NMN - A Promise to Vitality?

NMN - A Promise to Vitality?

Dr. Niveditha Navin

Whenever we see the youth brimming with energy, the first thought that comes to our mind is, “where does all this energy come from?” The answer is simple - The young mitochondria. Mitochondria as we all know are the cells’ energy dynamo. It is a prominent theory that aging is a key driver in the deterioration of mitochondria and is attributed to the diminishing levels of NAD+ (nicotinamide adenine dinucleotide). However, research suggests that it is possible to reverse this decay with dietary supplements that increase cellular life of a molecule called NAD+. NAD+, the linchpin for energy metabolism, is being studied by many scientists and has been found to be a promising ingredient for the ‘elixir of youth’.

THE ROLE OF NAD+

NAD+ plays a crucial role in various biological processes, including metabolism, aging, cell death, DNA repair, and gene expression (Rajman et al., 2018; Okabe et al., 2019). Thus, NAD+ is critical for human health and longevity. In mammalian cells, NAD+ is synthesized, predominantly through NMN to replenish the consumption by NADase participating in physiologic processes including DNA repair, metabolism and cell death.

NMN (Nicotinamide Mononucleotide) is a key intermediate byproduct of NAD+ in mammals that effectively enhance NAD+ synthesis. It is synthesized from nicotinamide, a water-soluble Vitamin B3 and 5′-phosphoribosyl-pyrophosphate (PRPP) by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme responsible for making NMN. Conversion of NMN into NAD+ is catalyzed by NMNATs.

The  question that follows biosynthesis is its mechanism of absorption and the bioavailability after oral administration. Bioavailability is the fraction of an administered dose that reaches the systemic circulation. In Rabinowitz study, 2018 it was found that NMN is mostly digested in the GI tract and liver. NMN levels in blood were found to increase with supplementation when compared to NR which becomes unstable upon reaching the bloodstream and is quickly degraded to NAM (nicotinamide). It is not increased with supplementation proving NMN to be bioavailable and stable in blood. Moreover, it was noted that in the experiment to observe the increase in NAD+ levels in mitochondria before and after addition of NMN, it was noted that supplementation with NMN restored mitochondrial NAD+ content.

NMN absorption from gut into blood circulation starts within 2-3 minutes and within 15 minutes is completely absorbed into tissues. There it is readily converted into NAD+ which is readily stored in tissues like liver, skeletal muscles and cortex. After 6 months of NMN administration in murine models there was a spike in NAD+ concentration observed in liver and adipose tissue.

POSSIBILITIES OF NMN

NMN can open up a new horizon in modern therapeutics. In human cells NMN is available as the source of cellular energy and is efficacious in suppressing age associated physiological decline. NMN has beneficial effects on a diverse array of key physiological functions and therapeutic implications in various disease models such as on liver diseases, cardiovascular, diabetes, DNA damage. In several preclinical disease models which includes myocardial and cerebral ischemia, neurodegenerative disorders and diabetes it has demonstrated beneficial pharmacological effects. Recent studies have suggested that NMN improves numerous neuronal functions in the brain improving cognition and memory. It has been noted to ameliorate high-fat diet induced hepatic insulin resistance and dyslipidemia by restoring NAD+ biosynthesis and SIRT activity. Long term NMN administration suppresses tissue inflammation and improves whole body insulin sensitivity.

Aging - a natural human phenomenon is characterised by down regulated energy owing to depletion of NAD+ in multiple organs like pancreas, liver, skin, adipose tissue, skeletal muscles and brain. The most recent discovery that’s caught everyone’s attention is the anti-aging and promotion of longevity that has made NMN more attractive as a potential therapeutic candidate and a versatile molecule. NMN supplementation can help boost NAD+ levels, indirectly enhancing sirtuin activity thereby uplifting the body metabolism. Sirtuins are a family of proteins that use NAD+ for their enzymatic activities. Thus, NMN can be said to be a promising natural compound that helps modify senescence  and “slow down” aging.

NMN shares similar properties like other NAD+ precursors- nicotinamide riboside (NR), nicotinic acid, and nicotinamide. However, NMN seems to have a strong advantage over NR, as whenever NR is used, it first needs to convert into NMN before it is converted to NAD+. NMN has quite a few strong advantages of its own. While assessing the efficiency to treat Friedreich’s Ataxia (FRDA), a rare inherited childhood heart disease, NMN was found successful where NR treatment failed. In a 12-week study of 2000 mg/day NR supplementation to assess the efficacy of improvement of glucose metabolism and insulin sensitivity in obese patients, NR did not improve glucose metabolism and insulin sensitivity. However, NMN is shown to effectively improve insulin sensitivity and plasma lipid profile in preclinical models. Moreover, unlike NMN, nicotinic acid, and nicotinamide have several disadvantages such as hepatotoxicity or flushing in terms of their therapeutic application.

IS NMN SAFE?

Coming to the most important part - human safety. The molecule is considered safe and non-toxic, even at high concentrations in mice and in human study. Recently, an international collaborative team between Keio University School of Medicine in Tokyo and Washington University School of Medicine in St Louis has started the phase I human clinical study for NMN. The aim of this initial study was to assess the safety and the bioavailability of NMN in humans. Ten healthy volunteers were recruited, and the safety and the time course of blood NMN concentrations was evaluated. This recent clinical trial in Japan demonstrated NMN to be safe and well-tolerated at the recommended dosage. The Phase I study has been successful and proven NMN to be safe for oral consumption as it is effectively metabolized in healthy individuals without causing any significant deleterious effects.

There are also several clinical trials underway to prove NMN’s efficacy in various physiological conditions. The advantage of developing NMN as a nutraceutical could possibly aim to save time and provide a critical scientific foundation for development of NMN as an anti-aging nutraceutical. Owing to all this research that is on horizon worldwide, NMN can be considered a promising and fascinating molecule from which we still have lots of potential to learn.

 

About Dr. Niveditha Navin

Dr Navin is a clinical research specialist, who holds a degree in dentistry. After completing her postgraduate diploma in clinical research, she has experience working as a clinical affairs specialist in the pharmaceutical industry. She is passionate about medicine and wishes to carve a distinct niche in the field of research.

 

References

  1. Rajman L et al.. Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence. Cell Metab. 2018 Mar 6;27(3):529-547.
  2. Okabe K et al. Implications of altered NAD metabolism in metabolic disorders. J Biomed Sci. 2019 May 11;26(1):34.
  3. Yoshino J et al. NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR. Cell Metab. 2018 Mar 6;27(3):513-528.
  4. Poddar, Saikat Kumar et al. Nicotinamide Mononucleotide: Exploration of Diverse Therapeutic Applications of a Potential Molecule. Biomolecules. 2019 Jan 21;9(1):34.
  5. Yoshino, Jun et al. “Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice.” Cell metabolism vol. 14,4 (2011): 528-36.
  6. Quantitative Analysis of NAD Synthesis-Breakdown Fluxes (Liu, Rabinowitz, 2018)
  7. Radenkovic, Dina et al. “Clinical Evidence for Targeting NAD Therapeutically.” Pharmaceuticals (Basel, Switzerland) vol. 13,9 247. 15 Sep. 2020.
  8. 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.

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