Search Results (32)

Heart failure represents the terminal stage in the development of many cardiovascular diseases, and its pathological mechanisms are closely related to disturbances in energy metabolism and mitochondrial dysfunction in cardiomyocytes. In recent years, nicotinamide adenine dinucleotide (NAD⁺), a core coenzyme involved in cellular energy metabolism and redox homeostasis, has been shown to potentially ameliorate heart failure through the regulation of mitochondrial function. This review systematically investigates four core mechanisms of mitochondrial dysfunction in heart failure: imbalance of mitochondrial dynamics, excessive accumulation of reactive oxygen species (ROS) leading to oxidative stress injury, dysfunction of mitochondrial autophagy, and disturbance of Ca²⁺ homeostasis. These abnormalities collectively exacerbate the progression of heart failure by disrupting ATP production and inducing apoptosis and myocardial fibrosis. NAD⁺ has been shown to regulate mitochondrial biosynthesis and antioxidant defences through the activation of the deacetylase family (e.g., silent information regulator 2 homolog 1 (SIRT1) and SIRT3) and to increase mitochondrial autophagy to remove damaged mitochondria, thus restoring energy metabolism and redox balance in cardiomyocytes. In addition, the inhibition of NAD⁺-degrading enzymes (e.g., poly ADP-ribose polymerase (PARP), cluster of differentiation 38 (CD38), and selective androgen receptor modulators (SARMs)) increases the tissue intracellular NAD⁺ content, and supplementation with NAD⁺ precursors (e.g., β-nicotinamide mononucleotide (NMN), nicotinamide riboside, etc.) also significantly elevates myocardial NAD⁺ levels to ameliorate heart failure. This study provides a theoretical basis for understanding the central role of NAD⁺ in mitochondrial homeostasis and for the development of targeted therapies for heart failure. Full article

Background/Objectives: Supplementation with nicotinamide mononucleotide (NMN), a key nicotinamide adenine dinucleotide (NAD⁺) intermediate, exerts anti-aging, anti-obesity, and anti-diabetic effects in animal experiments. However, previous studies have evaluated NMN supplementation using oral administration in drinking water or by intraperitoneal administration. No studies have reported whether NMN exerts beneficial effects when incorporated into the diet. The diet is a multicomponent mixture of many nutrients that may interact with each other, thus weakening the effects of NMN. In the present study, we evaluated whether dietary NMN intake protects obese diabetic db/db mice from obesity-related metabolic disorders, such as dyslipidemia, hepatic steatosis, hyperglycemia, and hyperinsulinemia. Methods: Five-week-old male db/db mice were randomly assigned to two groups and fed for four weeks either a control diet containing 7% corn oil and 0.1% cholesterol (CON group, n = 6) or a diet supplemented with 0.5% NMN (NMN group, n = 5). Results: After 4 weeks of feeding, dietary NMN intake alleviated obesity, hypertriglyceridemia, and hepatic triglyceride accumulation in db/db mice. Respiratory gas analysis indicated that dietary NMN intake significantly enhanced energy expenditure by suppressing carbohydrate oxidation and increasing fat oxidation after 3 weeks of feeding. Additionally, the suppression of the increase in plasma triglyceride (TG) levels by dietary NMN intake was attributable to a reduction in hepatic TG levels through the suppression of fatty acid synthesis and the enhancement of fatty acid β-oxidation in the liver. Furthermore, the improvement in hepatic fatty acid metabolism induced by dietary NMN intake was partially responsible for the significant increase in plasma adiponectin and soluble T-cadherin levels. Conclusions: This is the first report to show that dietary NMN intake but not oral administration in drinking water or intraperitoneal administration alleviates body fat mass and hypertriglyceridemia by enhancing energy expenditure, with preferential promotion of fat oxidation, the enhancement of hepatic lipolysis, and the suppression of hepatic lipogenesis in db/db mice. Full article

