There's a gas your body makes every second of every day that decides whether your blood vessels are open or closing down. It controls your blood pressure. Blood flow to your brain. How much oxygen actually reaches your muscles. Whether plaque seeds on your artery walls or slides past.
Three scientists shared the 1998 Nobel Prize in Medicine for working out what it does. Most people have never heard of it.
I sat down with Dr Nathan Bryan for Pushing the Limits — he has spent 25 years on this molecule, published over 100 peer-reviewed papers, and is the only person to have made a solid dose form of nitric oxide gas. That conversation changed how I run assessments on complex clients. Listen to the full interview here.
But there's a layer Nathan and I didn't get to in that episode, and it's the one I want to put in front of you now. Some people are genetically set up to make less nitric oxide than everyone else — from birth. Same diet, same training, same discipline, different output. If that's you, every single thing on the list below costs you more than it costs the person next to you.
Here's what nitric oxide does, what's destroying yours, and what your genes have to do with it.
What nitric oxide actually is
Nitric oxide is a signalling molecule — how cells communicate with one another. What makes it strange is that it's a gas, and as Nathan put it, once your body produces it, it's gone in less than a second.
You cannot store it. It's made on demand, used instantly, and destroyed. Which means anything that interferes with production or destroys it on contact does so in real time, all day, every day.
In that fraction of a second it does an enormous amount of work. It's produced in the endothelium — the single layer of cells lining every blood vessel you own, which laid flat would cover a tennis court. When it's released, the vessel relaxes and opens. Oxygen and nutrient delivery goes up. Circulation improves. It reduces inflammation in that vessel lining, which is the process that drives cardiovascular disease in the first place.
It's also a neurotransmitter in your central nervous system. And it's how your immune cells kill invading pathogens — they mobilise to the site of infection and generate nitric oxide to destroy bacteria and stop viruses replicating.
There's a piece almost nobody knows about, and it's the one that stopped me in my tracks given I run a hyperbaric clinic. Nitric oxide controls oxygen release from haemoglobin. Jonathan Stamler's work showed that the handoff — where red blood cells release oxygen into tissue and pick up carbon dioxide — only functions if nitric oxide signalling is intact. Without it, oxygen binds to haemoglobin and doesn't come off where it's needed. People become systemically hypoxic while their lungs are working perfectly.
That's also, as Nathan explained, part of why hyperbaric oxygen works at all. It increases nitric oxide production, which mobilises stem cells, which repair and replace dysfunctional tissue.
What deficiency actually looks like
Run the list backwards and the symptoms are predictable. Nathan's summary: high blood pressure, sexual dysfunction, heightened susceptibility to viral and bacterial infection, memory loss and mild cognitive decline that — uncorrected — progresses toward vascular dementia and Alzheimer's.
Add exercise intolerance. Add poor recovery. Add the slow creep of cardiovascular disease, which remains the number one killer of men and women worldwide.
None of these look like "nitric oxide deficiency" when they walk into a clinic. They look like ageing, stress, or bad luck.
The decline nobody warns you about
Population data going back a couple of decades shows we lose roughly 10 to 12 percent of endothelial function per decade, starting in the late teens and early twenties. By 40 or 50, you have about half the enzyme function you had as a young adult.
That was the historical picture. What Nathan is seeing clinically now is worse — men in their early twenties with erectile dysfunction and the vascular age of a 50 or 60 year old.
That's not a slow generational drift. That's a collapse.
You have two pathways, not one
This is the part that reorganised my thinking.
Pathway one runs on an enzyme called nitric oxide synthase, found in your endothelium and in almost every other cell type. It converts the amino acid L-arginine into nitric oxide gas. It depends on a set of cofactors and substrates to work.
Pathway two is the backup, and it doesn't use an enzyme at all. It runs on bacteria.
You eat inorganic nitrate, found mostly in green leafy vegetables. Humans have no nitrate reductase enzyme — we physically cannot make that first conversion ourselves. Specific bacteria living in your mouth do it for you, reducing nitrate to nitrite. Your saliva concentrates the nitrite. You swallow it, and stomach acid converts it to nitric oxide gas.
Nathan's reasoning for why this backup must exist is elegant: if nitric oxide were this critical, evolution would never have given us a single point of failure.
