NMN (Nicotinamide Mononucleotide)

Background/Objectives: High blood pressure remains a primary modifiable risk factor for cardiovascular disease. Nicotinamide mononucleotide (NMN) has emerged as a promising supplement; however, its efficacy with respect to blood pressure in humans is unclear. This meta-analysis systematically evaluated the effects of various NMN supplements on resting systolic blood pressure (SBP) and diastolic blood pressure (DBP) in adults with elevated blood pressure. Methods: A systematic literature search was conducted to identify eligible randomized controlled trials (RCTs) using the databases PubMed/MEDLINE, Scopus, Web of Science, and EBSCO from their inception to 13 December 2025. R software was used to combine the data from the included original trials using a common-effects model. Subgroup analyses were performed based on age, baseline body mass index, geographical location, intervention duration, NMN dosage, and baseline blood pressure. Results: A total of 349 participants from 10 RCTs with 11 intervention arms were included. Compared with the placebo, NMN supplementation was associated with a statistically significant but modest reduction in resting DBP (WMD, -2.15 mmHg; 95% CI: -3.68 to -0.61). In contrast, the reduction in resting SBP was not statistically significant. Notably, subgroup analyses revealed that NMN supplementation resulted in a significant reduction in SBP specifically among participants aged 60 years and older (WMD: -3.94 mmHg; 95% CI: -7.06 to -0.82). Conclusions: Our findings provide preliminary and suggestive evidence that NMN supplementation may be associated with a small reduction in resting DBP and a modest beneficial effect on resting SBP in adults aged 60 years and older. However, the potential of NMN as a viable candidate for early-stage blood pressure management requires confirmation through long-term, large-scale, high-quality RCTs in future clinical studies.

Nicotinamide adenine dinucleotide (NAD⁺) declines with age, motivating "NAD⁺-boosting" strategies ranging from lifestyle interventions to supplementation with NAD⁺ precursors (e.g., nicotinamide riboside [NR], nicotinamide mononucleotide [NMN]) and, in some wellness settings, parenteral NAD⁺ administration. We conducted a PRISMA-guided systematic review of peer-reviewed human and rodent intervention studies (January 2010-October 2025) evaluating NAD-related compounds administered orally or parenterally. We identified 113 eligible studies: 33 human intervention studies (28 randomized; 5 nonrandomized) and 80 rodent studies. In rodent models, NAD⁺ augmentation was frequently associated with improvements in metabolic, mitochondrial, inflammatory, and functional outcomes, although effects varied across models and endpoints. In humans, oral NR and NMN consistently demonstrated biochemical target engagement (circulating (plasma/whole blood) or cellular (e.g., PBMC) NAD-related metabolites) and were generally well tolerated over weeks to months; however, effects on functional, metabolic, vascular, and other healthspan-relevant outcomes were heterogeneous and often null or endpoint-specific. No eligible outcomes trials evaluated intravenous or intramuscular NAD⁺ itself for anti-aging or wellness indications. One nonrandomized intravenous NMN study met inclusion criteria and primarily contributed short-term safety and biomarker information. An intravenous NAD⁺ pharmacokinetic pilot lacking eligible clinical outcomes was identified as contextual evidence only. Overall, NAD⁺ augmentation shows clear biological activity, but clinical effectiveness for anti-aging or wellness outcomes remains inconclusive. Larger, well-designed randomized trials with longer follow-up and prespecified clinically meaningful endpoints are needed, particularly for parenteral approaches.

PURPOSE: Oocyte quality declines with age and metabolic stress, largely due to mitochondrial dysfunction and NAD⁺ depletion. Nicotinamide mononucleotide (NMN), a precursor of NAD⁺, has emerged as a potential intervention to restore cellular energy metabolism. This study systematically reviews preclinical evidence on NMN supplementation and integrates transcriptomic analysis of human oocytes to assess its relevance in human fertility. METHODS: A systematic review was conducted following PRISMA guidelines across Medline, Embase, and Scopus (January 2015-October 2024). Seven high-quality original studies were included after screening and bias assessment. Data were synthesised through thematic analysis and pathway annotation. Additionally, single-oocyte RNA sequencing was performed on 46 human oocytes at germinal vesicle, metaphase I, and metaphase II stages to profile NAD⁺-related gene expression. RESULTS: Across animal models, NMN supplementation has been shown to improve mitochondrial regulation, reduce oxidative stress, and modulate apoptotic and inflammatory pathways in response to metabolic, environmental, and ageing stress. Transcriptomic analysis identified 900 differentially expressed genes between germinal vesicle and metaphase II oocytes, with significant changes in mitochondrial and oxidative stress-related genes (i.e. SIRT3, DNM1L, SOD1), aligned with NMN's known mechanisms of action. CONCLUSIONS: NMN supplementation shows improvements for oocyte function across diverse preclinical models. Human transcriptomic data further highlight mitochondrial and oxidative pathways as key regulatory points during oocyte maturation. Standardised protocols and clinical trials are needed to evaluate NMN's translational potential in the context of human reproduction. © 2025. The Author(s).

