Healthy Aging

Are You Nitric Oxide Deficient? Part 1 of 2

Dr. Nathan Bryan, Ph.D., on common etiologies of inadequate nitric oxide production, and the problems it causes

Biography: Nathan S. Bryan, Ph.D., is an international leader in molecular medicine and nitric oxide biochemistry. Specifically, Dr. Bryan was the first to describe nitrite and nitrate as indispensable nutrients required for optimal cardiovascular health. He was the first to demonstrate and discover an endocrine function of nitric oxide via the formation of S-nitrosoglutathione and inorganic nitrite.

Dr. Bryan has been involved in nitric oxide research for the past 18 years and has made many seminal discoveries in the field. Many of these discoveries and findings have transformed the development of new therapeutic agents for the treatment and prevention of human disease.

Dr. Bryan has published a number of highly cited papers and authored or edited five books. More about his work can be found at www.drnathansbryan.com.

NutritionInFocus: Let’s start with some basics here; nitrites, nitrates, nitric oxide: what’s what, and how do they relate? Are these molecules good, bad, or both potentially?

Dr. Bryan: There’s been an evolution of the perspective of nitrites and nitrates; back in the 50’s and 60’s we were taught these were dangerous food additives that formed nitrosamines that caused cancer. Then, fast-forward to 30 or 40 years later, the National Toxicology Program had put nitrites and nitrates through long term safety trials and found no evidence of carcinogenicity whatsoever. Then, in the late 80’s and early 90’s nitric oxide (NO) was discovered, and it was realized that nitrite and nitrate could be formed endogenously from NO.[1] This really told us in the scientific community that nitrite and nitrate are part of the normal NO metabolism. NO really is one of the most important molecules produced in the human body, so important, in fact, that in 1998 a Nobel Prize was awarded for the discovery of NO. These things in the scientific community really told us a lot about nitrite and nitrate: they weren’t toxic food additives that caused cancer and they were actually really important metabolites that can be utilized (as we understand now) to form NO.

However, this message hasn’t necessarily translated to consumer awareness and the messaging of food companies or other marketing. People thought for years that nitrites/nitrates were mainly found in cured and processed meats, but really the greater burden of exposure is from eating green leafy vegetables, and less than 5% of nitrites/nitrates that we are taking in is from bacon or hotdogs or other cured and processed meats. In fact, this is the reason that a diet rich in vegetables can lower blood pressure, because these nitrites/nitrates are metabolized and converted to NO, and NO dilates blood vessels and lowers blood pressure.

If nitrites/nitrates were harmful, then we would see vegetarians having a higher incidence of cancer and cardiovascular disease. Epidemiological data shows this is not the case, and that vegetarians have lower rates of these conditions, which we now understand, mechanistically, may be due to the presence of nitrites/nitrates which increase NO levels in the body, improving vasodilation, blood flow, and even mitochondrial function.

If the body can’t make NO or if you are not getting enough nitrite/nitrate in the diet, this puts you at risk of every single age-related and chronic degenerative disease.

So, the answer really is NO is good for you, as are nitrites and nitrates, these are all-natural molecules produced in the body.[2],[3] The data show us they really have the opposite effects of what we were told 40 years ago: over 160,000 published scientific papers show us that if the body can’t make NO or if you are not getting enough nitrite/nitrate in the diet, this puts you at risk of every single age-related and chronic degenerative disease.

NutritionInFocus: If nitrates are inert and nitrites are what they must convert to, why aren’t we advocating people eat more bacon?

Dr. Bryan: The problem is that you really can’t eat enough bacon to get the amount of nitrite/nitrate that the body needs to produce NO. However, when we consider cured and processed meats, the potential problem has always been nitrosamine; it has never been nitrites and nitrates. However, nitrites can form nitrosamines under certain conditions. In modern meat-curing processes, when manufacturers add sodium nitrite to these products, they also add ascorbic acid or structural analog known as erythrobate, compounds that prevent nitrosamine formation.[4] This really makes the nitrosamine story go out the window.

If you are a meat eater and eat one to two servings of cured or processed meat weekly, the relative risk of cardiovascular disease, cancer, and all-cause mortality is about 1.15 to 1.23, although some studies show it may be even lower.[5],[6],[7],[8] At 1.15 this is probably within the noise, due to some confounder that probably wasn’t noted for, and a moderate level of consumption of these things cannot be pointed to as causative.[9] For comparison, the relative risk of cancer associated with smoking or asbestos exposure is up around 10 to 40.[10],[11],[12]

We see ads now for things like nitrite-free bacon or organically cured sausages – but this is really deceptive marketing because we need nitrites to preserve them, and there is no replacement for it. Despite using alternate processes to produce nitrites, these products still contain them.[13] Nitrites in these products prevent botulism or bacterial overgrowth, lipid oxidation, and gives these products a shelf life so can eat them safely.[14] Over the years, rather than adding sodium nitrite, manufacturers have added celery salt (which contains nitrate) and a starter culture of bacteria which converts nitrates to nitrites.[15] The challenge with that approach is that the level of protective nitrites is highly variable – the nitrate content of celery salt is variable; the bacteria activity is variable – giving them an unknown safety profile, and it really is better to just use the original process because we have known for years that there is no evidence of toxicity from having nitrites or nitrates in the diet.[16]

That all said, when one eats a plant-based diet they are not only are getting higher levels of nitrites and nitrates, they also are getting additional essential vitamins and minerals, and an abundance of polyphenols and phytonutrients that are found at higher levels in these foods and have important health effects. The antioxidants found in these plants also not only naturally inhibit nitrosamine formation like ascorbate and erythrobate do,[17] they also facilitate the reduction of nitrate to NO.

