arteries, they are continuously making nitric oxide. Unfortunately, we can’t measure it. We can measure byproducts. In other words, we can measure nitrite, NO2- and nitrate, NO3-. Because no is oxidized. That’s how it’s broken up. It’s oxidized to nitrite and nitrate. So you can measure that. It’s good in laboratory animals, but not in humans.
Dr. Mark Hyman:
Not great. Not great for going to your doctor and having it checked out.
Dr. Louis Ignarro:
Well, because nitrates and nitrates are present in all the foods we eat. If you like beets, and spinach and Brussels sprouts, and you like to eat bacon, and so on, all those foods are loaded with nitrite, nitrate. So you’ll have a very, very high background level. Although it’s been attempted, you cannot measure changes in nitric oxide production that way.
Dr. Mark Hyman:
But symptomatically, there’s ways people can know, right? I mean …
Dr. Louis Ignarro:
Sure. Absolutely.
Dr. Mark Hyman:
So what would be the kind of symptoms people might have?
Dr. Louis Ignarro:
What we have typed, we meaning the scientific community, not I. But anyone with hypertension, that’s been examined clinically using invasive methods to measure NO, it’s been shown that NO production by the arterial endothelial cells is diminished. Okay? People who are obese have absolutely low levels of nitric oxide produced by endothelial cells. People who lead a sedentary lifestyle, the same. People who have been subjected to physical activity, just even minor physical activity, walking fast, riding a stationary bike, and there’s ways to measure indirectly nitric oxide production. I can tell you about that in a second. That NO goes up. The way you measure NO indirectly is you put something like a blood pressure cuff on your finger, and it’s made tight. Then the blood flow in your arm is stopped just for a few seconds. Then the tourniquet is released, that will cause blood flow to go through the finger.
Dr. Louis Ignarro:
There’s something called flow, blood flow dependent vasodilation. In other words, when you release that cuff, and you allow the blood to flow through the hand, the blood flow, because it creates a force against the arteries, that’s called shear stress. That stimulates the arteries to make enormous amounts of nitric oxide. That’s good, because you want to dilate all the blood vessels there that have just been constricted. So NO is released to dilate the blood vessels and allow blood flow. That’s what happens during exercise in all of your skeletal muscle, by the way. But you can measure that flow dependent vasodilation. That’s a pretty darn good measure of your capacity to make nitric oxide. So if you run that test, which is expensive, usually you have to go to a clinic, whatever, for now anyway. You can determine how much NO you can make. What we know is that people who lead an unhealthy lifestyle, if I just leave it at that, make substantially less nitric oxide, that’s been borne out every time.
Dr. Mark Hyman:
That’s amazing. So everybody’s listening and probably wondering, how do I boost my nitric oxide levels? You talk in your work about a lot of things, nutraceuticals, diet, protein, exercise, breathing, the microbiome, all these things, I want to get into all this. So let’s start with the conversation about diet and nutraceuticals or supplements and how they can affect your nitric oxide production.
Dr. Louis Ignarro:
Okay, so I’ll make this as brief as I can. It’s clear from the work so many people have done that a healthy balanced diet is the best way to maintain your adequate production and action of nitric oxide. What do I mean by healthy diet?
Dr. Mark Hyman:
Yeah.
Dr. Louis Ignarro:
You know all about that. My goodness, that’s been your career and your pharmacy and everything else. I mean, we have to eat healthy. What does healthy mean? Stay away from saturated fats? Look, I like a hamburger once in a while. Once every two months, I have a juicy, fatty hamburger, it’s not going to kill me, it tastes good. I get it out of my system. But then I eat fish. Fish is my healthy protein.
Dr. Louis Ignarro:
There are plant proteins of course that are healthy, but I stay away from meats most of the time, even chicken. I mean chicken’s okay. But as soon as you start eating the skin of the chicken, forget it. That’s loaded with saturated fat. So I like eating fish for my healthy protein. You do have to have healthy protein. But like many diets out there, which I don’t want to talk about unless you do, I do not lower my carbs. I’m a firm believer that 30% of your diet should be carbs, but healthy carbs. Not potato chips, not packaged foods. None of that garbage.
