What is Nicotinamide Mononucleotide (NMN)

What is NMN?

NMN stands for nicotinamide mononucleotide, a molecule naturally occurring in all life forms. At the molecular level, NMN is a ribo-nucleotide. Nucleotides are the basic structural units of nucleic acids like RNA and DNA. Structurally, NMN is composed of a nicotinamide group, a ribose sugar and a phosphate group (Figure 1). NMN is the direct precursor of nicotinamide adenine dinucleotide (NAD+) and is thought to increase NAD+ levels in cells.

Chemical Structure of NMN

Nicotinamide mononucleotide (NMN) molecule
Figure 1

What is Nicotinamide adenine dinucleotide (NAD+)?

NAD+ is an essential coenzyme required for life and cellular functions. A coenzyme is a ‘helper’ molecule, boosting activation of enzymes.

What does NAD+ do? What is NAD+ used for?

NAD+ has an effect on molecular machineries regulating DNA repair and metabolism. Without NAD+, an organism would die. As David Sinclair says, “...the loss of NAD+ as we age, and the resulting decline in sirtuin activity, is thought to be a primary reason our bodies develop diseases when we are old but not when we are young.”

How is Nicotinamide adenine dinucleotide (NAD+) made in the body?

NAD+ is produced from its precursors. NMN is an immediate precursor to NAD+. Conversion of NMN to NAD+ occurs when NMN meets the enzyme “NMN adenylyl-transferase.” The enzyme attaches another nucleotide to the phosphate of NMN phosphate, making it NAD+.

How does NAD function as a coenzyme?

NAD+ is used as a coenzyme for sirtuins and poly (ADP-ribose) polymerase (PARP). NAD+ plays an especially active role in metabolic processes, such as glycolysis, the TCA Cycle (AKA Krebs Cycle or Citric Acid cycle), and electron transport chain.

NAD+ acts as a ligand binding to enzymes and as an electron carrier accepting and donating electrons. This function makes it an effector: it binds to and affects the biological activity of proteins. In this way, NAD+ can decrease or increase enzyme activity, gene expression, and cell signaling.

How does NAD+ help control DNA Damage?

As organisms get older, they accrue DNA damage due to environmental factors such as radiation, pollution, and imprecise DNA replication. According to the current aging theory, the accumulation of DNA damage is the main cause of aging. Almost all cells contain the ‘molecular machinery’ to repair this damage. This machinery consumes NAD+ and energy molecules. Therefore, excessive DNA damage can drain valuable cellular resources.

One important DNA repair protein, PARP (Poly (ADP-ribose) polymerase), depends on NAD+ to function. Older individuals experience decreased levels of NAD+.7 The accumulation of DNA damage as a result of the normal aging process leads to increased PARP, which causes decreased NAD+ concentration. This depletion is exacerbated by any further DNA damage in the mitochondria.

PARP1 is ‘Middleman’ of DNA Repair

PARP1 attracts DNA machinery to repair DNA

Schematic of How PARP1 Helps Repair Damaged DNA

NMN is used to make NAD+, PAP1 uses NAD+

How does NAD+ affect sirtuins (the longevity genes) activity?

NAD+ is required for the activation of sirtuins. Sirtuins are a family of enzymes, using NAD+ to remove chemical groups (acetyl groups). Sirtuins participate in cellular stress response and damage repair as well as insulin secretion.Sirtuins are implicated in aging processes and aging-related health conditions, such as neurodegenerative diseases and diabetes. The function of sirtuins is dependent upon NAD+ levels.

A number of sirtuins play a role in health problems associated with type 2 diabetes. Namely, sirtuins are thought to regulate insulin sensitivity and insulin secretion.11 This is why NAD+ plays a role in how quickly the body absorbs sugar from the blood (glucose tolerance) and insulin regulation. NMN has promising therapeutic effects on glucose tolerance and insulin secretion in diabetic mice.