Background/Objectives: Athletic performance matters for athletes and fitness enthusiasts. Scientific dietary intervention may boost athletic performance alongside training. Intermittent fasting, like time-restricted fasting (TF), may enhance metabolic health. NAD⁺ supplement nicotinamide mononucleotide (NMN) improves mitochondrial activity. Both potentially boost athletic performance. However, whether TF combined with NMN treatment can further enhance athletic ability is unclear. Methods: Healthy Kunming mice were utilized to test the effects of NMN and TF on the athletic performance of mice. To simulate the in vivo state and further verify the role of TF and NMN, low glucose combined with NMN was used to intervene in C2C12 cells. The exercise capacity of mice was evaluated through motor behavior experiments. At the same time, blood gas analysis and kit tests were used to assess oxygen uptake capacity and post-exercise oxidative stress levels. Muscle development and mitochondrial function were examined through gene expression, protein analysis, and enzyme activity tests, and the distribution of intestinal microbiota and short-chain fatty acid content were also analyzed. Results: The results show that TF combined with NMN improved mitochondrial dynamics and biosynthesis, mitochondrial respiratory function, and oxidative metabolism. Then, the intervention enhanced mice’s endurance, limb strength, motor coordination, and balance and reduced oxidative damage after exercise. Moreover, TF combined with NMN significantly increased the gut microbiota diversity and upregulated Ruminococcus, Roseburia, and Akkermansia in intestinal bacteria and short-chain fatty acids, which are associated with athletic performance. Conclusion: TF combined with NMN enhanced mitochondrial function, improved energy metabolism, modulated the gut microbiota and short-chain fatty acids, and affected muscle fiber transformation, ultimately leading to an overall improvement in exercise performance. These findings provide a theoretical framework for expanding the application of NMN and TF in kinesiology. Full article

Background: Vascular smooth muscle cells (VSMCs) senescence exacerbates vascular diseases like atherosclerosis and hypertension. Angiotensin II (Ang II) is a strong inducer of VSMCs senescence, causing vascular damage, though its exact mechanism is unclear. Nicotinamide mononucleotide (NMN), a NAD⁺ precursor, has gained attention for its anti-senescence potential, yet its role in inhibiting VSMCs senescence is not fully understood. Methods: This study assessed senescence markers, including β-galactosidase activity (SA-β-gal) and the senescence-associated secretory phenotype (SASP), in mouse VSMCs treated with Ang II alone or with NMN and relevant activators/inhibitors. Results: Compared to controls, SA-β-gal levels and SASP secretion significantly increased in Ang II-exposed cells. In contrast, NMN reduced the expression of both markers. NMN also reversed Ang II-induced VSMCs senescence by downregulating KLF4 and p16 through AMPK activation, which Ang II inhibited, while decreasing mRNA levels of key SASP components. The effects of the AMPK activator AICAR were similar to those of NMN, whereas the AMPK inhibitor Compound C negated NMN’s effects. Conclusions: In summary, NMN mitigates Ang II-induced mouse VSMCs senescence via the AMPK/KLF4/p16 pathway. This study underscores the anti-senescence effects of NMN on mouse VSMCs, supporting further exploration of its potential as a food supplement for preventing and treating vascular senescence. Full article

