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NMN / NR — NAD⁺ precursors
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In one pass NMN and NR are two raw materials the body uses to make NAD⁺, and in recent years they have been sold as anti-aging supplements. Not this — NMN reverses aging — Human randomized trials show only that blood NAD+ levels rise; there are zero data on the outcomes that matter, lifespan or healthy lifespan.
Educational content, not medical advice — consult a clinician.
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Chapter 1
NAD⁺ and the raw materials for it
and are two raw materials the body uses to make , and in recent years they have been sold as anti-aging supplements. NAD⁺ is one of the busiest molecules in the cell: it picks up electrons released by metabolism and carries them into the mitochondria to make energy (see Niacin). It also has a second job as a raw material that a group of enzymes cuts apart and uses up, so a fresh batch has to be made.
In mice and in some human tissues, NAD⁺ falls with age, and that is where this business starts. The body refills it mainly through a recycling line: it picks up the leftover nicotinamide and, by way of nicotinamide mononucleotide (NMN), builds it back into NAD⁺. Nicotinamide riboside (NR) sits one step before NMN. Taking NMN or NR means adding feedstock to that recycling line.
The niacin, NR, and NMN sold on the shelf all end up in the same NAD⁺ pool, yet their prices differ a lot.
In mice and in some human tissues, NAD⁺ falls with age, and that is where this business starts. The body refills it mainly through a recycling line: it picks up the leftover nicotinamide and, by way of nicotinamide mononucleotide (NMN), builds it back into NAD⁺. Nicotinamide riboside (NR) sits one step before NMN. Taking NMN or NR means adding feedstock to that recycling line.
The niacin, NR, and NMN sold on the shelf all end up in the same NAD⁺ pool, yet their prices differ a lot.
Mechanism · Why NAD⁺ falls with age
Massudi 2012, in human skin samples, and Camacho-Pereira 2016, in several mouse tissues, both observed falling with age. In people, how far it falls varies widely with the tissue and the method, and there is no single figure. This is the starting point of the whole market for anti-aging NAD⁺ supplements.Why it falls does not seem to be a shortage of raw material:
Older people's dietary niacin and tryptophan do not suddenly run short.NAMPT, the rate-limiting enzyme of the recycling line, did not decline with age in mouse tissues or in human fat samples (Camacho-Pereira 2016).What clearly grows is the consumption side. Three kinds of enzymes downstream use up NAD⁺:
1. The family (SIRT1-7): deacetylase enzymes, often called longevity genes, which use NAD⁺ sparingly
2. PARP1/2: called on in an emergency when DNA is damaged, using a lot at once
3. CD38: an enzyme that specifically cuts NAD⁺ apart (an NADase). In mice it rose to at least 2-3 times its young level in old liver, fat, muscle, and spleen, while PARP1 and SIRT1 expression did not rise with age. In human fat samples, CD38 mRNA in older people was up to about 2.5 times that in younger people
Mice with CD38 knocked out no longer lose NAD⁺ with age, and that is the basis for treating CD38 as the main explanation. Know its limits: this causal chain was shown in mice. In people, only half of it, the rise in CD38, has been seen so far.
That also sets what topping up the raw material can do. It can raise the pool: Martens 2018 gave middle-aged and older adults 1000 mg of a day for 6 weeks, and NAD⁺ in peripheral blood mononuclear cells (a type of white blood cell) was about 60% higher than during the placebo period. But it does not reduce consumption. The mechanism predicts that after stopping, the level returns to its old balance; that step has not been properly measured in people.
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Background · Three products, one pool
First, the full map of routes in. Besides the recycling line, the body has two longer backup routes. One slowly builds from scratch out of tryptophan (de novo synthesis). The other assembles it from niacin via nicotinic acid mononucleotide (NaMN); this is the Preiss-Handler path the old drug niacin takes. All three roads end at the same NAD⁺ pool. That is the premise of every price comparison that follows: the destination is the same, and what differs is the entrance, the price, and the evidence.Niacin (nicotinic acid, NA): in 1955 it was found to lower cholesterol, and for decades since it has been used as a lipid drug. That effect needs large doses of 2-3 g a day, and the flushing and liver-damage side effects are real. It changes lipid numbers, but adding it on top of a statin did not reduce cardiovascular events (two large trials, AIM-HIGH and HPS2-THRIVE; the vitamin B3 story covers this in detail). It is the cheapest.Nicotinamide riboside (): brands such as Tru Niagen (Niagen), commercialized in 2013, usually 200-1000 mg a day.Nicotinamide mononucleotide (): brands such as Renue, Wonderfeel, and many influencer labels, usually 250-1000 mg a day, and the most expensive.
