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 nucleic acid RNA. In form it consists of a nicotinamide group, a ribose and a phosphate group. It is a precursor molecule of the essential molecule nicotinamide adenine dinucleotide (NAD+) and is one way in which NAD+ levels in the cell can be increased.
Before we dive into NMN proper, we should understand a little about NAD+ metabolism.
What is NAD+?
NAD+ is a critical coenzyme found in all living cells and is essential to life. 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. NAD+ is one of the most versatile molecules in the body, and is an area of intense focus for aging research.
What does NAD+ do?
Found in the cells of all mammals, NAD+ is essential for life and is linked closely to metabolism and aging. It serves many critical functions in our cells, such as electron transport, cell signaling, and DNA repair. Accumulating evidence suggests that NAD+ systemically declines with age in a variety of organisms, including rodents and humans, and contributes to the development of age-related diseases.
For this reason, there is a great deal of interest in interventions that increase NAD+ to more youthful levels. Fasting and caloric restriction have been shown to increase NAD+ levels and boost the activity of the sirtuins, aka the longevity genes, as their activity relies on the presence of NAD+. In mice, fasting boosted NAD+ levels and sirtuin activity and appears to slow down aging.
While NAD+ and its precursors are also present in some kinds of foods, the concentrations are really too low to have a significant influence on the intracellular concentration of NAD+. There are a number of NAD+ precursor molecules sold as dietary supplements that appear to increase NAD+ levels, including nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and nicotinic acid (niacin).
The diagram below shows how these precursors, including NMN, 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.
The history of NMN research
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), a family of proteins involved in a number of cellular processes, such as DNA repair, genomic stability, and programmed cell death, which is known as apoptosis. 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 again led by Dr. David Sinclair used NMN to reverse DNA damage in mice by increasing NAD+ levels, thus increasing the activity of PARP so that it could repair DNA damage [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 in young vs 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.
What foods contain NMN?
It can be found naturally in a number of foods, such as avocado, broccoli, cabbage, cucumber, and edamame. While these kinds of foods are an excellent source of nutrition some people opt to use dietary supplements to increase their intake of NMN beyond what just eating these foods can achieve.
How is NMN created?
NMN is created using the B vitamins present in the body. 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 and somewhat address this shortfall.
It is also possible for NMN to be created from NR by the addition of a phosphate group. It was originally thought that NMN could not enter the cell without first becoming NR; however, this was shown to be incorrect in 2019, when a new transporter channel was discovered [5].
The study showed that the Slc12a8 gene encodes a specific NMN transporter that allows the molecule to enter cells without the need to be converted to NR first. No doubt this discovery came as an unpleasant surprise to manufacturers and distributors of NR.
Is NMN safe?
It is generally regarded as safe in animals, and the results were promising enough that a Japanese lab conducted a human clinical trial of NMN, which showed that it is well tolerated when given as a single dose [6]. The Sinclair Lab at Harvard Medical School also showed that long-term (one-year) oral administration of NMN to mice does not have toxic effects.
This has yet to be replicated in humans, though there are large numbers of people taking NMN as a dietary supplement today and few negative reports. Future studies should now focus on the long-term safety and efficacy.
Does NMN have side effects?
As of now, there have been no reported side effects reported in humans taking NMN supplements. The bulk of studies on NMN have been carried out on mice and rats and these typically show positive effects on metabolism, liver, skin, muscle, and brain function, as well as improved bone structure, vascular health, reproduction, immune system function, and lifespan. If these benefits will translate to people is now starting to be explored and there are a few clinical trials in progress or being prepared.
Obviously, if you do decide to become an early adopter and take an NMN supplement, you should bear in mind you are essentially self experimenting. You should cease using it immediately if you experience any adverse side effects and your doctor.
The future of NMN research and use
It is relatively early days for NMN, and there is currently a lack of human data, with the exception of the safety study in Japan. That has not stopped NMN from being marketed as a dietary supplement and a NAD+ booster. It has proven popular with those confident of its usefulness as an anti-aging compound despite the lack of human evidence. However, the high cost may be prohibitive to some people seeking the fountain of youth and more cost effective precursors such as NMNH could potentially replace it.
There are more human trials underway, and hopefully in the near future, we will see some data from them that will give us more insight on how useful NMN is in humans in the context of aging and healthy longevity.
Disclaimer
This article is only a very brief summary, is not intended as an exhaustive guide, and 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.
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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.
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