The purpose of this study was to examine whether supplementation of ultra- and nanofiltered colostrum-based products, combined with egg yolk extract, nicotinamide mononucleotide (NMN), quercetin, alpha-ketoglutarate, white button mushroom, and celery seed extracts (the formula was patented by 4Life Research Company, USA and named as AgePro), modulate the functional activity of natural killer (NK) cells in vivo. We found that this supplement, taken orally in two capsules twice a day for 30 days, significantly enhanced the cytotoxic activity of NK cells. This was evidenced by the increased NK cell-mediated killing of carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled K562 human myeloid leukemia cells. As expected, this effect was dependent on the ratio between the effector (E) (e.g., peripheral blood mononuclear cells (PBMCs)) and target (T) (e.g., K562) cells, illustrating maximal killing of K562 cells at a 50:1 E/T ratio. Of note, increased NK-mediated killing of K562 cells after taking AgePro correlated with increased perforin release, evidenced by the CD107a degranulation assay. In concordance with these findings, taking of AgePro for 1 month increased production of several cytokines and chemokines, including IL-1β, IL-1Rα, IL-6, IL-8, IL-10, IFN-γ, TNF-α, G-CSF, PDGF-AA, PDGF-AB/BB, GRO, MCP-1, MCP-3, and MIP-1α, in PBMCs co-cultured with K562 cells. Of note, increased production of the cytokines correlated with the activation state of PBMCs, as evidenced by increased expression of the surface activation markers (e.g., the interleukin-2 receptor alpha chain—CD25). A strong correlation was found between NK-based cytotoxic activity and the production of IL-1β, IL-6, TNF-α, and MIP-1α. Importantly, no increase in the aforementioned soluble factors and activation markers was detected in PBMCs cultured alone, thereby illustrating the potent immunoregulatory activity of AgePro only in the presence of the harmful target cells. Hematological parameters also remained unchanged over the entire study period. Collectively, we show herein the significant enhancement of the cytotoxic activity of NK cells against target tumor cells after taking AgePro for 1 month. Notably, this effect was observed for all age groups, including young, adult, and elderly participants. Moreover, a significant improvement in NK cytotoxic activity was also detected for participants with low basal (e.g., before taking AgePro) numbers of NK-mediated killing. The enhancement of NK-based cytotoxicity was associated with an increased release of several cytokines and chemokines involved in regulating a broad spectrum of mechanisms outside the cell-mediated cytotoxicity and killing of target cells. Of note, spontaneous activation of PBMCs, particularly NK cells, was not detected after taking AgePro. Given that spontaneous activation of autoreactive lymphocytes is a feature associated with autoimmunity and taking into account our data illustrating the AgePro-induced activation of NK cells detected only in the presence of the potentially harmful cells, we conclude that our innovative product exhibits potent immunoregulatory activity and high safety profile. Full article

Background: Nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) are intermediary products in NAD+ metabolism. NMN and NR supplementation can elevate NAD+ levels in tissues, addressing health issues associated with aging and obesity. However, the impact of NMN and NR on atherosclerosis remains incompletely elucidated. Methods: C57BL/6J and Apolipoprotein E knockout (ApoE^−/−) mice were used to explore the impact of NMN and NR supplementation on serum lipids, fatty liver, and atherosclerosis. Additionally, various suppliers, administration protocols, and doses on ApoE^−/− mice were investigated. Results: The intragastric administration of NMN (300 mg/kg) and NR (230 mg/kg) reduced body weight, serum lipids, and fatty liver but aggravated atherosclerosis in ApoE^−/− mice after 4 months of administration with different suppliers. Atherosclerosis also deteriorated after 2 months of different NMN administration protocols (intragastric and water administration) in ApoE^−/− mice with existing plaques. The effects of NMN were dose-dependent, and doses around 100 mg/kg had little harmful effects on atherosclerosis. Conclusions: NMN and NR improve dyslipidemia and fatty liver but promote atherosclerosis in ApoE^−/− mice. These findings emphasize the safe dosage for the clinical trials of NMN. Full article

Inflammation disrupts the normal function of granulosa cells (GCs), which leads to ovarian dysfunction and fertility decline. Inflammatory conditions such as polycystic ovary syndrome (PCOS), primary ovarian insufficiency (POI), endometriosis, and age-related ovarian decline are often associated with chronic low-grade inflammation. Nicotinamide mononucleotide (NMN) is an important precursor of NAD⁺ and has gained attention for its potential to modulate cellular metabolism, redox homeostasis, and mitigate inflammation. This study investigated the protective roles of NMN against lipopolysaccharide LPS-mediated inflammation in GCs. The results of this experiment demonstrated that LPS had negative effects on GCs in term of reduced viability and proliferation rates and upregulated the production of pro-inflammatory cytokines, including interleukin-1 beta (IL-1β), interleukin-6 (IL-6), cyclooxygenase-2 (Cox-2), and tumor necrosis factor-alpha (TNF-α). Notably, the levels of NAD⁺ and NAD⁺/NADH ratio in GCs were reduced in response to inflammation. On the other hand, NMN supplementation restored the NAD⁺ levels and the NAD⁺/NADH ratio in GCs and significantly reduced the expression of pro-inflammatory markers at both mRNA and protein levels. It also enhanced cell viability and proliferation rates of GCs. Furthermore, NMN also reduced apoptosis rates in GCs by downregulating pro-apoptotic markers, including Caspase-3, Caspase-9, and Bax while upregulating anti-apoptotic marker Bcl-2. NMN supplementation significantly reduced reactive oxygen species ROS and improved steroidogenesis activity by restoring the estradiol (E2) and progesterone (P4) levels in LPS-treated GCs. Mechanistically, this study found that NMN suppressed the activation of the TLR4/NF-κB/MAPK signaling pathways in GCs, which regulates inflammatory processes. In conclusion, the findings of this study revealed that NMN has the potential to reduce LPS-mediated inflammatory changes in GCs by modulating NAD⁺ metabolism and inflammatory signaling pathways. NMN supplementation can be used as a potential therapeutic agent for ovarian inflammation and related fertility disorders. Full article