INTRODUCTION: Sarcopenia is associated with the loss of skeletal muscle function and mass. Nicotinamide precursors, such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), have received attention for their potential to improve NAD+ levels and mitigate age-related sarcopenia in preliminary models, though evidence on their effects in older adults remains inconclusive. METHODS: We searched PubMed, Cochrane Library, Web of Science, and Scopus to identify randomized controlled trials (RCTs), comparing NR or NMN vs. placebo. A random-effects meta-analysis was employed to determine their impact on measures of sarcopenia such as skeletal muscle index (SMI), handgrip strength (HGS) and gait speed. A narrative synthesis was used for 5-time chair stand test (5CST), short physical performance battery (SPPB), timed-up-and-go (TUG), 6-min walking distance (6MWD), leg and chest press 80% 1RM (repetition maximum) and thigh muscle mass. RESULTS: Included participants had a mean age range from 60.9 to 83 years. NMN supplementation showed no significant effects on SMI (n = 3; mean difference (MD): -0.42, 95% confidence interval (CI): -0.99 - 0.14, I2 = 63%, p = 0.14), HGS (One study estimating left grip; n = 5; MD: 0.61, 95%CI: -0.89 - 2.10, I2 = 0%, p = 0.42; One study estimating right grip; n = 5; MD: 0.45, 95%CI: -1.06 - 1.96, I2 = 0%, p = 0.56), gait speed (n = 4; MD: -0.01, 95%CI: -0.08 - 0.06, I2 = 0%, p = 0.79), or 5CST (n = 2; MD: -0.21, 95%CI: -0.70 - 0.29, I2 = 11%, p = 0.41). Additionally, our narrative synthesis showed that NMN did not improve knee extension strength, SPPB, or thigh muscle mass. NR supplementation was associated with a longer 6MWD among individuals with peripheral artery disease. However, lower scores in the SPPB and slower 5CST were observed in those with mild cognitive impairment. CONCLUSIONS: Current evidence does not support NMN and NR supplementation for preserving muscle mass and function in adults with mean age of over 60 years. Future research should explore supplementation dosage, NAD+ baseline deficiency, and combined interventions. © 2025 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodic

PURPOSE OF REVIEW: Supplementation of nicotinamide mononucleotides (NMN) has been claimed to improve metabolic function. We reviewed human randomised controlled trials (RCTs) of NMN to evaluate its effect on markers of glucose and lipid metabolism. RECENT FINDINGS: Eight RCTs on NMN (dosage ranged 250-2000 mg/d for a duration of 14 days to 12 weeks) involving a total of 342 middle-age/older adults (49% females, mainly non-diabetic) reporting at least one outcome on glucose control or lipid profile published in 2021-2023 were reviewed. The random-effects meta-analyses indicated no significant benefit of NMN on fasting glucose, fasting insulin, glycated hemoglobin, homeostatic model assessment for insulin resistance and lipid profile. Based on the small number of RCTs involving mainly relatively healthy adults, short-term supplementation of NMN of 250-2000 mg/d did not show significantly positive impacts on glucose control and lipid profile. © 2024. The Author(s).

BACKGROUND: Alzheimer's disease (AD) is a progressive neurocognitive disorder. There is no cure for AD. Maintenance on intracellular levels of nicotinamide adenine dinucleotide (NAD+) has been reported to be a promising therapeutic strategy for the treatment of AD. NAD+ precursors that represent candidate targets include nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). OBJECTIVE: This systematic review provides insights into the potential therapeutic value of NAD+ precursors including NMN and NR, for the treatment of AD using preclinical and clinical studies published in the last 5 years. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol was followed to systematically search the literature using two databases. RESULTS: We found 3 studies that used NMN to treat AD in preclinical murine models. However, human clinical trials using NMN as a therapeutic intervention in AD was not available in the current literature. We also found 4 studies that investigated the potential benefits of NR for the treatment of AD in preclinical models. We also found 2 human clinical trials that showed marked improvements in plasma and neuroimaging biomarkers, and cognitive measures following supplementation with NR. CONCLUSIONS: Results of preclinical and clinical studies confirm the potential benefits of NAD+ precursors for the treatment of AD. However, further clinical studies are required to confirm the increasingly important value of NAD+ precursors as effective pharmacological interventions in the clinic.

INTRODUCTION: Nicotinamide Mononucleotide (NMN) has gained attention as a precursor to Nicotinamide Adenine Dinucleotide (NAD+) in recent years, commonly utilized in anti-aging therapies. The anti-aging effects of NMN on muscle and liver functions in middleaged and elderly people are still unclear. OBJECTIVE: Based on available randomized controlled trials, we conducted a meta-analysis to evaluate the impact of NMN on muscle and liver functions in middle-aged and elderly individuals. METHODS: We conducted searches on three electronic databases (PubMed, Embase, Web of Science) for randomized controlled trials involving NMN interventions in middle-aged and elderly populations. Through the Cochrane Handbook, we assessed the specific methodological quality. All statistical analyses were obtained by Stata15, and statistical significance was set as P<0.05. RESULTS: There were 412 participants from 9 studies in this meta-analysis. Based on changes in gait speed (SMD: 0.34 m/s, 95%CI [0.03, 0.66] p = 0.033), NMN had significant effects on muscle mass. Moreover, NMN had a better effect on ALT (SMD: -0.29 IU/L, 95%CI [-0.55, -0.03] p = 0.028). Subgroup analysis indicated that administering a small dose of NMN exerted the most prominent impact on Homeostasis Model Assessment-Insulin Resistance (HOMA-IR). CONCLUSION: NMN has positive efficacy in enhancing muscle function, reducing insulin resistance and lowering aminotransferase levels in middle-aged and elderly individuals. NMN is an encouraging and considerable drug for anti-aging treatment.

