Summary
- The oxidised form of nicotinamide adenine dinucleotide (NAD+) is important to cellular energy (ATP) production by helping to shuttle electrons within cells. It's also a cofactor for various enzymes that affect processes involved in countering ageing, such as DNA repair.
- Many people take NAD+ precursors in the hope of slowing ageing. The most popular are nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), the effects of which are likely very similar.
- In humans and other animals, oral NR and NMN both raise levels of NAD+ and some related metabolites in certain cells (e.g., blood cells) and tissues, but this effect is not ubiquitous.
- Scientists and people in the supplement industry are interested in alternative ways of raising cellular NAD+ levels. For example, there's a multi-ingredient supplement intended to simultaneously provide NAD+ precursors while also targeting enzymes involved in NAD+ synthesis and degradation. The study on this supplement was not compelling, however.
- NR and NMN have some beneficial health effects in mice but have not consistently been found to extend mouse lifespan.
- To date, clinical research on NR and NMN has shown some very modest positive effects on a few outcomes (e.g., inflammatory markers in blood). Most research has been on NR.
- Clinical trials suggest NR and NMN are safe at relative doses lower than those used in research on other animals, even if a study of mice suggests there might be some potential for kidney toxicity.
- A recent series of experiments showed that ergothioneine, an amino acid in abundance in mushrooms, might produce many of its benefits by boosting cellular NAD+. Other research on ergothioneine is also very promising. It's currently unclear if ergothioneine is a more effective way of raising NAD+ than NR or NMN.
- NR and NMN are both very expensive when taken in doses used in clinical trials, so their cost: benefit ratio is not very good at all.
- In 2022, the US Food and Drug Administration (FDA) changed its stance, so NMN can no longer be sold as a dietary supplement. This shift is dubious.
Why take NR or NMN?
To understand the rationale behind taking these supplements, we first need to go on a biochemical detour. Bear with me while we get nerdy in this section... or just jump to a subsequent section if you want to skip the foreplay and head to the actual effects of supplementation.
NR and nicotinamide are forms of vitamin B3 (niacin), while NMN is a close relative of NR (it's basically NR with a phosphate group stuck on it). They are all NAD+ precursors, so many people are taking one of these (or trigonelline, an alkaloid found in coffee) to try to boost cellular NAD+. Cellular NAD+ levels matter, in part because NAD+ has key roles in redox reactions, which involve transferring electrons between reactants. NAD+ gets "reduced", meaning it gains an electron, and in doing so it forms NADH and harnesses the energy liberated from the chemical bond that's just been broken. Through this action, NAD+ channels electrons between fundamental pathways through which your cells generate energy (ATP), including glycolysis, which involves burning sugar in the cytosol of a cell, and the Krebs cycle, which takes place in mitochondria.
NAD+ has some other pivotal functions. It's a cofactor for non-redox enzymes that speed chemical reactions important to warding off aging. Two groups of these enzymes are especially noteworthy. One is the poly (ADP-ribose) polymerase (PARP) enzymes, a family of 17 proteins that are instrumental to the early repair of damaged DNA. The other is the sirtuin enzyme family, seven proteins that are also involved in DNA repair as well as mitochondrial quality control, metabolism, and the coordination of timing of cellular processes.
DNA is almost constantly bombarded by stressors inciting damage and mutations, so DNA damage tends to accumulate over time and effective DNA repair mechanisms are essential to healthy ageing. Repairing this damage is part of the reason why cellular NAD+ levels tend to dwindle with increasing age. This effect occurs in many tissues, from skin to muscle to liver to brain. Another reason NAD+ declines is there's another group of enzymes (NADases) that chew up NAD+, in particular in the face of chronic inflammation.
Your body uses three main pathways to keep NAD+ levels in check, but the biggest contributor to NAD+ in most tissues is the NAD+ salvage pathway, which recycles NAD+ from nicotinamide. In this pathway, NMN is an intermediary between nicotinamide and NAD+, and NR is a precursor to NMN. Note, however, that if you supplement NMN, it actually gets converted to NR first so it can pass through cell membranes.
In summary, the logic behind supplementing nicotinamide, NR, or NMN is to keep the NAD+ salvage pathway in high gear, in turn supporting ATP production and keeping DNA damage, chronic inflammation, and other forms of dysregulation in check. This logic would fall apart if supplementation didn't actually raise NAD+ though... so, does it?