One pathway can compensate for the other. But when both go down, you're nitric oxide deficient — and then, as he put it, you start developing symptoms, then disease.
Why your genetics change this equation
Here's where I depart from the interview, because this is my clinical territory rather than Nathan's research focus.
The enzyme pathway is coded by your DNA. And there is real, common variation in how well that machinery is built.
NOS3 is the gene for the endothelial enzyme itself. There are common variants in it that leave you running a lower-output version of the machine. Same fuel, smaller engine.
I want to be accurate about what this means. These variants are associated in the research with endothelial dysfunction, hypertension and coronary artery disease — but the effect size for any single person is modest. A single gene variant is not destiny, and anyone selling it as destiny is selling something. What it tells you is where your margin for error sits.
The enzyme also requires a cofactor to function, and when that cofactor runs short something genuinely nasty happens: the enzyme uncouples. It stops producing nitric oxide and starts producing free radicals instead — which then destroy whatever nitric oxide you had left.
This is the mechanism Nathan calls uncoupling, and it's what he means by endothelial dysfunction. His list of what drives it: oxidative stress, an inflammatory diet, insufficient exercise, and exposure to glyphosate, pesticides and other environmental toxicants.
Now overlay genetics. Some people carry variants that leave them with a more fragile cofactor supply and a slower ability to clear the free radicals doing the damage. It takes less oxidative pressure to tip their enzyme from producer to destroyer, and every insult costs them more than it costs the person next to them.
That's the picture I look for — and it's why a single-gene result tells you very little. What matters is how the variants interact with each other and with everything else in your history.
The things quietly destroying yours
Antiseptic mouthwash. Two out of three Americans use it, often two or three times a day. The logic was sound in the 1980s — poor oral hygiene correlates with heart attack and stroke, so kill the bacteria. Then the human microbiome got mapped and we learned that the bacteria in and on our bodies outnumber our own cells ten to one, and the overwhelming majority are symbionts doing metabolic work we can't do ourselves. Including nitrate reduction.
In 2019 Nathan's group established causality. They took normotensive, healthy young medical and dental students, gave them mouthwash twice daily for seven days, and changed nothing else — no diet change, no exercise change. Blood pressure rose 20 to 30 mmHg in several of them. They induced clinical hypertension by killing mouth bacteria.
His analogy is the right one: you wouldn't take an antibiotic every day for the rest of your life because of the collateral damage. The same logic applies to an antiseptic in your mouth.
Antacids and proton pump inhibitors. These shut down both pathways simultaneously. On the enzyme side, they cause a buildup of a metabolite that inhibits nitric oxide production. And on the bacterial side, even if you have perfect oral flora and swallow nitrite-rich saliva, that nitrite needs stomach acid to become nitric oxide. No acid, no conversion.
Nathan cites data showing markedly higher incidence of heart attack, stroke and dementia in long-term users. I see the downstream picture constantly in my own practice — mineral malabsorption on organic acids testing, dysbiosis, poor protein breakdown.
Vaping. This is the one I made a full video about, because the mechanism is so much worse than people assume. Every puff floods the endothelium with free radicals from the nicotine and the heated liquid. Those free radicals destroy nitric oxide on contact. Sustained oxidative stress uncouples the enzyme — so the machine that made your nitric oxide starts making the free radicals that destroy it. And the aerosol disrupts the oral environment your backup pathway depends on.
The finding that ends the argument: in controlled human studies, a single vaping session measurably impaired flow-mediated dilation — even with nicotine-free liquid. It isn't just the nicotine, and it isn't the smoke. I break the whole mechanism down here.
Why your beetroot powder probably did nothing
I was a professional ultra-endurance athlete. I drank beetroot juice for years believing I was raising my nitric oxide. Nathan's assessment of that market is blunt, and I've had to sit with it.
After the 2012 London Olympics, when it emerged that athletes were drinking litres of beetroot juice, dozens of companies flooded the market. Nathan has tested essentially every product available. Most contain no measurable nitrate, no nitrite, and no nitric oxide activity whatsoever. His term for them is "dead beets" — they turn your urine pink and do nothing else.
Even genuine beetroot has a problem: it only works if your oral bacteria are intact. Roughly one in three people have the right flora to make the conversion.
