Nitric Oxide

By Caitlin Taylor So 

Edited and approved by Stephen C. Rose, Ph.D.

Nitric oxide is one of those molecules that sounds suspiciously like a wellness scam. You hear the name and immediately picture a man in wraparound sunglasses trying to sell you a crimson pre-workout powder with a title like VASCULAR OBLITERATOR 9000. Fair enough. But nitric oxide is real, biologically central, and not remotely trivial. It helps regulate vascular tone, blood flow, platelet activity, and signaling in several tissues, including the nervous and immune systems.[1,2] In other words, this is not some fringe molecule hiding in a supplement aisle. It is one of the body’s quiet workhorses.

The problem is what happens next. Once a molecule becomes popular, the internet does what the internet does: it takes something true, glues it to five half-truths, adds a shirtless thumbnail, and by lunch you are supposed to believe that humming in traffic, pounding beet powder, and heroically sniffing through your nostrils will buy you immortality. Okay—slow down. Nitric oxide matters. It does not, by itself, explain every disease of aging, nor does every alleged “nitric oxide hack” deserve to survive first contact with evidence.[1,3]

Most nitric oxide in the vasculature is generated by nitric oxide synthase, especially endothelial nitric oxide synthase, which converts L-arginine into nitric oxide. There is also a second route—the nitrate-nitrite-nitric oxide pathway—in which nitrate from food is converted by oral bacteria and then further reduced in the body.[1,2,5] That second pathway is part of why diet, oral ecology, and vascular health keep showing up in the same sentence.

Why does this matter for aging? Because one of the recurring features of vascular aging is reduced nitric oxide bioavailability. As oxidative stress and inflammation rise, the endothelium becomes less able to do its easygoing job of telling blood vessels when to relax. The result is stiffer arteries, worse endothelial function, and a cardiovascular system that starts behaving like a garden hose with anger issues.[1,3,4] That does not make low nitric oxide the single villain in the story. Aging is more annoying than that—multifactorial, tangled, and resistant to grand unifying slogans. But reduced nitric oxide signaling is clearly part of the plot.[3,4]

So what actually seems to help? First, nitrate-rich plant foods. Leafy greens and beets are the headliners here, and for good reason. Dietary nitrate from plant foods can support nitric oxide homeostasis, and meta-analytic data suggest that nitrate-rich beetroot interventions can lower systolic blood pressure in some settings, especially in people with hypertension.[5,7,11] This is where the original food list had the right instinct even when it got a little overcaffeinated: arugula, spinach, lettuce, bok choy, celery, and beetroot are real players. Watermelon is a bit different—it contributes citrulline rather than nitrate—but it still belongs in the broader conversation.

Second, stop casually nuking the oral bacteria that help run the nitrate-to-nitrite step. The mouth is not just a cavity with opinions; it is part of the pathway. A systematic review found that nitrate exposure can shift the oral microbiome in ways consistent with greater nitrate-reducing capacity,[5] and newer human data link frequent over-the-counter mouthwash use with lower serum nitrite levels.[6] This does not mean mouthwash is evil or that you should swish with pond water in the name of endothelial freedom. It means the “kill everything” approach may come with tradeoffs, especially when done habitually.

Third, exercise. Regular physical activity remains one of the least glamorous and most dependable ways to support vascular function. Reviews of vascular aging show that exercise—particularly aerobic exercise—can improve endothelial function and help preserve nitric oxide bioavailability with age.[4] In people with hypertension, exercise interventions improve nitric-oxide-related measures and endothelial function overall.[8] That is the unsexy truth of health science: while supplement companies are busy naming powders after thunderstorms, your brisk walk is over there quietly doing biochemistry.

What about antioxidants, sunlight, sleep, hydration, nasal breathing, humming, and acupuncture? Some of these ideas have a kernel of plausibility. Oxidative stress can reduce nitric oxide bioavailability, so in a broad physiologic sense a diet rich in plant foods helps.[1,4,11] The paranasal sinuses do generate nitric oxide, and a small physiologic study found that humming briefly increased nasal nitric oxide about fifteen-fold during the act itself.[10] That is delightful and weird and exactly the kind of fact that makes human biology fun. But turning it into a longevity prescription would be like discovering that revving an engine makes noise and then concluding that the noise is the transportation plan. Interesting mechanism? Yes. Established strategy for longer life? No.

