Nicotinamide mononucleotide maintains cytoskeletal stability and fortifies mitochondrial function to mitigate oocyte damage induced by Triocresyl phosphate.

Triocresyl phosphate (TOCP) was commonly used as flame retardant, plasticizer, lubricant, and jet fuel additive. Studies have shown adverse effects of TOCP on the reproductive system. However, the potential harm brought by TOCP, especially to mammalian female reproductive cells, remains a mystery. In this study, we employed an in vitro model for the first time to investigate the effects of TOCP on the maturation process of mouse oocytes. TOCP exposure hampered the meiotic division process, as evidenced by a reduction in the extrusion of the first polar body from oocytes. Subsequent research revealed the disruption of the oocyte cell cytoskeleton induced by TOCP, resulting in abnormalities in spindle organization, chromosome alignment, and actin filament distribution. This disturbance further extended to the rearrangement of organelles within oocytes, particularly affecting the mitochondria. Importantly, after TOCP treatment, mitochondrial function in oocytes was impaired, leading to oxidative stress, DNA damage, cell apoptosis, and subsequent changes of epigenetic modifications. Supplementation with nicotinamide mononucleotide (NMN) alleviated the harmful effects of TOCP. NMN exerted its mitigating effects through two fundamental mechanisms. On one hand, NMN conferred stability to the cell cytoskeleton, thereby supporting nuclear maturation. On the other hand, NMN enhanced mitochondrial function within oocytes, reducing the excess reactive oxygen species (ROS), restoring meiotic division abnormalities caused by TOCP, preventing oocyte DNA damage, and suppressing epigenetic changes. These findings not only enhance our understanding of the molecular basis of TOCP induced oocyte damage but also offer a promising avenue for the potential application of NMN in optimizing reproductive treatment strategies.

ß-Nicotinamide mononucleotide supplementation prolongs the lifespan of prematurely aged mice and protects colon function in ageing mice.

Ageing is defined as the degeneration of physiological functions in numerous tissues and organs of an organism, which occurs with age. As we age, the gut undergoes a series of changes and weaknesses that may contribute to overall ageing. Emerging evidence suggests that ß-nicotinamide mononucleotide (NMN) plays a role in regulating intestinal function, but there is still a lack of literature on its role in maintaining the colon health of ageing mice. In our research, Zmpste24-/- mice proved that NMN prolonged their life span and delayed senescence. This study was designed to investigate the effects of long-term intervention on regulating colon function in ageing mice. Our results indicated that NMN improved the pathology of intestinal epithelial cells and intestinal permeability by upregulating the expression of intestinal tight junction proteins and the number of goblet cells, increasing the release of anti-inflammatory factors, and increasing beneficial intestinal bacteria. NMN increased the expression of the proteins SIRT1, NMNAT2, and NMNAT3 and decreased the expression of the protein P53. It also regulated the activity of ISCs by increasing Wnt/ß-catenin and Lgr5. Our findings also revealed that NMN caused a significant increase in the relative abundance of Akkermansia muciniphila and Bifidobacterium pseudolongum and notable differences in metabolic pathways related to choline metabolism in cancer. In summary, NMN supplementation can delay frailty in old age, aid healthy ageing, and delay gut ageing.

The therapeutic perspective of NAD+ precursors in age-related diseases.

Nicotinamide adenine dinucleotide (NAD+) is the fundamental molecule that performs numerous biological reactions and is crucial for maintaining cellular homeostasis. Studies have found that NAD+ decreases with age in certain tissues, and age-related NAD+ depletion affects physiological functions and contributes to various aging-related diseases. Supplementation of NAD+ precursor significantly elevates NAD+ levels in murine tissues, effectively mitigates metabolic syndrome, enhances cardiovascular health, protects against neurodegeneration, and boosts muscular strength. Despite the versatile therapeutic functions of NAD+ in animal studies, the efficacy of NAD+ precursors in clinical studies have been limited compared with that in the pre-clinical study. Clinical studies have demonstrated that NAD+ precursor treatment efficiently increases NAD+ levels in various tissues, though their clinical proficiency is insufficient to ameliorate the diseases. However, the latest studies regarding NAD+ precursors and their metabolism highlight the significant role of gut microbiota. The studies found that orally administered NAD+ intermediates interact with the gut microbiome. These findings provide compelling evidence for future trials to further explore the involvement of gut microbiota in NAD+ metabolism. Also, the reduced form of NAD+ precursor shows their potential to raise NAD+, though preclinical studies have yet to discover their efficacy. This review sheds light on NAD+ therapeutic efficiency in preclinical and clinical studies and the effect of the gut microbiota on NAD+ metabolism.