NAD+ works with Sirtuins to Slow Aging

NMN is used to make NAD+, sirtuins use NAD+

According to some research, studying these sirtuins provide a promising path toward understanding brain diseases (pathologies) such as Alzheimer’s disease.4 Other research suggests increased activation of the sirtuins offers neuroprotection in mouse models of multiple sclerosis.6

How does NAD+ affect metabolism? How does NAD+ affect Cellular Respiration?

Without NAD+, human metabolism slows and toxic byproducts accumulate. Metabolism can be broken down into three primary steps: glycolysis, citric acid cycle (aka TCA cycle or Krebs cycle) and electron transport chain. All of these processes use NAD+ but in different ways and in different parts of the cell. Mitochondrial dysfunction can be mitigated by therapeutically treating for low concentrations of NAD+ in the cells.2

How is NMN Synthesized In the Body?

NMN is made from B vitamins in the body. The enzyme responsible for making NMN in the body is called nicotinamide phosphoribosyltransferase (NAMPT). NAMPT attaches nicotinamide (a vitamin B3) to a sugar phosphate called PRPP (5’-phosphoribosyl-1-pyrophosphate). NMN can also be made from ‘nicotinamide riboside’ (NR) through the addition of a phosphate group.

‘NAMPT’ is the rate-limiting enzyme in the production of NAD+. This means lower levels of NAMPT cause decreased NMN production, resulting in decreased NAD+ levels. Adding precursor molecules like NMN can also speed up NAD+ production.

Methods to increase NAD+ levels

Fasting or reducing calorie intake has been shown to increase NAD+ levels and sirtuins activity. Caloric restrictions allow mice to live longer lives by increasing NAD+, slowing the aging process by boosting sirtuin activity. Although NAD+ is present in some foods, the concentrations are too low to affect intracellular concentrations. Taking certain supplements, such as NMN, has been shown to increase NAD+ levels.

NMN as a NAD+ supplement

Intracellular concentrations of NAD+ decrease from aging as normal cellular functions deplete NAD+ supplies over time. Healthy levels of NAD+ are thought to be restored by supplementation with NAD+ precursors. According to research, precursors such as NMN and nicotinamide riboside (NR) are viewed as supplements of NAD+ production, increasing concentrations of NAD+.8

David Sinclair, a NAD+ researcher from Harvard, says, “Feeding or administering NAD+ directly to organisms is not a practical option. The NAD+ molecule cannot readily cross cell membranes to enter cells, and therefore would be unavailable to positively affect metabolism. Instead, precursor molecules to NAD+ must be used to increase bioavailable levels of NAD+.” This means NAD+ cannot be used as a direct supplement, because it is not easily absorbed. NAD+ precursors are more easily absorbed than NAD+ and are more effective supplements.

How are NMN supplements absorbed and distributed throughout the body?

NMN specific transporters, found in the gut of mice, potentially allow easy absorption into the bloodstream. Taking NMN as a supplements works better than direct supplementation with NAD+, because NMN is a smaller molecule. NAD+ cannot easily enter the body because of the organization of cell membranes creates a barrier. The membrane has a waterless space which prevents ions, polar molecules, and large molecules from entering without the use of transporters. It was once thought that NMN must be altered before entering cells. Now, evidence shows NMN can enter cells directly through an NMN specific transporter in the cellular membrane.

NMN specific transporters have been discovered in a study showed that NMN is quickly utilized to synthesize NAD+.10 Furthermore, injections of NMN result in increased NAD+ in many regions in the body including the pancreas, fat tissue, the heart, skeletal muscle, kidneys, testes, eyes, and blood vessels. Oral administration of NMN in mice increases NAD+ in the liver within 15 minutes.9

NMN is Quickly Converted to NAD+

NMN is converted to NAD+ that was tested in the liver

NMN Safety and Side Effects

NMN is considered safe in animals, and the results are promising enough that human trials have started. NMN is largely considered to be safe and not toxic, even at high concentrations in mice and a human study. Long-term (one-year) oral administration of NMN in mice does not have toxic effects.10 The very first clinical trial in humans was completed and the evidence supports the idea that NMN is not toxic at single dosages.