In other words, the price gap on the shelf does not buy you a higher destination, only a different entrance. Which entrance is the better deal can only be answered after looking at the consumption side and the human trials, and that is itself a signal: an ingredient list alone cannot tell you whether something is worth the money.
Chapter 2
What uses up NAD⁺
Why does the pool run shallow? The answer from mouse studies is that the problem is mainly a leak, not a slow tap.
Think of the NAD⁺ in a cell as a tank of water with three things draining it. , the enzymes often called longevity genes, are frugal and use one NAD⁺ per job. PARP rushes to repair DNA when it breaks and burns a large handful on each repair. CD38 cuts NAD⁺ apart in one stroke, and in old mice it rose to at least 2-3 times its young level in every tissue tested. The drain that clearly widens with age is CD38; in people, it has so far been seen rising only in fat tissue.
So taking or opens the tap wider. In trials, blood NAD⁺ stayed high for as long as people kept taking it, but the leak did not get smaller. The analogy has a limit too: more water in the tank does not mean a healthier person. That is a separate question, and only trials can answer it.
Think of the NAD⁺ in a cell as a tank of water with three things draining it. , the enzymes often called longevity genes, are frugal and use one NAD⁺ per job. PARP rushes to repair DNA when it breaks and burns a large handful on each repair. CD38 cuts NAD⁺ apart in one stroke, and in old mice it rose to at least 2-3 times its young level in every tissue tested. The drain that clearly widens with age is CD38; in people, it has so far been seen rising only in fat tissue.
So taking or opens the tap wider. In trials, blood NAD⁺ stayed high for as long as people kept taking it, but the leak did not get smaller. The analogy has a limit too: more water in the tank does not mean a healthier person. That is a separate question, and only trials can answer it.
Mechanism · How three enzymes use up NAD⁺
Those three things at the edge of the tank have these scientific names and habits.The family (SIRT1-7), the frugal type. They are deacetylases: each acetyl group they remove from a protein uses up one , producing nicotinamide and 2'-O-acetyl-ADP-ribose. Their affinity for NAD⁺ is low (a Michaelis constant, Km, of roughly 150-200 µM; measured values vary with substrate and conditions), which means their activity rises and falls as NAD⁺ goes up or down a little. The hypothesis that raising NAD⁺ activates sirtuins and extends lifespan rests on this point.
PARP1/2, the emergency type. When DNA breaks in one strand or both, PARP cuts NAD⁺ apart in large amounts and hangs chains of ADP-ribose on proteins at the damage site (poly-ADP-ribosylation). One event uses tens to hundreds of NAD⁺ molecules, far faster than sirtuins. UV light, oxidative stress, and chronic inflammation all keep triggering it. DNA damage accumulates with age, so how much extra PARP consumes during aging is still debated; in the mice of Camacho-Pereira 2016, PARP1 expression did not rise with age.
CD38, the one that grows with age. It is an NAD glycohydrolase that cuts NAD⁺ in one stroke into nicotinamide and cyclic ADP-ribose (cADPR, a small molecule that carries calcium signals). In mice, its protein, mRNA, and enzyme activity all rose with age, at least 2-3 times in every tissue. In human fat tissue, CD38 mRNA in older people was up to about 2.5 times that in younger people. Mice with CD38 knocked out were spared the age-related fall in NAD⁺. The same paper also found that CD38 is the main enzyme breaking down in the body, so part of the NMN you swallow is eaten by exactly this leak. Experimental CD38 inhibitors (such as 78c) are a separate line of research.
Put the three side by side. The activity of the first two mainly follows what your cells are doing (whether there is work to do, whether there is damage to repair); in mice the third follows age. So in mice, what age really drives is the CD38 path, while every supplement on the market works on the inflow side. In people, this chain is not yet complete.
