Healthy Aging

Say Yes to NO: Nitric Oxide

Support for heart health, sexual performance, and beyond

Nitric oxide (NO) is a tiny gas molecule produced in the blood vessels, nerves, and immune cells. Best known for its role in maintaining blood pressure, NO also mediates penile erections, supports healthy blood flow to the brain, enhances muscle oxygen use during exercise, and helps protect against infections. The release of NO may even contribute to the relaxation benefits of meditation practice.[1],[2],[3]

When it’s released by the endothelial cells that line the blood vessels, NO prompts the surrounding smooth muscles to relax, causing vasodilation (the widening of blood vessels) and thereby lowering blood pressure.[4] Unfortunately, NO production declines with age and blood pressure gradually rises.[5]

Lower NO levels are associated with the development of high blood pressure, heart disease, and erectile dysfunction.

Lower NO levels are associated with the development of high blood pressure, heart disease, and erectile dysfunction (ED).[6] ED is often treated with the drug known as sildenafil (sold under the brand name Viagra). However, sildenafil and similar drugs do not increase NO; instead, they augment NO-mediated pathways.[7]

Nearly half of all men over the age of 40 have some degree of ED.[8] Rather than being a condition specific to the penile blood supply, ED is frequently an early warning sign of coronary artery disease.[9] A decline in NO activity often precedes both conditions.[9]

The body has evolved two separate pathways for the production of NO. One pathway depends on an adequate supply of the amino acid L-arginine, which is produced from the amino acid L-citrulline and/or obtained from dietary sources, while the other pathway utilizes nitrates as precursors.[10] Let’s take a look at how these amino acids and other supplements boost NO levels.

Beetroot

Foods such as beets and dark leafy greens are high in nitrates, which are thought to contribute to the health benefits of vegetable-rich diets.[11],[12],[13],[14] Dietary nitrates enter the circulation and go to the muscles, where they serve as a reservoir that can be accessed on demand when NO is needed.[15],[16],[17] Higher nitrate intakes are associated with a lower risk of hypertension, heart attack, and/or stroke.[18],[19],[20],[21]

Beetroot has been shown to increase NO levels and lower blood pressure in men and women of various ages.

Beetroot is an excellent source of nitrates and is often used for supplementation, either as a juice or powder.[22] Beetroot has been shown to increase NO levels and lower blood pressure in men and women of various ages.[23],[24],[25],[26],[27],[28] Two recent reviews of clinical trials confirmed that individuals consuming beetroot juice had significantly lower blood pressures on average than control groups, suggesting that beetroot should be considered as a component of a healthy lifestyle.[29],[30]

Beetroot supplementation may also boost exercise performance.[31],[32],[33],[34] Performance benefits have been noted following either a single dose or long-term supplementation in recreational runners and in trained athletes.[35],[36],[37],[38] Although not all studies have yielded positive results, a systematic review of the evidence concludes: “The available results suggest that supplementation with beetroot juice can improve cardiorespiratory endurance in athletes.”[39]

As NO serves a key role in the function of the innate immune system (the immune system’s first line of defense), beetroot may also help ward off infections. The ingestion of beetroot increases exhaled NO in healthy individuals, which may be predictive of its effects in preventing upper respiratory infections.[40] In a study done with 76 college students, beetroot supplementation was shown to reduce the symptoms of cold and sickness during final exams.[41] Low levels of exhaled NO correlated with symptoms of respiratory infection,[42] and the reduction in cold symptoms was associated with an increase in exhaled NO.[42]

Arginine and citrulline

Arginine is a conditionally essential amino acid, the need for which depends on the health status of the individual. Arginine and an arginine precursor known as citrulline participate in the urea cycle in the liver, the metabolic process by which highly toxic ammonia is converted to urea for urinary excretion. Arginine also serves as a supply source for NO production via an enzyme known as nitric oxide synthase (NOS).[43],[44],[45],[46] Not surprisingly, low arginine levels can limit NO production.[47] However, one of the drawbacks of supplementing with arginine alone to achieve these effects is the very short amount of time it remains in circulation.[48]

Reductions in resting blood pressure with L-citrulline supplementation may have major implications for individuals with prehypertension and hypertension.

