NAD+ Precursor NR Improves Physical Performance but not Resveratrol: New Clinical Study

NR (nicotinamide riboside) improves the walking performance of individuals with cardiovascular disease, but adding resveratrol does not improve performance further.

By Griffin Dean

Key Points: 

  • One gram (g) of NR for six months improves the walking performance of cardiovascular disease patients. 
  • Adding 125 milligrams (mg) of resveratrol does not improve walking performance, suggesting resveratrol blocks the effects of NR. 
  • However, after accounting for adherence to supplementation, both NR alone and NR + resveratrol improve walking performance.   

Dietary choices and a lack of exercise can promote the buildup of plaque in our arteries called atherosclerosis, the leading cause of death worldwide. When these plaques burst, they foster blood clots that can cause a heart attack or stroke. Before bursting, they can also reduce blood flow to organs, including our arm and leg muscles. Such is the case with peripheral artery disease (PAD) — atherosclerosis of the limbs. 

Individuals with lower limb PAD have difficulty walking due to reduced blood flow to their leg muscles, which could impair mitochondria. For this reason, researchers from Northwestern University tested whether NR — known to enhance mitochondria — could improve the walking performance of these individuals. Furthermore, they tested whether the anti-aging molecule resveratrol could amplify the effects of NR. 

NR Improves Walking Performance  

The chemical structure of nicotinamide riboside (N.R.).

To evaluate walking ability, lower limb PAD patients were asked to walk up and down a 100-foot hallway for six minutes. The results showed that, after taking 1 g of NR for six months, the participants were able to walk an additional 23 feet. In contrast, the participants who took a placebo for six months walked 35 feet less. Hence, those who supplemented with NR were able to walk 58 feet more than those who took the placebo. 

The participants were also asked to walk on a treadmill for as long as possible before feeling pain in their legs. It was found that the participants who took NR could walk on the treadmill 2.1 minutes longer than the placebo group. Together, with the 6-minute walking test, these findings demonstrate that NR can improve the physical performance of lower limb PAD patients. 

NR + Resveratrol Does Not Improve Walking Performance 

The chemical structure of N.R. and resveratrol.

Resveratrol is a plant-based molecule called a polyphenol, which can be found in grapes, and thus wine. The Northwestern researchers note that resveratrol could enhance the effects of NR. Therefore, they conducted the six-minute walking test on individuals who took both 1 g of NR and 125 mg of resveratrol for 6 months. However, compared to the placebo group, this combination had no clinically significant effect, increasing walking distance by only 12 feet. 

For the treadmill test, it was found that the participants who took NR and resveratrol walked 1.7 minutes longer than the placebo group. However, this was not statistically significant. Together, considering the results from NR alone, these findings suggest that resveratrol blocks the beneficial effects of NR on walking performance in lower limb PAD patients. 

Accounting for Adherence

Upon further analysis, the researchers noticed that participants in the NR + resveratrol group did not adhere to supplementation as much as participants in the NR-only group. Notably, participants were more likely to have liquid stool as a result of NR + resveratrol supplementation vs only NR. This side effect could explain the lower adherence to taking NR + resveratrol. 

Ultimately, after accounting for the adherence problem, the researchers found that both NR alone and NR + resveratrol improved the 6-minute walking distance of the participants. These findings suggest that resveratrol neither blocks nor improves the beneficial effects of NR on walking performance in lower limb PAD patients.

Why NR Works for Lower Limb PAD Patients and Not Others 

The authors of the study point out that no previous research has shown NR improves walking performance, despite this outcome being measured. They cite a study of heart failure patients in which 2 g of NR had no effect on the 6-minute walking test. To explain this, the authors mention that heart failure patients do not have lower limb artery blockages, which increases reactive oxygen species (ROS) in muscle. 

NR is known to reduce ROS levels by increasing NAD+ levels and improving the health of mitochondria. Therefore, it could be that NR counteracts muscle ROS and mitochondrial impairments in the leg muscles of lower limb PAD patients. However, studies of obese men have shown that NR does not raise muscle NAD+ levels. Thus, more studies are needed to determine how NR improves walking performance. 

One possibility is that NR rejuvenates muscle stem cells, which are responsible for building muscle. The Northwestern researchers showed that muscle stem cell abundance was increased in the calf muscles of the participants who took NR. Thus, it can be speculated that NR could help repair the leg muscles of lower limb PAD patients. 


McDermott, M. M., Martens, C. R., Domanchuk, K. J., Zhang, D., Peek, C. B., Criqui, M. H., Ferrucci, L., Greenland, P., Guralnik, J. M., Ho, K. J., Kibbe, M. R., Kosmac, K., Peterson, C. A., Sufit, R., Tian, L., Wohlgemuth, S., Zhao, L., Zhu, P., & Leeuwenburgh, C. (2024). Nicotinamide riboside for peripheral artery disease: The NICE randomized clinical trial. Nature Communications, 15(1), 1-11.

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