Do NR and NMN increase NAD+?
Yes.
In some people.
And only in some tissues.
Looking at studies of NMN supplementation, effects on tissue NAD+ are very variable, ranging from minimal to substantial increases. Responses to NR seem to be similarly heterogeneous, and a review of NR's effects on NAD+ levels in blood and muscle reported that while the 300 mg dose approved by the US Food and Drug Administration increased blood levels by 40 to 59%, it didn't affect muscle concentrations. (Nicotinamide does get into muscle, but in healthy people it doesn't get readily converted to NAD+, so any extra probably just gets methylated and excreted in urine as NAD+ metabolites.) Encouragingly, there is some evidence that NR can increase NAD+ levels in the brain, as shown in a study of Parkinson's disease patients taking 1,000 mg NR daily for 30 days. Other research on healthy older adults has found that 1,000 mg NR daily for 6 weeks increased NAD+ levels in little membrane-bound particles (extracellular vesicles) released by neurons to communicate with other cells, again suggesting positive effects on nervous system NAD+.
There are probably a few factors that explain why NR and NMN have such variable effects between people and between cell types. One is variation in the enzymes involved in synthesising and breaking down NAD+. For example, activity of the rate-limiting enzyme in the pathway, nicotinamide phosphoribosyltransferase (NAMPT), tends to wane with age. Another is that NAD+ levels are regulated locally — even within cells. In a single cell, the nucleus, cytoplasm, and mitochondria each have their own, siloed NAD+ pools.
Scientists partnered with the supplement industry have tried to address this by both providing an NAD+ precursor (in this case, nicotinamide) and other nutraceuticals to attempt to increase NAMPT, minimise nicotinamide methylation (which aids its salvage, for methylation increases nicotinamide excretion), and inhibit the enzymes (NADases) that gorge on NAD+.
Nice idea.
The problem is that the one study on it so far didn't provide compelling evidence that it works any better than NR or NMN, finding a 27% increase in blood NAD+ after 4 weeks of supplementation. This is lower than most studies of NR. It also didn't find significant effects on levels of inflammatory cytokines in blood plasma. It did find a couple of positive effects, but the statistical analysis wasn't corrected for multiple testing, so it's possible the positive results were spurious.
In summary, the effects of NR and NMN on tissue NAD+ levels are very variable. But what about the hard outcomes we're most interested in, such as lifespan and physiological and functional measures of health?
Does NR or NMN extend lifespan in other animals?
Initial experiments by Charles Brenner and his colleagues found that NR increased replicative lifespan in yeast. This was a promising finding, but frankly many things extend replicative lifespan in yeast, and most of these don't affect lifespan in mammals when later tested.
Subsequent research by the Interventions Testing Program (often considered the gold standard of this type of research) gave mice an appropriate daily dose of NR in the diet, starting at 8 months of age (arguably the mouse equivalent of starting in your 20s). The NR had no effect on lifespan.
More recent research on NMN using a different, inbred strain of mice found that adding NMN to drinking water beginning in midlife (age 13 months) did extend both median and maximum lifespan by about 8%, although this effect was confined to female mice. At the time of writing, this research is just in a pre-print journal, meaning it hasn't been subjected to the scrutiny of review by other scientists.
Finally, while nicotinamide did have some positive effects on metabolic health when added to the diets of the same inbred strain of mice starting at age 12 months, it did not affect lifespan.
Overall, the weight of the evidence suggests that using NAD+ precursors probably don't affect mouse lifespan.
Effects of NR and NMN in clinical trials
In general, excusing the opinions of people with a vested interest in NR or NMN, it appears that NR and NMN are largely interchangeable, and any differences between supplementing them seem bound to be very minor. NR has received the lion's share of clinical research interest and funding, however. Please also note that several products containing NR or NMN alongside other active ingredients (e.g., NR plus pterostilbene) have been studied, but for brevity we've not focused on these multi-ingredient products here.
The first clinical trial of NR was published in 2016. Most of the studies since have involved only a small number of people and focused on safety. Overall, clinical research on NR has documented some small, positive effects, but the effects seem to be so modest as to not be clinically meaningful, as detailed in a review of the 25 clinical studies on NR that had been done up to the time of the review (July 2023).
