Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures

Elhassan, Yasir S; Kľučková, Katarína; Fletcher, Rachel; Schmidt, Mark S.; Garten, Antje; Doig, Craig; Cartwright, David; Oakey, Lucy; Burley, Claire V.; Jenkinson, Ned; Wilson, Martin; Lucas, Samuel J. E.; Akerman, İldem; Seabright, Alex P.; Lai, Yu‐Chiang; Tennant, Daniel A.; Nightingale, Peter; Wallis, Gareth A.; Manolopoulos, K.; Brenner, Charles; Philp, Andrew; Lavery, Gareth G.

doi:10.1016/j.celrep.2019.07.043

Cited by 272 publications

(316 citation statements)

References 71 publications

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“…The compiled results from the present study do not corroborate findings obtained in preclinical studies and challenge whether NAD + precursor supplementation will translate to improved mitochondrial health in human skeletal muscle. Our results align with a recently published randomized, placebo-controlled crossover study investigating the effects of NR 1 g/day for 21 days in 12 aged (70-80 years) males (Elhassan et al 2019). In this study, NR did not augment NAD + levels in skeletal muscle, although nicotinic acid adenine dinucleotide (NAAD) as well as NAM degradative products increased upon NR supplementation, suggesting oral bioavailability of NR to skeletal muscle.…”

Section: Figure 7 Hierarchical Clustering Analysis On the Subset Ofsupporting

confidence: 91%

“…However, this did not confer changes in mitochondrial respiration or content (Elhassan et al . ). Although positive outcomes from clinical trials are still lacking, in vitro studies have demonstrated effects of NR on mitochondria in several human cell types.…”

Section: Discussionmentioning

confidence: 97%

“…In this study, NR did not augment NAD + levels in skeletal muscle, although nicotinic acid adenine dinucleotide (NAAD) as well as NAM degradative products increased upon NR supplementation, suggesting oral bioavailability of NR to skeletal muscle. However, this did not confer changes in mitochondrial respiration or content (Elhassan et al 2019). Although positive outcomes from clinical trials are still lacking, in vitro studies have demonstrated effects of NR on mitochondria in several human cell types.…”

Section: Figure 7 Hierarchical Clustering Analysis On the Subset Ofmentioning

confidence: 89%

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Nicotinamide riboside does not alter mitochondrial respiration, content or morphology in skeletal muscle from obese and insulin‐resistant men

Dollerup

Chubanava

Agerholm

et al. 2019

The Journal of Physiology

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101

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Key points This is the first long‐term human clinical trial to report on effects of nicotinamide riboside (NR) on skeletal muscle mitochondrial function, content and morphology. NR supplementation decreases nicotinamide phosphoribosyltransferase (NAMPT) protein abundance in skeletal muscle. NR supplementation does not affect NAD metabolite concentrations in skeletal muscle. Respiration, distribution and quantity of muscle mitochondria are unaffected by NR. NAMPT in skeletal muscle correlates positively with oxidative phosphorylation Complex I, sirtuin 3 and succinate dehydrogenase. Abstract Preclinical evidence suggests that the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide riboside (NR) boosts NAD+ levels and improves diseases associated with mitochondrial dysfunction. We aimed to determine if dietary NR supplementation in middle‐aged, obese, insulin‐resistant men affects mitochondrial respiration, content and morphology in skeletal muscle. In a randomized, placebo‐controlled clinical trial, 40 participants received 1000 mg NR or placebo twice daily for 12 weeks. Skeletal muscle biopsies were collected before and after the intervention. Mitochondrial respiratory capacity was determined by high‐resolution respirometry on single muscle fibres. Protein abundance and mRNA expression were measured by Western blot and quantitative PCR analyses, respectively, and in a subset of the participants (placebo n = 8; NR n = 8) we quantified mitochondrial fractional area and mitochondrial morphology by laser scanning confocal microscopy. Protein levels of nicotinamide phosphoribosyltransferase (NAMPT), an essential NAD+ biosynthetic enzyme in skeletal muscle, decreased by 14% with NR. However, steady‐state NAD+ levels as well as gene expression and protein abundance of other NAD+ biosynthetic enzymes remained unchanged. Neither respiratory capacity of skeletal muscle mitochondria nor abundance of mitochondrial associated proteins were affected by NR. Moreover, no changes in mitochondrial fractional area or network morphology were observed. Our data do not support the hypothesis that dietary NR supplementation has significant impact on skeletal muscle mitochondria in obese and insulin‐resistant men. Future studies on the effects of NR on human skeletal muscle may include both sexes and potentially provide comparisons between young and older people.