Evidence · Pairing precursors with a CD38 blocker
If this mouse logic also holds in people, the approach more likely to work would not be or alone but topping up the raw material while blocking CD38. A few current lines of research:78c: an experimental CD38 inhibitor that restored the pool and improved metabolism in aged mouse models (Tarragó 2018, Cell Metab)Apigenin: a natural flavonoid in celery and parsley that inhibits CD38 in lab dishes; there is no evidence that taking it by mouth reaches a working concentration in the human bodyLuteolinidin and quercetin: weak CD38 inhibitors in lab dishes
This is why some researchers are reserved about NMN or NR on their own: it is like adding water to a leaking bathtub while nobody patches the leak.
In reality there is no leak repair to buy, because no CD38 inhibitor has been approved by regulators and shown to be safe in people. What you see at the pharmacy and online is all the water-adding kind, that is, precursor supplements.
That does not make NMN and NR useless. The short-term rise in NAD⁺ is real, and a few small signals show up on (lab or physiological values, not the disease itself); the chapter on human trials, further on, lists them one by one. But marketing them as reversing aging does not hold up even at the level of mechanism.
Chapter 3
How the craze took off
The and craze grew, to a large extent, around one person: David Sinclair, a Harvard genetics professor and author of *Lifespan*. He is an accomplished biologist and an accomplished promoter, and he has also founded related companies. With those roles stacked together, many people cannot tell which claims are research findings and which are a business story.
The most common mismatches are three. Mouse experiments are retold as rejuvenation for humans. The longevity hypothesis, weakened by later research, is still used as a selling point in ads. And the person recommending it runs a related business himself.
So a Harvard professor recommends it measures fame, not clinical evidence.
The most common mismatches are three. Mouse experiments are retold as rejuvenation for humans. The longevity hypothesis, weakened by later research, is still used as a selling point in ads. And the person recommending it runs a related business himself.
So a Harvard professor recommends it measures fame, not clinical evidence.
Myth · Four places the science and the pitch diverge
At four points, the academic signal and the commercial story do not line up. Here they are one by one.1. Does rejuvenate mice?
Mills 2016 (Cell Metab) gave normally aging mice oral NMN for 12 months, at 300 mg/kg a day in the high-dose groupAge-related weight gain was held down, and energy metabolism, activity, insulin sensitivity, blood lipids, and eye function all improvedIt was not rejuvenation, and it did not show a clearly longer lifespan; the experiment was never designed to measure lifespanThe media retelling was Harvard scientists discover a longevity moleculeConverted by the usual body-surface-area method, that dose comes to about 1800 mg a day for a 75 kg person, far above most commercial NMN doses
2. Are the longevity genes?
Early experiments in yeast and worms suggested that calorie restriction activates sirtuins and that extra Sir2 extends lifespanBurnett 2011 (Nature) rechecked this and found that, once genetic-background effects were removed, extra Sir2 did not extend lifespan in worms or fruit fliesThe sirtuin longevity hypothesis has been downgraded in research, while the commercial story still uses it
3. Podcasts made it a hit
In 2019 Sinclair did a long interview on Joe Rogan's show; more podcasts and health influencers followed, and and NMN took off in the mass marketThis is a template for nutrition marketing in the podcast era: one celebrity scientist plus one celebrity host
4. The recommender's own business interests
Sinclair founded Sirtris (later bought by GlaxoSmithKline and then shut down), and he co-founded Life Biosciences and MetroBiotech, which is developing NMN as a drugThese ties are not violations, but you should know about them before buyingThe review most often cited in the literature (Rajman 2018) also comes from his lab, and its conclusion is about animals: restoring NAD⁺ in old or diseased animals can improve health and extend lifespan
The first point deserves a pause. The dose-conversion step is almost always skipped in the retelling. The amount that worked in mice, scaled to a person, is several times a commercial dose, so even if the mouse result held exactly as reported, the bottle in your hand may not be on the same scale. The mechanism makes sense, the animals showed it, and the dose you take matches are three independent facts; drop one and the whole chain of reasoning breaks.
In practice · Is the bottle what the label says?
The main players in the market:On the side: ChromaDex's Tru Niagen (Niagen) is the leading brand, with a standard dose of 300 mg a day. Its NR ingredient is generally recognized as safe (GRAS) in the United States and has been the subject of New Dietary Ingredient (NDI) notifications to the FDA. Conze 2019, the safety trial cited here, was funded by this company. Several generic brands also exist.