Safety and efficacy of long-term nicotinamide mononucleotide supplementation on metabolism, sleep, and nicotinamide adenine dinucleotide biosynthesis in healthy, middle-aged Japanese men.

Obesity and aging are major risk factors for several life-threatening diseases. Accumulating evidence from both rodents and humans suggests that the levels of nicotinamide adenine dinucleotide (NAD+), a regulator of many biological processes, declines in multiple organs and tissues with aging and obesity. Administration of an NAD+ intermediate, nicotinamide mononucleotide (NMN), replenishes intracellular NAD+ levels and mitigates aging- and obesity-associated derangements in animal models. In this human clinical study, we aimed to investigate the safety and effects of 8-week oral administration of NMN on biochemical, metabolic, ophthalmologic, and sleep quality parameters as well as on chronological alterations in NAD+ content in peripheral tissues. An 8-week, single-center, single-arm, open-label clinical trial was conducted. Eleven healthy, middle-aged Japanese men received two 125-mg NMN capsules once daily before breakfast. The 8-week NMN supplementation regimen was well-tolerated; NAD+ levels in peripheral blood mononuclear cells increased over the course of NMN administration. In participants with insulin oversecretion after oral glucose loading, NMN modestly attenuated postprandial hyperinsulinemia, a risk factor for coronary artery disease (n = 3). In conclusion, NMN overall safely and effectively boosted NAD+ biosynthesis in healthy, middle-aged Japanese men, showing its potential for alleviating postprandial hyperinsulinemia.

Improving lysosomal ferroptosis with NMN administration protects against heart failure.

Myocardial mitochondria are primary sites of myocardial energy metabolism. Mitochondrial disorders are associated with various cardiac diseases. We previously showed that mice with cardiomyocyte-specific knockout of the mitochondrial translation factor p32 developed heart failure from dilated cardiomyopathy. Mitochondrial translation defects cause not only mitochondrial dysfunction but also decreased nicotinamide adenine dinucleotide (NAD+) levels, leading to impaired lysosomal acidification and autophagy. In this study, we investigated whether nicotinamide mononucleotide (NMN) administration, which compensates for decreased NAD+ levels, improves heart failure because of mitochondrial dysfunction. NMN administration reduced damaged lysosomes and improved autophagy, thereby reducing heart failure and extending the lifespan in p32cKO mice. We found that lysosomal damage due to mitochondrial dysfunction induced ferroptosis, involving the accumulation of iron in lysosomes and lipid peroxide. The ameliorative effects of NMN supplementation were found to strongly affect lysosomal function rather than mitochondrial function, particularly lysosome-mediated ferroptosis. NMN supplementation can improve lysosomal, rather than mitochondrial, function and prevent chronic heart failure.

Assessing the Effects of Nicotinamide Mononucleotide Supplementation on Pulmonary Inflammation in Male Mice Subchronically Exposed to Ambient Particulate Matter.

