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Challenging the Current Thinking on NR Supplementation

Researchers discuss data challenging the proposal that NR supplementation improves the function of the cell’s powerhouse, the mitochondria, in humans.

(BWFolsom | iStock)
By Bennett M. Sherman

Numerous studies published in the last few decades support the idea that declining structure and function of the cell’s powerhouse, the mitochondria, are associated with obesity, insulin resistance, and type 2 diabetes for rodent models and human tissues. Studies have also implicated impairments in metabolism that stem from reduced levels of a molecule called nicotinamide adenine dinucleotide (NAD+), an essential molecule for cellular energy production and cellular health maintenance, in these diseases. Alterations in lifestyle choices, such as exercise and calorie intake reductions, remain the best options to improve mitochondrial health in the human body to combat these metabolic diseases. However, some scientists have considered the possibility that supplementation with an NAD+ precursor nicotinamide riboside (NR) could mitigate these diseases as well.

A commentary by Moore and Mucinski from the Harry S. Truman Memorial Veterans Medical Centre in Missouri published in The Journal of Physiology critiqued a clinical trial performed by Dollerup et al. (2020) that did not provide evidence for the proposal that NR supplementation improves NAD+ content and mitochondrial function in human skeletal muscle. Their commentary discussed how the data obtained in the study by Dollerup and colleagues ran counter to the prevailing idea that NR supplementation can increase NAD+ levels and improve mitochondrial function in human tissue.

Researchers have sought to therapeutically target NAD+ to increase its abundance in cells with the B3 vitamin NR. Studies have shown that NR can increase NAD+ levels in the blood and tissue of rodents, which led to increased NAD+ bioavailability–the amount of NAD+ that has an active effect when introduced to the body–and protection against insulin resistance and obesity in mice fed a high-fat diet. Recent data has also indicated that NR supplementation increases NAD+ bioavailability and is well tolerated in humans, but it has remained unclear whether NR supplementation improves insulin resistance and mitochondrial function in people.


Vitamin B3. Vitamin B3 complex includes three forms: nicotinamide, niacin, nicotinamide riboside.

The recently-published study investigated the effects of NR supplementation for 12 weeks to find whether NR administration is safe and improves insulin sensitivity and mitochondrial function. The team of scientists administered 1,000 mg of NR twice daily to some obese males from a cohort of 40 men randomized to receive NR or placebo for 12 weeks. This recent report published in The Journal of Physiology also evaluated the effects of supplementing with NR on skeletal muscle mitochondrial content, respiration (a measure of oxygen consumption indicative of metabolism), and mitochondrial shape in obese men.

The data from this study challenge the current thinking that supplementation with an NAD+ precursor like NR improves mitochondrial function in human skeletal muscle. These results align instead with another recently-published study from Elhassan et al. (2019) demonstrating that NR supplementation in a small cohort of aged men from 70-80 years old did not affect metabolic function. The data from the study that Elhassan and colleagues performed indicated no changes in NAD+ levels or skeletal muscle mitochondrial function, which does not fit with the existing data from supplementing rodents with NR. “The studies from Dollerup et al. indicate that further scientific evidence is required before recommending the use of NR supplementation or other NAD+ precursors,” stated Moore and Mucinski in their article.

Although the data do not support current thinking that NR enhances mitochondrial structure and function in human skeletal muscle, the study only included middle-aged males with obesity and insulin resistance. Future studies could examine whether NR supplementation has a significant effect on populations of different age, sex, and more severe metabolic disease states like type 2 diabetes. The possibility also exists that NR supplementation improves NAD+ content and mitochondrial function in specific human tissues other than skeletal muscle, such as adipose, liver, or immune cells. Different tissues could have distinct levels of NAD+ bioavailability, and the possibility remains that human skeletal muscle has low bioavailability.

“It would also be interesting to explore whether other supplementation strategies aimed at boosting NAD+ metabolism, such as nicotinamide mononucleotide [NMN], have differing effects compared to NR supplementation,” said the authors of the article. Perhaps NMN, another precursor to NAD+, has different effects on NAD+ bioavailability in human skeletal muscle. Clinical trials investigating the effects of NMN supplementation in humans are underway and could provide insight into this matter.

Source

Moore MP, Mucinski JM. Impact of nicotinamide riboside supplementation on skeletal muscle mitochondria and whole-body glucose homeostasis: challenging the current hypothesis. J Physiol. 2020 Aug;598(16):3327-3328. doi: 10.1113/JP279749. Epub 2020 Jun 16. PMID: 32463114.

References
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  2.  Elhassan YS, Kluckova K, Fletcher RS, Schmidt MS, Garten A, Doig CL, Cartwright DM, Oakey L, Burley CV, Jenkinson N, Wilson M, Lucas SJE, Akerman I, Seabright A, Lai YC, Tennant DA, Nightingale P, Wallis GA, Manolopoulos KN, Brenner C, Philp A, Lavery GG. Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures. Cell Rep. 2019 Aug 13;28(7):1717-1728.e6. doi: 10.1016/j.celrep.2019.07.043. PMID: 31412242; PMCID: PMC6702140.
  3.  Fang EF, Lautrup S, Hou Y, Demarest TG, Croteau DL, Mattson MP, Bohr VA. NAD+ in Aging: Molecular Mechanisms and Translational Implications. Trends Mol Med. 2017 Oct;23(10):899-916. doi: 10.1016/j.molmed.2017.08.001. Epub 2017 Sep 9. PMID: 28899755; PMCID: PMC7494058.
  4.  Hesselink MK, Schrauwen-Hinderling V, Schrauwen P. Skeletal muscle mitochondria as a target to prevent or treat type 2 diabetes mellitus. Nat Rev Endocrinol. 2016 Nov;12(11):633-645. doi: 10.1038/nrendo.2016.104. Epub 2016 Jul 22. PMID: 27448057.
  5.  Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, Chonchol M, Seals DR. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018 Mar 29;9(1):1286. doi: 10.1038/s41467-018-03421-7. PMID: 29599478; PMCID: PMC5876407.
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