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