What is NMN?

NMN or nicotinamide mononucleotide is a safe and efficient precursor to NAD+, the essential coenzyme and key metabolite found in every cell of the human body, and involved in over 500 different cellular reactions. Read on to explore what NMN is, how our bodies turn NMN into NAD+, and the benefits of NMN supplementation.

 

What is NMN?

In the past two decades, scientists, doctors, and early adopters of health trends and technology have increasingly focused their research and attention on one molecule: nicotinamide adenine dinucleotide (NAD+). Specifically: the potential health benefits of getting more of it to replace what we lose with time—about half our NAD+ by middle age. How do they do it? While there are three approaches that have been explored in the lab, only supplementation with NAD+ precursors is safe and effective in humans at this point in time. Those precursors are nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), ingredients in our NR and NMN supplements, Basis and Signal.   

The molecule NMN is a nucleotide made up of a nitrogenous base (nicotinamide), a sugar (ribose), and a phosphate group (see figure below). You may recognize nucleotides as subunits or fundamental building blocks of nucleic acids—DNA and RNA—but they also serve as cofactors in cellular signaling and metabolism. ATP, the energy currency of the cell, is also a nucleotide. It’s the difference in the nitrogenous base that determines the function of the nucleotide. 

The main role of NMN is as an intermediate or step in the creation of NAD+. It’s found in the cell primarily in the nucleus, mitochondria, and cytoplasm. Scientists think it’s possible that we get a sufficient amount of NMN in our diet to support the NAD+ biosynthesis required for normal functioning, but not to replace the NAD+ lost with age. You’ll find a small amount of NMN in edamame, broccoli, cucumber, cabbage, avocado, and some fruit. Our cells also synthesize NMN in two ways: from nicotinamide (NAM, the water-soluble form of vitamin B3), or from NR. Both of these are also found in foods and as supplements. From there, the NMN is converted into NAD+ (see figure below).

Figure adapted from Yoshino et al

 

What is NAD+?

It’s worth repeating that the reason there’s so much scientific interest in nicotinamide mononucleotide is because it enhances the biosynthesis of NAD+, which has been linked to various health benefits in the ever-expanding field of NAD+ research. NAD+ is a coenzyme present in every living cell, from bacteria to birds to humans, and it plays an essential role in cellular energy metabolism and mitochondrial function. Without it: no cellular energy, no life. Beyond energy production, NAD+ is vital for maintaining healthy DNA, activating sirtuins, and fueling hundreds of integral processes at the cellular level.

NAD+ is essential to our health and survival, and research shows that by middle age we have about half the amount we had in our youth—a finding that’s been confirmed in various tissues, including the blood, skin, and brain. One prominent NAD+ researcher has put it this way: "It’s one of the most important molecules for life to exist, and without it, you’re dead in 30 seconds.” 

A recent study published in Nature Aging illustrates the role of NAD+ in aging. Researchers profiled metabolites in the muscle tissue from younger and older adults, finding that NAD+ was one of the most depleted metabolites in older adults. In physically impaired older adults, NAD+ levels were especially depleted, while adults who exercised rigorously had NAD+ levels similar to those of young adults. These results confirm previous findings—that there is a correlation between NAD+ levels and age—and demonstrate that NAD+ abundance is directly associated with a healthy aging status

 

How do we make NAD+?

As we mentioned previously, nicotinamide mononucleotide is a precursor to NAD+. To better understand how NMN becomes NAD+, it’s important to understand all of the ways we’re able to generate NAD+. For that, we look to the NAD+ biosynthetic pathways represented in the figure below.

Figure schematic created with Biorender.com

 

What this shows is that there are three independent pathways to generate NAD+: 

  • The kynurenine pathway (or de novo synthesis pathway), which creates NAD+ from the dietary amino acid tryptophan.
  • The Preiss–Handler pathway, which uses dietary nicotinic acid (NA), also known as niacin.
  • The NAD+ salvage pathway, which repurposes the nicotinamide (NAM)—the nitrogenous base of NMN we mentioned earlier—created as a byproduct of the enzymatic activities of NAD+-consuming enzymes. In other words, when a molecule of NAD+ is used by a sirtuin, for example, part of the NAD+ connects with the sirtuin and the NAM splits off and enters the salvage pathway where it’s recycled. 

What about NMN (and NR, for that matter)? If you look closely at the salvage pathway you’ll see that NMN is an essential stop along the path to creating NAD+. NR is converted to NMN in the cell before becoming NAD+. There’s a lot of complexity here, but the key takeaway is that both NMN and NR are elements of the NAD+ biosynthesis pathways, and NR always becomes NMN before it is transformed into NAD+. 

