Nicotinamide mononucleotide (NMN): Benefits and Side Effects

NMN is a naturally occurring molecule and a popular dietary supplement marketed as a NAD+ booster.

What is NMN?

NMN is short for nicotinamide mononucleotide, a naturally occurring molecule present in all species. On the molecular level, it is a ribonucleotide, a basic structural unit of the nucleic acid RNA. It consists of a nicotinamide group, a ribose, and a phosphate group.

NMN is a precursor of nicotinamide adenine dinucleotide (NAD+), a molecule that may be useful in slowing down some aspects of aging. NAD+ serves many critical functions in our cells, such as electron transport, cell signaling, and DNA repair.

Nicotinamide Adenine Dinucleotide (NAD): Benefits and Research

Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells. It is a dinucleotide, which means that it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base, and the other contains nicotinamide.
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Accumulating evidence suggests that as we age, our levels of NAD+ decline, increasing our risk of age-related diseases.

This is where the NAD+ precursor NMN comes in. Some researchers believe that if we can restore that lost NAD+, we could not only slow down aging but also delay various age-related diseases. Whether or not restoring NAD+ metabolism in humans will slow down aging or support healthy longevity is still an unanswered question, though the animal data is promising.

What foods contain NMN?

NMN can be found naturally in foods such as avocado, broccoli, cabbage, cucumber, and edamame. Here is how much NMN is found in some common foods.

While these kinds of foods are an excellent source of nutrition, dietary NMN supplements are also available. These supplements typically come in doses of between 100 – 500 mg, although an optimal dose has yet to be determined in people.

Fasting and caloric restriction also appear to increase NAD+ levels and boost the activity of sirtuins, aka the longevity genes. It is suggested that their activity relies on the presence of NAD+. In mice, fasting boosted NAD+ levels and sirtuin activity, and it appears to slow down aging.

NMN is one of multiple NAD+ precursors

Other NAD+ precursors include nicotinamide riboside (NR) and nicotinic acid (niacin). This diagram shows how these precursors lead to the creation of NAD+.

More recently, reduced nicotinamide mononucleotide (NMNH) has emerged as a possible contender for the most efficient NAD+ boosting precursor molecule [1]. However, NMNH is not currently a commonly available dietary supplement, and more research is needed before that happens.

How was NMN discovered?

While the history of NMN research is naturally intertwined with the history of NAD+, we will only list a few specific studies of note.

Back in 1963, Chambon, Weill, and Mandel discovered that NMN provided the cellular energy needed to activate an important nuclear enzyme [2]. This led to the discovery of poly (ADP-ribose) polymerases (PARPs). These are a family of proteins involved in a number of cellular processes, such as DNA repair, genomic stability, and programmed cell death. PARPs and their activity are also linked to changes in lifespan in different species.

In 2014, a team of researchers led by Dr. David Sinclair demonstrated that NMN can extend the lifespan of mice [3]. In 2017, researchers used NMN to reverse DNA damage in mice by increasing NAD+ levels [4].

In 2020, researchers used NMN to improve blood flow and neurovascular health in aged mice [5]. It also appeared to reverse some age-related changes to gene expression. From a total of 590 genes that are different between young and old animals, treatment with NMN reversed 204 of those genes back towards youthful expression levels.

Also in 2020, a group of researchers demonstrated that treatment with NMN restores neurovascular coupling (NVC) in aged mice [6]. NVC deficiency appears to be a major factor in the age-related decline of cognitive and motor functions.

How is NMN created?

NMN is created in the human body with B vitamins as precursors. The enzyme that makes NMN is known as nicotinamide phosphoribosyltransferase (NAMPT). NAMPT attaches  a form of vitamin B3 called nicotinamide to the sugar phosphate 5’-phosphoribosyl-1-pyrophosphate (PRPP).

NAMPT is the rate-limiting enzyme in the production of NAD+, which means that lower levels of NAMPT mean decreased NMN production and thus decreased NAD+ levels. This also means that by administering additional NMN, the rate of NAD+ production can be increased to somewhat address this shortfall.

It is also possible for NMN to be created from NR by the addition of a phosphate group. Some researchers suggested that NMN could not enter the cell without first becoming NR. However, in 2019, a new NMN transporter channel was identified, showing that it can [7].

The study found that the Slc12a8 gene encodes a specific NMN transporter that allows the molecule to enter cells without being converted to NR first. This discovery certainly came as an unpleasant surprise to the manufacturers and distributors of NR supplements.

Human studies of NMN

The bulk of studies on NMN have been carried out on mice and rats. These have shown positive effects on metabolism, liver, skin, muscle, and brain function as well as improved bone structure, vascular health, reproduction, immune system function, and lifespan. Human studies on people taking NMN are in their early days, but there is some limited data of interest.