On the side: brands such as Wonderfeel, Renue, ProHealth, and DoNotAge, plus large volumes of white-label product imported from China. The cost of making raw NMN in China is now very low, but purity varies widely.
Quality risks:
Sandalova 2024 tested NMN and urolithin A supplements that are easy to buy online or at pharmacies. Measured content differed widely from the label, ranging from 28.6% more than the label to none at all (-100%).In 2022 the US FDA said that because NMN had first entered study as a drug (MetroBiotech's MIB-626), it no longer met the definition of a dietary supplement. That position was later revisited, enforcement never followed, and the market kept running. For its legal status now, go by the FDA's current documents.
You may not be buying what you think you are buying: this always applies, and it applies most in lanes where the mechanism is fashionable and regulation is murky.
By contrast, niacin as a prescription lipid drug is regulated by the FDA, its content is stable, and it costs far less. It takes the Preiss-Handler path and ultimately raises the same pool.
Chapter 4
What human trials found
Between reversing aging and what human trials have actually measured lies a wide gap.
The double-blind randomized trials completed so far tell the same story. Taking or does raise in the blood, and it looks safe in the short term. But on the outcomes you could feel yourself (exercise capacity, blood lipids, inflammation, body fat, blood pressure, heart and lung fitness) almost every result is no different from placebo. Small positive signals have shown up in a few subgroups or single measures (systolic blood pressure in people whose pressure was high, and insulin sensitivity in muscle). The samples were only a few dozen people each, and the signal was often the one significant result in that trial.
No randomized trial in people has shown that NMN or NR extends lifespan, prevents cancer, cardiovascular events, or dementia, or clearly improves fitness, strength, or cognition. What exists is a genuinely higher NAD⁺ pool plus a few small signals on (lab or physiological values), and the certainty of that evidence is low. The marketing rests on a persuasive mechanism, success in mice, and a Harvard endorsement, not on trials that measured disease.
The double-blind randomized trials completed so far tell the same story. Taking or does raise in the blood, and it looks safe in the short term. But on the outcomes you could feel yourself (exercise capacity, blood lipids, inflammation, body fat, blood pressure, heart and lung fitness) almost every result is no different from placebo. Small positive signals have shown up in a few subgroups or single measures (systolic blood pressure in people whose pressure was high, and insulin sensitivity in muscle). The samples were only a few dozen people each, and the signal was often the one significant result in that trial.
No randomized trial in people has shown that NMN or NR extends lifespan, prevents cancer, cardiovascular events, or dementia, or clearly improves fitness, strength, or cognition. What exists is a genuinely higher NAD⁺ pool plus a few small signals on (lab or physiological values), and the certainty of that evidence is low. The marketing rests on a persuasive mechanism, success in mice, and a Harvard endorsement, not on trials that measured disease.
Evidence · Four trials, read one by one
As you read, watch the string of no difference after each trial; it says more than the positive result in front of it.Martens 2018 (Nat Commun): nicotinamide riboside (), healthy middle-aged and older adults aged 55-79; 30 enrolled and 24 completed
1000 mg of NR a day and placebo, 6 weeks each, crossover design, double-blind in peripheral blood mononuclear cells was about 60% higher than during placebo, so the mechanism holdsSystolic blood pressure tended to fall across all participants. In the 13 people whose baseline pressure was elevated (systolic 120-139 mmHg), systolic pressure was about 9 mmHg lower than on placebo, but this was an exploratory analysis done after the fact, and the authors state that no statistical conclusion can be drawn from itMaximal oxygen uptake, exercise capacity, motor function, and similar measures: no difference
Yoshino 2021 (Science): nicotinamide mononucleotide (), 25 postmenopausal women with prediabetes who were overweight or obese (13 on NMN, 12 on placebo)
250 mg of NMN a day for 10 weeks, double-blindMuscle insulin sensitivity (measured with a clamp test of how fast glucose is taken up) was about 25% higher than before treatment, with no change on placeboOther whole-body metabolic measures (body fat, blood lipids, blood pressure, heart and lung fitness, and so on): no differenceA small sample, with only this one main measure significant
Igarashi 2022 (NPJ Aging): NMN, 42 healthy men aged 65 or older
250 mg a day for 12 weeks, double-blindBlood NAD⁺ rose. Walking speed and left-hand grip showed nominal improvements, which the authors themselves say need validating in larger trials; body composition did not changeNo such as death, cognition, or cardiovascular events
Conze 2019 (Sci Rep): NR, 140 overweight but otherwise healthy adults
100-1000 mg a day (three doses: 100, 300, or 1000 mg) for 8 weeks; a safety and pharmacokinetic trial funded by the maker of NRWhole-blood NAD⁺ rose with dose within 2 weeks and stayed up for the rest of the trial; nobody reported flushing, and adverse events did not differ from placeboIt was not designed for efficacy and did not measure benefits in metabolism or exercise performance
Set side by side, the four trials show two things. First, the positive signals all sit in a subgroup or a single measure: the blood-pressure drop appeared only in the group with elevated pressure, and only in an after-the-fact analysis; muscle insulin sensitivity rose while other whole-body metabolic measures did not move. Second, the samples range from a few dozen to just over a hundred people, a size that can only look at , not hard endpoints. So not measured and measured and found absent are two different things, and current evidence supports only the first. That is exactly the width of the gap between the mechanism holds and it helps you.