BACKGROUND: Chronic lung injury and dysregulated cellular homeostasis in response to particulate matter (PM) exposure are closely associated with adverse health effects. However, an effective intervention for preventing the adverse health effects has not been developed. OBJECTIVES: This study aimed to evaluate the protective effects of nicotinamide mononucleotide (NMN) supplementation on lung injury and elucidate the mechanism by which NMN improved immune function following subchronic PM exposure. METHODS: Six-week-old male C57BL/6J mice were placed in a real-ambient PM exposure system or filtered air-equipped chambers (control) for 16 wk with or without NMN supplementation in drinking water (regarded as Con-H2O, Exp-H2O, Con-NMN and Exp-NMN groups, respectively) in Shijiazhuang City, China (n=20/group). The effects of NMN supplementation (500mg/kg) on PM-induced chronic pulmonary inflammation were assessed, and its mechanism was characterized using single-cell transcriptomic sequencing (scRNA-seq) analysis of whole lung cells. RESULTS: The NMN-treated mice exhibited higher NAD+ levels in multiple tissues. Following 16-wk PM exposure, slightly less pulmonary inflammation and less collagen deposition were noted in mice with NMN supplementation in response to real-ambient PM exposure (Exp-NMN group) compared with the Exp-H2O group (all p<0.05). Mouse lung tissue isolated from the Exp-NMN group was characterized by fewer neutrophils, monocyte-derived cells, fibroblasts, and myeloid-derived suppressor cells induced by subchronic PM exposure as detected by scRNA-seq transcriptomic analysis. The improved immune functions were further characterized by interleukin-17 signaling pathway inhibition and lower secretion of profibrotic cytokines in the Exp-NMN group compared with the Exp-H2O group. In addition, reduced proportions of differentiated myofibroblasts and profibrotic interstitial macrophages were identified in the NMN-supplemented mice in response to PM exposure. Furthermore, less immune function suppression and altered differentiation of pathological cell phenotypes NMN was related to intracellular lipid metabolism activation. DISCUSSION: Our novel findings suggest that NMN supplementation mitigated PM-induced lung injury by regulating immune functions and improving lipid metabolism in male mice, providing a putative intervention method for prevention of human health effects associated with PM exposure. https://doi.org/10.1289/EHP12259.

Reversing Acute Kidney Injury through Coordinated Interplay of Anti-Inflammation and Iron Supplementation.

Acute kidney injury (AKI) induced by ischemia reperfusion is closely related to mitochondrial dysfunction. Nicotinamide adenine dinucleotide (NAD+ ) can enhance the mitochondrial function and restrain the following inflammation, but it is hardly delivered and lacks renal targeting ability. To address these problems, herein, an ultrasmall Fe3 O4 nanoparticle is used as a carrier to deliver nicotinamide mononucleotide (NMN), a precursor of NAD+ . An outstanding sophistication of the current design is that once NMN is attached on the surface of Fe3 O4 nanoparticles through its phosphate group, the remaining part is structurally highly similar to nicotinamide riboside, which provides an opportunity to deliver the NAD+ precursor into renal cells through nicotinamide riboside kinase 1 on the cell membrane. It is demonstrated that NMN-loaded Fe3 O4 nanoparticles can effectively reverse AKI induced by ischemia reperfusion. In-depth studies indicate that a well-timed iron replenishment following anti-inflammation treatment plays a determined role in recovering AKI, which distinguishes the current study from previous strategies centering on anti-ROS (reactive oxygen species), anti-inflammation, or even iron elimination.

Dietary Supplementation With NAD+-Boosting Compounds in Humans: Current Knowledge and Future Directions.

Advancing age and many disease states are associated with declines in nicotinamide adenine dinucleotide (NAD+) levels. Preclinical studies suggest that boosting NAD+ abundance with precursor compounds, such as nicotinamide riboside or nicotinamide mononucleotide, has profound effects on physiological function in models of aging and disease. Translation of these compounds for oral supplementation in humans has been increasingly studied within the last 10 years; however, the clinical evidence that raising NAD+ concentrations can improve physiological function is unclear. The goal of this review was to synthesize the published literature on the effects of chronic oral supplementation with NAD+ precursors on healthy aging and age-related chronic diseases. We identified nicotinamide riboside, nicotinamide riboside co-administered with pterostilbene, and nicotinamide mononucleotide as the most common candidates in investigations of NAD+-boosting compounds for improving physiological function in humans. Studies have been performed in generally healthy midlife and older adults, adults with cardiometabolic disease risk factors such as overweight and obesity, and numerous patient populations. Supplementation with these compounds is safe, tolerable, and can increase the abundance of NAD+ and related metabolites in multiple tissues. Dosing regimens and study durations vary greatly across interventions, and small sample sizes limit data interpretation of physiological outcomes. Limitations are identified and future research directions are suggested to further our understanding of the potential efficacy of NAD+-boosting compounds for improving physiological function and extending human health span.

Nicotinamide adenine dinucleotide metabolism and arterial stiffness after long-term nicotinamide mononucleotide supplementation: a randomized, double-blind, placebo-controlled trial.

