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Nicotinamide adenine dinucleotide (NAD + ) is an essential metabolite for fundamental biological phenomena, including aging. Nicotinamide mononucleotide (NMN) is a key NAD + intermediate that has been extensively tested as an effective NAD + -boosting compound in mice and humans. However, the accurate measurement of NMN in biological samples has long been a challenge in the field. Here, we have established an accurate, quantitative methodology for measuring NMN by using liquid chromatography-triple quadrupole mass spectrometry (LC-MS/MS) with double isotopic NMN standards. In this new methodology, the matrix effects of biological samples were properly adjusted, and the fate of NMN could be traced during sample processing. We have demonstrated that this methodology can accurately quantitate NMN levels in mouse plasma and confirmed quick, direct NMN uptake into blood circulation and cells. This double isotope-mediated LC-MS/MS (dimeLC-MS/MS) can easily be expanded to other NAD + -related metabolites as a reliable standard methodology for NAD + biology., (© 2024. The Author(s).)

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 β 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)., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The effects of two different mitochondrial-targeted drugs, SS-31 and NMN, were tested on Old mouse hearts. After treatment with the drugs, individually or Combined, heart function was examined by echocardiography. SS-31 partially reversed an age-related decline in diastolic function while NMN fully reversed an age-related deficiency in systolic function at a higher workload. Metabolomic analysis revealed that both NMN and the Combined treatment increased nicotinamide and 1-methylnicotinamide levels, indicating greater NAD + turnover, but only the Combined treatment resulted in significantly greater steady-state NAD(H) levels. A novel magnetic resonance spectroscopy approach was used to assess how metabolite levels responded to changing cardiac workload. PCr/ATP decreased in response to increased workload in Old Control, but not Young, hearts, indicating an age-related decline in energetic capacity. Both drugs were able to normalize the PCr/ATP dynamics. SS-31 and NMN treatment also increased mitochondrial NAD(P)H production under the higher workload, while only NMN increased NAD + in response to increased work. These measures did not shift in hearts given the Combined treatment, which may be owed to the enhanced NAD(H) levels in the resting state after this treatment. Overall, these results indicate that both drugs are effective at restoring different aspects of mitochondrial and heart health and that combining them results in a synergistic effect that rejuvenates Old hearts and best recapitulates the Young state., (© 2020 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

The commitment to specific T lymphocytes (T cell) lineages is governed by distinct transcription factors, whose expression is modulated through epigenetic mechanisms. Unravelling these epigenetic mechanisms that regulate T cell differentiation and function holds significant importance for understanding T cells. Menin, a multifunctional scaffolding protein, is implicated in various cellular processes, such as cell proliferation, cell cycle control, DNA repair and transcriptional regulation, primarily through epigenetic mechanisms. Existing research indicates Menin's impact on T cell differentiation and function, while a comprehensive and systematic review is currently lacking to consolidate these findings. In the current review, we have highlighted recent studies on the role of Menin in T cell differentiation and function, focusing mainly on its impact on the memory Th2 maintenance, Th17 differentiation and maintenance, CD4 + T cell senescence, and effector CD8 + T cell survival. Considering Menin's crucial function in maintaining effector T cell function, the potential of inhibiting Menin activity in mitigating inflammatory diseases associated with excessive T cell activation has also been emphasised., (© 2024 John Wiley & Sons Ltd.)

Aging is a significant risk factor for impaired tissue functions and chronic diseases. Age-associated decline in systemic NAD + availability plays a critical role in regulating the aging process across many species. Here, we show that the circulating levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) significantly decline with age in mice and humans. Increasing circulating eNAMPT levels in aged mice by adipose-tissue-specific overexpression of NAMPT increases NAD + levels in multiple tissues, thereby enhancing their functions and extending healthspan in female mice. Interestingly, eNAMPT is carried in extracellular vesicles (EVs) through systemic circulation in mice and humans. EV-contained eNAMPT is internalized into cells and enhances NAD + biosynthesis. Supplementing eNAMPT-containing EVs isolated from young mice significantly improves wheel-running activity and extends lifespan in aged mice. Our findings have revealed a novel EV-mediated delivery mechanism for eNAMPT, which promotes systemic NAD + biosynthesis and counteracts aging, suggesting a potential avenue for anti-aging intervention in humans., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Nicotinamide mononucleotide (NMN) is a biosynthetic precursor of NAD + known to promote cellular NAD + production and counteract age-associated pathologies associated with a decline in tissue NAD + levels. How NMN is taken up into cells has not been entirely clear. Here we show that the Slc12a8 gene encodes a specific NMN transporter. We find that Slc12a8 is highly expressed and regulated by NAD + in the murine small intestine. Slc12a8 knockdown abrogates the uptake of NMN in vitro and in vivo . We further show that Slc12a8 specifically transports NMN, but not nicotinamide riboside, and that NMN transport depends on the presence of sodium ion. Slc12a8 deficiency significantly decreases NAD + levels in the jejunum and ileum, which is associated with reduced NMN uptake as traced by doubly labeled isotopic NMN. Finally, we observe that Slc12a8 expression is upregulated in the aged murine ileum, which contributes to the maintenance of ileal NAD + levels. Our work identifies the first NMN transporter and demonstrates that Slc12a8 has a critical role in regulating intestinal NAD + metabolism.