The most consistent findings have been an increase in NAD+ and some of its metabolites as well as minor reductions in some markers of inflammation in blood cells. There's also some evidence that NR can reduce blood pressure, at least in people with high blood pressure, and improvements in cardiovascular function might help explain some minor gains in physical function (how far people can walk in six minutes) in people with cardiovascular disease. NR has also been studied for its effects in several less prevalent diseases, such as ataxia telangiectasia, chronic obstructive pulmonary disease, heart failure, and Parkinson's disease. However, some of this research is hard to interpret due to flaws in study design (e.g., uncontrolled, "open-label" research, meaning the patients knew they were getting NR, making it impossible to know if any effects were just placebo ones). Much of the research has not looked at relevant functional outcomes either.
Regarding NMN, there have now been several studies of its effects on metabolic and cardiovascular health in middle-aged and older adults. A systematic analysis of these studies concluded that supplementation with 250 to 2,000 mg daily for two to 12 weeks did not affect any of the measures of insulin and blood sugar regulation tested, nor did it affect blood lipids. In contrast, another systematic review of studies of NMN intake by middle-aged and older adults reported that NMN did somewhat improve walking speed.
Are NR and NMN safe?
In short, yes, they both seem to be quite safe at the doses tested.
Regarding NR, the FDA has granted a 300 mg dose of NR "Generally Regarded as Safe" status. Remember that this dose is far lower than that used in many of the clinical trials though.
Regarding NMN, a study published in a pre-print journal reported that, contrary to expectations, NMN appeared to damage the kidneys of male mice late in life. This raises a very small red flag though, for clinical trials on NMN have indicated it is well tolerated.
NR and NMN: Consider the cost: benefit ratio
Many purportedly anti-aging (gerotherapeutic) single-ingredient supplements cost a lot of money. Among the priciest is Mitopure — at the time of writing, 60 x 250-mg softgels cost $125 on Amazon, and since a 1,000 mg daily dose was most beneficial in the trial of the product, that's $125 for just a 15-day supply of a single ingredient with very modest effects.
Ouch.
NR is quite dear too. The best-studied NR product is TruNiagen, which is around $50 for a month of 300 mg per day, the FDA-approved dose. Most studies have used higher doses than this though — often 1,000 mg per day, the price of which is roughly $115 per month.
Pure NMN is no longer so readily available in the US since the 2022 FDA ruling against it. If you try hard enough, you can probably track it down for quite similar prices to NR though.
Nicotinamide, meanwhile, is inexpensive. However, nicotinamide supplementation has only really been shown to be advantageous in certain clinical contexts (e.g., treating some skin diseases and pellagra, which results from vitamin B3 deficiency).
Another way to increase NAD+ levels: might ergothioneine be more effective?
You'll notice that we don't use NR, NMN, or nicotinamide in our products. This is because we're simply not impressed by the research on any of them.
This raises the question about whether our product raises NAD+ levels. While we don't have a randomised clinical trial we can point to, we think it most likely does, in part because of one specific ingredient in the Morning Blend.
Ergothioneine, a natural product found in mushrooms, has so far been found to have an impressively diverse array of positive effects on health, as we have highlighted here. Some of these effects might be because ergothioneine raises NAD+ in cells, as shown by a recent series of experiments.
The mechanism is quite different from NR, NMN, or nicotinamide. Rather than providing a precursor to NAD+, ergothioneine is used by a protein to make hydrogen sulfide. This gas then modifies a large set of proteins in ways that improve mitochondrial function, increase ATP production, and increase NAD+. What's particularly interesting is that this NAD+ enhancement was seen in skeletal muscle, a tissue with NAD+ levels typically unresponsive to NR and NMN. Cells love ergothioneine and do their best to take it up and hold on to it. Given the ubiquity of transporters for ergothioneine across tissues and the organelles within their cells, it seems likely that some of ergothioneine's widespread benefits among tissues are mediated in part by increasing NAD+.
Watch this space though — these findings are preliminary!
NR, NMN, or NOT: final verdict
The rationale behind using NAD+ precursors does make some sense. Yet the actual effects of NAD+ precursors such as NR and NMN on clinically relevant outcomes have been underwhelming.
As always, we need more research — especially trials with more people looking at more meaningful outcomes. It's likely that there are certain clinical populations that will benefit from judicious use of NR or NMN. However, the supposition that NR or NMN is an anti-aging panacea is simply not supported by research to date, and there are other gerotherapeutic supplements that appear to hold substantially greater promise.