In 2020, a Japanese lab conducted a human clinical trial of NMN, which showed that it is well tolerated when given as a single dose [8]. The results of a 2021 study suggested that NMN enhances aerobic capacity in amateur runners [9]. While the study did have some limitations, there were limited but measurable improvements.

Another 2021 human study suggests that NMN improved muscle glucose metabolism in prediabetic women and yielded clinically relevant results [10].

In May 2022, the data from a multicenter NMN clinical trial was published with some modest but interesting results [11]. The data suggested that NMN was increasing energy levels and could be interpreted as an anti-aging effect, albeit it relatively small in this case. That said, NAD+ levels also increased in the placebo participants not taking NMN. These results require futher investigation and a larger study, as this one was fairly small at only 66 people.

The future of NMN research

There is currently fairly limited human data, but that has not stopped NMN from being enthusiastically marketed as a dietary supplement and a NAD+ booster. It has proven popular with people who are confident of its usefulness as an anti-aging compound despite the lack of strong human evidence.

However, the high cost may be prohibitive to some people seeking the fountain of youth. It could be that more cost-effective precursors such as NMNH or other methods may replace it.

After all, to be truly effective in slowing down aging, a supplement not only needs to work, it also needs to be affordable. Currently, the price of NMN and NR is beyond the reach of the average person, and that is a problem that needs to be solved.

However, we have not yet been able to firmly conclude that NMN supplements actually work to slow down aging. Fortunately, there are more human trials underway that will hopefully tell us just how useful NMN is in this respect.

NMN side effects

While the data for long term administration of NMN in humans is scarce, large numbers of people take it as a dietary supplement with few negative reports. However, more studies focused on long-term safety and efficacy should be conducted.

Obviously, if you do decide to become an early adopter and take an NMN supplement, you should bear in mind that you are essentially self experimenting. You should cease using it immediately if you experience any adverse side effects and consult your doctor.

Disclaimer

This article is only a brief summary and is not intended as an exhaustive guide. The article is based on the interpretation of research data, which is speculative by nature. This article is not a substitute for consulting your physician about which supplements may or may not be right for you. We do not endorse supplement use nor any product or supplement vendor, and all discussion here is for scientific interest.

Literature

[1] Dollerup, O. L., Christensen, B., Svart, M., Schmidt, M. S., Sulek, K., Ringgaard, S., … & Jessen, N. (2018). A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. The American journal of clinical nutrition, 108(2), 343-353.

[2] Chambon, P., Weill, J. D., & Mandel, P. (1963). Nicotinamide mononucleotide activation of a new DNA-dependent polyadenylic acid synthesizing nuclear enzyme. Biochemical and biophysical research communications, 11(1), 39-43.

[3] North, B. J., Rosenberg, M. A., Jeganathan, K. B., Hafner, A. V., Michan, S., Dai, J., … & van Deursen, J. M. (2014). SIRT2 induces the checkpoint kinase BubR1 to increase lifespan. The EMBO journal, e201386907.

[4] Li, J., Bonkowski, M. S., Moniot, S., Zhang, D., Hubbard, B. P., Ling, A. J., … & Sinclair, D. A. (2017). A conserved NAD+ binding pocket that regulates protein-protein interactions during aging. Science, 355(6331), 1312-1317.

[5] Kiss, T., Nyúl-Tóth, Á., Balasubramanian, P., Tarantini, S., Ahire, C., Yabluchanskiy, A., … & Ungvari, Z. (2020). Nicotinamide mononucleotide (NMN) supplementation promotes neurovascular rejuvenation in aged mice: transcriptional footprint of SIRT1 activation, mitochondrial protection, anti-inflammatory, and anti-apoptotic effects. GeroScience, 1-20.

[6] Tarantini, S., Valcarcel-Ares, M. N., Toth, P., Yabluchanskiy, A., Kiss, T., Ballabh, P., … & Ungvari, Z. (2020). Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. The FASEB Journal, 34(S1), 1-1.

[7] Grozio, A., Mills, K. F., Yoshino, J., Bruzzone, S., Sociali, G., Tokizane, K., … & Imai, S. I. (2019). Slc12a8 is a nicotinamide mononucleotide transporter. Nature metabolism, 1(1), 47-57.

[8] Irie, J., Inagaki, E., Fujita, M., Nakaya, H., Mitsuishi, M., Yamaguchi, S., … & Okano, H. (2019). Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men. Endocrine journal, EJ19-0313.

[9] iao, B., et al. Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study. Journal of the International Society of Sports Nutrition (2021).

[10] Yoshino, M., Yoshino, J., Kayser, B. D., Patti, G. J., Franczyk, M. P., Mills, K. F., … & Klein, S. (2021). Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science, 372(6547), 1224-1229.

[11] Huang, D. A Multicentre, Randomized, Double Blind, Parallel Design, Placebo Controlled Study to Evaluate the Efficacy and Safety of Uthever (NMN Supplement), an Orally Administered Supplementation in Middle Aged and Older Adults. Frontiers in Aging, 26.