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Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and ...

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#1 Engadin

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Posted 06 November 2019 - 06:34 PM


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C O M P L E T E   T I T L E :   Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures

 

 

 

F U L L   T E X T   S O U R C E :   Cell Reports

 

 

 

 

Highlights

 
• NR supplementation in aged subjects augments the skeletal muscle NAD+ metabolome
 
• NR supplementation does not affect skeletal muscle mitochondrial bioenergetics
 
• NR supplementation reduces levels of circulating inflammatory cytokines
 
 
Summary
 
Nicotinamide adenine dinucleotide (NAD+) is modulated by conditions of metabolic stress and has been reported to decline with aging in preclinical models, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD+ metabolome and if it can alter muscle mitochondrial bioenergetics. We supplemented 12 aged men with 1 g NR per day for 21 days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways, without altering mitochondrial bioenergetics. NR also depressed levels of circulating inflammatory cytokines. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR.
 
 
 
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Introduction
 
Aging is characterized by a decline in metabolic and physiological functions of all organs within the body. A hallmark feature of aging is the progressive loss of skeletal muscle mass and function that can progress to sarcopenia, which is associated with significant morbidity and mortality and substantial healthcare costs (Kim and Choi, 2013, Sousa et al., 2016). Exercise is considered a frontline modality to combat age-related muscle decline (Costford et al., 2010). However, nutritional strategies may also offer an effective countermeasure to age-associated morbidities and promote healthy muscle aging (Bogan and Brenner, 2008).
 
Nicotinamide adenine dinucleotide (NAD+) homeostasis is critical to cell and organismal function. In addition to its classical role in redox metabolism, NAD+ is a substrate for enzymes such as sirtuins, poly-ADPribose polymerases (PARPs), and cyclic ADPribose synthetases that regulate key cellular processes of energy metabolism, DNA damage repair, and calcium signaling (Yoshino et al., 2018). Improving NAD+ availability via the supplementation of the NAD+ precursor nicotinamide riboside (NR) (Bieganowski and Brenner, 2004, Trammell et al., 2016a) has emerged as a potential strategy to augment tissue-specific NAD+ homeostasis and improve physiological function (Elhassan et al., 2017). A range of physiological stresses associated with the depletion of NAD+ and/or nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) have been ameliorated with NR supplementation in mice, including prevention of noise-induced hearing loss (Brown et al., 2014), resistance to weight gain (Cantó et al., 2012), reduction of blood glucose, hepatic steatosis and neuropathy on a high-fat diet (Trammell et al., 2016b), improvement of cardiac function in genetic cardiomyopathy (Diguet et al., 2018), and prevention of cortical neuronal degeneration (Vaur et al., 2017). Depletion of the enzyme nicotinamide phosphoribosyltransferase (NAMPT), rate-limiting for NAD+ biosynthesis, in mouse skeletal muscle severely diminishes NAD+ levels and induces sarcopenia. Oral repletion of NAD+ with NR in this model rescued pathology in skeletal muscle in a cell-autonomous manner (Frederick et al., 2016). However, recent data in mice tracing NAD+ fluxes questioned whether oral NR has the ability to access muscle (Liu et al., 2018). Thus, whether oral NR can augment the human skeletal muscle NAD+ metabolome is currently unknown.
 
A decline in NAD+ availability and signaling appears to occur as part of the aging process in many species (Gomes et al., 2013, Mouchiroud et al., 2013), though there is a paucity of data to confirm that this is the case in human aging. NR and nicotinamide mononucleotide (NMN) are reported to extend life spans (Zhang et al., 2016) and enhance metabolism in aged mice (Mills et al., 2016). To date, NR supplementation studies in humans have focused on cardiovascular (Martens et al., 2018), systemic metabolic (Dollerup et al., 2018), exercise (Dolopikou et al., 2019), and safety (Conze et al., 2019) end-points, but have not addressed advanced aging, tissue metabolomic changes, or effects on muscle metabolism and function.
Herein, we set out to study if oral NR is available to aged human skeletal muscle and whether potential effects on muscle metabolism can be detected. We conducted a 21-day NR supplementation intervention in a cohort of 70–80-year-old men in a placebo-controlled, double-blind, crossover trial. We demonstrate that NR augments the skeletal muscle NAD+ metabolome, inducing a gene expression signature suggestive of downregulation of energy metabolism pathways, but without affecting muscle mitochondrial bioenergetics or metabolism. Additionally, we show that NR suppresses specific circulating inflammatory cytokine levels.
 
