Newsletter #320: Nitrate, Mortality, & The Importance of Context
Nitrates have historically been one of the more controversial molecules in nutrition science.
On the one hand, nitrates have been linked to an array of benefits. When converted to nitric oxide, they cause our blood vessels to widen and become more elastic, which elicits reductions in blood pressure and greater blood flow to tissues throughout the body, including the muscles and the brain. This leads to better vascular health, enhanced cognition, and even improved athletic performance.
Yet, as early as the 1950s, nitrate and nitrite were implicated in certain cancers, and observational literature has been conflicted on the long-term effects of dietary nitrate in humans. As a result, the WHO has set an acceptable daily intake limit of 222 mg per day for a 60-kg person, which is easily exceeded if you consume even modest amounts of nitrate-containing vegetables. How can we sort this out?
Here is a clue as to what might be going on here. If you’ve followed research that tests nitrates, you may have noticed that it is usually administered to participants in the form of beetroot juice or green smoothies. Why would they not just use a pill?
There is a very good reason why researchers go to this trouble. Taking sodium nitrate in isolation does not appear to be as effective. For instance, when researchers had subjects ingest 800 mg of nitrate in the form of fresh blended vegetables, levels of plasma nitrate and nitrite went up and blood pressure reliably declined. But when the same participants consumed the same dose from sodium nitrate, they did not observe the same benefits. And similarly, when trained athletes drank beetroot juice, they performed better at high-intensity cycling, but failed to see improvements in oxygen consumption when they attempted the same trial using sodium nitrate.
It hasn’t been clear precisely why, but the context in which nitrates are consumed seems to strongly determine their effects within the body, for better and for worse. So in order to figure out whether nitrates are, on balance, good for us or bad, we need more granular observational data that doesn’t merely capture how much nitrate is in the diet, but where it is coming from. For instance, nitrates and nitrites are often added to processed meats, due to their preservative properties. Is it possible that these artificial forms are more harmful, while naturally occurring nitrates are relatively benign?
To get to the bottom of this, a team of Australian researchers, including Nicola Bondonno whom we interviewed on our show a few years back, conducted perhaps the most detailed source-specific analysis of nitrate intake and all-cause mortality to date. Let’s take a look at what they found.
This Week’s Research Highlight
Dietary nitrates from plant foods are associated with lower risk of mortality — but nitrate from other sources shows the opposite association.
Researchers at Edith Cowan University in Western Australia analyzed data from 52,247 participants in the Danish Diet, Cancer and Health Study — a large cohort of older adults living in the greater Copenhagen and Aarhus metropolitan areas. At the beginning of the study, participants were free of cardiovascular disease, and had no history of cancer.
Prior to their first study visit, subjects provided detailed dietary data, from which the researchers were able to calculate nitrate intake through comprehensive databases, and identify how much nitrate was coming from either animal products or vegetables. They were also able to estimate nitrate exposure through drinking water by looking at data on nitrate concentrations in tap water at the address(es) at which each participant had lived close to enrollment in the study.
So, not only were the researchers able to estimate the habitual nitrate content of the diet of each of these participants, but they were also able to separate it by source: foods from plant sources, foods from animal sources, and tap water. Furthermore, for animal sourced foods, they were able to distinguish between naturally occurring nitrates in animal flesh versus the nitrates/nitrites that accompany additives in processed meats like bacon, sausage, etc.
Participants were followed for an average of 24 years, to see how their nitrate exposure influenced mortality, as well as cause of death.
Subjects were split into five categories (quintiles) based on their nitrate intake from each major dietary source. Compared to participants in the lowest quintile of plant-sourced nitrate intake (average of 22 mg per day), those in the highest quintile (average of 77 mg per day) had a 17% lower risk of all-cause mortality, a 22% lower risk of cardiovascular mortality, and a 14% lower risk of cancer mortality.
In contrast, higher intakes of animal-sourced nitrates and nitrites was associated with higher mortality — and this was true for both naturally occurring nitrates as well as those from additives. Participants with the greatest intake of nitrates from additive-treated meat sources had a 19% higher risk of dying from any cause, and the highest quintiles of naturally occurring nitrates and nitrites from animal sources were linked to 9% and 25% higher risk of all-cause mortality, respectively.
Finally, higher consumption of nitrate from tap water was also associated with greater risk of dying from any cause. Importantly, this association became substantially stronger after restricting the analysis to pure water, and not including water that was used to make tea, coffee, or fruit syrup (we’ll come back to this shortly). After adjustment, the highest intake of nitrate from tap water was linked to a 19% higher risk of all-cause mortality and 26% higher risk of cardiovascular mortality.
