A fair amount of effort is presently put towards the exploration of supplements derived from vitamin B3 compounds (nicotinamide, niacin, nicotinamide riboside) that act as precursors to enable the manufacture of nicotinamide adenine dinucleotide (NAD). NAD is an important component in mitochondrial activity, and levels decline with age. Some portion of the loss of mitochondrial function, implicated in the progression of many age-related conditions, is due to NAD insufficiency. There is a rich history of the use of high doses of vitamin B3 as an intervention, most of it predating modern understanding of the role of NAD in mitochondrial biochemistry, but less work carried out with the deliberate intent of raising NAD levels.

Nicotinamide mononucleotide, discussed here, and nicotinamide riboside are the compounds of choice for modern studies aimed at raising NAD levels and assessing the resulting effects on health and tissue function, though groups like Nuchido are trying to broaden that portfolio. While this is becoming an energetic part of the field, attracting more interest over time, the data is beginning to suggest that the established means of NAD precursor supplementation are inferior to regular moderate exercise, and particularly strength training, when it comes to raising NAD levels. It remains to be seen how this settles out in the years ahead, given more scientific work on the topic.

Nicotinamide adenine dinucleotide (NAD) is a vital metabolic redox co-enzyme found in eukaryotic cells and is necessary for over 500 enzymatic reactions. It plays a crucial role in various biological processes, including metabolism, aging, cell death, DNA repair, and gene expression. The deficiency of NAD+ is closely associated with diverse pathophysiologies, including type 2 diabetes (T2D), obesity, heart failure, Alzheimer’s disease (AD), and cerebral ischemia. The NAD+ levels decline in multiple organs with age, and this contributes to the development of various age-related diseases. Therefore, NAD+ supplementation could be an effective therapy for the treatment of the conditions mentioned above.

Nicotinamide mononucleotide (NMN) is one of the intermediates in NAD+ biosynthesis. In mammalian cells, NAD+ is synthetized, predominantly through NMN, to replenish the consumption by NADase participating in physiologic processes including DNA repair, metabolism, and cell death. Recent preclinical studies have demonstrated that the administration of NMN could compensate for the deficiency of NAD+, and NMN supplementation was able to effect diverse pharmacological activities in various diseases.

Given that NMN has shown high efficacy and benefits in various mouse models of human disease, several clinical trials of NMN have been conducted to investigate its clinical applicability. This has led to some capsule formulations of NMN being approved and put on the market as health supplements. The first phase I human clinical study for NMN is to examine the safety and bioavailability of NMN in human bodies. Recently, it was reported that a single oral administration of NMN up to 500 mg was safe and effectively metabolized in healthy subjects without causing severe adverse events. The major final metabolites of NMN were significantly increased in a dose-dependent manner by NMN administration.

A phase II study is also underway to assess the safety of long-term NMN in healthy subjects, the kinetics of NMN and metabolites of NAM, and the effect of daily administration of NMN on glucose metabolism. Other clinical trials of NMN are ongoing to examine the effect of NMN on insulin sensitivity, endothelial function, blood lipids, body fat and liver fat, and fat tissue and muscle tissue markers of cardiovascular and metabolic health. Additionally, a study has been initiated to evaluate the effect of long-term oral administration of NMN on various hormones in healthy volunteers. Recently, a new clinical study was initiated to evaluate the effect of NMN oral administration on the body composition in elderly persons.

In summary, despite the tremendous research efforts aimed at exploiting the therapeutic potential of NMN to treat metabolic and aging-related diseases, the clinical and toxicological evidence to support its utility is currently insufficient. Thus, further research is needed to increase the prospects of developing drugs based on NMN.

Link: https://doi.org/10.3389/fcell.2020.00246