Citrulline is named after watermelon (Citrullus vulgaris) which is its only real dietary source.[49],[50] Supplemental citrulline helps lower blood pressure by serving as a precursor to arginine, which then generates NO.[51] Unlike arginine, supplemental citrulline is not extensively metabolized in the gut, and it is therefore more effective at increasing NO levels in circulation.[43],[52] A recent review concludes, “Reductions in resting blood pressure with L-citrulline/watermelon supplementation may have major implications for individuals with prehypertension and hypertension.”[51]

Citrulline also may be helpful for men with ED. Although it’s clear that testosterone plays an important role in sexual function via several processes, including the stimulation of NO release,[53]  a number of men with ED have low arginine and/or citrulline levels.[54] By supporting adequate NO synthesis, citrulline supplementation may improve erectile function in these cases.[55],[56],[57]

Citrulline also may help the body fight infectious diseases. For example, malaria is caused by the parasite Plasmodium falciparum, which causes arginine deficiency and interferes with NO production.[58],[59] NO deficiency is implicated in the development of cerebral malaria (CM), the most severe manifestation of the disease.[60] In fact, individuals with malaria were found to have extremely low blood levels of arginine, citrulline, and NO.[61],[62],[63] A pre-clinical study has shown that an injection of citrulline restored arginine levels and significantly decreased the mortality associated with CM.[64]

Glutathione

 As the master antioxidant in human cells, glutathione (GSH) strongly protects against oxidative stress. Population studies suggest that diets high in antioxidants, along with antioxidant supplementation, help prevent cardiovascular diseases.[65] GSH is required to sustain NO production,[66] and supplementation with both GSH and citrulline has an additive effect on NO levels.[67]

When levels of GSH are insufficient, the enzyme that forms NO becomes “uncoupled:” it stops producing NO and switches instead to producing toxic superoxides.[68] A nutritional strategy that includes GSH support may minimize this uncoupling and protect NO levels as well as reducing production of these toxic metabolites.[65]

Carnitine and taurine

Carnitine and taurine also help support NO production and vascular function. Both carnitine and taurine are synthesized in the body, but not always in amounts sufficient to support optimal function.

Carnitine and NO work together to improve energy utilization in skeletal muscle.[69],[70],[71] Propionyl-L-carnitine (PLC) is a form of supplemental carnitine shown to stimulate NO production, boost muscle carnitine, and facilitate the transport of free fatty acids into the mitochondria, where they can be used as fuel.[72] Long-term PLC supplementation (four to eight weeks) has been shown to improve exercise performance.[73],[74] PLC also improves the efficacy of sildenafil (Viagra) for men with ED due to prostate removal.[75]

Taurine has been shown to increase NO in part by reducing the levels of ADMA (asymmetric dimethylarginine), a naturally occurring inhibitor of NO synthesis.[76],[77] A randomized, double-blind, placebo-controlled study of 120 individuals with modestly elevated blood pressure showed that 12 weeks of taurine supplementation (1.6 g daily) lowered systolic blood pressure by an average of 7.2 mmHg.[78] A meta-analysis of seven peer-reviewed studies concluded: “These preliminary findings suggest that ingestion of taurine at the stated doses and supplementation periods can reduce blood pressure to a clinically relevant magnitude, without any adverse side effects.”[79]

In healthy men exercising in the heat, taurine supplementation increased the time to exhaustion.

In an additional study of healthy men exercising in the heat, taurine supplementation increased the time to exhaustion while decreasing core temperature and lactic acid levels, some of which may be attributed to improvements in blood circulation.[80]

Summary

 Nutrients that promote NO formation – like beetroot, arginine, citrulline, carnitine, glutathione, and taurine – can support heart, vascular, and sexual health during aging, help the body fight infections, and boost exercise performance under many different settings. In sum, after considering the evidence on nutrients that induce NO, you may just want to say yes to NO!

Although the nutrients mentioned in this post have a history of safe use in adults,[81],[82],[83] if you are experiencing heart problems or are taking medications for blood pressure or ED, it is always important to consult with your physician before taking supplements.

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