Dr. Mark Hyman:
What do you mean by healthy carbs?
Dr. Louis Ignarro:
Oh, I mean, the most colorful fruits and vegetables you can eat.
Dr. Mark Hyman:
Yes.
Dr. Louis Ignarro:
The most powerful antioxidants. Remember, antioxidants can increase nitric oxide. Why? Because the antioxidants destroy the free radicals that go after nitric oxide to destroy the nitric oxide. So antioxidants will boost nitric oxide simply by stabilizing the molecule. We’ve done a lot of work on that. But most of it’s been done by everybody else. But the darker the fruit, for example, the better the antioxidant.
Dr. Louis Ignarro:
Pomegranate juice, everybody knows pomegranate. If you ever get it on a white shirt, you can never get the stain off. That is a dark fruit. Same thing with blueberries, strawberries, any kind of berry. Let’s go to the plant family. Spinach, Popeye knew all about nitric oxide before anybody else did. I mean spinach is very healthy. Kale, my goodness, kale, Brussels sprouts, dark green leafy vegetables. My wife and I have that every single day. I just think that those carbs are so important because they’re loaded with antioxidants. Fats are also important. You need fats for energy. But unsaturated fat. I’m lucky I’m Italian because my parents never used anything but olive oil.
Dr. Mark Hyman:
Olive oil.
Dr. Louis Ignarro:
That’s what I use. Olive oil, I put it in everything except my coffee. Okay? We use olive oil. If you want to eat unsaturated fats from food, avocado is one of many good examples. You just have to watch the calories. Whenever you’re consuming any kind of fat, whether it’s saturated or unsaturated, if your goal is to watch your weight, then just practice a little caloric restriction, and you’ll be fine. There’s my statements right there.
Dr. Mark Hyman:
I think you’re eating lots of good fish and fruits and vegetables. It’s definitely a healthy diet and you’re cutting out the starch and sugar and the junk. 100% agree. I think there is some question about the variations in the population, how some people can tolerate saturated fat better than others. Dr. Ronald Kraus, actually should have him on the podcast, is one of the leading lipidologists. You might have heard of him or know him in fact.
Dr. Louis Ignarro:
Yes, yes, yes.
Dr. Mark Hyman:
He’s challenged some of the orthodoxy about saturated fat. So I think there’s still a debate about this, but I think you’re right. For example, for me, I know I I’m someone who genetically I don’t think I can tolerate a lot of saturated fat whereas I’ve seen other patients do really well. So it’s really like the N of one or personalized medicine on that. 100% agree.
Dr. Louis Ignarro:
Right, right.
Dr. Mark Hyman:
So let’s talk about the supplements you develop because I’m really curious about what can we do because the other thing you talk about is protein. We haven’t really discussed it but the precursor or the building block of nitric oxide is an amino acid called arginine, which is found in a lot of foods including almonds, it’s very high in Argentine.
Dr. Louis Ignarro:
Yes.
Dr. Mark Hyman:
So tell me about what we can do in terms of the protein we should be eating, like the nitric oxide that the arginine this needed to get our nitric oxide produced. What are the best sources of that and then one of the supplements that you’ve been using to actually help boost nitric oxide levels?
Dr. Louis Ignarro:
Sure, I think that after we discovered that our arteries can produce nitric oxide, another group actually discovered the enzyme, a group from Johns Hopkins discovered the enzyme that makes nitric oxide and that you refer to as nitric oxide synthase, or NO synthase. What they showed was that like any other enzyme, a substrate is required, right, to be converted to product. So the substrate for NO synthase is arginine, one of the 20 or so basic amino acids that found in all protein. So arginine is converted to nitric oxide by this enzyme.
Dr. Louis Ignarro:
If you have an arginine deficiency, you’re going to make less NO. If you have excess arginine, you’ll be safe. You’ll be able to make the normal amount of nitric oxide. Unless of course there are other underlying problems. You can make a lot of NO, but if you’re not taking in sufficient antioxidants, if you are obese, especially morbidly obese, then you can take in all the arginine you want, and your NO levels are not going to be very high.
