Reduced Nicotinamide Mononucleotide (NMNH): The New and Best NAD+ precursor for anti-aging and longevity?

Introduction: 

In recent years, researchers have shown an actively keen interest in studying Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR) as precursors for Nicotinamide Adenine Dinucleotide (NAD). NAD is a key coenzyme that is essential for life and found in all life forms, therefore, comprising a very important and interesting area of focus around aging research. While dietary supplement manufacturers have hoarded the market with various costly NMN products claiming to provide their benefits to the consumers, recent research has uncovered a new potential precursor in the form of reduced NMN (NMNH), which is up for further research and exploration.

Functional role of NMN:

Overall, NAD facilitates the repairing of the DNA and age-related genes, it supports glycolysis and Krebs cycle, participates in redox reactions, and electron transport chain within the mitochondria. NAD also supports a multitude of enzymatic reactions and key processes in cells during its downstream activities, altogether making it a very interesting area of research among scientists. 

Benefits of NMN:

NMN has been studied and explored in animal models as a potential:

· Anti-aging agent, and

· Neuroprotective agent

 NMN is commonly sold as a dietary supplement to restore NAD levels in the body. Dietary supplement manufacturing companies have aggressively marketed products with NMN claiming these very benefits as NAD supports DNA repair and activates sirtuins. 

 NMN did not depict any obvious toxicity or deleterious effects upon long-term usage as shown in its animal trials. Additionally, it also:

· Suppressed age-associated body weight gain,

· Promoted physical activity,

· Enhanced energy metabolism,

· Improved insulin sensitivity,

· Improved plasma lipid profile,

· Improved ameliorated eye function 

Chemical & Physical features of NMN:

NMN is organically known as ‘3-Carbamoyl-1-[5-O-(hydroxyphosphinato)-β-D-ribofuranosyl] pyridinium'. The chemical structure of NMN and NR are almost the same with the exception that NMN has an additional phosphate group (fig. 1), thus also making it a large molecule. Some scientists believe that due to its large size, NMN can’t cross a cellular membrane and needs to be converted to NR before entering cells, or otherwise, it will need a transporter, such as Slc12a8, specific to NMN.

(Fig. 1) NMN vs NR

Reduced NMN:

Introduction to reduced NMN: The latest research on animal models has shown that reduced Nicotinamide Mononucleotide (NMNH) is a new potent NAD+ precursor. It is believed that this new form of NMN can increase NAD levels to a much higher extent and that too faster than NMN or NR. 

NMNH is a fluorescent molecule, in contrast to NMN. The molecular formulae for NMNH isC₁₁H₁₇N₂O₈P and it is also known as '1-(5-O-phosphono-beta-D-ribofuranosyl)-1,4-dihydropyridine-3-carboxamide Reduced nicotinamide nucleotide’.

Molecular structure of NMNH

Metabolism of reduced NMN: NMNH metabolizes through a pathway that is independent of NRK and NAMPT. Both NRK and NAMPT help carry out the process of phosphoribosylation of intracellular nicotinamide into NMN or NR. So far, only one enzymatic activity is known to produce NMNH. It is the reduced nicotinamide adenine dinucleotide (NADH) diphosphatase activity of the human peroxisomal Nudix hydrolase hNUDT1232 and the murine mitochondrial Nudt13.

Production of NMNH at scale for testing: Researchers were able to design and develop a new method for purifying NMNH at scale to explore further the role of this molecule in NAD metabolism. They found that NMNH is effectively metabolized to NAD in mammalian cells and also confirmed that its synthesis route is independent of NRK and NAMPT.

Discovery of additional benefits: Interestingly, scientific researchers also found that in vivo effects of NMNH administration in mice effectively raised the NAD levels in the blood and various tissues, including in the kidney, and to a greater extent than NMN does when used at the same concentration. Scientists also concluded the therapeutic potential of NMNH in protecting renal proximal tubular epithelial cells from hypoxia/reoxygenation‐induced injury by accelerating processes involved in tubular regeneration. This is considered a crucial event in ischemic acute kidney injury (AKI). 

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NMN VS reduced NMN:

· Potency: To understand the potency of NMNH, scientists supplemented AML12 mouse hepatocytes with different concentrations of either NMN or NMNH. At each concentration tested, NMNH provided a much more significant increase in cellular NAD levels than NMN.

Scientists concluded that NMNH was able to significantly increase NAD even at a concentration that was 10 times lower (5 µM) than that required for NMN. The increase in NAD levels reached a plateau at NMNH supplementation concentrations of 500 µM. At the concentration of 500 µM, NMNH achieved almost 10 times increase in the NAD concentration, while NMN was only able to only double NAD concentration in the cells even at a higher concentration of 1 mM.

Not only this, but NMNH also proved itself as a faster precursor by resulting in a significant increase in NAD levels in just 15 minutes.

· Stability: The trial results show that upon NMNH supplementation, NAD increased steadily for up to 6 hours and then remained stable for 24 hours. However, NMN reached its plateau in just 1 hour. Although, this could have most likely been because of the saturation of the NMN recycling pathways to NAD. ⁽¹⁾

· Pricing(cost): Considering that scientists anticipate needing a significantly lower dose of NMNH as compared to NMN and still produce better results than those achieved by very high doses of NMN, the price point for the end consumer might stay at a lower side especially when compared to what consumers are paying for NMN in the present market scenario. However, as the concept of NMNH is still new and researchers are working on methods to produce it at scale, the cost may vary based on how costly or economical the manufacturing methods and requirements are! 

Reduced NMN supplement availability:

As the concept of reduced NMN as a precursor for NAD has been quite recent and still under study, the availability of reduced NMN supplements may take some time. The latest study suggests that the reduced form of NMN i.e., NMNH may prove itself to be a strong contender to be used as a standard of choice for boosting NAD levels. However, it will need to be tested further in human trials to establish its efficacy and safety for human usage. 

Reduced NMN suppliers recommended:

It is difficult to recommend any suppliers for NMNH at present for the reason that scientists are still working to further research and establish its use in humans with significant efficacy and safety. Furthermore, they are also working on how to produce NMNH at scale, which means it is not expected to enter the commercial market anytime soon. Please search NMN suppliers here at www.pharmasources.com to enquire more details.

Sources:

1. https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.202001826R 

2. https://www.lifespan.io/news/reduced-nicotinamide-mononucleotide-is-a-new-nad-precursor/

3. https://www.youtube.com/watch?v=VX2W2I0adNc

4. https://www.cell.com/cell-metabolism/fulltext/S1550-4131(16)30495-8

5. https://blogs.scientificamerican.com/guest-blog/beyond-resveratrol-the-anti-aging-nad-fad/

6. https://www.nmn.com/precursors/nmn-vs-nr

7. https://pubchem.ncbi.nlm.nih.gov/compound/Nmnh