Does nicotinamide riboside increase atherosclerosis?
A new mouse study adds to a genetics study from last year.
Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are often recommended as anti-aging supplements. I’ve taken them both myself.
Niacin (vitamin B3) has been prescribed at high levels by doctors for a couple of decades for heart disease. Since the mid-1940s, niacin has been added to white bread, and more recently, most cereals, enriched rice, and processed foods.
A little background on niacin:
The body makes niacin and also gets niacin from food. Tryptophan is an amino acid that is used in the body in several ways, one of which is for niacin synthesis.
There are several terms used for vitamin B3, which can make it confusing.
Niacin (nicotinic acid) is a form of vitamin B3, and when taken in large amounts, it causes the niacin flush. It’s been prescribed for years to lower LDL cholesterol.
Niacinamide (nicotinamide) is a niacin derivative that is also available as a supplement. It is usually called non-flushing niacin.
Nicotinamide riboside (NR) is a newer form of niacin that is more biologically active. It more readily adds to the NAD+ pool in cells.
NAD+ is essential for cellular energy production, and levels decline in aging. This decline can be offset, to some extent, by supplementing with nicotinamide riboside or NMN. Both of these supplements are promoted for longevity and healthspan.
Which makes a couple of studies that have come out in the past year rather concerning…
Study on genetics, niacin consumption, and atherosclerosis:
A 2024 study by researchers at the Cleveland Clinic shows that higher levels of niacin consumption may increase the risk of heart disease, especially in people with certain genetic variants.
Here’s an image from the study that explains the different inputs from niacin and what happens to them.
The results showed that circulating levels of 2PY and 4PY, which are metabolites formed from excess niacin, were associated with increased major cardiovascular events. Importantly, some people have genetic variants that increase the niacin metabolites.
Thus, there is a gene-diet interaction: higher niacin intake combines with genetic susceptibility to increase the risk of major cardiovascular events.
The researchers found that 4PY, one of the metabolites from excess niacin, promoted vascular inflammation. People with higher 4PY levels (top 25%) had a more than doubled risk of major adverse cardiovascular events — e.g. heart attack, stroke, heart failure. Not good…
The Cleveland Clinic study was pretty compelling, with a clear connection between higher niacin metabolite levels and increased risk of cardiovascular events. But it focused on dietary niacin, hypothesizing that eating a lot of fortified food was causing problems for some of us.
But what about nicotinamide riboside? Did I really need to give up one of my favorite supplements?
New study directly looking at NR, 4PY, and atherosclerosis (but in mice):
A new study in the journal Atherosclerosis tries to answer my questions.
The researchers used a strain of mice that is more likely to have high cholesterol and develop atherosclerosis. They fed the mice a high cholesterol diet along with either a low, medium, or high dose of nicotinamide riboside. Their goal was to try to figure out why clinical trials involving niacin show that it decreases LDL but doesn’t change the number of deaths or hospitalizations for cardiovascular events.[ref]
The results showed that the high dose of NR increased atherosclerotic plaque lesions, increased 4PY (niacin metabolite from above), and also increased several inflammatory markers. Their conclusion was that high dose NR is “not atheroprotective”. The medium and low doses didn’t promote atherosclerosis.
Here’s a screenshot of their graphical overview:
The conclusion of their paper states: “Originally, supplements like NR and other NAD+ precursors were thought to be beneficial to activate all sirtuins and garner their positive effects. Meanwhile, an increasing number of studies revealed that the effects of boosting NAD+ at high dosages depend on the context. Notably, they may not be protective and even cause harm in certain conditions.”
Where does this leave me…
Well, I still don’t know how much NR (or NMN or niacin) is too much. The dosage information can’t really be extrapolated from the mouse study to apply to humans. Where does the balance lie with supplementing to reverse the decreased NAD+ seen in aging? Stay tuned - hopefully, more research will help answer this question.
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