Nicotinamide adenine dinucleotide is essential for life
The coenzyme nicotinamide adenine dinucleotide (NAD+) serves critical functions in our cells, such as electron transport, cell signaling, and DNA repair. Found in the cells of all mammals, NAD+ is essential for life and is linked closely to metabolism and aging.
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).
More recently, reduced nicotinamide mononucleotide (NMNH) has emerged as a possible contender for the most efficient NAD+ boosting 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 NMN-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]. Treatment with NMN 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.
How the NAD+ precursor nicotinamide mononucleotide is 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.
Nicotinamide mononucleotide safety
NMN 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 of NMN.
The future of nicotinamide mononucleotide
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 becoming marketed as a dietary supplement, and it has proven popular with those confident of its usefulness. NMN are widely available for those willing to be early adopters with brands such as Elevant and Novos being some of the more visible producers of NMN supplements. However, the cost of NMN supplements may be prohibitive to some people and more cost effective precursors such as NMNH could potentially replace them.
There are more human trials underway with NMN, 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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