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Evidence · Why no large hard-endpoint trial exists
Why are there no large randomized trials? That question is worth thinking about in itself.The endpoints are too far away. A lifespan endpoint needs 10-20 years of follow-up and thousands of people; a cardiovascular-event endpoint also needs thousands of people and 3-5 years. Trials on that scale are very expensive, beyond what a single supplement company can carry.
Nobody has a reason to run them. On the US regulatory path, is sold as a supplement and can reach the market without any efficacy trial, so makers have no incentive to run hard-endpoint trials. Academic researchers would need large public funding, which has not appeared yet. The only product on a drug path is MetroBiotech's MIB-626, and if it succeeds, NMN will be even harder to sell as a supplement.
Compare with drugs. Statins have dozens of large randomized trials with cardiovascular events and death as endpoints, together enrolling well over a hundred thousand people. For metformin, researchers have proposed a large trial (TAME) to test whether it delays several diseases of aging, and that trial has not been completed. NMN and : none.
So when you read claims about NMN and NR, keep three kinds of evidence apart:
A roughly 60% rise in blood is a mechanistic signal, not a health outcomeImprovement in old mice is a preclinical signal, not evidence in peopleDavid Sinclair takes it himself every day is an anecdote, not a randomized trial
None of this means they cannot work. It means the strength of the current evidence does not match the strength of the marketing. This lane is worth following, but not worth betting everything on.
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Chapter 5
Should you buy? Niacin costs less
The least intuitive fact: the same pool can be filled by niacin through the Preiss-Handler path and by and through the recycling path, yet the prices differ a lot, and niacin is far cheaper.
So the real question is not which brand is best but three things: what you actually want (a longer life? better lipids? less insulin resistance? or just a higher NAD⁺ level?), which side effects you can accept, and which layer of regulation you trust. Put the price, dose, regulatory status, and evidence of the three routes side by side, and most people's answer will differ from the one the ads give.
Keep one more thing in mind: niacin is cheap, but it is a drug. Large doses cause flushing and can harm the liver, so it should not be treated as a casual supplement. And when a marketing story tells you that supplement X reverses aging but never mentions a far cheaper old drug on the same pathway, that silence is itself a marketing signal.
So the real question is not which brand is best but three things: what you actually want (a longer life? better lipids? less insulin resistance? or just a higher NAD⁺ level?), which side effects you can accept, and which layer of regulation you trust. Put the price, dose, regulatory status, and evidence of the three routes side by side, and most people's answer will differ from the one the ads give.
Keep one more thing in mind: niacin is cheap, but it is a drug. Large doses cause flushing and can harm the liver, so it should not be treated as a casual supplement. And when a marketing story tells you that supplement X reverses aging but never mentions a far cheaper old drug on the same pathway, that silence is itself a marketing signal.
