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Nicotinamide adenine dinucleotide (NAD + ) has emerged as a critical co-substrate for enzymes involved in the beneficial effects of regular calorie restriction on healthspan. As such, the use of NAD + precursors to augment NAD + bioavailability has been proposed as a strategy for improving cardiovascular and other physiological functions with aging in humans. Here we provide the evidence in a 2 × 6-week randomized, double-blind, placebo-controlled, crossover clinical trial that chronic supplementation with the NAD + precursor vitamin, nicotinamide riboside (NR), is well tolerated and effectively stimulates NAD + metabolism in healthy middle-aged and older adults. Our results also provide initial insight into the effects of chronic NR supplementation on physiological function in humans, and suggest that, in particular, future clinical trials should further assess the potential benefits of NR for reducing blood pressure and arterial stiffness in this group. Declining NAD + levels have been linked to aging-associated pathologies. Here the authors present results of a double-blind, randomized crossover trial on 30 healthy middle-aged individuals to show that nicotinamide riboside effectively elevates NAD + levels in humans, appears to be well tolerated, and may have potential to improve cardiovascular parameters.

Nicotinamide riboside (NR) is a newly discovered nicotinamide adenine dinucleotide (NAD + ) precursor vitamin. A crystal form of NR chloride termed NIAGEN is generally recognized as safe (GRAS) for use in foods and the subject of two New Dietary Ingredient Notifications for use in dietary supplements. To evaluate the kinetics and dose-dependency of NR oral availability and safety in overweight, but otherwise healthy men and women, an 8-week randomized, double-blind, placebo-controlled clinical trial was conducted. Consumption of 100, 300 and 1000 mg NR dose-dependently and significantly increased whole blood NAD + (i.e., 22%, 51% and 142%) and other NAD + metabolites within 2 weeks. The increases were maintained throughout the remainder of the study. There were no reports of flushing and no significant differences in adverse events between the NR and placebo-treated groups or between groups at different NR doses. NR also did not elevate low density lipoprotein cholesterol or dysregulate 1-carbon metabolism. Together these data support the development of a tolerable upper intake limit for NR based on human data.

Abstract Context Nicotinamide adenine dinucleotide (NAD) levels decline with aging and age-related decline in NAD has been postulated to contribute to age-related diseases. Objective We evaluated the safety and physiologic effects of NAD augmentation by administering its precursor, β-nicotinamide mononucleotide (MIB-626, Metro International Biotech, Worcester, MA), in adults at risk for age-related conditions. Methods Thirty overweight or obese adults, ≥ 45 years, were randomized in a 2:1 ratio to 2 MIB-626 tablets each containing 500 mg of microcrystalline β-nicotinamide mononucleotide or placebo twice daily for 28 days. Study outcomes included safety; NAD and its metabolome; body weight; liver, muscle, and intra-abdominal fat; insulin sensitivity; blood pressure; lipids; physical performance, and muscle bioenergetics. Results Adverse events were similar between groups. MIB-626 treatment substantially increased circulating concentrations of NAD and its metabolites. Body weight (difference −1.9 [−3.3, −0.5] kg, P = .008); diastolic blood pressure (difference −7.01 [−13.44, −0.59] mmHg, P = .034); total cholesterol (difference −26.89 [−44.34, −9.44] mg/dL, P = .004), low-density lipoprotein (LDL) cholesterol (−18.73 [−31.85, −5.60] mg/dL, P = .007), and nonhigh-density lipoprotein cholesterol decreased significantly more in the MIB-626 group than placebo. Changes in muscle strength, muscle fatigability, aerobic capacity, and stair-climbing power did not differ significantly between groups. Insulin sensitivity and hepatic and intra-abdominal fat did not change in either group. Conclusions MIB-626 administration in overweight or obese, middle-aged and older adults safely increased circulating NAD levels, and significantly reduced total LDL and non-HDL cholesterol, body weight, and diastolic blood pressure. These data provide the rationale for larger trials to assess the efficacy of NAD augmentation in improving cardiometabolic outcomes in older adults.

Nicotinamide adenine diphosphate (NAD⁺) is a novel messenger RNA 5′ cap in Escherichia coli, yeast, mammals, and Arabidopsis. Transcriptome-wide identification of NAD⁺-capped RNAs (NAD-RNAs) was accomplished through NAD captureSeq, which combines chemoenzymatic RNA enrichment with high-throughput sequencing. NAD-RNAs are enzymatically converted to alkyne-RNAs that are then biotinylated using a copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction. Originally applied to E. coli RNA, which lacks the m⁷G cap, NAD captureSeq was then applied to eukaryotes without extensive verification of its specificity for NAD-RNAs vs. m⁷G-capped RNAs (m⁷G-RNAs). In addition, the Cu2+ ion in the CuAAC reaction causes RNA fragmentation, leading to greatly reduced yield and loss of full-length sequence information. We developed an NAD-RNA capture scheme utilizing the copper-free, strain-promoted azide–alkyne cycloaddition reaction (SPAAC). We examined the specificity of CuAAC and SPAAC reactions toward NAD-RNAs and m⁷G-RNAs and found that both prefer the former, but also act on the latter. We demonstrated that SPAAC-NAD sequencing (SPAAC-NAD-seq), when combined with immunodepletion of m⁷G-RNAs, enables NAD-RNA identification with accuracy and sensitivity, leading to the discovery of new NAD-RNA profiles in Arabidopsis. Furthermore, SPAAC-NAD-seq retained full-length sequence information. Therefore, SPAAC-NAD-seq would enable specific and efficient discovery of NAD-RNAs in prokaryotes and, when combined with m⁷G-RNA depletion, in eukaryotes.