And the arginine supplements are worse than useless in exactly the people who need help most. If your enzyme is uncoupled, it doesn't convert arginine — so more arginine doesn't produce more nitric oxide. Nathan's image: it's like putting fuel in a car with a blown engine. You were never out of fuel. Two trials bear this out — high-dose arginine given to post-infarct patients killed more people than placebo, and patients with peripheral arterial disease got worse.
That is exactly the population most likely to have a compromised enzyme. Which is the whole argument for knowing your genetics before you spend money on supplements.
And your greens may not be what they were. Nutrient density in vegetables dropped roughly 78 percent between the 1940s and 2010. Nitrate content varies 50 to 60-fold by region depending on soil, sunlight and lightning activity. Organically grown vegetables typically contain five to ten times less nitrate than conventional, because organic certification restricts nitrogen-based fertilisers.
On the nitrate-causes-cancer story: it collapsed decades ago. Around 85 percent of dietary nitrate comes from green vegetables and only about 5 percent from cured meats. If nitrate caused cancer, vegetarians and the Japanese would have the highest rates. They have the lowest.
What testing actually buys you
Nathan developed salivary test strips years ago and has since moved away from relying on them. Worth understanding why: a low reading is trustworthy — if you're low, you're low. But a positive reading can mislead, because an active oral infection produces an immune response the strip picks up. Someone with textbook deficiency symptoms can test pink.
His fallback is symptoms: erectile dysfunction, unsafe blood pressure, diabetes, exercise intolerance, memory decline.
Genetics gives you something neither of those does — it tells you about your baseline before symptoms arrive.
This is what I keep coming back to with clients. Testing doesn't hand you a diagnosis. It hands you a priority list.
Two people run the same protocol and get completely different results, and most of the time the difference isn't discipline. It's that one of them was fighting a headwind nobody had measured. When I can see a lower-output NOS3 variant sitting alongside compromised antioxidant handling, the conversation changes entirely. Mouthwash stops being a minor note and becomes non-negotiable. Nitrate intake stops being general advice and becomes a daily target. Arginine comes off the list. Oxidative load — including vaping — becomes the first thing we address rather than the fifth.
You can't change your NOS3 variant. You can change every single thing that variant makes you more vulnerable to.
What to do
Stop destroying it first. Nothing you add outranks removal. Antiseptic mouthwash goes. Chronic antacid use needs a serious conversation with whoever prescribed it. If you vape or smoke, that's the single highest-leverage change available and it isn't close.
Feed the nitrate pathway. Rocket, spinach, beetroot, celery — real dietary nitrate, daily, not occasionally.
Use your body. Shear stress — blood moving fast across the endothelium — is the primary physiological trigger for the enzyme. It's a large part of why exercise lowers blood pressure. Sunlight on skin also releases nitric oxide stored in the dermis.
Know your baseline. If you're over 45, training hard, managing blood pressure, or watching a family history of cardiovascular disease or dementia, your nitric oxide genetics are worth knowing. A full panel, not a single gene.
Frequently asked questions
Can I test my nitric oxide levels at home?
Salivary strips give useful information when they read low. A positive result can be a false reassurance if you have an active oral infection. Genetic testing tells you about capacity rather than a single moment's reading.
Does taking arginine boost nitric oxide?
Only if your enzyme is functioning. In people whose enzyme has uncoupled — the people most likely to be deficient — it doesn't work, and trial evidence suggests it can cause harm.
If I have a NOS3 variant, am I destined for high blood pressure?
No. Effect sizes for individual variants are modest. It tells you where your margin for error is, not what will happen to you.
Is vaping really worse than people think for this?
For nitric oxide specifically, yes. It hits all three points of the system, and controlled studies show impairment even from nicotine-free aerosol.
Listen to the full conversation with Dr Nathan Bryan — nitric oxide, the two pathways, mouthwash, antacids, and where supplementation genuinely helps. Podcast page | Watch on YouTube
Watch: Nitric Oxide — The Molecule Your Vape Is Destroying — the full breakdown on YouTube
Want to know your own nitric oxide genetics? I run full genetic panels and one-to-one assessments for exactly this kind of question — how your variants interact with each other and with everything else in your picture. Book a consult here.