How Does NMN Work? The Science Behind NAD+ and NMN
If you’re well-versed in the wellness world and interested in anti-aging, you have no doubt heard of NMN. But many people aren’t sure exactly how it works on a cellular level, how it transforms into NAD+, or what it’s actually doing in the body. For all of our biochemistry-loving and biohacking nerds out there, this one is for you. We’ll dive into the details about what exactly NMN is, how it works for health and longevity, and the cellular pathways NMN undergoes to become NAD+.
NAD+ and NMN 101
The underlying reason why NMN is so supportive of healthy aging is due to its role as a precursor to another compound called NAD+, or nicotinamide adenine dinucleotide. NAD+ is a vital molecule that every cell in our body needs—without NAD+, we’d die instantly.
The primary role of NAD+ is as a coenzyme that helps other enzymes to function correctly. These enzymes aid hundreds of processes inside our bodies, ranging from brain cell growth to repairing DNA to assisting mitochondria to generate energy from food. Essentially, NAD+ plays a critical role in maintaining cellular and metabolic functions, which translates to better health and longevity of our cells, organs, and bodies as a whole.
With NAD+ depletion, every organ system starts to run at suboptimal levels, leading to metabolic disorders, increases in blood pressure, heart function decline, cognitive impairment, liver and kidney conditions, muscle loss, and even external symptoms, like wrinkles or hair loss.
And NAD+ is not only required for maintaining life but also for having a long life. However, as it turns out, most people experience a drop in NAD+ activity as they age. Some research has found that levels of this crucial coenzyme can drop by as much as 50% between the ages of 40 and 60, with an additional decline upon reaching older age.
How Does NMN Work? The Cellular Science
If NAD+ is so crucial to our health, you may wonder why we can’t just supplement with NAD+ itself. Put simply, orally taken NAD+ cannot easily cross over membrane barriers to enter cells—it would first have to be converted into NMN before it could be taken up by the cell. So, as a direct precursor to NAD+, NMN supplements can essentially skip a step and boost NAD+ inside cells.
NMN (and other NAD+ precursors) participates in the NAD+ biosynthesis pathway. Also known as the “NAD salvage pathway,” this internal recycling program produces NAD+ from unused compounds related to niacin (vitamin B3), which can include niacinamide, nicotinamide (NAM), NMN, NR, and nicotinic acid.
Nicotinamide is converted into NMN by an enzyme called NAMPT (nicotinamide phosphoribosyltransferase), followed by a transformation of NMN into NAD+. (Or you can simply take NMN itself.) This pathway is referred to as a recycling program because unused portions of NAD+ can be recycled after they’re consumed. After the body uses a molecule of NAD+, the leftover component is NAM—a metabolic byproduct from enzymes that use NAD+—which can turn into more NMN.
The NAD salvage pathway is dependent on the activity of NAMPT. Thus, NAMPT is thought to be the enzyme responsible for controlling NAD+ levels in the body.
NMN can also be generated by the consumption of NR (nicotinamide riboside), as enzymes called NR kinases (NRKs) modify NR to become NMN. This is why, when supplementing with NR, you’ll need an extra step of first converting NR into NMN before it can become NAD+.
There are other pathways by which NAD+ can be made, including the kynurenine (de novo) pathway and the Preiss-Handler pathway, which involve tryptophan or nicotinic acid as starting compounds, respectively.
The NMN Transporter
Another piece of the NAD puzzle was uncovered in 2019 when researchers identified an “elusive transporter” that shuttles NMN into cells to be converted into NAD. This NMN-specific transporter—a protein encoded by the gene Slc12a8—uses a sodium ion to transport NMN across cell membranes in the intestine to be converted directly into NAD+ rather than using NR as an intermediary first.
The research team discovered that Slc12a8 is a specific transporter for NMN, meaning that other compounds aren’t able to enter cells directly through that pathway. Our cells attempt to maintain a consistent fuel supply by increasing the amounts of the NMN transporter in times of low NAD+, which would then enable NMN to be quickly converted into NAD+. However, as much as our cells try to combat the decline in NAD+ with this mechanism, there is still a bottleneck of NAD+ production that occurs with increased age, which is why NMN is so crucial.
This also suggests an evolutionary advantage to having a specific NMN transporter. Specialized biological structures like this are energetically expensive. Since NMN can be found in minute quantities in some foods, this suggests an evolutionary advantage for our ancestors who were able to utilize more of the NMN they were taking in through dietary sources. We can take greater advantage of this adaptation today by increasing our deliberate intake of NMN.
How Does NMN Work for Healthy Aging?
You may wonder: why do NAD+ levels drop, anyway? While there are many potential reasons, many scientists think that the abundance of enzymes and proteins that depend on NAD+ can deplete its levels as we age. For example, a family of enzymes called PARP is known to repair DNA. While this is a beneficial function, the accumulation of DNA damage with age leads to excessive activation of the NAD-dependent PARP enzymes, thereby depleting NAD+ stores.
