Nicotinamide Riboside helps build muscle energy and strength

Especially in Peripheral Artery Disease

Nicotinamide Riboside

Vitamin B-3 is an important precursor to the enzyme cofactor nicotinamide adenine dinucleotide. NAD is involved in important reduction-oxidation reactions, including the metabolism of glucose. It also aids the functioning of enzymes known as sirtuins, which have been implicated in aging. Cells can make NAD from NR via the enzyme nicotinamide riboside kinase (NRK).

Scientists once thought NR was an obscure nutrient used mainly by the flu bacterium Haemophilus influenzae. But Charles Brenner, then at Dartmouth College, discovered that NR is also taken up by fungi, yeast, and humans (Cell 2004, DOI: 10.1016/s0092-8674(04)00416-7). He found it in cows’ milk along with niacin and niacinamide, together more commonly known as vitamin B-3. Brenner proposed that NR is a third form of vitamin B-3. - MM Bomgardner.

NR supplementation in mice:

NAD levels decline in multiple tissues with age or in disease. Frederick et al. show that impaired intramuscular NAD synthesis compromises skeletal muscle mass and strength over time but can be quickly restored with an oral NAD precursor. Upregulation of the NAD salvage pathway preserves exercise performance in aged mice. [NAMPT = nicotinamide phosphoribosyltransferase, which is also known as visfatin or PBEF in humans]

• Mice with 85% NAD depletion in skeletal muscle are grossly normal as young adults

• Reduced NAD content impairs mitochondrial function and fiber integrity over time

• Progressive muscle dysfunction can be reversed by the NAD precursor NR (Nicotinamide Riboside)

• Preventing muscle NAD loss during aging partially preserves exercise performance

NAD is an obligate co-factor for the catabolism of metabolic fuels in all cell types. However, the availability of NAD in several tissues can become limited during genotoxic stress and the course of natural aging. The point at which NAD restriction imposes functional limitations on tissue physiology remains unknown. We examined this question in murine skeletal muscle by specifically depleting Nampt, an essential enzyme in the NAD salvage pathway. Knockout mice exhibited a dramatic 85% decline in intramuscular NAD content, accompanied by fiber degeneration and progressive loss of both muscle strength and treadmill endurance. Administration of the NAD precursor nicotinamide riboside rapidly ameliorated functional deficits and restored muscle mass despite having only a modest effect on the intramuscular NAD pool. Additionally, lifelong overexpression of Nampt preserved muscle NAD levels and exercise capacity in aged mice, supporting a critical role for tissue-autonomous NAD homeostasis in maintaining muscle mass and function. - Frederick, et al.

Peripheral Artery Disease disability

Does NR work for humans, too? A recent report describes the results of a half year treatment with oral NR supplementation, on ability to walk, in those with compromised circulation.

People with lower extremity peripheral artery disease (PAD) have increased oxidative stress, impaired mitochondrial activity, and poor walking performance. NAD+ reduces oxidative stress and is an essential cofactor for mitochondrial respiration. Oral nicotinamide riboside (NR) increases bioavailability of NAD+ in humans. Among 90 people with PAD, this randomized double-blind clinical trial assessed whether 6-months of NR, with and without resveratrol, improves 6-min walk distance, compared to placebo, at 6-month follow-up. At 6-month follow-up, compared to placebo, NR significantly improved 6-min walk (+7.0 vs. −10.6 meters, between group difference: +17.6 (90% CI: + 1.8,+∞). Among participants who took at least 75% of study pills, compared to placebo, NR improved 6-min walk by 31.0 meters and NR + resveratrol improved 6-min walk by 26.9 meters. In this work, NR meaningfully improved 6-min walk, and resveratrol did not add benefit to NR alone in PAD. A larger clinical trial to confirm these findings is needed. - MM McDermott, et al.

Figure A depicts the 6-month change in 6-min walk (primary outcome) results for N = 90 participants. Mixed models for repeated measures (MMRM) were used to compare 6-month change in 6-min walk distance between the NR + resveratrol and placebo groups and between the NR alone and placebo groups using baseline, 3-month, and 6-month values for 6-min walk distance, adjusting for age, sex, race, and baseline 6-min walk. The a priori statistical analysis plan defined a one-sided P value of <0.10 to define statistical significance. The circle represents NR alone, the square represents NR + resveratrol, and the triangle represents placebo. Figure B depicts 3-month change in 6-min walk (secondary outcome) for N = 90 participants. Mixed models for repeated measures (MMRM) were used to compare change in 6-min walk distance between the NR + resveratrol and placebo groups and between the NR alone and placebo groups using baseline, 3-month, and 6-month values for 6-min walk distance, adjusting for age, sex, race, and baseline 6-min walk. The a priori statistical analysis plan defined a one-sided P value of <0.10 to define statistical significance. The circle represents NR alone, the square represents NR + resveratrol, and the triangle represents placebo. Figure C depicts 6-month change in 6-min walk among the 60 participants who took at least 75% of study pills. Mixed models for repeated measures (MMRM) were used to compare 6-month change in 6-min walk distance between the NR + resveratrol and placebo groups and between the NR alone and placebo groups using baseline, 3-month, and 6-month values for 6-min walk distance, adjusting for age, sex, race, and baseline 6-min walk. The a priori statistical analysis plan defined a one-sided P value of <0.10 to define statistical significance. The circle represents NR alone, the square represents NR + resveratrol, and the triangle represents placebo. - MM McDermott, et al.

Got Milk?

So, do we have to buy expensive dietary supplements in order to ‘beef up’ our quadraceps?

No.

Instead, get a gallon of ice cream and enjoy a tasty milkshake!

Cow milk typically contained 12 umol NAD+ precursor vitamins/L, of which 60% was present as nicotinamide and 40% was present as NR. Nicotinic acid and other NAD+ metabolites were below the limits of detection. Milk from samples testing positive for Staphylococcus aureus contained lower concentrations of NR (Spearman r = 20.58, P = 0.014), and NR was degraded by S. aureus. Conventional milk contained more NR than milk sold as organic. Nonetheless, NR was stable in organic milk and exhibited an NMR spectrum consistent with association with a protein fraction in skim milk. - SAJ Trammell, et al.

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REFERENCES

MM Bomgardner. Firms feud over purported age-fighting molecule. ChromaDex and Elysium Health duke it out over rights to vitamin-like nicotinamide riboside. August 19, 2018 Chem Eng News Volume 96, Issue 33. https://cen.acs.org/business/consumer-products/Firms-feud-over-Niagen-purported/96/i33

DW Frederick, et al. Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle. Cell Metabolism 24, 269–282, August 9, 2016

MM McDermott, et al. Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial, Nature Communications (2024). DOI: 10.1038/s41467-024-49092-5

SAJ Trammell, et al. Nicotinamide Riboside Is a Major NAD+ Precursor Vitamin in Cow Milk .J Nutr 2016 May;146(5):957-63 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879052/