A surge of public interest in NMN supplementation has been observed in recent years. However, whether NMN supplements are effective in improving metabolic health remains unclear. The objective of the review was to assess the effects of NMN supplementation on fasting glucose, triglycerides, total cholesterol, LDL-C, and HDL-C in adults. Studies were located by searching four databases (PubMed, Embase, Cochrane, and Web of Science). Two reviewers independently conducted title/abstract and full-text screening, data extraction, and risk-of-bias assessment. Of the 4049 records reviewed, 12 studies with a total of 513 participants met the criteria for analysis. Random-effects meta-analyses found an overall significant effect of NMN supplementation in elevating blood NAD levels. However, most of the clinically relevant outcomes were not significantly different between NMN supplementation and control group. Risk-of-bias assessment using RoB2 showed some concerns in seven studies and high risk of bias in the other five studies. Together, our findings suggest that an exaggeration of the benefits of NMN supplementation may exist in the field. Although the limited number of eligible studies was sufficiently powered to detect changes in the abovementioned primary outcomes, more studies are needed to conclude about the exact effects of NMN supplementation.

OBJECTIVE: Aging is associated with decreased nicotinamide adenine dinucleotide (NAD) levels, which in turn cause dysfunctional mitochondria and indirectly affect a myriad of diseases. Intracellular nicotinamide phosphoribosyltransferase (iNAMPT) serves as a central rate-limiting enzyme in NAD synthesis, making it an indispensable health mediator. This meta-analysis examined the effect of exercise training on the expression of iNAMPT in humans. METHODS: We searched PubMed, Scopus, ClinicalTrials.gov, and the International Clinical Trials Registry Platform for studies published between the inception of the database and July 5, 2023. Using the common-effect model, evidence for the change in iNAMPT following exercise training was synthesized as Cohen's d. RESULTS: The search yielded five eligible studies. The overall effect size is 0.81, with a 95% confidence interval of 0.55 to 1.07. Therefore, a random adult will have a 71.7% probability that iNAMPT will be up-regulated following exercise training. In general, exercise training resulted in a 1.46-fold increase in iNAMPT. Our probability statistics indicate that subgroups of interest may differ practically. Specifically, there is a 79.3% probability of increased iNAMPT in men, compared to a 69.0% probability in the overall population; young adults have a 75.6% probability of having an increased iNAMPT, whereas aged adults have a 68.7% probability; and, iNAMPT has a 75.1% probability increase after aerobic exercise and a 66.4% probability increase after resistance exercise. CONCLUSION: Exercise training is effective for increasing iNAMPT levels in skeletal muscles. This essential enzyme regulates not only cellular energetics but also healthspan. Therefore, exercise should be promoted as a natural slow-aging lifestyle.

Nicotinamide adenine dinucleotide (NAD+) is an essential pyridine nucleotide that is present in all living cells. NAD+ acts as an important cofactor and substrate for a multitude of biological processes including energy production, DNA repair, gene expression, calcium-dependent secondary messenger signalling and immunoregulatory roles. The de novo synthesis of NAD+ is primarily dependent on the kynurenine pathway (KP), although NAD+ can also be recycled from nicotinic acid (NA), nicotinamide (NAM) and nicotinamide riboside (NR). NAD+ levels have been reported to decline during ageing and age-related diseases. Recent studies have shown that raising intracellular NAD+ levels represents a promising therapeutic strategy for age-associated degenerative diseases in general and to extend lifespan in small animal models. A systematic review of the literature available on Medline, Embase and Pubmed was undertaken to evaluate the potential health and/or longevity benefits due to increasing NAD+ levels. A total of 1545 articles were identified and 147 articles (113 preclinical and 34 clinical) met criteria for inclusion. Most studies indicated that the NAD+ precursors NAM, NR, nicotinamide mononucleotide (NMN), and to a lesser extent NAD+ and NADH had a favourable outcome on several age-related disorders associated with the accumulation of chronic oxidative stress, inflammation and impaired mitochondrial function. While these compounds presented with a limited acute toxicity profile, evidence is still quite limited and long-term human clinical trials are still nascent in the current literature. Potential risks in raising NAD+ levels in various clinical disorders using NAD+ precursors include the accumulation of putative toxic metabolites, tumorigenesis and promotion of cellular senescence. Therefore, NAD+ metabolism represents a promising target and further studies are needed to recapitulate the preclinical benefits in human clinical trials. Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.

BACKGROUND: β-Nicotinamide mononucleotide (NMN) inhibits acute inflammation in injured animal tissues. AIM: We examined whether NMN supplementation attenuates inflammation induced by blood flow restriction-resistance exercise (BFR-exercise) in human skeletal muscle. METHODS: Eleven untrained men (22.8 ± 1.5 y) completed a randomized, placebo-controlled, counterbalanced crossover trial, receiving either Placebo or NMN (1200 mg/d) for 7 d, with a 3-week washout between conditions. Multiple muscle biopsies were obtained before and after BFR-exercise. RESULTS: BFR-exercise-induced significant muscle necrosis at 0 h, which resolved within 24 h in both conditions. NMN supplementation suppressed exercise-induced increases in TNF-α and IL-10 mRNA but delayed the rise in p21 mRNA, suggesting attenuated inflammatory signaling and delayed myogenic differentiation. The resolution of infiltrating cells from necrotic regions was moderately delayed by NMN. BFR-exercise increased the mitochondrial content in exercised muscle by 171% after 24 h of recovery. However, this adaptation was abolished with NMN. Immunofluorescence staining with TOM20 and myeloperoxidase (MPO) revealed that infiltrating phagocytes carried substantially more mitochondria than myofiber cytoplasm, forming a diffusion gradient toward damaged regions of myofibers. This concentration difference between phagocytes and myofibers was further confirmed using COX4 immunostaining in biopsied muscle from an additional participant. CONCLUSIONS: NMN supplementation, while inhibiting inflammatory signaling in exercised human skeletal muscle, may also suppress mitochondrial replenishment from phagocytes to repairing myofibers.