Background Advances in hematopoietic cell transplantation (HCT) have led to marked improvements in survival. However, adolescents and young adults (AYAs) who undergo HCT are at high risk of developing sarcopenia (loss of skeletal muscle mass) due to the impact of HCT-related exposures on the developing musculoskeletal system. HCT survivors who have sarcopenia also have excess lifetime risk of non-relapse mortality. Therefore, interventions that increase skeletal muscle mass, metabolism, strength, and function are needed to improve health in AYA HCT survivors. Skeletal muscle is highly reliant on mitochondrial energy production, as reflected by oxidative phosphorylation (OXPHOS) capacity. Exercise is one approach to target skeletal muscle mitochondrial OXPHOS, and in turn improve muscle function and strength. Another approach is to use “exercise enhancers”, such as nicotinamide riboside (NR), a safe and well-tolerated precursor of nicotinamide adenine dinucleotide (NAD + ), a cofactor that in turn impacts muscle energy production. Interventions combining exercise with exercise enhancers like NR hold promise, but have not yet been rigorously tested in AYA HCT survivors. Methods/design We will perform a randomized controlled trial testing 16 weeks of in-home aerobic and resistance exercise and NR in AYA HCT survivors, with a primary outcome of muscle strength via dynamometry and a key secondary outcome of cardiovascular fitness via cardiopulmonary exercise testing. We will also test the effects of these interventions on i) muscle mass via dual energy x-ray absorptiometry; ii) muscle mitochondrial OXPHOS via an innovative non-invasive MRI-based technique, and iii) circulating correlates of NAD + metabolism via metabolomics. Eighty AYAs (ages 15-30y) will be recruited 6–24 months post-HCT and randomized to 1 of 4 arms: exercise + NR, exercise alone, NR alone, or control. Outcomes will be collected at baseline and after the 16-week intervention. Discussion We expect that exercise with NR will produce larger changes than exercise alone in key outcomes, and that changes will be mediated by increases in muscle OXPHOS. We will apply the insights gained from this trial to develop individualized, evidence-supported precision initiatives that will reduce chronic disease burden in high-risk cancer survivors. Trial registration ClinicalTrials.gov, NCT05194397. Registered January 18, 2022, https://clinicaltrials.gov/ct2/show/NCT05194397 {2a}.

Nicotinamide adenine dinucleotide (NAD+) depletion has been postulated as a contributor to the severity of COVID‐19; however, no study has prospectively characterized NAD+ and its metabolites in relation to disease severity in patients with COVID‐19. We measured NAD+ and its metabolites in 56 hospitalized patients with COVID‐19 and in two control groups without COVID‐19: (1) 31 age‐ and sex‐matched adults with comorbidities, and (2) 30 adults without comorbidities. Blood NAD+ concentrations in COVID‐19 group were only slightly lower than in the control groups (p < 0.05); however, plasma 1‐methylnicotinamide concentrations were significantly higher in patients with COVID‐19 (439.7 ng/mL, 95% CI: 234.0, 645.4 ng/mL) than in age‐ and sex‐matched controls (44.5 ng/mL, 95% CI: 15.6, 73.4) and in healthy controls (18.1 ng/mL, 95% CI 15.4, 20.8; p < 0.001 for each comparison). Plasma nicotinamide concentrations were also higher in COVID‐19 group and in controls with comorbidities than in healthy control group. Plasma concentrations of 2‐methyl‐2‐pyridone‐5‐carboxamide (2‐PY), but not NAD+, were significantly associated with increased risk of death (HR = 3.65; 95% CI 1.09, 12.2; p = 0.036) and escalation in level of care (HR = 2.90, 95% CI 1.01, 8.38, p = 0.049). RNAseq and RTqPCR analyses of PBMC mRNA found upregulation of multiple genes involved in NAD+ synthesis as well as degradation, and dysregulation of NAD+‐dependent processes including immune response, DNA repair, metabolism, apoptosis/autophagy, redox reactions, and mitochondrial function. Blood NAD+ concentrations are modestly reduced in COVID‐19; however, NAD+ turnover is substantially increased with upregulation of genes involved in both NAD+ biosynthesis and degradation, supporting the rationale for NAD+ augmentation to attenuate disease severity. Whole blood NAD+ levels were only modestly reduced in patients hospitalized with COVID‐19 but the circulating levels of NAD+ metabolites, 1‐methylnicotinamide and nicotinamide were markedly elevated. The expression levels of NAD consuming/degrading enzymes as well as of enzymes involved in NAD synthesis were markedly upregulated consistent with increased NAD+ turnover. The circulating levels of NAD+ metabolite, 2‐PY were associated with risk of death and transfer to intensive care.