 
Results
 
Oral NR Is Safe and Well-Tolerated in Aged Adults
 
Twelve aged (median age of 75 years) and marginally overweight (median BMI of 26.6 kg/m2; range 21–30), but otherwise healthy, men were recruited and orally supplemented with 1-g NR per day for 21 days in a placebo-controlled, randomized, double-blind, crossover design, with 21 days’ washout period between phases. Baseline characteristics of participants are included in Table S1. NR chloride (Niagen) and a placebo were provided as 250-mg capsules (ChromaDex), and subjects were instructed to take two in the morning and two in the evening. All participants completed the study visits (5 in total) and assessments according to protocol (Figure S1). Visit 1 was a screening and enrollment visit, while visit 4 was after the washout period, and only fasting blood and 24-h urine were collected. The protocol design for visits 2, 3, and 5 included muscle biopsy, fasting blood analyses, glucose tolerance test, muscle arterio-venous difference technique, venous occlusive plethysmography, and indirect calorimetry analysis (Figure S1). NR was well tolerated, and screening for a range of hematological and clinical biochemistry safety parameters (including renal, liver, and thyroid functions) revealed no adverse effects (Table S2). No clinical adverse events were reported during the intervention in either phase. Of note, four participants (33.3%), blinded to the intervention arm, self-reported a noticeable increase in libido while on NR. There were no such reports while on the placebo.
 
 
Oral NR Augments the Skeletal Muscle NAD+ Metabolome
 
To assess the effects of NR supplementation on NAD+ metabolism, we used a targeted liquid chromatography-mass spectrometry (LC-MS/MS) method (Trammell and Brenner, 2013) to quantify the NAD+ metabolome in skeletal muscle, whole venous blood, and urine. We examined the NAD+ metabolome in skeletal muscle biopsies from all participants in a fasted state at baseline and after the NR and placebo phases, 14 h after the last dose and prior to the physiological assessments. Samples were collected 14 h after the last dose so participants could attend in a fasted state, as well as to evaluate the effects of longer-term NR administration rather than those of an acute dose. Fourteen metabolites were measured in muscle extracts (Figures 1 and S2A; Table S3). NR was detectable in muscle but was not elevated in the NR supplementation period (NR 1.4 pmol/mg μM versus placebo 1.25 pmol/mg; p = 0.23). Consistent with nicotinic acid adenine dinucleotide (NAAD) as a highly sensitive biomarker of NR supplementation and an enhanced rate of NAD+ synthesis (Trammell et al., 2016a), we found that oral NR resulted in a 2-fold increase in muscle NAAD (NR 0.73 pmol/mg versus placebo 0.35 pmol/mg; p = 0.004), without an increase in NAD+ (NR 210 pmol/mg versus 197 pmol/mg; p = 0.22). NR supplementation did not affect muscle nicotinamide (NAM) (NR 92.0 pmol/mg versus placebo 86.5 pmol/mng; p = 0.96). However, remarkably, we detected 5-fold increases in the products of NAM methylation clearance pathways; N-methyl nicotinamide (MeNAM; NR 1.45 pmol/mg versus placebo 0.35 pmol/mg; p = 0.006), N1-methyl-2-pyridone-5-carboxamide (Me-2-py; NR 6.6 pmol/mg versus placebo 1.1 pmol/mg; p < 0.001), and N1-methyl-4-pyridone-5-carboxamide (Me-4-py; NR 1.6 pmol/mg versus placebo 0.3 pmol/mg; p < 0.001) (Figures 1 and S2A; Table S3).
 