Oxidative stress is a significant factor in the death of granulosa cells (GCs), leading to follicular atresia and consequently limiting the number of dominant follicles that can mature and ovulate within each follicular wave. Follicular fluid contains a diverse array of metabolites that play crucial roles in regulating GCs’ proliferation and oocyte maturation, which are essential for follicle development and female fertility. However, the mechanisms behind metabolite heterogeneity and its effects on GCs’ function remain poorly understood. Here, we identified elevated nicotinamide levels in the follicular fluid of high-prolificacy sheep, correlated with oxidative stress in GCs, by an integrated analysis. In vitro experiments demonstrated that supplementation with β-nicotinamide mononucleotide (NMN) significantly increased the levels of nicotinamide adenine dinucleotide (NAD+) and adenosine triphosphate (ATP) in GCs. NMN treatment effectively reduced Lipopolysaccharide (LPS)-induced apoptosis and mitigated mitochondrial dysfunction, while also decreasing the production of reactive oxygen species (ROS), thereby enhancing the activity of the antioxidant defense system. Importantly, NMN treatment improved the impairments in steroid hormone levels induced by LPS. Mechanistically, the protective effects of NMN against GCs function were mediated via the AMPK/mTOR pathway. Collectively, our findings elucidate the metabolic characteristics associated with sheep prolificacy and demonstrate that NMN effectively protects GCs from LPS-induced dysfunction and enhances ovarian responsiveness via the AMPK/mTOR pathway. These findings also position NMN as a potential novel metabolic biomarker in enhancing ovarian function. Full article

As the sole producers of insulin under physiological conditions, the normal functioning of pancreatic β cells is crucial for maintaining glucose homeostasis in the body. Due to the high oxygen and energy demands required for insulin secretion, hypoxia has been shown to play a critical role in pancreatic β-cell dysfunction. Lipid metabolism abnormalities, a common metabolic feature in type 2 diabetic patients, are often accompanied by tissue hypoxia caused by metabolic overload and lead to increased free fatty acid (FFA) levels. However, the specific mechanisms underlying FFA-induced β-cell dysfunction remain unclear. Nicotinamide mononucleotide (NMN), a naturally occurring bioactive nucleotide, has garnered significant attention in recent years for its effectiveness in replenishing NAD⁺ and alleviating various diseases. Nevertheless, studies exploring the mechanisms through which NMN influences β-cell dysfunction remain scarce. In this study, we established an in vitro β-cell dysfunction model by treating INS-1 cells with palmitate (PA), including control, PA-treated, and PA combined with NMN or activator/inhibitor groups. Compared to the control group, cells treated with PA alone showed significantly reduced insulin secretion capacity and decreased expression of proteins related to the NAD⁺/AMPK/SIRT1/HIF-1α pathway. In contrast, NMN supplementation significantly restored the expression of pathway-related proteins by activating NAD⁺ and effectively improved insulin secretion. Results obtained using HIF-1α and AMPK inhibitors/activators further supported these findings. In conclusion, our study demonstrates that NMN reversed the PA-induced downregulation of the NAD⁺/AMPK/SIRT1/HIF-1α pathway, thereby alleviating β-cell dysfunction. Our study investigated the mechanisms underlying PA-induced β-cell dysfunction, examined how NMN mitigates this dysfunction and offered new insights into the therapeutic potential of NMN for treating β-cell dysfunction and T2DM. Full article