NutritionInFocus: In addition to diet, what are some of the main things that affect the body’s ability to produce NO?

Dr. Bryan: The microbiome is really becoming more important to human health than we ever realized. People have been focusing to a great extent on the gut bacteria and how this impacts health for numerous years, seeing enormous benefits from things like fecal transplant and the use of probiotics to affect it. In our research, we focused on the oral bacteria as it is well-established to play a role in NO production.

You can do all the right things – exercise, eat lots of leafy vegetables – but by using mouthwash regularly you are effectively killing your body’s ability to make NO.

One of the things we discovered over past decade is that people need the right type of oral bacteria to reduce nitrate (NO3-) to nitrite (NO2-), from which NO is produced (see Figure 1). The problem is that over 200 million Americans are waking up every day and using an antiseptic mouthwash to kill the bacteria in their mouth, which they have been told to do for good oral hygiene. However, when they do this, they are unknowingly killing the good nitrate-reducing bacteria as well.[18],[19] They can do all the right things – exercise, eat lots of leafy vegetables – but by using mouthwash regularly they are effectively killing their body’s ability to make NO. Their blood pressure goes up, and puts them at increased risk for heart attack, stroke, dementia, and all of the conditions that come along with poor blood flow.

Common therapies that negatively affect nitric oxide production

We’ve really only studied chlorhexidine in our studies, it is the strongest antiseptic mouthwash on the market and is available as a prescription for chronic halitosis.[20] We used this because we wanted to eradicate all the bacteria and see what happened. Other people have looked at things like alcohol-based mouthwash and found similar effects,[21] but we really don’t know about natural mouthwashes. It has been challenging to get funding for many of these studies. That said, there really is no mouthwash that I am aware of that selectively kills the bad guys and preserves the good guys.

Another thing is that antibiotics do the same thing; if you take an oral antibiotic you are not only killing the bad, you are killing the good bacteria as well. Antibacterial soaps, hand cleansers, all that – these things are killing the bacteria in your body that are doing very important things such as producing NO.

Unfortunately, we have not been able to develop a probiotic that contains any of the bacteria we have determined to be important for the oral production of nitrites from nitrates. I have tested a lot of the probiotics that are on the market and none contain any of the bacteria we have identified to be important. We also haven’t found any probiotic strain that helps reestablish this good flora in the oral cavity, replenishing the nitrate-reducing bacteria.

Another major hurdle in NO production is antacids, or proton pump inhibitors (PPIs). These drugs completely shut down NO production. Studies have shown people that have been on PPIs for three to five years have a 35 to 40% higher incidence of heart attack and stroke.[22] This really creates a problem for clinicians because these drugs weren’t meant for chronic use, yet you can get many of them over the counter and people use them daily because their reflux is intolerable. It’s really difficult to get people off these medications.

NutritionInFocus: How do PPIs shut down NO production?

Dr. Bryan: There’s actually two ways they do this. When we swallow our saliva, it is enriched in nitrite, produced by the oral nitrate-reducing bacteria. When the saliva reaches the acidic environment of the stomach, nitrite becomes protonated and generates NO gas (see Figure).[23] But if the stomach is not acidic then you are not generating NO in the lumen of the stomach.

PPIs do what no other drug has been shown to do and shut down total body NO production which is a very bad scenario.

The second thing PPIs do is inhibit an enzyme called DDAH (dimethylarginine dimenthyl-aminohydrolase) and this leads to an accumulation of asymmetric dimethylarginine (ADMA) which is a competitive inhibitor with arginine for the binding to nitric oxide synthase (NOS),[24] so you’re also basically shutting down this pathway for production of NO as well. So, PPIs do what no other drug has been shown to do and shut down total body NO production which is a very bad scenario.

People have to get off these drugs because your body can’t heal without stomach acid – you have poor absorption of vitamins and minerals in your foods; you can’t break down proteins to amino acids, so you get these peptide antigens that are absorbed across the gut which is the basis for food allergies; you get Helicobacter pylori overgrowth and ulcerations; and some people actually can have reflux due to stomach acid suppression. In my opinion these are some of the most dangerous drugs on the market today, as they lead to the progression of so many chronic diseases. You really have to restore normal stomach acid production, or your body cannot heal.

NutritionInFocus: What might be the first sign/symptom someone has of having inadequate NO production?