 

How to get more NMN, NR, and NAD+?

First, you might be wondering why you can’t just take NAD+. That’s a good question. The reason is that the NAD+ molecule can’t cross cell membranes and get into cells. If we want more NAD+, we have to consume something that transforms into NAD+.

As the previous figure suggests, it’s possible to get the NAD+ precursors tryptophan and niacin through diet, although there’s no evidence to suggest that one can maintain, much less increase, levels of NAD+ with food alone. Are there other ways? Exercise helps. A recent study has shown that levels of NAD+ in muscle seem to remain consistent in later life when older adults maintain a fairly rigorous exercise regimen of multiple hour-long exercise sessions per week. This doesn’t tell us what’s happening in other organs and tissues beyond muscle, however.

This brings us to supplementation. In the case of NMN (in Signal) and NR (in Basis), they both bypass what’s called the “rate-limiting step” in the biosynthetic pathway. This is important because it tells us that NMN and NR are both efficient ways to get more NAD+. And in fact, both have been shown to increase levels of NAD+ in humans. We’ll focus on NMN here. We’ve explained elsewhere how NR becomes NAD+. In short, though, NR is a very efficient precursor to NAD+ because it’s taken up by cells and converted directly via NRK1 and NRK2 pathways to NMN and then to NAD+. Our own clinical trial showed that Basis increases NAD+ in whole blood by up to 40%, safely and sustainably.

NMN is also a very efficient precursor to NAD+. A study published in Frontiers in Nutrition found that giving healthy adults 250mg of NMN per day increased their levels of NAD+ by approximately 40%, in a safe and sustained manner over the course of a 12-week trial. This study also showed that when participants discontinued NMN supplementation, NAD+ levels returned to pre-supplementation levels. NMN may also be favored by different parts of the body. In a study in mice, Grozio et al. showed that NMN has its own dedicated transporter called Slc12a8 that allows it to get directly into the cell. What’s more, an animal study shows that Slc12a8 is highly expressed in certain tissues including the small intestine. This suggests that NMN and NR may each offer unique and synergistic benefits for someone looking to increase their NAD+ levels. You can read more about the differences between NR and NMN here.

 

What are the benefits of NMN?

A variety of studies in humans and in animals suggest that there are many possible health benefits of nicotinamide mononucleotide. One important way that increasing NAD+ with NMN is helpful is that it promotes healthy metabolic aging at the cellular level by supporting mitochondrial health. As we age, our metabolism becomes dysregulated and less efficient. NMN can help get your metabolism back on track.

Here are the other ways that increasing NAD+ with NMN may be beneficial, according to the research:

  • A clinical trial published in the Journal of the International Society of Sports Nutrition by Liao et al. examined the effects of NMN supplementation on middle-aged runners’ oxygen utilization capabilities. The results corroborate preclinical studies: Oral supplementation of NMN supports the body’s ability to absorb and use oxygen, which is important for athletic endurance. 
  • Yoshino et al. demonstrated in a clinical study published in the journal Science that oral supplementation with NMN provided metabolic benefits to aged women with prediabetes by supporting healthy muscle insulin sensitivity.
  • Many animal studies have looked at the role of NMN in improving health and disease. While further research is required to determine if these benefits can be extended to humans, these preclinical studies show that NMN supplementation can, among other things, improve blood flow and increase athletic endurance in elderly mice, and support brown fat thermogenesis. Other animal studies show that NMN can enhance mitochondrial function; improve cognition; improve biomarkers in age-induced type-2 diabetic mice; protect kidney function; restore gene expression linked to circadian rhythm, inflammatory response and oxidative stress; and improve hepatic insulin sensitivity.

    Are there side effects of NMN supplementation? 

    No adverse events were reported in the clinical trials mentioned above and no study of increasing NAD+ levels in humans has reported serious side effects of any kind. That said, like any intervention, it will be necessary to track the long-term effects of upregulating NAD+ to better understand the benefits and continue to ensure that there are no side effects.

     

    Is NMN an anti-aging molecule?

    While many stories in the media characterize nicotinamide mononucleotide as an anti-aging molecule, no human studies support this idea. Right now we know that NMN is safe and boosts NAD+ levels. Animal and human studies demonstrate that NMN supplementation offers benefits related to oxygen utilization, athletic endurance, and muscle insulin sensitivity. The science of NMN supplementation is evolving fast, however, as researchers seek to understand other ways that restoring levels of the essential molecule NAD+ can support healthy aging. Meanwhile, several other clinical trials are underway, studying fatigue associated with COVID-19, cardiometabolic function, organ system biology, and more.

     

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