Nicotinamide adenine dinucleotide (NAD) is central to mitochondrial function, but declines with age. Mitochondria are the power plants of the cell, producing chemical energy store molecules to power cellular processes. When mitochondria run down, everything suffers. Thus a great deal of attention has been given over the years to approaches that might help to boost mitochondrial function in old individuals: mitochondrially targeted antioxidants; increasing NAD levels; transplantation of mitochondria; copying mitochondrial genes into the nucleus to provide resistance against mitochondrial DNA damage. The small molecule approaches widely deployed to date are arguably all marginal, at best on a par with structured exercise programs when it comes to improvement of health.
Nonetheless, attempting to improve mitochondrial function by the use of small molecules to restore youthful NAD levels has a long history, going back decades prior to the point at which researchers realized that the interventions were raising NAD levels. The primary approach here is to use vitamin B3 derivatives, and those have been employed at high doses in clinical trials for a long time. Only in more recent years have researchers started to focus on how the compounds derived from vitamin B3, such as niacin, nicotinamide riboside, and nicotinamide mononucleotide, interact with the synthesis and recycling of NAD, and deliberately aimed at raising NAD levels for therapeutic effect.
Today's paper reports on a small study that shows some benefit to nicotinamide mononucleotide supplementation in old patients. It is like other studies in that one might expect similar benefits from exercise, and also it is as interesting for what was not improved as it is for what was. We should expect to see more studies much like this, though it is worth remembering that, taken as a whole, looking over the range of trials conducted over decades, the evidence for NAD upregulation to be useful isn't as good as this small study might make it look. Larger trials have tended to fail to show significant impact on the treated conditions.
Aging- and age-related diseases have been shown to be closely related to decreased NAD+ levels. In animal studies, the administration of intermediate NAD+ metabolites, such as nicotinamide (NAM), nicotinamide mononucleotide (NMN), or nicotinamide riboside (NR), has been shown to increase NAD+ concentrations, which helped improve the health and extend the lifespan of the experimental animals. Thus, the potential of intermediate NAD+ metabolites in improving tissue rejuvenation in humans has led to multiple clinical trials on NR and NMN.
The results of NR clinical trials have been reported. In these trials, NR (100-2000 mg/day) was administered to healthy participants or individuals with obesity for a maximum of 12 weeks. Most NR clinical trials have reported the safety of NR administration and the elevation of NAD+ or NAD+ -related metabolites in the blood. The most recent report showed that NR increases the fat-free body mass in participants with obesity, although no effect was observed on insulin sensitivity, mitochondrial function, and hepatic and intramyocellular lipid accumulation.
Recently, for the first time, the safety of single-day NMN oral administration was reported in humans. Moreover, while the drafting of this paper was underway, a 10-week, randomized, placebo-controlled, double-blind trial to evaluate the effect of NMN supplementation on metabolic function in 25 postmenopausal women with prediabetes was reported, in which NMN supplementation increased muscle insulin sensitivity, insulin signaling, and remodeling in women with prediabetes who are overweight or obese. Furthermore, the effects of NMN supplementation combined with exercise training have been reported in healthy amateur runners aged 27-50 years. NMN dose-dependently increased the ventilatory threshold and improved aerobic capacity during exercise. However, evidence of the effects of human interventions with NMN remains limited for older adults.
Therefore, to elucidate the safety and efficacy of NMN administration in older adults, we conducted a placebo-controlled, randomized, double-blind, parallel-group study with the administration of 250 mg of NMN to 42 healthy men aged 65 years or more for 12 weeks. We demonstrated that NMN oral supplementation at 250 mg/day in healthy older men for 12 weeks was safe and well-tolerated and significantly increased the levels of NAD+ and NAD+-related metabolites in whole blood. Furthermore, NMN administration partly improved muscle performance, evaluated using gait speed and grip strength, in healthy older men. Conversely, no difference was observed in the indicators of vascular functions, such as assessed blood pressure and flow-mediated dilation. Chronic NMN supplementation did not affect the visceral or liver or spleen fat mass distribution. Likewise, NMN administration did not affect the homeostatic model assessment of insulin resistance (HOMA-IR), an indicator of hepatic insulin sensitivity in blood analysis. Adiponectin and interleukin 6 (IL-6), which are also related to insulin sensitivity, were unaffected by NMN administration. Lastly, the intervention exerted no observable effect on overall cognitive function.