 
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Figure 1NR Augments the Human Skeletal Muscle NAD+ Metabolome
Schematic representation of nicotinamide riboside (NR) metabolism within the nicotinamide adenine dinucleotide (NAD+) metabolome, accompanied by observed levels of metabolites measured using LC-MS/MS in skeletal muscle, whole blood, and urine at baseline and after each of the NR and placebo periods. NAD+ metabolomics data at the end of the washout period are shown in Table S3. Skeletal muscle data were normalized to the weight of the muscle pellet used for extraction. Urine data were normalized to urinary creatinine. Other metabolites are shown in Figure S2. Data are obtained from 12 participants at each phase and presented as mean ± SEM. Significance was set at p < 0.05 using paired t tests and represents the differences between NR and the placebo and between NR and baseline. The absence of significance symbols indicates a lack of statistical significance. BLQ, below limit of quantification; NMN, nicotinamide mononucleotide; NAAD, nicotinic acid adenine dinucleotide; NAM, nicotinamide; NAMOx, nicotinamide N-oxide; MeNAM, N-methyl nicotinamide; Me-2-py, N1-Methyl-2-pyridone-5- carboxamide.
 

 

In the blood, we measured 15 metabolites from each participant at baseline and following each of the NR, placebo, and washout periods (Figures 1 and S2B; Table S3). NR was also detectable in the blood but was not increased, compared to the placebo at 14 h after the last dose of NR (NR 0.16 μM versus placebo 0.15 μM; p = 0.31). This is expected, as the predicated Cmax for NR is approximately 3 h (Airhart et al., 2017). NR increased the concentrations of NAD+ >2-fold (NR 47.75 μM versus placebo 20.90 μM; p < 0.001) and NMN 1.4-fold (NR 1.63 μM versus placebo 1.13 μM; p < 0.001). A recent study reported that oral NR is rapidly metabolized in the liver to NAM, which can enhance tissue NAD+ metabolomes (Liu et al., 2018). However, chronic NR supplementation did not elevate NAM in the blood (NR 10.60 μM versus placebo 9.50 μM; p = 0.41). Again, NAM urinary clearance pathways were highly active following NR, with marked excess of MeNAM (NR 0.66 μM versus placebo 0.10 μM; p < 0.001), Me-2-py (NR 7.69 μM versus placebo 1.44 μM; p < 0.001), and Me-4-py (NR 3.82 μM versus placebo 0.48 μM; p < 0.001) (Figures 1 and S2B; Table S3). NR elevated blood NAAD levels by 4.5-fold (NR 0.18 μM versus placebo 0.04 μM; p < 0.001).
 
Urinary NAD+ metabolomics showed that NR was detectable and increased with NR supplementation (NR 41.5 μmol/mol creatinine versus placebo 31.7 μmol/mol creatinine; p = 0.02) (Figure 1). Furthermore, a near-20-fold increase in nicotinic acid riboside (NAR; NR-185.5 μmol/mol creatinine versus placebo-10.3 μmol/mol creatinine; p = 0.001) was observed. This observation may support the suggestion that NR supplementation leads to retrograde production of NAAD, nicotinic acid mononucleotide (NAMN), and NAR (Trammell et al., 2016a). However, direct NR transformation into NAR cannot be excluded. Unlike muscle and blood, NAM was elevated in the urine 2.5-fold (NR-282 μmol/mol creatinine versus placebo-106.5 μmol/mol creatinine; p = 0.004). These data establish the extent and breadth of changes to NAD+ metabolites in human muscle, blood, and urine after NR supplementation. The data indicate that oral NR greatly boosts the blood NAD+ metabolome without an increase in NAM, increases muscle NAD+ metabolism, and leads to the disposal of urinary clearance products.
 