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Section: Figure 7 Hierarchical Clustering Analysis On the Subset Ofsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 97%

Section: Figure 7 Hierarchical Clustering Analysis On the Subset Ofmentioning

confidence: 89%

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Nicotinamide riboside does not alter mitochondrial respiration, content or morphology in skeletal muscle from obese and insulin‐resistant men

Dollerup

Chubanava

Agerholm

et al. 2019

The Journal of Physiology

Self Cite

101

110

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“…Recently, the anti-inflammatory properties of NAD + -boosting compounds have been extended to the human scenario. The short-term administration (21 days) of NR to aged individuals increases NAD + levels in the muscle and reduces the expression of the inflammaging-associated cytokines IL-6, IL-5, and IL-2 [93]. This study opens a door for longer NR interventions in aged humans.…”

Section: Nad + Precursorsmentioning

confidence: 79%

Control of Inflammation by Calorie Restriction Mimetics: On the Crossroad of Autophagy and Mitochondria

Gabandé‐Rodríguez

Heras

Mittelbrunn

2019

Cells

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Mitochondrial metabolism and autophagy are two of the most metabolically active cellular processes, playing a crucial role in regulating organism longevity. In fact, both mitochondrial dysfunction or autophagy decline compromise cellular homeostasis and induce inflammation. Calorie restriction (CR) is the oldest strategy known to promote healthspan, and a plethora of CR mimetics have been used to emulate its beneficial effects. Herein, we discuss how CR and CR mimetics, by modulating mitochondrial metabolism or autophagic flux, prevent inflammatory processes, protect the intestinal barrier function, and dampen both inflammaging and neuroinflammation. We outline the effects of some compounds classically known as modulators of autophagy and mitochondrial function, such as NAD+ precursors, metformin, spermidine, rapamycin, and resveratrol, on the control of the inflammatory cascade and how these anti-inflammatory properties could be involved in their ability to increase resilience to age-associated diseases.

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“…Taken together, the findings collected by Dollerup and collaborators provide robust evidence that 12 weeks of NRS does not improve skeletal muscle mitochondrial respiration and whole-body glucose homeostasis in a population of obese and insulin-resistant men. In support of this conclusion, research recently published in Cell Reports shows in healthy elderly individuals that 250 mg of NRS twice a day for 21 days does not improve skeletal muscle mitochondrial bioenergetics and whole-body glucose homeostasis (Elhassan et al 2019). J Physiol 598.4 Collectively, these findings therefore challenge preclinical data obtained in animal models and indicate that NRS is ineffective in enhancing mitochondrial respiration and whole-body glucose homeostasis in obese insulin-resistant men.…”

mentioning

confidence: 95%

Nicotinamide riboside supplementation to improve skeletal muscle mitochondrial health and whole‐body glucose homeostasis: does it actually work in humans?

Leduc‐Gaudet

Dulac²,

Reynaud³

et al. 2020

The Journal of Physiology

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Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures

Abstract: Highlights d NR supplementation in aged subjects augments the skeletal muscle NAD + metabolome d NR supplementation does not affect skeletal muscle mitochondrial bioenergetics d NR supplementation reduces levels of circulating inflammatory cytokines

Cited by 272 publications

References 71 publications

Nicotinamide riboside does not alter mitochondrial respiration, content or morphology in skeletal muscle from obese and insulin‐resistant men

Nicotinamide riboside does not alter mitochondrial respiration, content or morphology in skeletal muscle from obese and insulin‐resistant men

Control of Inflammation by Calorie Restriction Mimetics: On the Crossroad of Autophagy and Mitochondria

Nicotinamide riboside supplementation to improve skeletal muscle mitochondrial health and whole‐body glucose homeostasis: does it actually work in humans?

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