Dr. Louis Ignarro:
So anyway, arginine is a great amino acid. This has come under some criticism. Some people, some scientists say that we have so much arginine in our body, it saturates all the sites. So adding more is not going to increase NO. I can tell you from our experiments and experiments of hundreds of others that nothing could be further from the truth. Sometimes we don’t understand something in science, that doesn’t mean it’s wrong. That just means we don’t understand it.
Dr. Louis Ignarro:
So we will make more nitric oxide if you take in more arginine. That’s been shown in mice and rabbits with atherosclerosis. It’s been shown in humans, a lot of great studies conducted in in Germany, so it’s good to consume arginine. Various ways you can do it. The richest source of arginine on a weight basis is, as you said, almonds. Actually walnuts are good too. All nuts have arginine, almonds the most. There’s a problem there.
Dr. Louis Ignarro:
Because if you eat a cup of almonds, you’re making huge amounts of NO. You’ll wind up with a 50 inch waistline in no time. I mean, it’s extremely caloric. But if you eat fish, all protein has arginine. There’s a lot of arginine in protein. So that’s why I always say, Mark, a healthy balanced diet. Don’t overdo this and overdo that and eliminate this. Human beings were not designed for that.
Dr. Mark Hyman:
But the diet we’re eating is very different than your grandparents ate in Italy 100 years ago, right?
Dr. Louis Ignarro:
For sure, for sure. Well, what they ate was good, because my father smoked camel cigarettes unfiltered for 70 years, he died at 96 years old without a cough.
Dr. Mark Hyman:
Oh geez.
Dr. Louis Ignarro:
Without a cough.
Dr. Mark Hyman:
Well, that’s good genetics right there.
Dr. Louis Ignarro:
My mom, same thing. My mom was overweight, she didn’t smoke, but she was overweight. She loved her cooking. She died at 91. So I’m blessed. I probably don’t even have to take care of myself and I’ll live well. I’ll be 80 years old in a few months. I feel good.
Dr. Mark Hyman:
That’s good. That’s good. UB Blake said I, “I wish I’d known I was gonna live so long.” He lived to be over 100, he says, “I would have taken better care of myself.”
Dr. Louis Ignarro:
I love that. I have to praise him for that.
Dr. Mark Hyman:
He smoked and drank. I think you have to have the APOE22 to get that. You might have the APOE22 and a bunch of other longevity genes, which is pretty awesome. So good for you. Yes. Okay. So what about just taking arginine? What if I just go to grocery and take arginine. Is that a good idea?
Dr. Louis Ignarro:
You can do that. When the work was published by us and other groups, I guess in the early 90s or late 90s, I should say. It was clear that arginine was important. So many, many of the companies developed arginine supplements. At the time, they were very expensive. They put arginine, for example, in capsules and so on. You have to be careful that way, because arginine has a terrible, terrible taste. So if you’re taking it in a capsule or many companies have made formulations of arginine mixed with flavors, and other substance to make it more palatable, so that you could take a couple of teaspoon fulls and make a solution and drink it. Those products have been extremely popular. I think there was a fellow his name was Dr. John Cook. He was at Stanford in 1998. He developed something called the Heart Bar, which was a chocolate bar loaded with 6000 milligrams of arginine.
Dr. Mark Hyman:
Wow.
Dr. Louis Ignarro:
I was a good customer. The only problem was that the chocolate bars tasted god awful. I mean, you literally had to close your nose when you ate them. Eventually, nobody would buy them. That was the end of the Heart Bar.
Dr. Mark Hyman:
That’s very funny.
Dr. Louis Ignarro:
I worked with the company we came up with, or they did, with a formulation that was really great. It’s very good tasting. I’ve been taking that since July of 2003. My wife and I did-
Dr. Mark Hyman:
Is it a powder? Is it a powder?
Dr. Louis Ignarro:
It’s a powder, it’s a powder that consists of five grams, that’s 5000 milligrams of arginine.
Dr. Mark Hyman:
Wow.
Dr. Louis Ignarro:
It also has some citrulline, which I’ll tell you about in a moment. Then it has of course, Vitamin C in it and newer formulations will probably contain pomegranate instead because it’s much more powerful anti oxidant. That’s the way that works. When we marketed that product, it’s really funny about a year later, I mean-
Dr. Mark Hyman:
What’s it called?