In practice · Comparing price, regulation, evidence
is nicotinamide riboside and is nicotinamide mononucleotide; both are intermediate raw materials the body uses to make , while niacin is an older, cheaper precursor.The three routes side by side (usual doses):
| Choice | Usual dose | Monthly cost | Regulatory status | Does it raise NAD⁺? |
|---|---|---|---|---|
| Niacin (prescription lipid drug) | 500 mg × 2 | Lowest | FDA-approved lipid drug | Yes; the textbook NAD⁺ precursor, whose deficiency causes pellagra |
| NR (Tru Niagen) | 300 mg | Middle | Generally recognized as safe in the US, with New Dietary Ingredient notifications | Yes; small randomized trials (Martens 2018, Conze 2019) |
| NMN (Renue, Wonderfeel, and others) | 500 mg | Highest | Disputed legal status | Yes; a small randomized trial (Yoshino 2021) |
Q1 What is your goal?
Longer life, anti-aging, dementia prevention: there is no human hard-endpoint evidence, so this is not a priority. The same money spent on sleep, exercise, diet, weight, and not smoking pays back far moreBetter blood lipids: niacin at 2-3 g a day changes lipid numbers, but large trials that added niacin on top of a statin (AIM-HIGH, HPS2-THRIVE) did not reduce cardiovascular events, and side effects increased (see Niacin). Lipid lowering is for a doctor to assess; do not buy niacin and treat yourselfInsulin resistance, prediabetes: weight loss and exercise come first. In the large randomized Diabetes Prevention Program (DPP) trial, lifestyle intervention cut new cases of diabetes by more than metformin did. Metformin is a prescription a doctor may consider. Berberine has only smaller trials. NMN has only Yoshino 2021, one trial of 25 people with one significant measureYou just want to try raising NAD⁺: niacin is cheapest, but it is a drug, and flushing, liver harm, and blood-sugar swings are real side effects, so it should not be treated as a casual supplement. NR sits in the middle. NMN carries the highest marketing premium
Q2 What risk can you accept?
Niacin: flushing (most people get it the first time, and tolerance builds), liver harm at large doses, blood-sugar disturbanceNR and NMN: good short-term safety data over weeks to months (Conze 2019); long term unknown
Q3 Which layer of regulation do you trust?
A drug regulated by the US FDA: niacinA supplement recognized as generally safe in the US, with New Dietary Ingredient notifications: NR (Tru Niagen)Disputed legal status, but a fashionable mechanism: NMN
When you read this table, notice that the last column compares whether NAD⁺ can be raised, not whether you get healthier. All three routes pass that column; the differences are price and regulatory status. The column none of them can fill is , and that column does not even appear in this table.
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Safety · Who should skip it, and NAD⁺ blood tests
These 5 groups should not take or :1. People on a tight budget: the same money spent on sleep, food, and exercise pays back far more.
2. People being treated for cancer, or being checked for it: tumor cells also depend on to run their metabolism, so by mechanism, extra raw material might help the tumor too. There are no human data on this, so do not add it yourself; ask the oncologist first.
3. People with chronic inflammation or an autoimmune disease: PARP and CD38 rise along with inflammation, and extra raw material might amplify some of those pathways; the data are unclear.
4. People who are pregnant or breastfeeding: there are no human data at all, so skip it.
5. People who want anti-aging while still staying up late, skipping exercise, smoking, and sitting all day: your bottleneck is not NAD⁺.
About NAD⁺ blood tests:
Some companies (such as Jinfiniti and NAD Quest) sell blood NAD⁺ tests costing a few hundred US dollars each.Do the results mean anything? Only partly. NAD⁺ levels differ widely between tissues such as liver, muscle, and brain, and the value in blood does not fully reflect what is happening in tissues.A low result does not necessarily mean you need NMN or NR; chronic inflammation, poor sleep, or active CD38 could all push it down.A high result does not show that anti-aging worked either.Often these tests are a marketing funnel: test low, so you need to supplement; supplement, then keep testing and keep paying.
Rather than paying to measure NAD⁺, watch your sleep quality, your energy in the morning, and how fast you recover after exercise. They cannot read out your NAD⁺ for you, but they are the things you actually want to improve.