Key Points NAD is an important redox factor and substrate in various signalling processes, in which it is irreversibly degraded to form molecules that are of key relevance to cellular homeostasis. Both NAD + -dependent metabolic and signalling pathways are altered in cancer cells, providing a number of potential drug targets. Permanent synthesis of NAD is essential to fuel bioenergetic processes and maintain balanced cell regulation. NAD + is synthesized from vitamin B 3 (niacin, including both nicotinamide and nicotinic acid) and the corresponding nucleosides. However, the predominant source to maintain NAD levels is nicotinamide (Nam), which arises endogenously from NAD + -dependent signalling processes. Therefore, nicotinamide phosphoribosyltransferase (NamPRT) is of outstanding importance, as it is the only human enzyme that salvages Nam into NAD + synthesis. NamPRT inhibitors are currently under scrutiny to evaluate their potential in cancer therapy based on NAD + depletion. Likewise, inhibitors of nicotinamide mononucleotide adenylyltransferases (NMNATs) have the potential to affect NAD levels, as these enzymes are required in all pathways of NAD + generation. Moreover, the expression of the three human isoforms is tissue- and cell compartment-specific, suggesting the possibility of more specific therapeutic approaches. However, so far, specific and potent inhibitors are not available. Several NAD-dependent signalling pathways are involved in the control of cell cycle progression, transcriptional regulation and DNA repair and have therefore been identified as promising targets in cancer therapy. The NAD + -dependent protein deacetylases (Sirtuins) SIRT1, SIRT3, SIRT6 and SIRT7 are also now of interest in the development of new cancer therapies. Inhibitors of polyADP ribose polymerases (PARPs) have a demonstrated potential in cancer therapy and have recently reached the clinical arena. Major current challenges in their use are selectivity towards specific PARP isoforms, potential impairment of DNA repair in healthy tissues and development of drug resistance. NAD is a vital molecule in all organisms and is a key component of both energy and signal transduction — processes that undergo crucial changes in cancer cells. NAD + -dependent signalling reactions involve the degradation of the molecule, so permanent nucleotide resynthesis through different biosynthetic pathways is crucial for incessant cancer cell proliferation. Is targeting of NAD metabolism a new therapeutic strategy for cancer treatment? NAD is a vital molecule in all organisms. It is a key component of both energy and signal transduction — processes that undergo crucial changes in cancer cells. NAD + -dependent signalling pathways are many and varied, and they regulate fundamental events such as transcription, DNA repair, cell cycle progression, apoptosis and metabolism. Many of these processes have been linked to cancer development. Given that NAD + -dependent signalling reactions involve the degradation of the molecule, permanent nucleotide resynthesis through different biosynthetic pathways is crucial for incessant cancer cell proliferation. This necessity supports the targeting of NAD metabolism as a new therapeutic concept for cancer treatment.

Genetic variants causing loss of function in the synthesis of nicotinamide adenine dinucleotide were shown to cause congenital malformations that comprise the VACTERL association. Niacin supplementation during gestation prevented similar defects in mouse models.

Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disorder. Impaired neuronal bioenergetics and neuroinflammation are thought to play key roles in the progression of AD, but their interplay is not clear. Nicotinamide adenine dinucleotide (NAD⁺) is an important metabolite in all human cells in which it is pivotal for multiple processes including DNA repair and mitophagy, both of which are impaired in AD neurons. Here, we report that levels of NAD⁺ are reduced and markers of inflammation increased in the brains of APP/PS1 mutant transgenic mice with beta-amyloid pathology. Treatment of APP/PS1 mutant mice with the NAD⁺ precursor nicotinamide riboside (NR) for 5 mo increased brain NAD⁺ levels, reduced expression of proinflammatory cytokines, and decreased activation of microglia and astrocytes. NR treatment also reduced NLRP3 inflammasome expression, DNA damage, apoptosis, and cellular senescence in the AD mouse brains. Activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) are associated with DNA damage and senescence. cGAS–STING elevation was observed in the AD mice and normalized by NR treatment. Cell culture experiments using microglia suggested that the beneficial effects of NR are, in part, through a cGAS–STING-dependent pathway. Levels of ectopic (cytoplasmic) DNA were increased in APP/PS1 mutant mice and human AD fibroblasts and down-regulated by NR. NR treatment induced mitophagy and improved cognitive and synaptic functions in APP/PS1 mutant mice. Our findings suggest a role for NAD⁺ depletion-mediated activation of cGAS–STING in neuroinflammation and cellular senescence in AD.