So, why exactly does it matter so much where nitrate comes from?
Well, after we consume nitrates, they can follow one of two potential pathways once they reach the gastrointestinal tract.
When dietary nitrate is absorbed through the small intestine and enters systemic circulation, some of it is taken up by, of all things, the salivary glands (I know, kind of weird). Nitrate-reducing oral bacteria reduce that nitrate to nitrite, which is swallowed and then absorbed again, where it undergoes further reduction to nitric oxide. Nitric oxide is what relaxes and widens the walls of blood vessels, producing the beneficial effects that were characterized above.
However, nitrates in the gut can alternatively be converted into compounds known as nitrosamines, which have been shown in animal models to produce malignant tumors. The carcinogenicity of nitrosamines, as well as other potential harmful effects, would explain why nitrates are sometimes associated with deleterious outcomes.
From Pinaffi-Langley et al, 2024
So, the obvious question here is what drives nitrosation? In other words, how can we steer dietary nitrates in the right direction?
The molecular fate of nitrate seems to hinge upon dietary factors that are along for the ride, and which ultimately influence the gastrointestinal milieu. This is why the source of the nitrates is so critical. It is thought that components of meat, such as heme iron and amines, contribute to nitrosation, which explains the greater mortality risk found with nitrates from animal-sourced foods. Meanwhile, antioxidant vitamins, polyphenols, and other naturally occurring compounds in vegetables inhibit nitrosation, and they help tilt nitrates toward the beneficial nitrate-nitrite-nitric oxide pathway. This reminds me of an earlier trial which found that combining inorganic nitrate with vitamin C lowered blood pressure and arterial stiffness in older adults — while nitrate by itself failed to move the needle.
(This would explain, by the way, why the association with tap water was strengthened when the researchers excluded coffee and tea. These beverages are rich sources of polyphenols, which would neutralize the potentially harmful effects of nitrates in drinking water.)
The key takeaway here is that dietary nitrate from plant foods does not need to be avoided, and if anything should be embraced. Indeed, one recent review characterized dietary nitrate from plant foods as "a conditionally essential nutrient for cardiovascular health based on its role in nitric oxide homeostasis." If you are looking for the best sources, the table below provides a good idea. As you can see, it’s not hard to attain a relatively high intake, especially if you regularly consume an arugula or spinach salad.
From Hord et al, 2009
Random Trivia & Weird News
Parrots have been taught to call each other on tablets and smartphones.
Parrots are intelligent and sensitive creatures, who need social contact in order to thrive. But domesticated birds may not be able to regularly interact with avian counterparts like they would in the wild.
To try to bridge this gap, researchers at Northeastern University investigated what would happen if parrots were trained to videocall other parrots via FaceTime.
The results seem to have been overwhelmingly positive. Birds initiated calls of their own volition, made friends with specific birds, and even learned new skills from one another. I suppose this shows that new communication technology isn’t all bad.
Photo by Matthew Modoono/Northeastern University
Podcasts We Loved This Week
- Richie Davidson: The science of mindfulness meditation and the four pillars of human flourishing. Via Brain Ponderings with Mark Mattson.
- Paddy Barrett: Cholesterol-lowering medication. Via Sigma Nutrition Radio.
Products We Like
Beet It Nitrate Sport Shots
It’s not too difficult to consume a diet rich in nitrates from vegetables, on a day-to-day basis. But sometimes it may be a bit cumbersome, especially if you are using nitrates for improving athletic performance (it’s not easy to eat a big salad right before a race or between sporting matches). Furthermore, nitrate content in plant foods can vary pretty dramatically, due to differences in soil content.
If you’re looking for the most efficient and most reliable way to get lots of nitrates in your diet, this is what you want. Beet It delivers ~400 mg of nitrate per serving in a portable 2.4 ounce shot.
Incidentally, Beet It also happens to be the product that many researchers, including Jonathan Burdette at Wake Forest, have used to examine beneficial effects of dietary nitrate (check out our interview with him).
humanOS Catalog Feature of the Week
Optimizing Nutrition with Smoothies
Another super efficient way to boost your nitrate intake is through smoothies. If you pour one of those 10 ounce bags of spinach into your blender, you could get anywhere from 250-500 mg of nitrates effortlessly.
In this course, we take a deep dive into phytochemicals in plants, where they are found, their powerful health effects, and how intelligently-devised smoothies can help optimize our intake of these awesome compounds. For a practical breakdown on building nutritious smoothies, please refer to our How-to Guide for smoothies.
Wishing you the best,
