Charles Brenner, PhD
A clinical study conducted at the University of Copenhagen, Aarhus University Hospital and the University of Iowa has provided the first human evidence of the potential for nicotinamide riboside (NR) to improve human health in obesity1. In the US and in many other industrialized countries, one third of adults are overweight and another third are obese2. Completed human studies have demonstrated that NR safely and significantly increases circulating nicotinamide adenine dinucleotide (NAD) levels in blood3, and may even reduce blood pressure and aortic stiffness in healthy adults4. In obese and diabetic mice, oral NR allowed animals to resist weight gain and fatty liver while reducing hyperglycemia and neuropathy5. To see whether these results can be translated to overweight people, clinical scientists needed to establish safety in overweight adults and determine what is the most promising health parameter to monitor.
While the basic biology of mice and people are similar, there are also differences, such that if the trials are not conducted with the best designs and aims, we could fail to see positive results. There was also the possibility that NR might not have been well tolerated in overweight populations or that NR might not move the needle on any health parameter in overweight people in an initial trial. The good news is that a completed and recently published randomized, double-blind clinical trial showed that NR is safe in obese men and that men receiving 2 grams of NR per day experienced a 2% reduction in their liver fat content compared to a 0.2% reduction in the placebo group (P = 0.13) in just 12 weeks1.
The major differences between obese laboratory mice and obese people are the following:
- Laboratory mice are inbred and all eat exactly what we give them, whereas people are genetically diverse and differ in our diets and physical activity.
- Mice get fat in 2-3 months of intense high-fat feeding whereas people typically get fat in decades of imbalance between our energy intake and our energy expenditure.
- Mice have a much faster metabolism than people: not only can they double their weight faster than people, they can respond to an intervention much more rapidly.
All of this suggests that one would need to conduct human trials with large numbers of participants for a long period of time, i.e., at least 6 months in order to see some benefits. But you can’t do a long study unless you know that your intervention is safe in a short study. And you don’t know what should be your primary endpoint until you start giving the intervention to people.
When we conducted our mouse study, NR simultaneously improved body weight, fatty liver, glycemic control and nerve function, such that it was hard to know what was the primary effect and which were the effects that followed from the primary effect5. Apart from safety, the primary endpoint in the Danish human obesity trial was insulin sensitivity and this was not improved by NR supplementation over 12 weeks1. However, though the group that got NR began the trial with 2.8% lower liver fat, they appeared to benefit from NR by virtue of a 2% reduction in fatty liver over the course of the trial. Moreover, of the 13 individuals in the NR arm of the trial with 5% fat content in their livers, 9 appeared to respond to NR in reduction of fatty liver. This trial also showed a tendency for the NR group to lower their low density lipoprotein cholesterol (P = 0.13).
Now that NR safety in obese men has been established and the potential for NR to improve fatty liver and cholesterol been suggested in this trial, future studies will be designed specifically to address lipid health and function in human obesity. Stay tuned!
Charles Brenner is the Roy J. Carver Chair & Head of Biochemistry and Founding Co-Director the Obesity Research & Education Initiative at the University of Iowa. The discoverer of NR as a vitamin precursor of NAD, Dr. Brenner’s intellectual property has been developed by ChromaDex to improve human wellness and to treat human diseases and conditions. He serves as a member of the ChromaDex scientific advisory board and as chief scientific adviser of ChromaDex. ChromaDex provided NR for all referenced animal and human studies. The Danish study was funded by the Novo Nordisk Foundation and the Danish Diabetes Academy.
1. Dollerup, O.L., et al., A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity and lipid-mobilizing effects. American Journal of Clinical Nutrition, 2018. in press.
2. Finkelstein, E.A., et al., Obesity and severe obesity forecasts through 2030. Am J Prev Med, 2012. 42(6): p. 563-70.
3. Trammell, S.A., et al., Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun, 2016. 7: p. 12948.
4. Martens, C.R., et al., Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD(+) in healthy middle-aged and older adults. Nat Commun, 2018. 9(1): p. 1286.
5. Trammell, S.A., et al., Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice. Sci Rep, 2016. 6: p. 26933.