Nicotinamide adenine dinucleotide (NAD⁺) is an essential metabolite that plays a crucial role in diverse biological processes, including energy metabolism, gene expression, DNA repair, and mitochondrial function. An aberrant NAD⁺ level mediates the development of cardiovascular dysfunction and diseases. Both in vivo and in vitro studies have demonstrated that nicotinamide mononucleotide (NMN), as a NAD⁺ precursor, alleviates the development of cardiovascular diseases such as heart failure, atherosclerosis, and myocardial ischemia/reperfusion injury. Importantly, NMN has suggested pharmacological activities mostly through its involvement in NAD⁺ biosynthesis. Several clinical studies have been conducted to investigate the efficacy and safety of NMN supplementation, indicating its potential role in cardiovascular protection without significant adverse effects. In this review, we systematically summarize the impact of NMN as a nutraceutical and potential therapeutic drug on cardiovascular diseases and emphasize the correlation between NMN supplementation and cardiovascular protection. Full article

Recent years have seen a surge in research focused on NAD+ decline and potential interventions, and despite significant progress, new discoveries continue to highlight the complexity of NAD+ biology. Nicotinamide mononucleotide (NMN), a well-established NAD+ precursor, has garnered considerable interest due to its capacity to elevate NAD+ levels and induce promising health benefits in preclinical models. Clinical trials investigating NMN supplementation have yielded variable outcomes while shedding light on the intricacies of NMN metabolism and revealing the critical roles played by gut microbiota and specific cellular uptake pathways. Individual variability in factors such as lifestyle, health conditions, genetics, and gut microbiome composition likely contributes to the observed discrepancies in clinical trial results. Preliminary evidence suggests that NMN’s effects may be context-dependent, varying based on a person’s physiological state. Understanding these nuances is critical for definitively assessing the impact of manipulating NAD+ levels through NMN supplementation. Here, we review NMN metabolism, focusing on current knowledge, pinpointing key areas where further research is needed, and outlining future directions to advance our understanding of its potential clinical significance. Full article

Doxorubicin (DOX) is a potent chemotherapeutic agent known for its multi-organ toxicity, especially in the heart, which limits its clinical application. The toxic side effects of DOX, including DNA damage, oxidative stress, mitochondrial dysfunction and cell apoptosis, are intricately linked to the involvement of nicotinamide adenine dinucleotide (NAD⁺). To assess the effectiveness of the NAD⁺ precursor nicotinamide mononucleotide (NMN) in counteracting the multi-organ toxicity of DOX, a mouse model was established through DOX administration, which led to significant reductions in NAD⁺ in tissues with evident injury, including the heart, liver and lungs. NMN treatment alleviated both multi-organ fibrosis and mortality in mice. Mechanistically, tissue fibrosis, macrophage infiltration and DOX-related cellular damage, which are potentially implicated in the development of multi-organ fibrosis, could be attenuated by NAD⁺ restoration. Our findings provide compelling evidence for the benefits of NMN supplementation in mitigating the adverse effects of chemotherapeutic drugs on multiple organs. Full article

Sperm quality is an important indicator to evaluate the reproduction ability of animals. Nicotinamide mononucleotide (NMN) participates in cell energy metabolism and reduces cell oxidative stress. However, the effect and regulatory mechanism of NMN on porcine sperm quality are still unknown. Here, 32 Landrace boars were randomly assigned to four groups (n = 8) and fed with different levels of NMN (0, 8, 16 or 32 mg/kg/d) for 9 weeks, and then serum and semen samples of the boars were collected to investigate the function and molecular mechanism of NMN in sperm quality. The results showed that the dietary NMN supplementation significantly increased sperm volume, density and motility (p < 0.05). Interestingly, NMN apparently improved the antioxidative indexes and increased the levels of testosterone (p < 0.05) in serum. Furthermore, NMN upregulated the protein levels of sirtuin 3 (SIRT3), antioxidation and oxidative phosphorylation (OXPHOS), but downregulated the protein levels of apoptosis in semen. Mechanically, NMN protected sperm from H₂O₂-induced oxidative stress and apoptosis through SIRT3 deacetylation. Importantly, the SIRT3-specific inhibitor 3-TYP attenuated the antioxidation and antiapoptosis of NMN in sperm. Therefore, NMN exerts antioxidation and antiapoptosis to improve boar sperm quality via the SIRT3 signaling pathway. Our findings suggest that NMN is a novel potential boar antioxidative feed additive to produce high-quality porcine semen. Full article

