However, Dr. Sinclair recently said he takes NMN instead of NR based on research he did that found NR did not work at all, while NMN increased the endurance in older mice such that they were able to run twice as far as those on placebo.
NMN has much stronger record of benefit to humans in clinical studies
Over the last few years there have been several human clinical trials published with NR, while those with NMN have lagged behind, leading some people to conclude that NR is the “safer” bet.
Although there have been more than 11 clinical trials now published with NR, nearly all have failed to show any benefit in humans. The one possible exception being this 2021 research showing a reduction in the IL-6 marker of inflammation. We cover that below.
NMN treatment increased muscle insulin sensitivity
In this trial, the muscle insulin sensitivity was assessed as the rate of insulin-stimulated glucose disposal per kg of fat-free mass during the clamp procedure. In plain words, they measured how quickly and efficiently the glucose is taken up from blood in response to the insulin. A higher insulin-stimulated glucose disposal rate suggests higher insulin sensitivity, which is metabolically healthier.
After 10 weeks of NMN supplementation, but not placebo, the insulin-stimulated glucose disposal rate increased by 25 ± 7% in the subjects. This improvement in muscle insulin sensitivity is clinically relevant and is similar to the improvement observed after ~10% weight loss (equivalent to roughly 20 pounds weight loss in the subjects). This result suggests that NMN administration improved insulin sensitivity and potentially metabolic health by increasing NAD+ turnover instead of changing muscle NAD+ concentration.
See our full review here
NR did not improve insulin sensitivity in trials
In contrast to the insulin-sensitizing effects of NMN, the results from several randomized controlled trials conducted in middle-aged and older-adult men found that treatment with nicotinamide riboside (NR) did not affect whole-body or muscle insulin sensitivity. Even though, compared with the administration of 250 mg NMN in this trial, these NR trials used a higher dose of NR with a similar time: 2000 mg for 12 weeks in Dollerup et al. (2018); 1000 mg for 3 and 6 weeks in Elhassan et al. (2019) and Remie et al. (2020).
“Insulin sensitivity, endogenous glucose production, and glucose disposal and oxidation were not improved by NR supplementation.” (r)
“There were no changes in body weight, blood pressure, lipid profile, fasting glucose and insulin (Table S1), and homeostatic model assessment of insulin resistance…NR did not produce this effect in our trial “(r)
“However, no effects of NR were found on insulin sensitivity, mitochondrial function, hepatic and intramyocellular lipid accumulation, cardiac energy status, cardiac ejection fraction, ambulatory blood pressure, plasma markers of inflammation, or energy metabolism.”(r)
This may indicate that NMN, as the rate-limiting factor in NAD+ synthesis, provides more metabolic benefits than NR. However, due to the complexity of population heterogeneity and limitation of sample size, further studies are needed to address this question.
NMN enhances aerobic capacity in amateur runners: a randomized, double-blind study
In this six-week human study published July 8, 2021, researchers conclude that supplementation of Nicotinamide Mononucleotide (NMN) remarkably lifted ventilatory threshold (VT) in amateur runners. The benefit was dose-dependent and muscle-related.
The randomized, double-blind, placebo-controlled, four-arm clinical trial including 48 young and middle-aged recreationally trained runners of the Guangzhou Pearl River running team was conducted to investigate the effects of a combination of exercise training and supplementation with NMN.
▸ Improved ventilatory threshold even among healthy young athletes.
▸ The improved aerobic capacity is likely the result of enhanced O2 utilization of the skeletal muscle.
▸ The improvement is muscle, not cardiac, related.
▸ The improvement of aerobic capacity is dosage-dependent.
▸ Larger doses of NMN have better results.
▸ Results were after 6 weeks of supplementation
See our full review here
NR does show possible benefit for decreased inflammation in skeletal muscle
The Dollerup et al study mentioned above did not find any benefit for insulin sensitiviy that was a primary objective, but did find a significant decrease in the IL-6 marker for inflammation.
A limitation of this trial may be the number of participants or the duration of NR administration; however, the sample size was sufficient to detect NR-driven changes in the NAD+ metabolome, muscle transcriptional signature, and inflammatory profile. The transcriptional downregulation of mitochondrial gene sets also argues against the lack of a bioenergetic NR effect being due to the sample size. Further studies are needed to conceptualize some of the NR-mediated changes in this experimental medicine study.
Overall, these studies support that oral NR is available to human skeletal muscle, and they reveal anti-inflammatory NR properties, both of which may be beneficial in the context of aging, muscle, or inflammatory disease groups.
So far, published research shows more benefit for humans with NMN than NR. Of course these are very early days, and much more research is needed before we know which NAD+ boosting supplements are effective for what tissues or conditions.
Dr. Sinclair may prefer NMN to NR, but he has been saying since 2016 (at least) that it is likely different NAD+ precursors will be shown to have benefit on different tissues.
We also believe that other strategies such as lowering inflammation and decreasing CD38 to minimize NAD+ consumption will be proven to be beneficial to humans.