NMN Supplement: How Nicotinamide Mononucleotide Benefits You

NMN Supplement: How Nicotinamide Mononucleotide Benefits You
NMN (β-Nicotinamide mononucleotide) is a molecule that is naturally occurring in all life forms, including humans. NMN is naturally made from B vitamins in the body and, working together with Nicotinamide Riboside (NR), is a precursor to Nicotinamide adenine dinucleotide (NAD+).

NAD+ is a co-enzyme, which is involved in a great number of biochemical reactions, has been found to be a network node of a variety of biological processes. In human cells, NAD+ is synthetized, primarily through NMN, to replenish the consumption by NADase participating in physiologic processes, such as DNA repair, metabolism and cell death.

Studies have observed aberrant NAD+ metabolism in many diseases and researchers have found that supplementation of NMN has led to amelioration of the pathological conditions in some age-related diseases. The NAD+ production and consumption pathways, including NMN, are vital for the more precise understanding and therapy of age-related illnesses, such as diabetes, ischemia-reperfusion injury, heart failure, Alzheimer’s disease and retinal degeneration.

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What Is Nicotinamide adenine dinucleotide (NAD)

Nicotinamide adenine dinucleotide (NAD) is an essential metabolic redox co-enzyme, which is found in eukaryotic cells and is necessary for more than 500 enzymatic reactions. It plays a critical role in a great many biological processes, such as metabolism, aging, cell death, DNA repair and gene expression. That makes NAD+ critically important for human health and longevity.

The NAD+ co-enzyme was first discovered in early 20th century as a component, which enhanced the rate of alcohol fermentation in yeast extracts. Over the subsequent century, the co-enzyme’s chemical composition was established as an adenine, a reducing sugar group and a phosphate.

In the 1930s it was suggested that NAD+ could play a role in redox reactions and by 1960, it was assumed that all biochemical investigations on NAD+ had been discovered. Yet, in 1963 it was reported that NAD+ is a co-substrate for the addition of poly-ADP-ribose to proteins, which gave rise to a number of studies on poly-ADP ribose and poly-ADP-ribose polymerases.

Over the last decade, there was a renewed interest in NAD+, because of its association with sirtuins, which are a family of NAD-dependent protein deacylases. It was shown that mammalian sirtuins could metabolize NAD+ and that NAD+ had a protein ADP-ribosyltransferase activity.

In 2000 two researchers made the phenomenal discovery that yeast SIR2 (silent information regulator 2) and the mouse ortholog SIRT1 have NAD+-dependent protein deacetylase activity. Previously, several studies had demonstrated that sirtuins play a crucial role in regulating multiple cellular functions, including cell growth, energy metabolism, stress resistance, inflammation, and circadian rhythm neuronal function, among others.

The deficiency of NAD+ has been closely associated with diverse pathophysiologies, including type 2 diabetes (T2D), obesity, heart failure, Alzheimer’s disease (AD) and cerebral ischemia.

With age, the NAD+ levels decline in multiple organs, thus contributing to the development of various age-related diseases. This led researchers to conclude that NAD+ supplementation could be an effective therapy for the treatment of the conditions listed above.

What Is NMN

Nicotinamide mononucleotide (NMN) is one of the intermediates in the biosynthesis of NAD+. It is a bioactive nucleotide formed by the reaction between a phosphate group and a nucleoside containing ribose and nicotinamide (NAM).

NAM is directly converted to NMN by nicotinamide phosphoribosyltransferase (NAMPT). There are two anomeric forms of NMN called alpha and beta, with the latter being the active form.

NMN is found in many different types of natural foods, such as vegetables, fruits and meat. Edamame and broccoli contain 0.47 – 1.88 and 0.25 – 1.12 mg NMN / 100 g, respectively, whereas avocado and tomato contain 0.36 – 1.60 and 0.26 – 0.30 mg NMN / 100 g, respectively.

For perspective, note that raw beef contains only 0.06 – 0.42 mg NMN / 100 g. Recent preclinical studies have shown that the administration of NMN could compensate for the deficiency of NAD+ and was found to effect diverse pharmacological activities in various diseases.

NAD+ Levels Decline With Age

The decline in NAD+ biosynthetic pathways in the course of aging could be an explanation for the reduction of NAD+ levels. NAMPT is in control of NAD+ levels, thus influencing the activity of NAD-dependent enzymes, such as sirtuins and PARPs.

