About Dr. Nathan S. Bryan:
Dr. Nathan Bryan earned his undergraduate Bachelor of Science degree in Biochemistry from the University of Texas at Austin and his doctoral degree from Louisiana State University School of Medicine in Shreveport, where he was the recipient of the Dean’s Award for Excellence in Research. He pursued his post-doctoral training as a Kirschstein Fellow at Boston University School of Medicine in the Whitaker Cardiovascular Institute. In 2006, after a two-year postdoctoral fellowship, Dr. Bryan was recruited to join the faculty at the University of Texas Health Science Center at Houston by Ferid Murad, M.D., Ph.D., a 1998 Nobel Laureate in Medicine or Physiology.
Dr. Bryan has been involved in nitric oxide research for the past 25 years, making numerous seminal discoveries in the field. Dr. Bryan is a successful entrepreneur and the Founder, Chairman, and CEO of Bryan Therapeutics, Inc., a privately held, clinical-stage biotechnology company actively engaged in the discovery and development of nitric oxide-based therapies. BTI has active drug development programs in heart disease, Alzheimer’s Disease, and topical drugs for diabetic ulcers and non-healing wounds. Dr. Bryan’s consumer line of products is one of the most successful nitric oxide products on the market, and he is an international leader in molecular medicine and nitric oxide biochemistry.
How did you get involved in nitric oxide research?
I’ve always had an interest in science and medicine, even dating back to high school. After graduating with a Bachelor of Science Degree in Biochemistry from the University of Texas, I enrolled at the LSU School of Medicine in Shreveport to pursue a Ph.D. in Molecular and Cellular Physiology. This was just after a Nobel Prize was awarded for the discovery of nitric oxide in 1998. Dr. Lou Ignarro, one of the scientists who won the Nobel Prize, came to speak at LSU and lectured on his role in the discovery of nitric oxide. I had the fortunate opportunity to meet with Dr. Ignarro one-on-one, and he told me that whoever figures out how to restore the production of nitric oxide in humans will change the world and the landscape of medicine and healthcare. Well, that got my attention.
At that time, I was already training under a pharmacologist who had been involved in nitric oxide research for the previous 20 years. I had the perfect mentor and the perfect research environment to singularly focus on nitric oxide biochemistry and physiology. During my Ph.D. work, we developed a method to measure and detect nitric oxide in biological systems, providing our research team with a unique tool to discover what others could not. I completed my Ph.D. in under three years, then moved to Boston for a postdoctoral fellowship at Boston University School of Medicine. There, I continued my research focus on nitric oxide.
What is nitric oxide?
Nitric oxide is a naturally produced gas that acts as a signal transduction molecule. Once produced, it is gone in less than one second. However, in its very short lifespan, it activates a number of other second messenger systems that regulate blood pressure, circulation, oxygen delivery, stem cell mobilization, fight off infections, regulate cellular energy production, and ultimately influence all aspects of what we know regarding health and longevity.
How is nitric oxide involved in promoting longevity and preventing disease?
The field of longevity, or how to live a longer and healthier life that is free from disease, is a growing discipline. Three primary objective endpoints determine the measure of longevity and vitality.
The first is the length of our telomeres, or the ends of the chromosomes. Shorter telomeres are associated with a shorter lifespan, while longer telomeres indicate a longer lifespan.
Second is the number of mitochondria per cell and how well those mitochondria produce cellular energy. Lower numbers of dysfunctional mitochondria are associated with all age-related chronic diseases.
Third, is the ability of our own stem cells to mobilize to repair and replace dysfunctional cells.
Fascinatingly, nitric oxide is the molecule that controls and regulates all three of those objective readouts of longevity. Nitric oxide prevents our telomeres from getting shorter, induces mitochondrial biogenesis, and improves the efficiency of energy production in each mitochondrion. It is the signal that tells our own stem cells to mobilize and differentiate so they can repair and replace dysfunctional cells.
Suppose you lose the ability to produce sufficient nitric oxide. In that case, you will develop shorter telomeres and mitochondrial dysfunction, which prevents you from repairing or replacing cells, making it difficult for you to recover from injury and develop diseases. Nitric oxide is the Holy Grail of longevity.
How is it produced in the body?
There are two primary pathways for nitric oxide production. The first to be discovered was by the enzyme nitric oxide synthase (NOS). This enzyme is found in most cells in the body and, through a 5-electron multi-step oxidation reaction, converts L-arginine into nitric oxide, with L-citrulline as a by-product of the reaction. This enzymatic reaction requires eight different cofactors and substrates, as well as the NOS enzyme, to be functional.
The second pathway is through our diet, requiring specific oral bacteria and stomach acid production. This is a reductive pathway whereby inorganic nitrate, found commonly in green leafy vegetables, is intentionally concentrated in our salivary glands about 90 minutes after consuming a meal. It is then secreted in our saliva to be metabolized by oral nitrate, reducing bacteria to produce nitrite. Now, the saliva is enriched in nitrite, and once it is swallowed, it enters the acidic environment of the stomach, where nitric oxide gas is produced. For this pathway to be fully optimized, we must consume sufficient nitrate in our diet, we must have the right oral bacteria, and our stomach must be acidic.