In a study of Japanese men published in November 2019, subjects had increased levels of bilirubin in their blood following NMN administration12. Even so, levels of bilirubin were still within normal range. Future studies should focus on long-term safety and efficacy of taking NMN. There are currently no other known side effects from taking NMN.

Conclusion

NAD+ is a coenzyme involved in cellular metabolism. Levels of NAD+ in cells (intracellular levels) decrease as people age. Decreased levels of NAD+ are correlated with aging and may impede insulin sensitivity, neuroprotection, genome protection, efficient energy metabolism, and stress resistance. Preliminary research suggests that some conditions associated with decreased NAD+ might benefit from administering precursor molecules such as NMN.

JOURNAL REFERENCES
  1. Vincenzo Carafa, Dante Rotili, Mariantonietta Forgione, Francesca Cuomo, Enrica Serretiello, Gebremedhin Solomon Hailu, Elina Jarho, Maija Lahtela-Kakkonen, Antonello Mai, Lucia Altucci. Sirtuin functions and modulation: from chemistry to the clinicClin epigenetics, 2016; DOI: 10.1186/s13148-016-0224-3.
  2. Niels J. Connell, Riekelt H. Houtkooper, Patrick Schrauwen. NAD+ metabolism as a target for metabolic health: have we found the silver bullet? Diabetologia, 2019; DOI: 10.1007/s00125-019-4831-3.
  3. Julia Evangelou.  “Natural compound reduces signs of aging in healthy mice.” ScienceDaily.com.  27 October, 2016.  Web. 16 January. 2020.
  4. Henryk Jęśko, Przemysław Wencel, Robert P. Strosznajder, Joanna B. Strosznajder. Sirtuins and Their Roles in Brain Aging and Neurodegenerative Disorders. Neurochem Res, 2017; DOI: 10.1007/s11064-016-2110-y.
  5. Ann Katrin-Hopp, Patrick Grüter, Michael O. Hottiger. Regulation of Glucose Metabolism by NAD+ and ADP-RibosylationCells, 2019; DOI: 10.3390/cells8080890.
  6. Vamshi K.C. Nimmagadda, Tapas K. Makar, Krish Chandrasekaran, Avinash Rao Sagi, Jayanta Ray, James W. Russell, Christopher T Bever Jr. SIRT1 and NAD+ precursors: Therapeutic targets in multiple sclerosis a reviewJ Neuroimmunol, 2017; DOI: 10.1016/j.jneuroim.2016.07.007.
  7. Katalin Sas, Elza Szabó, László Vécsei. Mitochondria, Oxidative Stress and the Kynurenine System, with a Focus on Ageing and Neuroprotection. Molecules, 2018; DOI: 10.3390/molecules23010191.
  8. Yue Yang, Anthony A. Sauve. NAD+ metabolism: Bioenergetics, signaling and manipulation for therapyBiochim Biophys Acta, 2016; DOI: 10.1016/j.bbapap.2016.06.014.
  9. Jun Yoshino, Kathryn F. Mills, Myeong Jin Yoon, Shin-ichiro Imai. Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet- and Age-Induced Diabetes in MiceCell Metab, 2011; DOI: 10.1016/j.cmet.2011.08.014.
  10. Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, Imai SI. Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice. Cell Metab, 2016; DOI: 10.1016/j.cmet.2016.09.013.
  11. Shuang Zhou, Xiaoqiang Tang, Hou-Zao Chen. Sirtuins and Insulin ResistanceFront Endocrinol (Lausanne), 2018; DOI: 10.3389/fendo.2018.00748.
  12. Irie J, Inagaki E, Fujita M, et al. Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men, 2019 Nov 2]. Endocr J. 2019;10.1507/endocrj.EJ19-0313. doi:10.1507/endocrj.EJ19-0313

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