Natural Nicotinamide Adenine Dinucleotide (NAD + ) precursors have attracted much attention due to their positive effects in promoting ovarian health. However, their target tissue, synthesis efficiency, advantages, and disadvantages are still unclear. This review summarizes the distribution of NAD + at the tissue, cellular and subcellular levels, discusses its biosynthetic pathways and the latest findings in ovary, include: (1) NAD + plays distinct roles both intracellularly and extracellularly, adapting its distribution in response to requirements. (2) Different precursors differs in target tissues, synthetic efficiency, biological utilization, and adverse effects. Importantly: tryptophan is primarily utilized in the liver and kidneys, posing metabolic risks in excess; nicotinamide (NAM) is indispensable for maintaining NAD + levels; nicotinic acid (NA) constructs a crucial bridge between intestinal microbiota and the host with diverse functions; nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) increase NAD + systemically and can be influenced by delivery route, tissue specificity, and transport efficiency. (3) The biosynthetic pathways of NAD + are intricately intertwined. They provide multiple sources and techniques for NAD + synthesis, thereby reducing the dependence on a single molecule to maintain cellular NAD + levels. However, an excess of a specific precursor potentially influencing other pathways. In addition, Protein expression analysis suggest that ovarian tissues may preferentially utilize NAM and NMN. These findings summarize the specific roles and potential of NAD + precursors in enhancing ovarian health. Future research should delve into the molecular mechanisms and intervention strategies of different precursors, aiming to achieve personalized prevention or treatment of ovarian diseases, and reveal their clinical application value., (© 2024 Federation of American Societies for Experimental Biology.)

This study aimed to investigate the protective effect of nicotinamide mononucleotide (NMN) on testicular spermatogenesis in aluminum chloride (AlCl 3 )-exposed rats and to elucidate the potential underlying mechanism. The results indicated that AlCl 3 -induced testicular damage, leading to reduced sperm quality, increased apoptosis, decreased cell proliferation, and impaired Sertoli cell function in rats. Additionally, glycolytic metabolism was observed to be hindered. However, after NMN treatment, there was a noticeable improvement in testicular damage among the rats, marked by increased sperm quality, reduced apoptosis, enhanced cell proliferation, improved Sertoli cell function, and an activated glycolytic metabolism. The findings of this study suggest that NMN alleviates testicular spermatogenesis impairment induced by AlCl 3 exposure through the inhibition of spermatogenic cell apoptosis, promotion of spermatogenic cell proliferation, and activation of glycolytic pathways. The study contributes an experimental foundation for potential future clinical applications of NMN in cases of AlCl 3 -exposed spermatogenic dysfunction., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Circadian disruption such as shift work, jet lag, has gradually become a global health issue and is closely associated with various metabolic disorders. The influence and mechanism of circadian disruption on renal injury in chronic kidney disease (CKD) remains inadequately understood. Here, we evaluated the impact of environmental light disruption on the progression of chronic renal injury in CKD mice. By using two abnormal light exposure models to induce circadian disruption, we found that circadian disruption induced by weekly light/dark cycle reversal (LDDL) significantly exacerbated renal dysfunction, accelerated renal injury, and promoted renal fibrosis in mice with 5/6 nephrectomy and unilateral ureteral obstruction (UUO). Mechanistically, RNA-seq analysis revealed significant immune and metabolic disorder in the LDDL-conditioned CKD kidneys. Consistently, renal content of ATP was decreased and ROS production was increased in the kidney tissues of the LDDL-challenged CKD mice. Untargeted metabolomics revealed a significant buildup of lipids in the kidney affected by LDDL. Notably, the level of β-NMN, a crucial intermediate in the NAD + pathway, was found to be particularly reduced. Moreover, we demonstrated that both β-NMN and melatonin administration could significantly rescue the light-disruption associated kidney dysfunction. In conclusion, environmental circadian disruption may exacerbate chronic kidney injury by facilitating inflammatory responses and disturbing metabolic homeostasis. β-NMN and melatonin treatments may hold potential as promising approaches for preventing and treating light-disruption associated CKD., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hepatocellular carcinoma (HCC) is a common malignancy worldwide. Herein, we investigated the role of nicotinamide mononucleotide (NMN) in HCC progression. HCC cells were treated with NMN (125, 250, and 500 μM), and then nicotinamide adenine dinucleotide (NAD + ) and NADH levels in HCC cells were measured to calculate NAD + /NADH ratio. Cell proliferation, apoptosis, autophagy and ferroptosis were determined. AMPK was knocked down to confirm the involvement of AMPK/mTOR signaling. Furthermore, tumor-inhibitory effect of NMN was investigated in xenograft models. Exposure to NMN dose-dependently increased NAD + level and NAD + /NADH ratio in HCC cells. After NMN treatment, cell proliferation was inhibited, whereas apoptosis was enhanced in both cell lines. Additionally, NMN dose-dependently enhanced autophagy/ferroptosis and activated AMPK/mTOR pathway in HCC cells. AMPK knockdown partially rescued the effects of NMN in vitro. Furthermore, NMN treatment restrained tumor growth in nude mice, activated autophagy/ferroptosis, and promoted apoptosis and necrosis in tumor tissues. The results indicate that NMN inhibits HCC progression by inducing autophagy and ferroptosis via AMPK/mTOR signaling. NMN may serve as a promising agent for HCC treatment., (© 2024 Wiley Periodicals LLC.)