 
Oral NR Results in Downregulation of Gene Sets Associated with Energy Metabolism in Skeletal Muscle
 
We next assessed NR-mediated transcriptional changes in skeletal muscle. RNA sequencing followed by differential gene expression (DGE) analysis of muscle biopsies from the 12 participants revealed 690 upregulated and 398 downregulated genes between baseline and NR supplementation at p value < 0.05 (Figure 2A; Table S4). Using gene annotation analysis (gene set enrichment analysis [GSEA]) (Mootha et al., 2003, Subramanian et al., 2005), we examined the enrichment of genes that belong to known molecular pathways in our list of up- or downregulated genes. Our results suggest that genes significantly downregulated with NR supplementation were enriched in pathways relating to energy metabolism, including those of glycolysis, tricarboxylic acid (TCA) cycle, and mitochondria (Figure 2B; Table S5). This is consistent with the recent discovery that oral NR depresses mitochondrial membrane potential while improving blood stem cell production in mice (Vannini et al., 2019).
 
 
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Figure 2NR Supplementation Induces a Transcriptional Signature in Human Skeletal Muscle
 
(A) Differential gene expression analysis on baseline and NR-treated muscle samples (n = 12 at each phase). Volcano plot of differential gene expression between baseline and NR treated human muscle samples. Fold change (Log2, x axis) of gene expression is plotted against p value for differential gene expression (–Log10, y axis). Colored dots represent Ensembl genes that are either upregulated (in orange) or downregulated (in blue) upon NR supplementation at a p value < 0.05.
 
(B and C) Gene Ontology analysis of significantly dysregulated genes upon NR supplementation for (B) downregulated genes and © upregulated genes. Gene Ontology analysis was performed using GSEA. Bars represent the p value (–Log10) of overlap from hypergeometric distribution.
 
(D) Gene set enrichment analysis (GSEA) suggests that genes belonging to the gene set “glycolysis” are downregulated upon NR supplementation. The normalized enrichment score (NES) and nominal p value are presented on the top-left corner of the graph.
 
(E) As in (D), but for genes involved in the TCA cycle.
 
(F) As in (D), but for genes involved in the gene set “mitochondria.”
 
(G) A qPCR analysis of a select panel of downregulated genes identified through differential gene expression analysis. GAPDH was used as housekeeping gene. Error bars represent SEM (n = 12).
 
(H) As in (G), but for NAD+ pathway-related genes.
 
(I) Quantification of phosphoglycerate kinase 1 (PGK1), phosphoglucomutase 1 (PGM1), and pyruvate kinase M1 (PKM1) proteins using immunoblotting assay. Tubulin was used as a loading control.
Data are obtained from 12 participants at each phase and wherever relevant are presented as mean ± SEM. Significance was set at p < 0.05. The absence of significance symbols indicates a lack of statistical significance.

 

 

 

Pathways upregulated upon NR supplementation prominently belonged to Gene Ontology categories such as cell adhesion, actin cytoskeleton organization, and cell motility (Figure 2C). This supports a previously identified role for the NAD+-generating enzyme NR kinase 2b (Nrk2b) in zebrafish skeletal muscle cell adhesion (Goody et al., 2010).
 
We next examined all the genes that belonged to the glycolysis, mitochondrial, and TCA cycle pathways and found that they were predominantly downregulated following NR supplementation, whereas 10 control gene sets of the same size and expression level were not (Figures 2D–2F and S3A). Similarly, we found that the genes belonging to the Gene Ontology terms actin filament-based process, cell motility, and biological cell adhesion were mainly upregulated upon NR supplementation (Figures S3B and S3C).
 
In agreement with the DGE analysis, quantitative real-time PCR showed downregulation of selected genes involved in energy metabolism (Figure 2G). We found no changes in the transcript levels of key genes involved in NAD+ metabolism, corroborating the DGE analysis (Figure 2H). We also verified some of the upregulated targets by qPCR (Figure S3D) and undertook some immunoblotting validation (Figure S3D).
 
As it has previously been shown that NR increases glycolysis in mouse cardiac cells (Diguet et al., 2018), and because our data do not support an NR-mediated transcriptional upregulation of glycolysis related genes, we examined protein expression levels of glycolytic enzymes in our muscle biopsies and show them to be unchanged after NR (Figure 2I).
 