Dr. Louis Ignarro:
It’s called Niteworks, N-I-T-E-W-O-R-K-S. It’s called Night work, because at the time, we thought, scientists thought that most heart attacks and strokes occurred in the evening hours. Even though we can’t put claims on the bottle it, that it cures any disease or treats it or whatever, you can’t say anything like that, of course, because of the FDA and the SHEA rules. We just thought that, we said, “Good for your heart health.” That you’re allowed to say, and it is. We just thought, “Why not take it at night before you go to bed?”
Dr. Louis Ignarro:
But now we know that it doesn’t make any difference when you take it. As long as you take it, it doesn’t make any difference. The levels of NO go up, they stay up. You could take it in the morning, I take it in the morning, every single morning.
Dr. Mark Hyman:
Even once a day is enough to keep it all day long?
Dr. Louis Ignarro:
Yeah, yes, more or less. I mean, clinical studies have not been done. Those are very, very expensive to do. I mean, it didn’t feel that was necessary.
Dr. Mark Hyman:
But you’ve done animal studies looking at if you give arginine to these animals, their levels of nitric oxide increase.
Dr. Louis Ignarro:
Yes.
Dr. Mark Hyman:
In laboratory.
Dr. Louis Ignarro:
I’s interesting, we still don’t understand it completely. If you give the arginine every day, the NO synthase enzyme, for some reason, gets upregulated. So there’s actually more enzyme, maybe it’s because the enzyme sees more substrate, I thinks, “We got to have more enzyme.” I don’t know. But anyway, that means you get more NO production, and it stays up. Now, if you stop giving the arginine to the animals, takes three to five days, and it gradually goes down. So it’s very interesting.
Dr. Mark Hyman:
Amazing. Does it help lower blood pressure or would it help sexual function for people who take it?
Dr. Louis Ignarro:
Okay, well, now, number one-
Dr. Mark Hyman:
I know you can’t say anything in front of the FDA.
Dr. Louis Ignarro:
I have to be careful what I say.
Dr. Mark Hyman:
But just in theory, in theory.
Dr. Louis Ignarro:
You’re very famous, everybody listens to you, including the FDA. So we got to be careful what we say. I’m still working for this particular company. I have to be very careful what I say. Also unless it’s tested clinically, in a double controlled, placebo controlled trial, which it’s not, most supplements have not, what supplement company has $50 million to do a correct study for god sakes? Nobody does.
Dr. Louis Ignarro:
But yes, I can tell you because I gave this product to my mother, many people, my neighbors, and the gym, and so on. If you have hypertension, in many cases, this seemed to lower the blood pressure. But I can’t say that it was due to the product, could be a placebo effect. We have no evidence that this product in humans will lower the blood pressure. But the way I look at it is this, I look at the science. I’m a scientist, okay? I look at the science, this is a perfectly safe product. It makes all the sense in the world that if you give arginine, you’re going to make more nitric oxide. Everyone knows that nitric oxide lowers the blood pressure. But I don’t want to say that because that means everybody who buys the product is going to be telling everybody else to buy the product because it lowers the blood pressure. We can’t say that.
Dr. Mark Hyman:
I understand.
Dr. Louis Ignarro:
It’s very heart healthy, that I can say.
Dr. Mark Hyman:
That’s good. All right. So So besides the diet and the supplements, there’s things that are absolutely free that really improve nitric oxide. Exercise and breathing.
Dr. Louis Ignarro:
Of course. Yes. Breathing, yes.
Dr. Mark Hyman:
So talk about those two things.
Dr. Louis Ignarro:
Well, the exercise part is really fantastic. I had nothing to do with these studies. A group showed that when animals exercised, we all know there’s an increase in blood flow to the limbs. For example, mice or rats who were put on a treadmill, for 30 minutes or whatever, and they’re they’re running to keep up and so on without falling.
Dr. Louis Ignarro:
Then the tissues, the skeletal muscle was analyzed, it was found to have increased nitrite and nitrate, which means it made more NO, more in vivo studies were done. What it boils down to is this, when you exercise, your heart, your cardiac output goes up. You’re pumping more blood, there’s increased blood flow through your working skeletal muscle.
