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“Should I stop taking my NAD+ boosting supplement(s) because it may increase my risk of heart attack or stroke.”

That’s the question a well-informed patient of mine recently put to me, after she’d absorbed a slew of news articles reacting to a study that came out this past February in Nature Medicine: “A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk.” 

My answer was no, and I’ll explain why in a moment. But, first, let me set the stage. NAD+ is a crucial co-enzyme in the production of energy  that takes place in the mitochondria of our cells, a process that breaks down glucose and fatty acids and, after a complex series of reactions, delivers energy in the form of ATP molecules. (You may remember struggling with the Krebs cycle in high school biology -- NAD+ is a major player in the cycle.) In order to make NAD+, we need to consume vitamin B-3, or niacin, in our diet, found in meat, chicken, whole grains, legumes, nuts, and even more plentifully, in fortified foods like breads and cereals. We can also supplement, whether it’s the B-3 found in a simple multi or B-complex vitamin or in newer forms like NR (Nicotinamide Riboside) and NMN (Nicotinamide Mononucleotide) that I recommend to many of my patients, NAD+ precursors that are more bio-available and able to boost NAD+ in the cells more efficiently. 

With B-3, there is always the Goldilocks question – what is too little, what is too much, and what is just right? Too little niacin in the diet, you get pellagra, a vitamin-deficiency disease now just about eradicated in the West. But research on niacin as a therapy for cardiovascular disease suggested that you could go overboard, even before you reached tell-tale symptoms of toxicity like skin flushing or itching. The niacin therapy drove down LDL and raised HDL levels, as it was supposed to, but overall mortality looked to have slightly increased, suggesting that high-dosage niacin could have a pro-inflammatory effect that contributed to bad cardiovascular outcomes. And yet, to this day, researchers and statisticians still debate the conclusion that niacin supplementation can be harmful

The new study, out of the Cleveland Clinic, suggests  one explanation for the so-called “niacin paradox.” The researchers looked at just over 1,000 people in the original “discovery group” and found that subjects with the highest levels of a heretofore unknown NAD+ byproduct or metabolite, 4PY, had roughly twice as many heart attacks and strokes over a three-year period as the rest of the study participants. The researchers surmise that when people consume more niacin than their cells actually need, the excess gets converted into this nasty 4PY, making, in theory, high niacin levels a cardiac risk factor on a par with high blood pressure or high LDL cholesterol. The authors go so far as to suggest that it may be time to re-think the niacin-fortification of food, not to mention the NAD+ boosting supplements that I, and many, of my patients take. 

The researchers also did some sophisticated genetic analysis and found that study subjects with a particular genetic mutation (a so-called SNP or single nucleotide polymorphism) were far more likely to have the elevated level of the bad metabolite 4PY. It was this group which had higher levels of a molecule that is a known cardiac risk factor, that promotes the adhesion of white blood cells to the heart vessels, part of the plaque-formation process. 

So, why didn’t I recommend my patient lose the NR or NMN supplements she was taking? 

When you look more closely at the study, you see that the researchers haven’t yet established cause and effect. They don’t actually know how much B-3/niacin the study subjects actually consumed (either in food, fortified foods or supplements) nor did they measure their NAD+ levels. We are only made aware that higher levels of 4PY were associated with cardiovascular events. They also don’t know if these subjects with the high 4PY levels had the genetic mutation. Even so, their later analysis did not show that genetically elevated 4PY levels caused the cardiovascular events. Furthermore, all the subjects in the original study group had diagnosed cardiovascular disease which put them at much higher risk for heart attack and stroke in the first place.   

So, the Cleveland Clinic Study was interesting, there is a lot more we should understand about NAD+ metabolism and the production of 4PY levels before we can say excess niacin is the bad guy. It may be the case that people with CVD should be more conservative when it comes to supplementing with B-3. But it’s not changing the way I practice anti-aging medicine. I measure blood levels of intracellular NAD+ in all my patients. If their levels are already in the desirable range, then I don’t recommend NAD+ boosting supplements. If they’re not, I think there are good reasons in favor of taking them. And when I do, I rarely if ever recommend doses exceeding 500 mg, which is well below “high dose” niacin standards. 

While it’s true, there haven’t been clinical studies to establish the benefit of NR and NMN, there is a strong theoretical argument that these supplements enhance cellular energy production and fortify the cells’ defenses against inflammation and disease. They’ve been shown to extend longevity in animal studies. And as for curtailing niacin-fortified foods, based on the evidence we have to date, that’s an over-reach that strikes me as just plain silly. 

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