References · 10
- Rajman, L., Chwalek, K., & Sinclair, D. A. (2018). Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metabolism, 27(3), 529-547. 10.1016/j.cmet.2018.02.011
- Camacho-Pereira, J., Tarragó, M. G., Chini, C. C. S., et al. (2016). CD38 dictates age-related NAD decline and mitochondrial dysfunction through a SIRT3-dependent mechanism. Cell Metabolism, 23(6), 1127-1139. 10.1016/j.cmet.2016.05.006
- AIM-HIGH Investigators. (2011). Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. NEJM, 365(24), 2255–2267. 10.1056/NEJMoa1107579
- HPS2-THRIVE Collaborative Group. (2014). Effects of extended-release niacin with laropiprant in high-risk patients. NEJM, 371(3), 203–212. 10.1056/NEJMoa1300955
- Sandalova, E., Li, H., Guan, L., Raj, S. D., Lim, T. G., Tian, E., Kennedy, B. K., & Maier, A. B. (2024). Testing the amount of nicotinamide mononucleotide and urolithin A as compared to the label claim. GeroScience, 46(5), 5075-5083. 10.1007/s11357-024-01257-2
- Mills, K. F., Yoshida, S., Stein, L. R., Grozio, A., Kubota, S., Sasaki, Y., et al. (2016). Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metabolism, 24(6), 795-806. MICE: 12 months of oral NMN in regular chow-fed wild-type C57BL/6N mice during normal aging. Without obvious toxicity, NMN suppressed age-associated body weight gain, enhanced energy metabolism, promoted physical activity, improved insulin sensitivity and plasma lipids, and ameliorated eye function; the abstract reports no lifespan outcome (abstract, PMID 28068222). 10.1016/j.cmet.2016.09.013
- Burnett, C., Valentini, S., Cabreiro, F., Goss, M., Somogyvári, M., Piper, M. D., et al. (2011). Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature, 477(7365), 482-485. Worms and flies: standardizing genetic background and using appropriate controls abolished the reported lifespan extension from sirtuin overexpression. In C. elegans, outcrossing removed the longevity of a high-level sir-2.1 line while overexpression remained, and longevity co-segregated with a second-site mutation affecting sensory neurons; a long-lived dSir2 Drosophila strain was not long-lived relative to proper transgenic controls; dietary restriction extended fly lifespan independently of dSir2. The authors do not rule out a role for sirtuins but doubt the robustness of the earlier effects (abstract, PMID 21938067). 10.1038/nature10296
- Martens, C. R., Denman, B. A., Mazzo, M. R., et al. (2018). Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nature Communications, 9(1), 1286. Randomized, double-blind, placebo-controlled crossover, 2 x 6 weeks of nicotinamide riboside 500 mg twice daily: 30 healthy adults randomized, 24 completed (mean age 65). NR raised PBMC NAD+ by about 60% vs placebo. Blood pressure fell but not significantly after correction for multiple comparisons (systolic -3.9, diastolic -2.0 mmHg); in a post hoc subgroup with baseline systolic 120-139 mmHg (n = 13) systolic was about 9 mmHg lower on NR, an exploratory analysis from which, the authors say, no statistical inferences can be made (full text, PMC5876407; abstract, PMID 29599478). 10.1038/s41467-018-03421-7
- Yoshino, M., Yoshino, J., Kayser, B. D., et al. (2021). Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science, 372(6547), 1224-1229. 10-week randomized, placebo-controlled, double-blind trial in 25 postmenopausal women with prediabetes and overweight or obesity (NMN 250 mg/day n = 13, placebo n = 12). Muscle insulin sensitivity (clamp glucose disposal per kg fat-free mass) was 25 ± 7% higher after than before NMN (p < 0.01), a within-group change, and unchanged on placebo; body composition, blood pressure, fasting glucose and insulin, lipids, liver and adipose insulin sensitivity and muscle mitochondrial capacity did not change. Two authors disclosed NMN patent interests (full text, PMC8550608; abstract, PMID 33888596). 10.1126/science.abe9985
- Conze, D., Brenner, C., & Kruger, C. L. (2019). Safety and metabolism of long-term administration of NIAGEN (nicotinamide riboside chloride) in a randomized, double-blind, placebo-controlled clinical trial of healthy overweight adults. Scientific Reports, 9, 9772. 8-week randomized, double-blind, placebo-controlled trial in overweight healthy adults: NR 100, 300 or 1000 mg/day raised whole-blood NAD+ by 22%, 51% and 142% within 2 weeks; no flushing and no difference in adverse events vs placebo; LDL and 1-carbon metabolism unchanged. Funded by ChromaDex; two authors are ChromaDex employees and the third is inventor of intellectual property licensed by ChromaDex and its chief scientific adviser (abstract and COI, PMID 31278280). 10.1038/s41598-019-46120-z