Many animal studies have shown that oral administration of the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide mononucleotide (NMN) prevents the reduction of NAD+ levels in organs and tissues, helping alleviate aging-related diseases. However, there are very few clinical reports of NMN supplementation in humans. Thus, this study aimed to investigate the influence of a 12-week NMN oral supplementation on biochemical and metabolic health parameters. A 12-week randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted. A total of 36 healthy middle-aged participants received one capsule of either 125 mg NMN or placebo twice a day. Among the NAD+ metabolites, the levels of nicotinamide in the serum were significantly higher in the NMN intake group than in the placebo group. Pulse wave velocity values indicating arterial stiffness tended to decrease in the NMN intake group. However, no significant difference was found between the two groups. Long-term NMN supplementation at 250 mg/day was well tolerated and did not cause adverse events. NMN safely and effectively elevated NAD+ metabolism in healthy middle-aged adults. Additionally, NMN supplementation showed potential in alleviating arterial stiffness.

Importance of NAD+ Anabolism in Metabolic, Cardiovascular and Neurodegenerative Disorders.

The role of nicotinamide adenine dinucleotide (NAD+) in ageing has emerged as a critical factor in understanding links to a wide range of chronic diseases. Depletion of NAD+, a central redox cofactor and substrate of numerous metabolic enzymes, has been detected in many major age-related diseases. However, the mechanisms behind age-associated NAD+ decline remains poorly understood. Despite limited conclusive evidence, supplements aimed at increasing NAD+ levels are becoming increasingly popular. This review provides renewed insights regarding the clinical utility and benefits of NAD+ precursors, namely nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), in attenuating NAD+ decline and phenotypic characterization of age-related disorders, including metabolic, cardiovascular and neurodegenerative diseases. While it is anticipated that NAD+ precursors can play beneficial protective roles in several conditions, they vary in their ability to promote NAD+ anabolism with differing adverse effects. Careful evaluation of the role of NAD+, whether friend or foe in ageing, should be considered.

Enhancing the biosynthesis of nicotinamide mononucleotide in Lactococcus lactis by heterologous expression of FtnadE.

BACKGROUND: Nicotinamide mononucleotide (NMN), a key intermediate of nicotinamide adenine dinucleotide, plays an important in anti-aging and disease. Lactococcus lactis, an important probiotic lactic acid bacteria (LAB), has shown great potential for the biosynthesis of NMN, which will significantly affect the probiotic effects of the dairy products. RESULTS: We used the CRISPR/nCas9 technique to knockout nadR gene of L. lactis NZ9000 to enhance the accumulation of NMN by 61%. The nadE* gene from Francisella tularensis with codon optimization was heterologous in L. lactis NZ9000ΔnadR and has a positive effect on NMN production. Combined with optimization of the concentration of substrate nicotinamide, a final intracellular NMN titer was 2289 µmol L-1  mg-1 with 10 g L-1 nicotinamide supplement, which was 5.7-fold higher than that of the control. The transcription levels of key genes (pncA, nadD and prs1) involved in NMN biosynthesis were up-regulated by more than two-fold, indicating that the increase of NMN titer was attributed to FtnadE* heterologous expression. CONCLUSION: Our study provides a better understanding of the NMN biosynthesis pathway in L. lactis, and can facilitate NMN production in LAB via synthetic biology approaches. © 2022 Society of Chemical Industry.

[Degradation kinetics of ß-nicotinamide mononucleotide based on reliable HPLC quantitative method].