Nicotinamide adenine dinucleotide (NAD(H)) and its phosphorylated form NADP(H) are vitamin B3-derived redox cofactors essential for numerous metabolic reactions and protein modifications. Various health conditions are associated with disturbances in NAD+ homeostasis. To restore NAD+ levels, the main biosynthetic pathways have been targeted, with nicotinamide (Nam), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) being the most prominent boosters. However, while many preclinical studies have examined the effects of these precursors, a direct comparison in humans is lacking, and recent rodent research suggests that the NAD+-boosting effects of NR and NMN may depend on their microbial conversion to nicotinic acid (NA), a mechanism not yet confirmed in humans. Here we show in a randomized, open-label, placebo-controlled study in 65 healthy participants that 14 days of supplementation with NR and NMN, but not Nam, comparably increases circulatory NAD+ concentrations in healthy adults. Unlike the chronic effect, only Nam acutely and transiently affects the whole-blood NAD+ metabolome. Using ex vivo fermentation with human microbiota, we identify that NR and NMN give rise to NA and specifically enhance microbial growth and metabolism. We further demonstrate ex vivo in whole blood that NA is a potent NAD+ booster, while NMN, NR and Nam are not. Ultimately, we propose a gut-dependent model for the modes of action of the three NAD+ precursors with NR and NMN elevating circulatory NAD+ via the Preiss-Handler pathway, while rapidly absorbed Nam acutely affects NAD+ levels via the salvage pathway. Overall, these results indicate a dual effect of NR and NMN and their microbially produced metabolite NA: a sustained increase in systemic NAD+ levels and a potent modulator of gut health. ClinicalTrials.gov identifier: NCT05517122 . © 2026. The Author(s).

The study evaluated how ingestion of nicotinamide mononucleotide (NMN) for 12 weeks by older adults affected blood nicotinamide adenine dinucleotide (NAD +) levels and physical function, particularly walking function. Information concerning sleep, and stress was also collected as secondary endpoints. In this randomized, placebo-controlled, double-blind, parallel-group comparison study, 60 participants were randomly allocated into a placebo group or NMN group. Members of the NMN group consumed 250 mg/day NMN for 12 weeks. Motor function tests, blood NAD metabolite analysis, and questionnaires were conducted at the start of the study and 4 and 12 weeks after intake. This trial was registered at umin.ac.jp/ctr as UMIN000047871 on June 22nd, 2022.At primary outcome, at both 4 weeks and 12 weeks, the NMN and placebo groups had no significant differences in a stepping test. At secondary outcomes, after 12 weeks of NMN intake, the NMN group had a significantly shorter 4-m walking time than the placebo group as well as significantly higher blood levels of NAD + and its metabolites. A significant negative correlation was observed between the change in the 4-m walking time and the change in blood NAD + , N1-methyl-2-pridone-5-carboxamide (2-PY), and N1-methyl-4-pridone-3-carboxamide (4-PY) at 12 weeks. The NMN group had improved sleep quality at 12 weeks relative to the placebo group as evidenced by lower scores for "Daytime dysfunction" and "Global PSQI" on the Pittsburgh Sleep Questionnaire. No adverse effects related to test substance consumption were observed. Together, these results indicate that NMN intake could increase blood NAD + levels, maintain walking speed, and improve sleep quality in older adults. Interventions involving NMN aimed at maintaining walking speed could contribute to extended healthy life expectancy. © 2024. The Author(s), under exclusive licence to American Aging Association.

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. © 2023. The Author(s).

Comment in J Clin Endocrinol Metab. 2023 Aug 18;108(9):e897-e898. doi: 10.1210/clinem/dgad120. 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. © The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For per

In animal studies, β-nicotinamide mononucleotide (NMN) supplementation increases nicotinamide adenine dinucleotide (NAD) concentrations and improves healthspan and lifespan with great safety. However, it is unclear if these effects can be transferred to humans. This randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial included 80 middle-aged healthy adults being randomized for a 60-day clinical trial with once daily oral dosing of placebo, 300 mg, 600 mg, or 900 mg NMN. The primary objective was to evaluate blood NAD concentration with dose-dependent regimens. The secondary objectives were to assess the safety and tolerability of NMN supplementation, next to the evaluation of clinical efficacy by measuring physical performance (six-minute walking test), blood biological age (Aging.Ai 3.0 calculator), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and subjective general health assessment [36-Item Short Form Survey Instrument (SF-36)]. Statistical analysis was performed using the Per Protocol analysis with significant level set at p = 0.05. All 80 participants completed the trial without trial protocol violation. Blood NAD concentrations were statistically significantly increased among all NMN-treated groups at day 30 and day 60 when compared to both placebo and baseline (all p ≤ 0.001). Blood NAD concentrations were highest in the groups taking 600 mg and 900 mg NMN. No safety issues, based on monitoring adverse events (AEs), laboratory and clinical measures, were found, and NMN supplementation was well tolerated. Walking distance increase during the six-minute walking test was statistically significantly higher in the 300 mg, 600 mg, and 900 mg groups compared to placebo at both days 30 and 60 (all p < 0.01), with longest walking distances measured in the 600 mg and 900 mg groups. The blood biological age increased significantly in the placebo group and stayed unchanged in all NMN-treated groups at day 60, which resulted in a significant difference between the treated groups and placebo (all p < 0.05). The HOMA-IR showed no statistically significant differences for all NMN-treated groups as comp