Dr. Louis Ignarro:
Let’s take the legs for example. If you run, or the arms if your weight lift for sure. What we know now, so I’m jumping 15 years what we know now is whenever there’s increased blood flow through the arteries that go to your skeletal muscle, that increase in blood flow creates a force or pressure or shear force against the lining of the arteries. That triggers NO synthase activation. That’s well known, well worked out, hundreds of publications on this. Within seconds after this increase in blood flow, all your arteries in the skeletal muscle make huge amounts of nitric oxide.
Dr. Louis Ignarro:
I mean, Mother Nature is amazing. Of course you want to make nitric oxide. You want to dilate all the blood vessels in the skeletal muscle to accommodate that onrush of blood. Remember, blood carries oxygen, blood carries nutrients to the muscle, muscle needs it when it’s working. Also, for those of us like you and me who work out, we want the blood to wash out of the muscle as well. So that increased blood flow takes out lactic acid and pain producing metabolites. So to me, of all the stories, I think this is the most exciting and I had nothing to do with it. I mean, it’s just fantastic.
Dr. Mark Hyman:
That’s great.
Dr. Louis Ignarro:
That is the most important way I think our bodies make NO. That is why it is suicidal to lead a sedentary lifestyle. People don’t understand how important exercise is.
Dr. Mark Hyman:
What’s your workout routine, Dr. Ignarro?
Dr. Louis Ignarro:
Well, like I said, I will be 80 years old in a few months, in May.
Dr. Mark Hyman:
You’re looking good. You’re looking good. For those listening on the podcast, he looks great.
Dr. Louis Ignarro:
Okay, well listen to what I do. Okay, we have a pandemic. So, no more gym. I don’t go to the gym. That was my mainstay. I don’t go to the gym. I used to go to spin class. I used to work out a circus using the machines, free weights, none of that. I’m not going to put all that in my house. So I lucky I live in California. I live in Beverly Hills, Los Angeles area, very sunny. It’s like 75 degrees out there now.
Dr. Louis Ignarro:
My wife and I go bicycling in the hills of Beverly Hills four days a week. So we do about 110 miles a week on the bike. But we also walk. I used to run. I don’t run, I walk fast. I stopped running marathons about eight years ago. I ran 15 marathons before that. Those are real marathons, the 26.2 miles.
Dr. Mark Hyman:
Oh my goodness, that’s incredible. That means the last one, you were about 70 something.
Dr. Louis Ignarro:
Yes, the first one was at 64 years old, I think it was about 68 when I ran the last one, my knees gave out. My physician, my orthopedic guy said, “Lou, if you want to run another marathon, that’s fine. But I got to give you new knees first.” I said forget it. So I took up bicycling, and that’s what I do. I do yoga online. So I devote a lot of hours, a lot of hours per week to my body because if I’m going to take care of everybody else, I got to take care of me first. If I’m not here, I can’t do anything or anybody else.
Dr. Mark Hyman:
It’s the only one we got. Right. It’s true.
Dr. Louis Ignarro:
It’s the only one.
Dr. Mark Hyman:
You can trade it in for a new model.
Dr. Louis Ignarro:
Right.
Dr. Mark Hyman:
All right. So what about breathing? So exercise, everybody has got to exercise that’s clear for a lot of reasons, and nitric oxide production is a really good one. Tell us about breathing because how does your breathing affect this? I’m going to jump from that to a really exciting idea that you and others have developed by treating COVID-19.
Dr. Louis Ignarro:
Yeah, sure.
Dr. Mark Hyman:
So let’s jump into this sort of breathing part.
Dr. Louis Ignarro:
Okay. Once again, there was a really great study that was conducted, not by me, but by two of my really friendly scientific colleagues in Stockholm of all places. They showed about, oh, I don’t know 10 to 15 years ago, that they we’re looking at asthmatic patients. To make a long story short, the nasal passages, the nasal sinusoidal passages in your nose produce relatively large amounts of nitric oxide gas. Your mouth does not only the nose does.