 
Three Weeks of Oral NR Does Not Alter Skeletal Muscle Mitochondrial Bioenergetics or Hand-Grip Strength
 
Several preclinical studies suggest that NR enhances mitochondrial energy programs in skeletal muscle (Cantó et al., 2012, Frederick et al., 2016) through mechanisms that involve redox and sirtuins activation. Therefore, we undertook a detailed assessment of muscle mitochondrial respiration in biopsies after NR supplementation using high-resolution respirometry, the gold standard method for the ex vivo assessment of mitochondrial function. No differences were detected between the NR and placebo groups in skeletal muscle complex I- and complex II-mediated oxidative phosphorylation and maximal respiratory capacity, with (Figure 3A) and without (Figure 3B) the prior addition of the fatty acid conjugate octanoyl-carnitine. In line with this, the activity of citrate synthase, commonly used as a quantitative measure of mitochondrial content (Larsen et al., 2012) (Figure 3C), and mitochondrial copy number (mtDNA) (Phielix et al., 2008) (Figure 3D) were unchanged by NR supplementation. Similarly, levels of skeletal muscle biopsy mitochondrial resident proteins, directly involved in the electron transport chain, were unaltered upon NR supplementation (Figure 3E). We then tested whether the NR-driven increase in the NAD+ metabolome translates into higher sirtuin-mediated deacetylation activity, and we performed western blotting to assess pan-acetylation status, but again did not detect NR-mediated changes to muscle protein acetylation (Figure 3F).
 
 
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Figure 3Human Skeletal Muscle Mitochondrial Bioenergetics Remain Unaltered with NR Supplementation
 
(A) Mitochondrial respiration of permeabilized muscle fibers upon the addition of complex I and complex II substrates at baseline and after 3 weeks of supplementation of NR and the placebo. MG, malate and glutamate; D, ADP; S, succinate; c, cytochrome C; F, FCCP; Rot, rotenone. Data are normalized to muscle fiber weight.
 
(B) Mitochondrial respiration as per (A), but with the prior addition of the fatty acid conjugate octanoyl-carnitine to malate (MOct).
 
© Citrate synthase (CS) activity in human skeletal muscle at baseline and after NR and the placebo.
 
(D) Relative PCR expression of mitochondrial DNA (mtDNA) to nuclear DNA (nDNA) at baseline and after NR and the placebo, expressed as arbitrary units.
 
(E) Western blot showing the expression of selected mitochondrial proteins in skeletal muscle lysates compared to β-actin as housekeeping protein.
 
(F) Western blot showing the expression of acetylation proteins in skeletal muscle lysates compared to β-actin as housekeeping protein.
Data are obtained from 12 participants at each phase and wherever relevant are presented as mean ± SEM. Significance was set at p < 0.05. The absence of significance symbols indicates a lack of statistical significance.
 
 
 
Data from rodents suggest that NAD+ supplementation can improve the physiological function in skeletal muscle decline (Cantó et al., 2012, Frederick et al., 2016, Mills et al., 2016); thus, we used hand-grip strength as a surrogate marker for muscle function, but one cannot expect hand-grip strength to change after 3 weeks of NR supplementation and without muscle training. Hand-grip strength correlates with leg strength and is used for the diagnosis of sarcopenia and frailty, and it is a better predictor for clinical outcomes than low muscle mass (Lauretani et al., 2003). A decline in hand-grip strength is observed after the third decade of life (when median peak strength is 51 kg of force in men) (Dodds et al., 2014), dropping to median of 33.8 kg of force in our participants. A grip strength of <30 kg of force in men is a diagnostic criterion for sarcopenia (Cruz-Jentoft et al., 2010, Cruz-Jentoft et al., 2019). After 3 weeks of supplementation, we did not observe any differences in the participants’ peak hand-grip strengths (NR 32.5 kg versus placebo 34.7 kg; p = 0.96) or body-weight-adjusted relative strength (NR 2.4 versus placebo 2.3; p = 0.96) between NR and the placebo (Figure S4).
 