A study showed that the NAD+ levels and NAMPT protein levels declined substantially in multiple organs, including the pancreas, white adipose tissue (WAT) and the skeletal muscle of old mice.

Yet, another study found that exercise training increased NAMPT expression in the skeletal muscles. In yet another study NAD+ levels and exercise capacity were preserved in aged transgenic mice with muscle-specific NAMPT transgene expression.

All these results implied that the deficiency of NAMPT result in a reduction of NAD+ levels in the aged mice, and that exercise may raise NAMPT expression, thus restoring the NAD+ levels.

Inflammation and aging-related oxidative stress have been demonstrated to reduce the NAMPT-mediated NAD+ biosynthesis. Moreover, Nampt gene encoding is controlled by BMAL1 / CLOCK complex, a heterodimeric complex of core circadian transcription factors, which is suppressed by inflammatory cytokines.

Based on these findings, researchers have concluded that the development of chronic inflammation over the course of aging may contribute to the inhibition of NAMPT-mediated NAD+ biosynthesis and CLOCK / BMAL-mediated circadian machinery.

NAD+-Consuming Enzymes Are Activated With Age

The accumulation of DNA damage with age could activate Poly (ADP-ribose) polymerase PARP enzymes, among which PARP-1 is a major cellular NAD+-consuming enzyme.

Cockayne syndrome (CS) is an aging-related progressive neurodegeneration, which is a result of mutations in either Cockayne syndrome group A (CSA) or B (CSB) proteins.

In CS mice, researchers found that PARP inhibitor or NAD+ supplementation reversed decline in SIRT1 activation and mitochondrial function caused by aberrant PARP activation. Similarly, another inhibitor of PARP, PJ34, was found to boost the levels of NAD+, SIRT1 activity and oxidative metabolism.

In humans, researchers found that the level of NAD+ and mitochondrial function decreased partially through the regulation of SIRT3 as the expression and activity of the CD38 protein increased in various tissues during aging.

Administration of CD38 inhibitors were found to raise intracellular NAD+ levels and led to significantly higher NAD+ level in multiple organs.

So there are many ways of restoring NAD+ levels, which were depleted by aging or other diseases, such as improving NAMPT expression, providing NAD+ precursors or inhibiting NAD+, consuming enzymatic activities of PARP, CD38 and SARM1. At present, supplementation with NMN or NR is considered a highly efficient strategy of increasing NAD+ levels.

NMN and NR Seem to Increase NAD Levels More Effectively

Among the various NAD+ precursors, NMN and NR appear to increase NAD levels more effectively than nicotinamide (NAM) in rodents. As NAM acts as a feedback inhibitor to suppress sirtuins and PARPs, the benefits of increase in NAD+ levels may be compromised.

Moreover, because of the shorter resident time, high-dose administration, and some side effects of NAM, it was determined not to be the preferred choice, in comparison to NMN and NR.

It is not easy to compare NMN with NR, both of which are subjected to first-pass metabolism and the quick conversion to other NAD+ intermediates, prior to uptake in vivo. NR, unlike NMN, is unstable and quickly converted into NAM in murine plasma.

There are differences in the pharmacological effects of NMN and NR, which should be noted. It has been observed that NMN improves cardiac function in certain models, whereas NR does not.

Exploring the pharmacokinetics of NMN and NR in vivo could help determine the optimal concentrations of them in various regions and help us understand the mechanisms of their pharmacological actions.

The Takeaway

NAD+ metabolism has been demonstrated to be an essential part of the biochemical reaction, which acts as a link between various physiologic processes. As we age, weakened NAD+ biosynthesis and accelerated NAD+ consumption lead to dysfunction in multiple tissues.

Decreased NAD+ levels disturb many biochemical processes, such as abnormal deacetylation activity of sirtuins. Downstream alterations of abnormal sirtuin activity include transcription pattern, mitochondrial permeability, mtROS production and oxidative stress response.

As an intermediate in NAD+ biosynthesis, NMN has been shown to reinforce NAD+ metabolism and alleviate age-related pathologic processes. More exciting details of NAD+ metabolism pathway and applications of NMN are expected to emerge in the near future.

Image source: Wikimedia / Brettjweiss.