Dr. Louis Ignarro:
So what they worked out, I’m skipping through all the experiments, what they found was that your nose makes nitric oxide so that when you breathe in, when you inhale through your nose, the nitric oxide does several things. One, it relaxes the trachea and the bronchioles. In other words, the airways, the airways have smooth muscle, nitric oxide relaxes smooth muscle, arteries and airways. So the nitric oxide widens the bronchioles. So you can get more air into your lungs. That makes sense. But also when that nitric oxide gets into your lungs, it dilates the pulmonary arteries. So you’ll get your blood flow deep into your lungs to undergo oxygen exchange.
Dr. Louis Ignarro:
More recently, it was found that that same nitric oxide elicits anti microbial effects. In other words, nitric oxide is very, very strong in killing bacteria, parasites and certain viruses. So our lungs are exposed to the outside air, isn’t that right? I mean, we’re breathing air. We’re taking in germs, we’re taking in germs all the time through our nose. So it makes sense that Mother Nature would design the nose to make nitric oxide so it would go into the lungs when we breathe to keep those bugs from dividing, replicating and causing damage inside the lungs. So those are the three major effects of the nitric oxide in the lungs, and I think that’s an incredible study.
Dr. Mark Hyman:
But you can activate it through deep breathing. It’s not just any kind of breathing, you have to breathe in through your nose and out through your mouth.
Dr. Louis Ignarro:
Yes.
Dr. Mark Hyman:
Because you’re saying it just happens naturally as we breathe, but we can really magnify that and increase our nitric oxide bot how and when we breathe, so tell us about that.
Dr. Louis Ignarro:
Well, let me put it this way. Now, I’m not sure whether breathing in through your nose stimulates more NO formation. But But what I can tell you is this. If you’re breathing into your mouth, and not through your nose, your nose is still making nitric oxide, but it’s not getting in your lungs. It’s just hanging around there. So the idea, every time you inhale, whenever possible, you should breathe in through your nose.
Dr. Louis Ignarro:
Sometimes, if you’re running 100-yard dash or you’re climbing a mountain, it’s almost impossible to get enough air or oxygen through your nose. So of course you’re going to breathe through your mouth and inhale through your mouth because you got to get the oxygen in. But it’s good to have a balance of the two. So if you can remember, if people can remember to breathe in, to inhale through the nose, then they’re going to get a lot of nitric oxide benefits in the lungs.
Dr. Louis Ignarro:
Now, often I say, “Breathe out through the mouth.” Well, I’ve been criticized for that by people who do yoga. I’m not a yoga expert. They tell me, “Well, you should breathe out through your nose as well.” I guess it’s okay, as long as you breathe in through your nose, I don’t care how you’re breathing out.
Dr. Mark Hyman:
You’re good.
Dr. Louis Ignarro:
I think you’re good. However, sometimes in yoga, and I’ve had conversations with people, they’ll exhale through the mouth, okay, but they’ll do it slowly. Like they’ll make sounds on you do yoga like … Whatever. When you breathe out slowly through your mouth, you’re giving more time for the nitric oxide, which is constantly being made in the nose to build up. So that when you do breathe in through your nose, you’re going to have a lot more nitric oxide going in the lungs.
Dr. Mark Hyman:
Amazing.
Dr. Louis Ignarro:
So I was able to satisfy a few yogis with that.
Dr. Mark Hyman:
Oh good. You don’t want to get angry yogis at you.
Dr. Louis Ignarro:
Exactly.
Dr. Mark Hyman:
Nothing worse than a pack of angry yogis. All right. So let’s talk about something really fascinating, which is COVID-19. Because this is a pandemic that is now, as the recording of this podcast, has affected over 10 million Americans, killed almost a quarter million, globally 50 million. There’s right now clinical trials going on in hospitals using nitric oxide to help us treat COVID-19. So tell us about the mechanism, how it works, what they’re doing, what the studies are showing, if anything. So tell us about that because I think people really are probably wanting to hear about this.