OBJECTIVE: Nicotinamide adenine dinucleotide regulates various biological processes. Nicotinamide mononucleotide (NMN) increases its intracellular levels and counteracts age-associated changes in animal models. We investigated the safety and efficacy of oral nicotinamide mononucleotide supplementation in older patients with diabetes and impaired physical performance. METHOD: We carried out a 24-week placebo-controlled, double-blinded study of male patients with diabetes aged ≥65 years with reduced grip strength (<26 kg) or walking speed (<1.0 m/s). The primary end-points were to determine the safety of NMN oral administration (250 mg/day), and changes in grip strength and walking speed. The secondary end-points were to determine the changes in various exploratory indicators. RESULTS: We studied 14 participants aged 81.1 ± 6.4 years. NMN was tolerable without any severe adverse events. The changes in grip strength and walking speed showed no difference between the two groups: 1.25 kg (95% confidence interval -2.31 to 4.81) and 0.033 m/s (-0.021 to 0.087) in the NMN group, and -0.44 kg (-4.15 to 3.26) and 0.014 m/s (-0.16 to -0.13) in the placebo group, respectively. There were no significant differences in any exploratory indicators between the two groups. However, improved prevalence of frailty in the NMN group (P = 0.066) and different changes in central retinal thickness between the two groups (P = 0.051) was observed. CONCLUSION: In older male patients with diabetes and impaired physical performance, NMN supplementation for 24 weeks was safe, but did not improve grip strength and walking speed. Geriatr Gerontol Int 2023; 23: 38-43. © 2022 Japan Geriatrics Society. Safety evaluation of β-nicotinamide mononucleotide oral administration in healthy adult men and women. Fukamizu Y(1), Uchida Y(1), Shigekawa A(1), Sato T(1), Kosaka H(2), Sakurai T(3). Author information: (1)Research and Development Division, Mitsubishi Corporation Life Sciences Limited, 1-1-3 Yurakucho, Chiyoda-ku, Tokyo, 100-0006, Japan. (2)Takaishi Fujii Hospital, 1-14-25 Ayazono, Takaishi-shi, Ōsaka, 592-0014, Japan. (3)Research and Development Division, Mitsubishi Corporation Life Sciences

46. Sci Rep. 2022 Aug 24;12(1):14442. doi: 10.1038/s41598-022-18272-y. Safety evaluation of β-nicotinamide mononucleotide oral administration in healthy adult men and women. Fukamizu Y(1), Uchida Y(1), Shigekawa A(1), Sato T(1), Kosaka H(2), Sakurai T(3). Author information: (1)Research and Dev

Deteriorating sleep quality and physical or mental fatigue in older adults leads to decreased quality of life and increased mortality rates. This study investigated the effects of the time-dependent intake of nicotinamide mononucleotide (NMN) on sleep quality, fatigue, and physical performance in older adults. This randomized, double-blind placebo-controlled study evaluated 108 participants divided into four groups (NMN_AM; antemeridian, NMN_PM; post meridian, Placebo_AM, Placebo_PM). NMN (250 mg) or placebo was administered once a day for 12 weeks. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index. Fatigue was evaluated using the "Jikaku-sho shirabe" questionnaire. Grip strength, 5-times sit-to-stand (5-STS), timed up and go, and 5-m habitual walk were evaluated to assess the physical performance. Significant interactions were observed between 5-STS and drowsiness. 5-STS of all groups on post-intervention and drowsiness of the NMN_PM and Placebo_PM groups on mid- and post-intervention showed significant improvement compared with those in pre-intervention. The NMN_PM group demonstrated the largest effect size for 5-STS (d = 0.72) and drowsiness (d = 0.64). Overall, NMN intake in the afternoon effectively improved lower limb function and reduced drowsiness in older adults. These findings suggest the potential of NMN in preventing loss of physical performance and improving fatigue in older adults.

BACKGROUND: Nicotinamide adenine dinucleotide (NAD) precursors, nicotinamide mononucleotide (NMN), or nicotinamide riboside (NR) extend healthspan and ameliorate some age-related conditions in model organisms. However, early-phase trials of NAD precursors have yielded varying results and their pharmacokinetics remain incompletely understood. Here, we report the pharmacokinetics and pharmacodynamics of MIB-626, a microcrystalline unique polymorph βNMN formulation. METHODS: In this double-blind, placebo-controlled study, 32 overweight or obese adults, 55-80 years, were block-randomized, stratified by sex, to 1 000-mg MIB-626 once daily, twice daily, or placebo for 14 days. NMN, NAD, and NAD metabolome were measured using liquid chromatography-tandem mass spectrometry. RESULTS: Participant characteristics were similar across groups. MIB-626 was well tolerated and frequency of adverse events was similar across groups. Blood NMN concentrations on Day 14 in MIB-626-treated groups were significantly higher compared to placebo (1.7-times and 3.7-times increase above baseline in 1 000 mg once-daily and twice-daily groups in mean AUClast, respectively). MIB-626 treatment was associated with substantial dose-related increases in blood NAD levels. Blood levels of NAD metabolites were higher in NMN-treated participants on Days 8 and 14 than at baseline. Changes in NMN or NAD levels were not related to sex, body mass index, or age. Very little unmodified NMN was excreted in the urine. CONCLUSION: MIB-626 1 000 mg once-daily or twice-daily regimens were safe and associated with substantial dose-related increases in blood NAD levels and its metabolome. These foundational data that were obtained using a pharmaceutical-grade βNMN, standardized sample collection, and validated liquid chromatography-tandem mass spectrometry assays, should facilitate design of efficacy trials in disease conditions. © The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: [email protected].