 
Oral NR Does Not Alter Skeletal Muscle Blood Flow or Substrate Utilization
 
Recent mouse data showed that NMN increases angiogenesis and muscle blood flow (Das et al., 2018). Therefore, we used venous occlusive plethysmography to test forearm muscle blood flow in the participants in a non-invasive manner (Greenfield et al., 1963). At fasting, no NR-mediated differences were detected in muscle blood. Following oral glucose load, muscle blood flow gradually increases, but again with no differences between NR and the placebo (Figure 4A).
 
 
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Figure 4Forearm Muscle Blood Flow and Substrate Utilization Are Unaffected by NR Supplementation
 
(A) Muscle blood flow using venous occlusive plethysmography at baseline and after the NR and placebo phases. The green dotted line represents when 75 g of oral glucose load was taken.
 
(B and C) Muscle O2 consumption (B) and CO2 production © at baseline and after NR and the placebo. The green dotted line represents when 75 g of oral glucose load was taken.
 
(D and E) Muscle glucose uptake (D) and lactate release (E) at baseline and after NR and the placebo. The green dotted line represents when 75 g of oral glucose load was taken.
 
Data are obtained from 12 participants at each phase and presented as mean ± SEM. Significance was set at p < 0.05 using a paired t test. The absence of significance symbols indicates a lack of statistical significance.
 
 
 
We then used the arteriovenous difference method (see Method Details) to compare substrate utilization across the forearm muscle (between arterial blood supplying the muscle and venous blood drained from the muscle), with muscle blood flow taken into consideration (Bickerton et al., 2007). No differences were detected in O2 consumption (Figure 4B) and CO2 production (Figure 4C) between NR and the placebo at the fasting state and in response to oral glucose. Muscle glucose uptake was increased following oral glucose before a gradual decline. No changes were observed in muscle glucose handling with or without NR (Figure 4D). Oral glucose reduced lactate production from muscle, again without a difference in response between NR and the placebo (Figure 4E). These data suggest that the skeletal muscle transcriptomic signature of downregulated mitochondrial and glycolysis genes is undetectable when considered at a functional level.
 
 
Oral NR Does Not Alter Systemic Cardiometabolic Parameters
 
Several preclinical studies have described that NAD+ supplementation promotes a resistance to weight gain, ameliorates markers of cardiometabolic risk, and improves metabolic flexibility (Yoshino et al., 2018). As NR increased the circulating levels of the NAD+ metabolome, we reasoned that there was increased NAD+ availability and turnover in central and peripheral tissues and assessed for resultant cardiometabolic adaptations. Two studies—one of 12 weeks of NR supplementation at 2 g/day in subjects with obesity (Dollerup et al., 2018) and one of 6 weeks of NR supplementation at 1 g/day in older adults (Martens et al., 2018)—suggested potential benefits with respect to fatty liver and blood pressure, respectively. Data for participants at baseline and following NR or the placebo are reported in Table S1. There were no changes in body weight, blood pressure, lipid profile, fasting glucose and insulin (Table S1), and homeostatic model assessment of insulin resistance (HOMA-IR) (Figure 5A). A rebound increase in non-esterified fatty acids (NEFAs) has previously been associated with the nicotinic acid analog, acipimox (van de Weijer et al., 2015); however, NR did not produce this effect in our trial (Figure 5B). Glucose handling was studied using an oral glucose tolerance test, with no effect of NR measured in glucose levels during the 2-h test (Figure 5C). Following the oral glucose load and the consequent insulin stimulation, NEFA levels were appropriately suppressed, and no difference in this response was observed between NR and the placebo (Figure 5D). We also assessed metabolic flexibility using indirect calorimetry to derive respiratory exchange ratios (RERs; calculated as VCO2 expired/VO2 consumed), reflecting whole-body metabolic substrate use. Measurements were initiated in the fasted state and monitored during the response to the oral glucose load. The median fasting RER was appropriate at 0.72 and 0.73 for the NR and placebo periods, respectively (p = 0.68). In response to glucose, RER values significantly increased, indicating adequate switching from lipids toward carbohydrate utilization, with no differences in response to 3 weeks of NR supplementation observed at 2 h (RERs 0.83 and 0.84 for NR and the placebo, respectively) (Figure 5E).
 
 
 
 
 
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