Dr. Bryan: The result of a decrease in NO production is a decrease in blood flow, and clinically, this manifests in erectile dysfunction in both men and women. NO signals to blood vessels to open up and regulates blood flow upon demand. To have an erection you need an increase in blood flow, which means you need NO being produced. If the endothelial cells and the nerve endings that innervate those organs can’t make NO, and you can’t dilate the blood vessels and you can’t get an increase in blood flow. A high percentage of men over the age of 40 self-report erectile dysfunction, and there probably is another substantial percentage that don’t report because of the stigma they associate with it.

There is a very clear progression of cardiovascular disease that begins with the loss of NO production and the loss of blood flow regulation.

Because NO is a vasodilator and regulator of normal blood pressure, blood pressure will increase. Two out of three Americans have an increase in blood pressure, so this really is a lot of the population. Usually erectile dysfunction occurs before you get an increase in blood pressure,[25] and as things progress you begin to see this chronic inflammatory vascular disease with plaque deposition in the lining of the blood vessels, and the arteries become dysfunctional.[26] If you don’t correct this, the plaque becomes unstable, and you get a heart attack or a stroke, the number one killer of men and women worldwide. So, there is a very clear progression of cardiovascular disease that begins with the loss of NO production and the loss of blood flow regulation. However, very few people know about NO and how to restore normal production, so no wonder cardiovascular disease is the number one killer worldwide.

NutritionInFocus: Is there a way of testing NO levels?

Dr. Bryan: That’s part of the problem – you can’t go to your doctor and ask what your NO levels are; there is no standard lab test.[27],[28] What we have to do is rely on symptoms, so my mission has been to teach clinicians what the signs and symptoms of NO deficiency are. Now, there actually are FDA-cleared medical devices that can measure endothelial function,[29] so this can give you a sense of what your NO production capability is. This is very important because once you diagnose NO insufficiency, you can address it before problems hit because the loss of normal NO production precedes the structural changes by many years, sometimes even decades. So if you can get patients in their 20’s, 30’s, and 40’s an assessment of their NO production and if they are starting to show endothelial dysfunction, and you employ these lifestyle and therapeutic strategies to restore and improve endothelial function, by all bets you can prevent age-related disease, particularly cardiovascular disease, if you restore NO production.

We developed NO testing strips a number of years ago, but the challenge was that no one knew what NO was. So, the patient or consumer would say “How do I know I need this?” The test was a simple saliva test strip: you apply your saliva to the end of it and if you have sufficient total body NO production it turns pink, if you don’t, it stays white and tells us you are NO deficient.[30]

It is a good biochemical test and something to have in your toolbox, but a functional test always outweighs a biochemical test. It tells us you are NO deficient, but doesn’t tell us is why: is it because you have endothelial dysfunction, does the enzyme in your blood vessels not work to make NO, are you not eating enough green leafy vegetables or nitrate in your diet, is it because you are using antiseptic mouthwash and killing the good bacteria. But what’s clear is if you are depleted, you are depleted. So, then we eliminate the things that are inhibiting NO production and start doing things that promote NO: changing the diet, fixing stomach acid levels, getting moderate physical exercise, or taking nutritional supplements that increase NO production.

NutritionInFocus: Why is support for NO production important in the setting of age-related disease?

Dr. Bryan: Mechanistically, every age-related disease, every single human chronic disease, has a vascular component.[31] Whether it manifests in the kidney, the brain, the heart, the liver – there is one thing that is common in all those: it is called hypoxia or ischemia, or low blood flow. So, it’s a vascular problem.

Even Alzheimer’s and vascular dementia – its reduced blood flow to the prefrontal cortex, which over time, if you don’t fix and get blood flow to fire those synapses, you get dysfunction and lose your ability to recall memory. The common denominator in any brain/neurological disorder is a loss of regulation of blood flow, and that is all dependent on NO.[32],[33] In vascular dementia patients, we have shown hypoperfusion in certain regions of the brain with functional MRI, and employed NO-based technologies, and 30 days later the functional MRI shows their brain is being perfused and their cognition improves.

Every age-related disease, every single human chronic disease, has a vascular component. It’s really simple from a vascular point of view – if you don’t give the cells the oxygen and nutrients they need, then they become dysfunctional.

It’s really simple from a vascular point of view – if you don’t give the cells the oxygen and nutrients they need, then they become dysfunctional. And you do this through a healthy circulatory system, which produces NO on demand to perfuse the tissues and organs when needed, and limits the flow when it is not needed. We don’t have enough blood in our body to equally perfuse all the cells and tissues at any given time – that’s why we regulate the blood flow which is dictated by the production of NO. When you can’t make NO, you lose regulation, and bad things happen.

 

For further insights from Dr. Nathan Bryan on nitric oxide, the peroxynitrite issue, and nutritional tools that may help improve nitric oxide production, stay tuned for Part 2 of the interview with Dr. Bryan next week.

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Does the Paleo Diet Really Work?
Are You Nitric Oxide Deficient? Part 2 of 2

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