Nicotinamide mononucleotide (NMN), a direct precursor of the essential coenzyme nicotinamide adenine dinucleotide (NAD+), confers anti-aging effects and multiple health benefits. Engineered microorganisms represent a promising platform for sustainable industrial production of NMN. Here, the previously reported NMN-producing strain NMN008 was engineered to co-utilize glucose and glycerol for the biosynthesis of NMN from nicotinamide (NAM). First, the glycolytic genes pgi and pykA/pykF were sequentially deleted to disrupt glucose catabolism through the glycolytic pathway, thereby potentially improving precursor availability for NMN biosynthesis. Second, a feedback-resistant glycerol kinase mutant (glpK*) was introduced to enhance glycerol utilization, aiming to compensate for the growth defects associated with impaired glycolysis. These modifications enabled glycerol to primarily support cell growth and energy metabolism, while improving glucose allocation toward NMN biosynthesis by reducing its competitive consumption through glycolysis. As a result, the final strain achieved an NMN titer of 32.92 g/L in a 2 L bioreactor, representing a 26.28% increase in NMN production and a substantial 34.48% improvement in carbon conversion efficiency. Our research provides an effective strategy to achieve industrial-scale production of NMN, laying a foundation for the widespread application of NMN.

As the global population ages rapidly, delaying and preventing age-related diseases have become urgent priorities in public health and biomedical research. During aging, mitochondrial dysfunction is a core molecular hallmark and a common pathogenic mechanism underlying multiple age-related disorders. Age-related mitochondrial dysfunction typically manifests as diminished metabolic capacity, impaired organelle renewal, and disrupted redox homeostasis. These factors interact to form a feedback loop constraining mitochondrial adaptability. Specifically, the interdependent decline in NAD+ availability, impaired mitochondrial biogenesis, and excessive oxidative stress render single-pathway interventions ineffective in mitigating systemic functional impairments triggered by aging. To address this complex mechanism, this review presents a novel tri-axis anti-aging model encompassing three key compounds: nicotinamide mononucleotide/nicotinamide riboside (NMN/NR), pyrroloquinoline quinone (PQQ), and l-ergothioneine (EGT). Within this framework, NMN/NR serves as a broad NAD+-dependent regulator of mitochondrial homeostasis, with its most immediate effects on metabolic activation, while PQQ and EGT may further strengthen mitochondrial remodeling and redox resilience, respectively. While each compound has distinct functional emphases, they are highly mechanistically coupled, collectively forming a closed-loop network regulating mitochondrial number, function, and homeostasis. This review synthesizes preclinical and emerging clinical evidence supporting the standalone or combined use of NMN/NR, PQQ, and EGT across various diseases. Collectively, by conceptualizing mitochondrial aging as a systemic imbalance rather than isolated molecular defects, this paper highlights a three-axis model of NMN/NR, PQQ, and EGT. This framework offers a theoretical foundation for mitochondrial-targeted anti-aging interventions while laying the groundwork for future clinical research, nutritional interventions, and the development of multi-target combination strategies.

Autoimmunity remains challenging to treat without broad immunosuppression. We previously showed that anti-CD38 antibody can rapidly elevate platelet counts in refractory immune thrombocytopenia (ITP), but the underlying mechanism was unclear. Here we report that anti-CD38 antibody induces platelet recovery within 3 days, including after retreatment in relapsed cases. Mechanistically, CD38-mediated nicotinamide adenine dinucleotide (NAD+) depletion drives M1-like macrophage polarization with increased Fc gamma receptor I (FcγRI) expression, thereby promoting macrophage phagocytosis of opsonized platelets. In mice, CD38 inhibition or nicotinamide mononucleotide (NMN) supplementation restores NAD+, reprograms macrophages, downregulates FcγRI and prevents thrombocytopenia. In an ovalbumin immunization model, NMN treatment does not impair antigen-specific antibody production, supporting preservation of humoral responses. Based on these findings, we conducted a single-arm, open-label phase 1/2 trial of low-dose oral NMN (450 mg twice daily for 2 weeks) in adults with steroid-refractory or steroid-dependent ITP. Primary endpoints were safety/tolerability and platelet response (≥50 × 109 per liter within 2 weeks, confirmed by two consecutive measurements one or more days apart, without rescue therapy or dose escalation of thrombopoietin receptor agonists or corticosteroids). Among 25 enrolled patients, no dose-limiting toxicities or treatment-related serious adverse events occurred; NMN was well tolerated, with only mild treatment-related adverse events in 12% and non-severe infections (grade 1) in 8% of patients while immunoglobulin levels remained stable, consistent with preserved humoral immunity. Five patients (20.0%) met the primary platelet-response endpoint. In exploratory analyses, overall, 60% of patients achieved platelet counts more than 1.5× baseline during treatment, and 52% maintained responses through week 8. Together, these data identify the CD38-NAD+ axis as an immunometabolic checkpoint in ITP and support further exploration of NMN as a non-antibody-depleting metabolic strategy for antibody-mediated disease. ClinicalTrials.gov identifier: NCT06776510 .