To explore the stability characteristics of ß-nicotinamide mononucleotide(NMN) and provide data support for NMN production, preparation, and related product development, this study established a simple HPLC content determination method for NMN in simple substrate and investigated the degradation behavior, degradation products, and degradation kinetics of NMN under various chemical, physical, and biological conditions. The HPLC method employed a Welch Xtimate AQ-C_(18) column(4.6 mm×250 mm, 5 µm), a detection wavelength of 266 nm, a column temperature of 30 ℃, a flow rate of 1.0 mL·min~(-1), an injection volume of 5 µL, and a mobile phase consisting of methanol(A) and a 10 mmol·L~(-1) ammonium formate aqueous solution(B) with a gradient elution(0-6.7 min, 0-4% A; 6.7-13 min, 4%-18% A; 13-14.2 min, 18% A; 14.2-15 min, 18%-0 A; 15-22 min, 0 A). This method provided good separation between NMN and potential impurities and degradation products, and had a wide linear range, short analysis time, good durability, high accuracy, an average sample recovery rate of 98.71%, and an RSD of 1.2%. The instrument precision had an RSD of 0.26%, and the linearity within the examined range was excellent(R~2≥0.999 9). This method can be applied for NMN content determination in simple substrate. The degradation process of NMN in aqueous solution followed apparent first-order kinetics, with the degradation rate primarily influenced by high temperature and pH. NMN was more stable in low-temperature, neutral, or weakly acidic/alkaline environments. Strong acids or strong alkalis could accelerate its degradation, and its degradation rate was less affected by pepsin and trypsin. In an aqueous solution at room temperature, it followed the kinetic equation lg C_t=0.005 7t + 4.817 2, with t_(0.9) and t_(1/2) values of 95.58, 860.26 h, respectively. The results suggest that pH and temperature are the main factors affecting the stability of NMN in aqueous solution, and low temperature, moisture protection, and a weakly acidic environment are more conducive to the storage and application of NMN and its products.

A Narrative Review of Nicotinamide Adenine Dinucleotide (NAD)+ Intermediates Nicotinamide Riboside and Nicotinamide Mononucleotide for Keratinocyte Carcinoma Risk Reduction.

Oral nicotinamide (NAM) supplementation has been shown to decrease the incidence of keratinocyte carcinoma (KC) in high-risk skin cancer patients. NAM is a nicotinamide adenine dinucleotide (NAD+) intermediate and thus directly leads to increased NAD+. This increase in NAD+ is believed to be responsible for NAM’s impact on keratinocyte carcinoma risk. NAD+ has protective cellular effects and is a necessary cofactor for DNA repair, helping to prevent potentially oncogenic mutations. Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are NAD+ intermediates like NAM; however, their protective roles on cellular DNA and effects on cancer have been under-explored. Research into cellular metabolism and aging suggests that NR and NMN can lead to greater increases in NAD+ vs NAM. NR and NMN are safe and well-tolerated and are consequently currently undergoing investigation as agents able to protect against age-associated disease caused by NAD+ depletion. We hypothesize that oral supplementation with NR or NMN may lead to greater reductions in KC than NAM. J Drugs Dermatol. 2022;21(10): 1129-1132. doi:10.36849/JDD.6870.

Systematic Engineering of Escherichia coli for Efficient Production of Nicotinamide Mononucleotide From Nicotinamide.

Research studies on NAD+ have proven its crucial role in aging and disease. Nicotinamide mononucleotide (NMN), as the key intermediate of NAD+, plays a significant role in supplying and maintaining NAD+ levels. In the present study, a biocatalytic method for the efficient synthesis of NMN was established. First, Escherichia coli was systematically modified to make it more conducive to the biosynthesis and accumulation of NMN. Next, the performance of nicotinamide phosphoribosyltransferase from Vibrio bacteriophage KVP40 (VpNadV) was determined, which has the best catalytic activity to produce NMN from nicotinamide. The accumulation of extracellular NMN was further increased after the introduction of an NMN transporter. Fine-tuning of gene expression and copy number led to the synthesis of NMN at the yield of 2.6 g/L at the shake flask level. The introduction of a nicotinamide transporter, BcniaP, could not obviously increase the production of NMN at the shake flask level, but it decreased the production of NMN at the bioreactor level. Finally, the titer of NMN reached 16.2 g/L with a conversion ratio of 97.0% from nicotinamide, both of which are highest according to currently available reports. The fed-batch fermentation with direct supplementation of nicotinamide could facilitate the industrial-scale production of NMN compared to that achieved by the whole-cell catalysis process. These results also represent the highest reported yield of NMN synthesized from nicotinamide in E. coli.

Nicotinamide mononucleotide supplementation protects the intestinal function in aging mice and D-galactose induced senescent cells.