Nicotinamide adenine dinucleotide (NAD⁺) plays a pivotal role in various physiological processes within mammalian cells, including energy metabolism, redox homeostasis, and genetic regulation. In the majority of mammalian cellular contexts, NAD⁺ biosynthesis primarily relies on vitamin B3, including nicotinamide (NAM) and nicotinic acid (NA). The concept of NAD⁺ augmentation therapy has recently emerged as a promising strategy to mitigate aging-associated phenomena, termed rejuvenation. Despite the involvement of diverse enzymatic cascades in NAD⁺ biosynthesis, certain cellular environments exhibit deficiencies in specific enzymes, suggesting cell type-dependent variability in optimal NAD⁺ precursor selection. However, the optimization of NAD⁺ precursors for topical formulations has received scant attention thus far. In the present investigation, we sought to delineate the most efficacious precursor for augmenting NAD⁺ levels in human skin keratinocytes. Remarkably, NA supplementation led to a significant 1.3-fold elevation in intracellular NAD⁺ levels, even in the presence of nicotinamide phosphoribosyltransferase inhibition by FK866. Additionally, NA mononucleotide demonstrated a 1.5-fold increase (but not significant) in NAD⁺ levels following 100 μM application. Conversely, NAM and its derivatives failed to elicit a NAD⁺ response in keratinocytes. Notably, NA supplementation elicited up-regulation of mitochondrial superoxide dismutase (SOD2) and sirtuin 3 (SIRT3), indicative of its beneficial impact on mitochondrial function. Furthermore, NA mitigated rotenone-induced mitochondrial reactive oxygen species (ROS) accumulation. Collectively, these findings advocate for the potential utility of NA in topical applications aimed at skin rejuvenation. Full article

Psoriasis is one of several chronic inflammatory skin diseases with a high rate of recurrence, and its pathogenesis remains unclear. Nicotinamide mononucleotide (NMN), as an important precursor of nicotinamide adenine dinucleotide (NAD+), has been reported to be a promising agent in treating various diseases, its positive effects including those induced via its anti-inflammatory and antioxidant properties. For this reason, we have aimed to explore the possible role of NMN in the treatment of psoriasis. Psoriasis models were constructed with imiquimod (IMQ) stimulation for 5 days in vivo and with M5 treatment in keratinocyte cell lines in vitro. NMN treatment during the IMQ application period markedly attenuated excess epidermal proliferation, splenomegaly, and inflammatory responses. According to GEO databases, Sirtuin1 (SIRT1) levels significantly decreased in psoriasis patients’ lesion tissues; this was also the case in the IMQ-treated mice, while NMN treatment reversed the SIRT1 decline in the mouse model. Moreover, NMN supplementation also improved the prognoses of the mice after IMQ stimulation, compared to the untreated group with elevated SIRT1 levels. In HEKa and HaCaT cells, the co-culturing of NMN and M5 significantly decreased the expression levels of proinflammation factors, the phosphorylation of NF-κB, stimulator of interferon genes (STING) levels, and reactive oxygen species levels. NMN treatment also recovered the decrease in mitochondrial membrane potential and respiration ability and reduced mtDNA in the cytoplasm, leading to the inhibition of autoimmune inflammation. The knockdown of SIRT1 in vitro eliminated the protective and therapeutic effects of NMN against M5. To conclude, our results indicate that NMN protects against IMQ-induced psoriatic inflammation, oxidative stress, and mitochondrial dysfunction by activating the SIRT1 pathway. Full article