Chronic oxidative stress, mitochondrial dysfunction, impaired Nicotinamide adenine dinucleotide (NAD⁺) biosynthesis, and angiogenesis inhibition are key factors contributing to delayed diabetic wound healing. Restoring mitochondrial homeostasis through NAD⁺ replenishment and reactive oxygen species (ROS) elimination shows therapeutic potential, yet its effective translation requires multifunctional dressings that combine NAD⁺ supplementation, ROS-responsive antibacterial activity, and localized therapeutic agent delivery to advance diabetic wound healing. Herein, we developed a nanozyme-integrated ROS-responsive microneedle patch (NMN@Cu/CeO₂-MN) for co-delivering nicotinamide mononucleotide (NMN) and Cerium oxide copper nanozymes (Cu/CeO₂). NMN was electrostatically loaded into PEI-functionalized nanozymes to enhance NAD⁺ biosynthesis. The patch was constructed with a methacryloylated gelatin (GelMA)-based needle tip embedded with composite nanozymes and a polyvinyl alcohol/phenylboronic acid-modified poly-L-lysine (PVA/EPL-PBA) antibacterial needle base. This design enables sustained and localized delivery while providing robust antibacterial and pro-regenerative properties. NMN@Cu/CeO₂-MN promoted endothelial cell proliferation, migration, tube formation, and mitochondrial homeostasis by scavenging intracellular ROS and restoring NAD⁺ metabolism. In diabetic mice, the patch significantly enhanced M2 macrophage polarization, alleviated inflammation, and accelerated wound healing through activation of the SIRT1/Nrf2/HO-1 signaling pathway, accompanied by enhanced angiogenesis and collagen deposition. These findings suggest that NMN@Cu/CeO₂-MN represents a potent therapeutic strategy targeting mitochondrial dysfunction and metabolic imbalance in diabetic wound repair. © 2026. The Author(s).

Probiotics have garnered considerable attention due to their multifunctional properties, which encompass the maintenance of intestinal homeostasis, the modulation of immune responses, and the exertion of antioxidant activities. Thus, this study used the Caenorhabditis elegans model and in vitro techniques to assess the activity of gut microbiota from healthy individuals. The study investigated the anti-aging effects of the Lactobacillus paracasei JS-3 (JS-3) strain on C. elegans, as well as its regulatory role in the gut microbiota of elderly individuals. The results demonstrated that JS-3 significantly increased the mean lifespan of C. elegans by 28.02%, surpassing the 15.34% increase achieved with β-nicotinamide mononucleotide (NMN). Furthermore, JS-3 significantly increased the survival rate of C. elegans under thermal and oxidative stress conditions, improving their motility. Further analysis revealed that JS-3 reduced lipofuscin accumulation and lowered reactive oxygen species (ROS) levels within the C. elegans, while boosting antioxidant enzyme activity and decreasing malondialdehyde (MDA) content. These results demonstrate the considerable potential of JS-3 in anti-aging and antioxidant applications. In vitro fermentation results indicated that JS-3 effectively modulates the composition of gut microbiota in elderly populations, specifically by reducing the abundance of harmful bacterial genera while promoting the proliferation of beneficial bacterial genera, such as Bifidobacterium, Bacteroides, and Veillonella. These results suggest that JS-3 has the potential to be an anti-aging probiotic and provide a scientific rationale for developing novel anti-aging products.

BACKGROUND: Early embryo loss is an important factor affecting the reproductive capacity of cattle. Recent studies have revealed that during the process of embryonic genome activation (EGA), epigenetic modification, such as histone lactylation remodeling, is crucial for early embryonic development. However, the effects of histone lactylation on early embryonic development in bovines and the related mechanisms remain unknown. In this study, in vitro fertilized embryos were utilized to investigate the effects of histone lactylation on EGA and early embryo development in cattle. RESULTS: Histone lactylation, including pan-lysine lactylation, histone H3 lysine 9 lactylation, and histone H3 lysine 18 lactylation, occurred mainly in the nucleus and significantly decreased from the 8-cell stage to the morula stage and increased from the morula stage to the blastocyst stage. Decreased or increased levels of histone lactylation induced by GSKA or sodium lactate supplementation inhibited early bovine embryo development and blastocyst lineage differentiation. Furthermore, single-cell RNA sequencing data and 5-ethynyluridine staining revealed that a reduction in histone lactylation levels altered the expression of genes associated with DNA transcription and RNA polymerase activity, thereby impairing EGA. Importantly, β-nicotinamide mononucleotide rescued the inhibitory effects of GSKA supplementation on bovine EGA and early embryonic development. CONCLUSIONS: Histone lactylation maintains early bovine embryo development by regulating EGA. Our findings provide a theoretical reference for addressing early embryo loss and thereby increasing the reproductive capacity of cattle. © 2026. The Author(s).

INTRODUCTION: Developing interventions to delay aging and improve lifespan and healthspan is a critical goal in aging research. Individual geroprotective compounds fail to address the complexity, interconnectedness, and dynamic nature of biological systems, limiting success in significantly extending lifespan and improving health. This study investigates the effects of SRN-901-a novel oral combinatorial drug that consists of urolithin A, quercetin, nicotinamide riboside, alpha-lipoic acid, and Seragon's SRN-820-on lifespan extension, frailty reduction, disease-related gene expression pathways, metabolic aging, and the proteome in 18-month-old mice fed a Western diet. RESULTS: SRN-901-treated mice showed a significant increase of 33% in median remaining lifespan compared to placebo-treated mice. Cox proportional hazards analysis revealed a hazard ratio of 0.54, indicating that SRN-901 treatment was associated with a 46% reduction in the hazard of death. While rapamycin increased lifespan in adult mice, nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR) did not show significant differences in median lifespan compared to placebo. SRN-901 protected mice against increased frailty during aging, with baseline-normalized scores rising to 1.17 in treated mice and 1.57 in controls, corresponding to a 70% attenuation of frailty progression between pre-treatment (D-14) and post-treatment (D128; p < 0.001). Transcriptomic analyses revealed that SRN-901 modulates gene expression across pathways implicated in aging biology, including inflammation, apoptosis, and DNA repair, as well as gene sets associated with neurodegenerative disorders, including Alzheimer's disease. Metabolic profiling revealed that SRN-901 was associated with attenuation of several age-related metabolic shifts, resulting in a blood metabolite profile that more closely resembled that of younger mice. The upregulation of glutathione metabolism and other longevity-related pathways underscores SRN-901's role in enhancing cellular defenses against oxidative stress and maintaining metabolic health. DISCUSSION: These results highlight SRN-901 as a promising multi-compound candidate for extending li