The nicotinamide adenine dinucleotide (NAD+) level shows a temporal decrease during the aging process, which has been deemed as an aging hallmark. Nicotinamide mononucleotide (NMN), a key NAD+ precursor, shows the potential to retard the age-associated functional decline in organs. In the current study, to explore whether NMN has an impact on the intestine during the aging process, the effects of NMN supplementation on the intestinal morphology, microbiota, and NAD+ content, as well as its anti-inflammatory, anti-oxidative and barrier functions were investigated in aging mice and D-galactose (D-gal) induced senescent IPEC-J2 cells. The results showed that 4 months of NMN administration had little impact on the colonic microbiota and NAD+ content in aging mice, while it significantly increased the jejunal NAD+ content and improved the jejunal structure including increasing the villus length and shortening the crypt. Moreover, NMN supplementation significantly up-regulated the mRNA expression of SIRT3, SIRT6, nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), the catalytic subunit of glutamate-cysteine ligase (GCLC), superoxide dismutase 2 (SOD2), occludin, and claudin-1, but down-regulated the mRNA expression of tumor necrosis factor alpha (TNF-α). Specifically, in the D-gal induced senescent IPEC-J2 cells, 500 µM NMN restored the increased mRNA expression of interleukin 6 (IL6ST), IL-1A, nuclear factor (NF-κB1), and claudin-1 to normal levels to some extent. Furthermore, NMN treatment significantly affected the mRNA expression of antioxidant enzymes including NQO1, GCLC, SOD 2 and 3, and GSH-PX1, 3 and 4. In addition, 200 µM NMN enhanced the cell viability and total antioxidant capacity and lowered the reactive oxygen species level of senescent IPEC-J2 cells. Notably, NMN restored the down-regulated protein expression of occludin and claudin-1 induced by D-gal. The above data demonstrated the potential of NMN in ameliorating the structural and functional decline in the intestine during aging.

Insights into the NAD+ biosynthesis pathways involved during meiotic maturation and spindle formation in porcine oocytes.

Treatments that elevate NAD+ levels have been found to improve oocyte quality in mice, cattle, and pigs, suggesting that NAD+ is vital during oocyte maturation. This study aimed to examine the influence of different NAD+ biosynthetic pathways on oocyte quality by inhibiting key enzymes. Porcine oocytes from small antral follicles were matured for 44 h in a defined maturation system supplemented with 2-hydroxynicotinic acid [2-HNA, nicotinic acid phosphoribosyltransferase (NAPRT) inhibitor], FK866 [nicotinamide phosphoribosyltransferase (NAMPT) inhibitor], or gallotannin [nicotinamide mononucleotide adenylyltransferase (NMNAT) inhibitor] and their respective NAD+ pathway modulators (nicotinic acid, nicotinamide, and nicotinamide mononucleotide, respectively). Cumulus expansion was assessed after 22 h of maturation. At 44 h, maturation rates were determined and mature oocytes were fixed and stained to assess spindle formation. Each enzyme inhibitor reduced oocyte maturation rate and adversely affected spindle formation, indicating that NAD+ is required for meiotic spindle assembly. Furthermore, NAMPT and NMNAT inhibition reduced cumulus expansion, whereas NAPRT inhibition affected chromosomal segregation. Treating oocytes with gallotannin and nicotinamide mononucleotide together showed improvements in spindle width, while treating oocytes with 2-HNA and nicotinic acid combined showed an improvement in both spindle length and width. These results indicate that the salvage pathway plays a vital role in promoting oocyte meiotic progression, while the Preiss-Handler pathway is essential for spindle assembly.

NAD supplementation improves mitochondrial performance of cardiolipin mutants.

Cardiolipin (CL) deficiency causes mitochondrial dysfunction and aberrant metabolism that are associated in humans with the severe disease Barth syndrome (BTHS). Several metabolic abnormalities are observed in BTHS patients and model systems, including decreased oxidative phosphorylation, reduced tricarboxylic acid (TCA) cycle flux, and accumulated lactate and D-ß-hydroxybutyrate, which strongly suggests that nicotinamide adenine dinucleotide (NAD) redox metabolism may be altered in CL-deficient cells. In this study, we identified abnormal NAD+ metabolism in multiple BTHS model systems and demonstrate that supplementation of NAD+ precursors such as nicotinamide mononucleotide (NMN) improves mitochondrial function. Improved mitochondrial function in the Drosophila model was associated with restored exercise endurance, which suggests a potential therapeutic benefit of NAD+ precursor supplementation in the management of BTHS patients.

Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study.