Other NAD-dependent enzymes include the sirtuin family—a group of proteins commonly called “longevity genes.” Sirtuins also use NAD+ to repair damaged DNA, regulate metabolic function, and support chromosome integrity. But, similarly to PARPs, sirtuins have to work harder to mitigate the accumulation of cellular damage as we age, leading to increased consumption of NAD+. Unfortunately, as NAD+ levels drop with age, the functioning of sirtuins declines right alongside it—but boosting NAD+ via supplements can put a stop to this vicious cycle.
Sirtuins are highly involved in many vital processes regulating aging, from repairing DNA to supporting antioxidant pathways to boosting mitochondrial activity. However, when sirtuin activity drops, these processes can become dysfunctional and lead to aging or disease. Therefore, supporting your body’s NAD+ levels as you age with NAD+ precursors like NMN is essential for healthy sirtuin function, which, in turn, keeps your anti-aging activity flowing smoothly.
Another way that NMN may help to fight aging is by delaying cellular senescence. Simply put, senescence is when cells stop dividing and lose their function but remain in the body. This irreversible growth arrest causes these zombie-like cells to leave a trail of inflammatory debris in their wake, accelerating aging and causing additional inflammation. One way to slow this process may be by boosting NAD+, as seen in a 2016 study that found that restoring mitochondrial NAD+ levels in human stem cells delayed senescence and extended the lifespan of the cells.
What Does NMN Do for Health?
In yeast and mouse research, replenishing NAD+ levels has been found to not only reverse age-related organ and tissue damage but also increase lifespan. Two landmark studies found that the NAD+ precursors NMN (nicotinamide mononucleotide) and NR (nicotinamide riboside) extended the lifespan of mice and roundworms by 4.5% and 10%, respectively.
In humans, NMN supplementation has been found to support aspects of cardiovascular, cellular, physical, and metabolic health. For example, clinical studies have reported that NMN improves blood sugar sensing in postmenopausal women, supports muscle function in older men, and increases aerobic capacity in athletes.
Other research from the past couple of years has shown that NMN supports healthy cholesterol (HDL) levels, metabolic function, subjective markers of skin quality, and daytime energy. One small study even found that supplemental NMN lengthened telomeres—the protective endcaps on our chromosomes that are a proxy of biological age.
Key Takeaways
NMN is a powerful compound, acting as a direct precursor to NAD+—the essential coenzyme needed by all of our cells for healthy aging. From fighting DNA damage and oxidative stress to preventing telomere loss and supporting sirtuin activity, NMN is a smart choice for anyone looking to live a long and healthy life.
References:
Igarashi M, Nakagawa-Nagahama Y, Miura M, et al. Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men. NPJ Aging. 2022;8(1):5. Published 2022 May 1. doi:10.1038/s41514-022-00084-z
Kim M, Seol J, Sato T, Fukamizu Y, Sakurai T, Okura T. Effect of 12-Week Intake of Nicotinamide Mononucleotide on Sleep Quality, Fatigue, and Physical Performance in Older Japanese Adults: A Randomized, Double-Blind Placebo-Controlled Study. Nutrients. 2022;14(4):755. Published 2022 Feb 11. doi:10.3390/nu14040755
Liao B, Zhao Y, Wang D, Zhang X, Hao X, Hu M. Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study. J Int Soc Sports Nutr. 2021;18(1):54. Published 2021 Jul 8. doi:10.1186/s12970-021-00442-4
Niu KM, Bao T, Gao L, et al. The Impacts of Short-Term NMN Supplementation on Serum Metabolism, Fecal Microbiota, and Telomere Length in Pre-Aging Phase. Front Nutr. 2021;8:756243. Published 2021 Nov 29. doi:10.3389/fnut.2021.756243
Orlandi I, Alberghina L, Vai M. Nicotinamide, Nicotinamide Riboside and Nicotinic Acid-Emerging Roles in Replicative and Chronological Aging in Yeast. Biomolecules. 2020;10(4):604. Published 2020 Apr 15. doi:10.3390/biom10040604
Son MJ, Kwon Y, Son T, Cho YS. Restoration of Mitochondrial NAD+ Levels Delays Stem Cell Senescence and Facilitates Reprogramming of Aged Somatic Cells. Stem Cells. 2016;34(12):2840-2851. doi:10.1002/stem.2460
Yi L, Maier AB, Tao R, et al. The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial. Geroscience. 2023;45(1):29-43. doi:10.1007/s11357-022-00705-1
Yoshino M, Yoshino J, Kayser BD, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021;eabe9985. doi:10.1126/science.abe9985