Erratum in Pharm Sci Adv. 2026 Oct 08;4:100151. doi: 10.1016/j.pscia.2026.100151. Natural killer (NK) cells play a key role in the standard treatment of diffuse large B-cell lymphoma (DLBCL). However, NK cells in DLBCL patients frequently display an exhausted phenotype, which is associated with poor clinical outcomes. The metabolic mechanisms contributing to this functional impairment remain poorly understood. We assessed degranulation (CD107a), cytokine secretion (IFN-γ, TNF-α), mitochondrial activity, and lipid metabolism in NK cells from DLBCL patients and healthy donors. Dysregulated lipid species were identified by GC-MS lipidomics and validated in NK-92MI and primary NK cells. The functional involvement of CD36 was assessed using the specific inhibitor, with subsequent examination of its correlation with cytotoxic activity. NAD+ metabolism was evaluated via NAMPT and NAD+ levels, and rescue assays involved nicotinamide mononucleotide (NMN). For in vivo validation, a murine lymphoma model was treated with nicotinamide riboside (NR), and tumor-infiltrating NK cell function and lipid accumulation were analyzed. NK cells from DLBCL patients demonstrated significantly reduced proliferative capacity and cytotoxicity, accompanied by substantial lipid accumulation. This dysfunction was linked to upregulated CD36 expression and associated with ferroptosis-a form of regulated necrotic cell death. Mechanistically, CD36-mediated lipid uptake induced metabolic reprogramming and promoted ferroptotic cell death, concurrently depleting intracellular NAD+ levels. Importantly, supplementation with NAD+ precursors effectively reversed NK cell exhaustion and restored antitumor activity both in vitro and in vivo. CD36-driven lipid metabolic disruption leads to NK cell dysfunction and ferroptosis in DLBCL. Thus, restoration of NAD+ levels represents a promising therapeutic strategy to enhance NK cell effector function and improve antitumor immunity in DLBCL. © 2026 The Authors.

Nicotinamide adenine dinucleotide (NAD+) is crucial for cellular functions including DNA repair and metabolism. Nicotinamide mononucleotide adenylyltransferase (NMNAT) enzymes catalyze the final step of NAD+ synthesis from NMN and ATP. There are three NMNAT isoforms: NMNAT1, NMNAT2, and NMNAT3, located in the nucleus, cytoplasm, and mitochondria, respectively. Nuclear NAD+ promotes disease progression in NAD+-dependent cancers, and it is hypothesized that targeting NMNAT1 with small-molecule inhibitors could be an effective therapeutic strategy. Here, we identify an NMNAT1 inhibitor from a bioactive compound screen and report its effects on NAD+ levels and the viability of NMNAT1-dependent cancer cell lines. The compound AMI-1 is a known inhibitor of Protein Arginine N-Methyltransferase 1, and we find that it also inhibits NMNAT1 with similar potency. Additionally, we determined a cryo-EM structure of NMNAT1 bound to AMI-1 and revealed its mechanism of inhibition. This provides proof of principle for inhibiting NMNAT1 to target NAD+ metabolism in dependent cancers, while also highlighting that caution is warranted when interpreting studies using AMI-1 as a PRMT1 inhibitor, given its effect on NAD+ through NMNAT1.

BACKGROUND/OBJECTIVES: Supplementation of nicotinamide adenine dinucleotide (NAD) precursors has been investigated for its potential to counteract age-related physiological decline. While decreased NAD+ level is associated with conditions such as obesity and dyslipidemia, few studies have explored its metabolic impact in relatively young animals. Here, we hypothesized that nicotinamide mononucleotide (NMN) could alleviate high-fat diet-induced metabolic stress in young mice and sought to elucidate the underlying mechanisms. MATERIALS/METHODS: We first conducted a secondary analysis of hepatic transcriptome datasets from multiple NMN intervention studies to identify target pathways. Next, 11-week-old lean and obese C57BL/6N mice administrated NMN (500 mg/kg/day) for 1 mon were analyzed for metabolic parameters and gene expression for the target pathways. In vitro study using AML12 cell line was then conducted to confirm the effects of NMN. Additionally, transcriptomic data from liver-specific nicotinamide phosphoribosyltransferase (NAMPT)-deficient mice were analyzed to examine the relationship between NAD+ metabolism, endoplasmic reticulum (ER) stress, and circadian rhythm. RESULTS: The secondary analysis of hepatic transcriptome datasets revealed potential target pathways related to circadian regulation and hepatic ER stress. In mouse study, short-term NMN administration significantly decreased body weight and fat mass. NMN also alleviated hepatic ER stress response in vivo and in vitro. Additional analysis revealed that the mice with diet-induced metabolic stress or NAMPT deficiency led to phase shifts of the hepatic circadian core clock oscillation by advancing the peak time, while time-restricted feeding shifted the opposite, indicating the metabolic regulation of the circadian phase. CONCLUSION: Short-term NMN administration effectively attenuated obese condition in young mice and mitigated hepatic ER stress. The altered ER stress was regulated by NAMPT, potentially through the phase shift of the hepatic circadian rhythm. ©2026 The Korean Nutrition Society and the Korean Society of Community Nutrition.