A Clinical Trial on Beneficial Effects of NR on Walking Performance in PAD
Introduction
Elderly individuals are at a significantly higher risk for peripheral artery disease (PAD), a common vascular disorder. As the global population ages rapidly, the number of PAD cases is projected to rise further. People with PAD have increased oxidative stress, damaged skeletal muscle fibers, impaired mitochondrial activity, and poor walking performance, showing a high risk of cardiovascular and cerebrovascular events. Recently, a NICE randomized clinical trial uncovers that supplementation of nicotinamide riboside (NR) can improve the walking ability of PAD patients, opening up new opportunities for the treatment of PAD.About PAD
PAD is a chronic atherosclerosis disease in which stenoses or occlusions of the peripheral arteries result in insufficient blood flow/oxygen/nutrient delivery to the distal extremity, with the typical symptoms such as ischemic rest pain, numbness of extremity, intermittent claudication and weakness of body. Herein, the testing criteria of PAD are determined as follow: a toe brachial index < 0.70, ankle brachial index (ABI) ≤ 0.90, 70% or greater stenosis in a lower extremity artery on Duplex testing, or a post-exercise ABI decline of at least 20%.The potential significance of replenishing NR in PAD
As previous research demonstrated, oral administration of NR to boost NAD+ abundance can promote skeletal muscle SIRT1 expression, mitochondrial activity, limb strength as well as running endurance, activate endothelial nitric oxide synthase (eNOS) and reduce oxidative stress to increase the abundance of nitric oxide, a key vasodilator that can relax blood vessels and maintain their elasticity. All of these effects delivered by NR are contributive to the improvement of PAD.Research protocol
90 participants with PAD are randomly allocated into NR+resveratrol, NR+placebo, and placebo+placebo groups, and then are asked to take five pills daily for 6 months, including two 250 mg of NR pills (or placebo) twice daily and one 125 mg resveratrol (or placebo) once daily, followed by 3-month and 6-month follow-up.
NR's impact on 6-minute walk in PAD
NR meaningfully improves 6-min walk, and no added advantage is observed from resveratrol. Specifically, among participants who take at least 75% of study pills, NR improves 6-min walk by 31.0 meters and NR + resveratrol promote 6-min walk by 26.9 meters, as compared with placebo. In addition, NR increases satellite cell abundance in gastrocnemius muscle, compared to placebo, but does not affect muscle fiber type. Moreover, people randomized to NR + resveratrol report higher rates of diarrhea and higher rates of nausea or emesis, compared to those randomized to NR alone or placebo.
Conclusion
Supplementation of NR, to some exert, has shown potential to enhance walking performance in PAD patients. This NICE randomized clinical trial lays a preliminary foundation in establishing the feasibility of NR as a therapeutic intervention for PAD.Reference
[1] Khan NA, Auranen M, Paetau I, et al. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3. EMBO Mol Med. 2014;6(6):721-731. doi:10.1002/emmm.201403943
[2] Martens CR, Denman BA, Mazzo MR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018;9(1):1286. Published 2018 Mar 29. doi:10.1038/s41467-018-03421-7
[3] McDermott MM, Martens CR, Domanchuk KJ, et al. Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial. Nat Commun. 2024;15(1):5046. Published 2024 Jun 13. doi:10.1038/s41467-024-49092-5
[4] Zhang H, Ryu D, Wu Y, et al. NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016;352(6292):1436-1443. doi:10.1126/science.aaf2693
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