Once it is produced, what does it do, and what happens as it is metabolized?
Once nitric oxide gas is produced, it can diffuse in three dimensions. It reacts primarily with heme proteins, such as soluble guanylyl cyclase, in the smooth muscle that surrounds our blood vessels. This activation by nitric oxide leads to the production of the second messenger cyclic guanosine monophosphate (cGMP), which in turn activates several downstream signaling cascades. Nitric oxide can also react with hemoglobin in the lumen of the blood vessel to form inorganic nitrate (the same nitrate found in vegetables).
Nitric oxide can also be oxidized to nitrite, where it is transported throughout the entire body. Other metabolites of nitric oxide can bind to cysteine thiols on proteins or glutathione and be transported throughout the body. Nitric oxide acts as an autocrine, paracrine, and endocrine signaling molecule, meaning it can signal in the cell in which it is produced, in a neighboring cell, or be transported systemically, similar to other hormones.
What leads to a loss of enzymatic nitric oxide production (endothelial dysfunction)?
When the NOS enzyme becomes uncoupled, it can no longer produce nitric oxide from L-arginine. This uncoupling is due to oxidative stress. An uncoupled NOS produces superoxide, an oxygen radical that leads to more oxidative stress. When the NOS enzyme can no longer produce nitric oxide when activated, we call this endothelial dysfunction. Exercise can no longer stimulate nitric oxide production. Nasal breathing can no longer lead to nitric oxide production since the enzyme is no longer active.
Anything that leads to increased oxidative stress, such as a poor diet, smoking, excessive consumption of sugar and carbohydrates, exposure to infections or environmental toxins, and heavy metal exposure (including mercury, lead, aluminum, or other redox-active metals), will lead to NOS uncoupling and a loss of nitric oxide production. Deficiencies in magnesium, iron, and sulfur-containing compounds, as well as poor oxygen saturation and delivery, will also lead to a loss of nitric oxide production.
How do diet and nutrition affect nitric oxide production?
Based on what we know about the mechanism of how nitrate from our diet is metabolized into nitrite and nitric oxide, several steps in the process must be met. First, we must consume enough nitrate in our diet—at least 300-400 mg—in a single serving. Most Americans do not consume sufficient nitrates and, therefore, do not generate enough nitric oxide through this pathway. Furthermore, many Americans over-consume sugar and simple carbohydrates, which leads to oxidative stress, further leading to endothelial dysfunction, and shutting down nitric oxide from the other pathway. Therefore, diet can completely affect and shut down nitric oxide production from both pathways, and is likely the most crucial factor in nitric oxide production.
How is the oral microbiome involved in the production of nitric oxide?
Nitrate from our diet is inert in humans, as we do not have a nitrate reductase gene. Oral nitrate, which reduces bacteria that live on the back of the tongue, performs this action instead. These bacteria utilize nitrate from our diet to respire and convert the nitrate to nitrite. Without these bacteria, nitrate from our diet is excreted unchanged in the urine, feces, and sweat. We have found that people with the least diverse oral microbiome have fewer nitrate-reducing bacteria and tend to have higher blood pressure. A healthy oral microbiome is associated with higher nitric oxide production.
Do certain oral hygiene practices affect nitric oxide production?
Due to the necessity of oral bacteria in producing nitric oxide from the nitrate found in our diet, anything that destroys the oral microbiome disrupts and inhibits nitric oxide production. We, and others, have published that the use of antiseptic mouthwash kills most of the oral bacteria, including the good bacteria, and thus disrupts nitric oxide production, leading to an increase in blood pressure. Additionally, fluoride is an antiseptic, so all fluoride toothpastes destroy the oral microbiome and shut down nitric oxide production. A healthy microbiome is dependent upon a balanced salivary pH—people who have an acidic saliva experience oral dysbiosis and a deficiency in nitric oxide production.
Are there certain drug therapies that can lead to a loss of nitric oxide production?
Any drugs that cause oxidative stress, destroy the microbiome, or inhibit stomach acid production can lead to a loss of nitric oxide production. The most obvious drug therapy is antibiotics and antacids. Antibiotics obviously kill harmful bacteria, but they can also disrupt the non-pathogenic commensal bacteria. Antacids, specifically proton pump inhibitors (PPIs), completely shut down nitric oxide production from the NOS enzyme and from the nitrate-nitrite-nitric oxide pathway.
There is clear clinical data now that shows people who have taken PPIs for 3-5 years have a 30-40% increase in heart attacks, strokes, and Alzheimer’s disease. These drugs shut down nitric oxide production, decrease circulation, cause insulin resistance, decrease nutrient absorption, and cause chronic disease. Methylene blue is another medication that completely inhibits nitric oxide production and signaling and should only be used as needed for treatment; it should never be used prophylactically.
What is the greatest threat to the advancement of the nitric oxide field?