Dr. Louis Ignarro:
Yes, well, of course, first of all, inhaling nitric oxide gas as a drug is not new. This was started about 20 years ago. Newborns, many infants are born with pulmonary hypertension, they can’t breathe. Very invasive procedures where used to try to get to save these newborns, and most of them died. But Dr. Warren Zaypo at Massachusetts General Hospital, invented the use of inhaled nitric oxide to give to these newborns, and their lives were saved. After a few minutes of breathing nitric oxide, their arteries were perfect. There was no more hypertension. And they were able to go home in a couple of days.
Dr. Mark Hyman:
Wow.
Dr. Louis Ignarro:
It was such a miraculous. That’s why I call this nitric oxide the miracle drug, the miracle molecule of life. In fact, I’m going to write a book on that, the miracle molecule of life. But let’s get to COVID. So when this broke out, actually, we had a form of COVID breakout a number of years ago. People did in vitro experiments with nitric oxide. It seemed to kill the SARS-CoV-1 virus, I think back in 2008.
Dr. Louis Ignarro:
To make a long story short, then when this pandemics started, my friend, Dr. Zaypo, again at MGH decided to try giving patients inhaled nitric oxide, patients with severe COVID-19. It worked dramatically. Let me explain because it makes so much sense. Okay, first we have to understand how does COVID-19 kill people? Well, that virus has to get in the lungs. That’s number one. We all know that. That’s why we wear masks, practice social distancing. When the virus gets in the lungs, it attaches to where the oxygen is extracted in the alveoli.
Dr. Louis Ignarro:
The virus tends to then destroy the endothelial lining of the arteries, the endothelial arteries, and we haven’t talked about that, but the endothelial cells of the arteries are the only cells of the arteries that make nitric oxide. So these endothelial cells-
Dr. Mark Hyman:
Those are the lining of all …
Dr. Louis Ignarro:
The inner lining, the endothelial cells separate the flowing blood from the smooth muscle, that regulates the contraction and relaxation of the artery. So the endothelial nitric oxide will dilate the arteries to allow blood to flow through. As I mentioned earlier, that nitric oxide is also going to relax the bronchioles to have more air in. One of the protective roles of NO in our body is to kill microbes like viruses. So when the virus destroys the endothelium, these patients die of a massive thrombosis, they get a blood clot throughout the lungs, and you cannot reverse that. Remember, nitric oxide prevents blood clotting. If you take away the nitric oxide, you can’t prevent the blood clotting. So these patients die of pulmonary hypertension and massive blood clotting or thrombosis.
Dr. Louis Ignarro:
Okay, so now you’ll give the patient’s nitric oxide gas by inhalation. What happens? You’re replacing the nitric oxide that is no longer available from the endothelial cells. So the NO causes more air to go in because it’s relaxing the bronchioles. It immediately eliminates the high blood pressure in the lungs.
Dr. Louis Ignarro:
So blood can go deep, deep into the lungs to look for oxygen. Probably, most importantly, that steady administration of nitric oxide gas kills the SARS-CoV-2 virus that causes the COVID-19. After a few days, those patients come out of the ICU. After a week or so, they go home. So this is remarkable. So an initial color clinical trial was done to reveal this. In fact, pregnant women, very sick, pregnant women volunteered to go into the hospital at MGH to have this done.
Dr. Louis Ignarro:
Every single woman was cured, their babies developed normally. Some of those ladies delivered their babies in the hospital, they tested negative for the virus, and the other ladies went home and had their babies, outside the hospital later, and everyone tested negative. So that initiated a huge clinical trial now going on in five or six institutions worldwide, mostly in the US. Those results, I hope, I don’t know, they don’t tell me all these things, is the FDA controlled should be done by the end of the year.
Dr. Mark Hyman:
But it’s already an approved treatment, right? He’s using babies, so it’s FDA-approved as a treatment.
Dr. Louis Ignarro:
Exactly.
Dr. Mark Hyman:
Is it being used widely?
Dr. Louis Ignarro:
Well, it’s hard to give. The problem is to give nitric oxide, you have to have a special delivery device that cleans the nitric oxide before it gets in the lungs. Nitric oxide is very unstable. If you don’t give it properly, it’ll turn into really-
Dr. Mark Hyman:
An oxidant.