Supplements deserve their own reality check. L-arginine and L-citrulline are plausible tools because they feed into nitric oxide biology, and reviews suggest oral arginine can lower blood pressure modestly in some trials. But the evidence is heterogeneous, responses vary, and supplement formulas are all over the map.[9] This is a recurring theme in nitric oxide research: mechanism is not the same thing as guaranteed outcome. A compound can make sense on a whiteboard and still underwhelm in actual humans who sleep badly, eat inconsistently, take medications, and insist on treating physiology like a vending machine.

That matters because the downside of “nitric oxide boosters” is not imaginary. Products marketed for nitric oxide can cause gastrointestinal upset, headaches, dizziness, or excessive drops in blood pressure, and they are not a clever substitute for medical care.[9] If you have cardiovascular disease, kidney disease, very low blood pressure, or you already take medications that affect vascular tone, this is the part where “ask your clinician” stops being boilerplate and becomes good judgment.

The cleanest take-home is almost offensively ordinary. If you want to support nitric oxide biology, eat nitrate-rich vegetables, move regularly, avoid smoking, keep your mouth from becoming either a bacterial war zone or a neglected archaeological site, and be skeptical of any claim that promises a dramatic nitric-oxide makeover by Tuesday.[1,4-7,11] Nitric oxide is not a magic gas. It is one of the many molecules through which basic habits cash out into measurable physiology. And that, frankly, is more impressive than the hype: a tiny, short-lived molecule helping explain why the boring advice still wins.

References

1. Lundberg, J.O.; Weitzberg, E. Nitric oxide signaling in health and disease. Cell 2022, 185, 2853–2878.

2. Rafea, R.; Siragusa, M.; Fleming, I.The ever-expanding influence of the endothelial nitric oxide synthase. Basic Clin. Pharmacol. Toxicol. 2025, 136, e70029.

3. Mazuryk, O.; Oszajca, M.; Stochel, G.; Chlopicki, S. Nitric oxide signaling and sensing in age-related diseases. Antioxidants 2024, 13, 1213.

4. Moreau, K.L.; Clayton, Z.S.; DuBose, L.E.; Rosenberry, R.; Seals, D.R.Effects of regular exercise on vascular function with aging: Does sex matter?Am. J. Physiol. Heart Circ. Physiol. 2024, 326, H123–H137.

5. Moran, S.P.; Rosier, B.T.; Henriquez, F.L.; Burleigh, M.C.The effects of nitrate on the oral microbiome: A systematic review investigating prebiotic potential. J. Oral Microbiol. 2024, 16, 2322228. 

6. Guo, K.; Joshipura, K.; Ricart, J.; Patel, R.; Gower, B.; Andriankaja, O.; Morou-Bermudez, E. Association of over-the-counter mouthwash use with markers of nitric oxide metabolism, inflammation, and endothelial function: A cross-sectional study. Front. Oral Health 2025, 6, 1488286.

7. Benjamim, C.J.R.; Porto, A.A.; Valenti, V.E.; Sobrinho, A.C.S.; Garner, D.M.; Gualano, B.; Bueno Júnior, C.R. Nitrate derived from beetroot juice lowers blood pressure in patients with arterial hypertension: A systematic review and meta-analysis. Front. Nutr. 2022, 9, 823039. 

8. Liang, C.; Song, Z.; Yao, X.; Xiao, Q.; Fu, H.; Tang, L. Exercise interventions for the effect of endothelial function in hypertensive patients: A systematic review and meta-analysis. J. Clin. Hypertens. 2024, 26, 599–614. 

9. Khalaf, D.; Krüger, M.; Wehland, M.; Infanger, M.; Grimm, D.The effects of oral L-arginine and L-citrulline supplementation on blood pressure. Nutrients 2019, 11, 1679. 

10. Weitzberg, E.; Lundberg, J.O.N. Humming greatly increases nasal nitric oxide. Am. J. Respir. Crit. Care Med. 2002, 166, 144–145.

11. Pinaffi-Langley, A.C.d.C.; Dajani, R.M.; Prater, M.C.; Nguyen, H.V.M.; Vrancken, K.; Hays, F.A.; Hord, N.G.Dietary nitrate from plant foods: A conditionally essential nutrient for cardiovascular health. Adv. Nutr. 2024, 15, 100158.