In my opinion, the biggest threat to the advancement of the nitric oxide field is products marketed as nitric oxide supplements that do not, cannot, and will not provide any nitric oxide benefits. There are now hundreds of companies trying to exploit the growing popularity of nitric oxide and create products in this category. Most of these companies lack a comprehensive understanding of nitric oxide biochemistry, enzymology, and the processes required to produce nitric oxide in the human body. I hear people all the time report to me that they have taken “nitric oxide” in the past, but that they did not get any benefit or response from those products. Now, their interpretation is that nitric oxide is not essential or does not work for them.
The truth is that those companies and their bogus products failed them. If you provide nitric oxide to the human body or restore its natural production, the body will always respond, and people get better. There are companies out there, with absolutely no scientific backing, that throw in dozens of different ingredients and call their product a nitric oxide product. This is a dangerous, disingenuous, and deceptive trade practice. Nitric oxide biochemistry is complex, and companies that do not understand the science have no business selling such products.
How do consumers and physicians find a nitric oxide product that actually works?
They should look for products developed by real scientists who have actually published research in the nitric oxide field. Suppose the company or its scientific advisory board is not found on PubMed and has not published any original research on nitric oxide. In that case, there is a good chance their products will not meet the standard of excellence I have established in the field. Look for “nitriceuticals”, which is a term I coined years ago that represents products that actually produce nitric oxide gas. If your body has lost the ability to produce nitric oxide, then we must provide this gas to you in another way. That’s exactly what my products are designed to do. You can explore them at www.n1o1.com and learn more about our mission and research at www.bryantherapeutics.com
Furthermore, because I understand the mechanisms of production in the human body, my products repair and restore the function of the NOS enzyme, helping to restore the oral microbiome, so your body can produce nitric oxide on its own. It is not enough to give L-arginine, L-citrulline, or nitrate-based products. The problem for most people who are nitric oxide deficient is that they have lost the ability to utilize those components to produce nitric oxide.
What do you envision as the future of medicine and the role of nitric oxide?
The future of medicine is absolutely dependent upon safe and effective nitric oxide products and drug technology. All chronic disease is associated with loss of blood flow regulation, inflammation, oxidative stress, and immune dysfunction. Restoration of nitric oxide corrects all four of these conditions. The body cannot and will not heal or perform at its best without sufficient nitric oxide production.
My company is developing nitric oxide drug therapy for several human diseases, including heart disease and Alzheimer’s Disease. We also have a topical nitric oxide drug for diabetic ulcers and non-healing wounds. These drugs will revolutionize human health and improve the lives of patients all around the world.
What is your primary motivation or inspiration to do what you do?
I am motivated by the millions of lives we have changed over the past decade with my nitric oxide product technology. It started with saving my dad’s life. As a paraplegic, he was also battling diabetes, high blood pressure, and ulcers that refused to heal. By utilizing my nitric oxide products, we were able to get his blood pressure and diabetes under control. My topical nitric oxide was able to help heal a 4-year-old, non-healing wound that had become infected and life-threatening.
I recall my original conversation with Dr. Lou Ignarro, where he told me that if we could figure out how to restore nitric oxide production in humans, we would change the world. Well, we figured it out, and we are certainly changing the world. I have the pleasure of waking up every day to emails, voicemails, and texts from people whose lives have been positively changed after taking our products. There is no greater motivation or inspiration than seeing people’s lives changed and saved.
What are the vision or goals of your company?
Our vision is very clear; we aim to be the leader in nitric oxide products and drug therapy technology. Our goals are to continue innovating and providing safe, effective products that deliver nitric oxide gas and help restore the body’s ability to produce nitric oxide naturally. One of our current goals is to provide nitric oxide products in every major market segment around the world, and we have accomplished this with our dietary supplements. We also have a nitric oxide line of products in skin care and beauty, and we recently launched a nitric oxide and microbiome-friendly toothpaste. This is the first, and only, toothpaste that helps restore the production of nitric oxide. Additionally, we have a nitric oxide-friendly mouth rinse that targets the mouth microbiome to enhance the natural production of nitric oxide, which will be launching in a few weeks.
We are currently developing a line of pet and equestrian nitric oxide products to enhance the health of our pets and the performance of race horses and other performance horses. We have drugs going into phase three clinical trials through the FDA. We expect to be one of the most successful companies on the planet by addressing an enormous unmet need in health and longevity. We know the science of nitric oxide, we understand how the body produces nitric oxide, and we have product technology that provides nitric oxide and restores it to natural production. There is really no way for this not to change the world. We have come a long way, but we still have a lot to accomplish. However, there is nothing that will stop us now. We have a mission, and we are right on target.
Learn more about N1O1 at www.n1o1.com, and discover the science and research behind these products at www.bryantherapeutics.com.
About Michele Hughes
Michele Hughes is the visionary founder of Ageless and Timeless and the dynamic host of the Ageless and Timeless podcast. As a monthly contributor to TopDoctor Magazine, she offers powerful insights on wellness, longevity, and living fully at every stage of life. With a deep passion for health, vitality, and a role model for timeless elegance, Michele empowers audiences to embrace their highest potential and live with purpose and grace. Michele’s podcast, Ageless and Timeless, was one of 20 Inaugural Podcasts selected for the Muscle and Fitness Plus platform that began in 2023.
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