BACKGROUND: Recent studies in rodents indicate that a combination of exercise training and supplementation with nicotinamide adenine dinucleotide (NAD+) precursors has synergistic effects. However, there are currently no human clinical trials analyzing this. OBJECTIVE: This study investigates the effects of a combination of exercise training and supplementation with nicotinamide mononucleotide (NMN), the immediate precursor of NAD+, on cardiovascular fitness in healthy amateur runners. METHODS: A six-week randomized, double-blind, placebo-controlled, four-arm clinical trial including 48 young and middle-aged recreationally trained runners of the Guangzhou Pearl River running team was conducted. The participants were randomized into four groups: the low dosage group (300 mg/day NMN), the medium dosage group (600 mg/day NMN), the high dosage group (1200 mg/day NMN), and the control group (placebo). Each group consisted of ten male participants and two female participants. Each training session was 40-60 min, and the runners trained 5-6 times each week. Cardiopulmonary exercise testing was performed at baseline and after the intervention, at 6 weeks, to assess the aerobic capacity of the runners. RESULTS: Analysis of covariance of the change from baseline over the 6 week treatment showed that the oxygen uptake (VO2), percentages of maximum oxygen uptake (VO2max), power at first ventilatory threshold, and power at second ventilatory threshold increased to a higher degree in the medium and high dosage groups compared with the control group. However, there was no difference in VO2max, O2-pulse, VO2 related to work rate, and peak power after the 6 week treatment from baseline in any of these groups. CONCLUSION: NMN increases the aerobic capacity of humans during exercise training, and the improvement is likely the result of enhanced O2 utilization of the skeletal muscle. TRIAL REGISTRATION NUMBER: ChiCTR2000035138 .

Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women.

In rodents, obesity and aging impair nicotinamide adenine dinucleotide (NAD+) biosynthesis, which contributes to metabolic dysfunction. Nicotinamide mononucleotide (NMN) availability is a rate-limiting factor in mammalian NAD+ biosynthesis. We conducted a 10-week, randomized, placebo-controlled, double-blind trial to evaluate the effect of NMN supplementation on metabolic function in postmenopausal women with prediabetes who were overweight or obese. Insulin-stimulated glucose disposal, assessed by using the hyperinsulinemic-euglycemic clamp, and skeletal muscle insulin signaling [phosphorylation of protein kinase AKT and mechanistic target of rapamycin (mTOR)] increased after NMN supplementation but did not change after placebo treatment. NMN supplementation up-regulated the expression of platelet-derived growth factor receptor ß and other genes related to muscle remodeling. These results demonstrate that NMN increases muscle insulin sensitivity, insulin signaling, and remodeling in women with prediabetes who are overweight or obese (clinicaltrial.gov NCT03151239).

Nicotinamide mononucleotide ameliorates the depression-like behaviors and is associated with attenuating the disruption of mitochondrial bioenergetics in depressed mice.

BACKGROUND: Nicotinamide mononucleotide (NMN) has been shown to stimulate oxidative phosphorylation in mitochondria and to improve various pathologies in patients and mouse disease models. However, whether NMN mediates mitochondrial energy production and its mechanism of action in depressed animals remain unclear. METHODS: Mice were subcutaneously injected with corticosterone (CORT; 20 mg/kg) each day for 6 weeks, while another group was given an additional dose of NMN (300 mg/kg) by oral gavage in the last 2 weeks. Then, transcriptome analyses, metabolome analyses and transient gene knockdown in primary mouse cells were performed. RESULTS: NMN administration alleviated depression-like behavior and the liver weight to body weight ratio in a mouse model of CORT-induced depression. Transcriptome and metabolome analyses revealed that in depressed mice, NMN reduced the mRNA expression of genes involved in fatty acid synthesis, stimulation of ß-oxidation and glycolysis, and increased production of acetyl-coenzyme A for the tricarboxylic acid cycle. Importantly, NMN supplementation increased NAD+ levels to enhance sirtuin (SIRT)3 activity, thereby improving mitochondrial energy metabolism in the hippocampus and liver of CORT-treated mice. Sirt3knockdown in primary mouse astrocytes reversed the effect of NMN by inhibiting energy production, although it did not affect NAD+ synthesis LIMITATIONS: Group sample sizes were small, and only one type of primary mouse cell was used CONCLUSION: These results provide evidence for the beneficial role of NMN in energy production and suggest that therapeutic strategies that increase the level of NMN can be an effective treatment for depression.