Dr. Louis Ignarro:
Toxic materials, oxidant, and could kill you so so has to be given by special professionals, health professionals with special apparatus in hospital. These people are working day and night to develop a more portable method. What it’s going to be doing, we hope is to keep people out of the ICU. It’s going to be given to the staff working in hospitals and clinics as a preventive. In other words, they can breathe it a couple of times a day.
Dr. Mark Hyman:
It’s amazing. Yeah.
Dr. Louis Ignarro:
Then go into the ICU. It’s being used and hopefully more of it will be used. That’ll help bridge the gap between now and the development of an effective vaccine.
Dr. Mark Hyman:
But seems like it’s something that if there could be some kind of device that would be scalable and usable by the average person who’s sick at home, it would be amazing to be able to treat people so they’re not afraid of it. They get the virus, they use this inhalation machine, they give nitric oxide, they get over it faster, they don’t get really sick. They don’t end up in the hospitals. Right now, hospitals are being overwhelmed as we speak.
Dr. Louis Ignarro:
Yeah. I agree. As usual, you’re right on the mark, no pun intended. There are three companies that are developing, and I’m not included. Three different companies developing a portable device that actually makes … Normally the machines come with big nitric oxide and oxygen tanks. The two gases are mixed in a special chamber. You breathe it in and so on. But now portable devices are being made where there is a spark with a special spark plug, Iridium spark plug, that ignites the air. When you do that, it’s like lightning bolts in the sky.
Dr. Louis Ignarro:
When the lightning strikes, it makes nitric oxide in the air. That NO oxidizes to NO2, nitrogen dioxide. That’s air pollution. That’s what makes the air brown, that brown ring you see over New York City and Chicago and maybe Boston once in a while, is NO2, nitrogen dioxide. So these portable machines apparently can make nitric oxide safely and the person can just take it around and breathe in. They’re working on it, believe me, day and night. So maybe within six months, it’ll be available now.
Dr. Louis Ignarro:
In closing this discussion about COVID, I want to say something very important about these portable devices. The nitric oxide doesn’t just kill Coronavirus. The nitric oxide kills influenza virus. So let’s think outside the box. Let’s think ahead, five years from now. Virtually nobody gets the flu. Why? They’re carrying around these nitric oxide devices.
Dr. Mark Hyman:
Unbelievable.
Dr. Louis Ignarro:
They can just breathe in nitric oxide once in a while. Isn’t science beautiful?
Dr. Mark Hyman:
Wait. Did you just say that you discovered maybe the cure for the common cold?
Dr. Louis Ignarro:
Not me, not me. I like to pretend that.
Dr. Mark Hyman:
Well, I mean, you discovered nitric oxide and that has led to the treatments using inhaled nitric oxide that could save us from COVID and the common cold and the flu. That’s pretty remarkable. That you can go to bed at night feeling really good about, can’t you?
Dr. Louis Ignarro:
That’s true. There are two things I feel good about. One, the more I see about the development of nitric oxide to save lives, the better I feel because I know that if I hadn’t discovered it to start with, who knows where we would be? You’re absolutely right. I don’t talk about that. But if you had hidden cameras in the house, you would know that I’m very excited about that.
Dr. Mark Hyman:
You’d be walking around smiling all the time. Well, I’m just so thrilled that we got to have this conversation. It’s so inspiring. For those who listen to this and trying to remember what we talked about, we talked about this molecule, nitric oxide, which we all make, but we can increase through having high quality protein, through almonds, through taking arginine supplements, through exercise, through breathing techniques. Even maybe through the science that you develop, we can find a real way to treat COVID-19 and other viral infections. It’s just tremendous, tremendous work. I’m so inspired by what you do. I’ve known about your work for over 20 years. I’m in awe. I was so excited when we get to do this podcast together. So thank you so much for joining us, Dr. Ignarro. I can’t wait till your next Nobel Prize.
Dr. Louis Ignarro:
Yes, very good. Thank you, Dr. Hyman. This has been a great experience for me as well. Thank you.
Dr. Mark Hyman:
Thank you. For those of you listening to the podcast and loved it, please share with your friends and family on social media. I mean, everybody needs to hear this message. Leave a comment. We’d love to hear from you. Subscribe wherever you get your podcasts and we’ll see you next week on the Doctor’s Farmacy.