Purpose: The burden of ocular diseases has been gradually increasing worldwide. Various factors are suggested for the development and progression of ocular diseases, such as ocular inflammation, oxidative stress, and complex metabolic dysregulation. Thus, managing ocular diseases requires the modulation of pathologic signaling pathways through many mechanisms. Nicotinamide mononucleotide (NMN) is a bioactive molecule naturally found in life forms. NMN is a direct precursor of the important molecule nicotinamide adenine dinucleotide (NAD + ), an essential co-enzyme required for enormous cellular functions in most life forms. While the recent experimental evidence of NMN treatment in various metabolic diseases has been well-reviewed, NMN treatment in ocular diseases has not been comprehensively summarized yet. In this regard, we aimed to focus on the therapeutic roles of NMN treatment in various ocular diseases with recent advances., Methods: How we came to our current opinion with a recent summary was described based on our own recent reports as well as a search of the related literature., Results: We found that NMN treatment might be available for the prevention of and protection from various experimental ocular diseases, as NMN treatment modulated ocular inflammation, oxidative stress, and complex metabolic dysregulation in murine models for eye diseases such as ischemic retinopathy, corneal defect, glaucoma, and age-related macular degeneration., Conclusion: Our current review suggests and discusses new modes of actions of NMN for the prevention of and protection from various ocular diseases and can urge future research to obtain more solid evidence on a potential future NMN treatment in ocular diseases at the preclinical stages., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

NAD + availability decreases with age and in certain disease conditions. Nicotinamide mononucleotide (NMN), a key NAD + intermediate, has been shown to enhance NAD + biosynthesis and ameliorate various pathologies in mouse disease models. In this study, we conducted a 12-month-long NMN administration to regular chow-fed wild-type C57BL/6N mice during their normal aging. Orally administered NMN was quickly utilized to synthesize NAD + in tissues. Remarkably, NMN effectively mitigates age-associated physiological decline in mice. Without any obvious toxicity or deleterious effects, NMN suppressed age-associated body weight gain, enhanced energy metabolism, promoted physical activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies. Consistent with these phenotypes, NMN prevented age-associated gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metabolism and mitonuclear protein imbalance in skeletal muscle. These effects of NMN highlight the preventive and therapeutic potential of NAD + intermediates as effective anti-aging interventions in humans., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We tested the hypothesis that supplementation of nicotinamide mononucleotide (NMN), a key NAD(+) intermediate, increases arterial SIRT1 activity and reverses age-associated arterial dysfunction and oxidative stress. Old control mice (OC) had impaired carotid artery endothelium-dependent dilation (EDD) (60 ± 5% vs. 84 ± 2%), a measure of endothelial function, and nitric oxide (NO)-mediated EDD (37 ± 4% vs. 66 ± 6%), compared with young mice (YC). This age-associated impairment in EDD was restored in OC by the superoxide (O2-) scavenger TEMPOL (82 ± 7%). OC also had increased aortic pulse wave velocity (aPWV, 464 ± 31 cm s(-1) vs. 337 ± 3 cm s(-1) ) and elastic modulus (EM, 6407 ± 876 kPa vs. 3119 ± 471 kPa), measures of large elastic artery stiffness, compared with YC. OC had greater aortic O2- production (2.0 ± 0.1 vs. 1.0 ± 0.1 AU), nitrotyrosine abundance (a marker of oxidative stress), and collagen-I, and reduced elastin and vascular SIRT1 activity, measured by the acetylation status of the p65 subunit of NFκB, compared with YC. Supplementation with NMN in old mice restored EDD (86 ± 2%) and NO-mediated EDD (61 ± 5%), reduced aPWV (359 ± 14 cm s(-1) ) and EM (3694 ± 315 kPa), normalized O2- production (0.9 ± 0.1 AU), decreased nitrotyrosine, reversed collagen-I, increased elastin, and restored vascular SIRT1 activity. Acute NMN incubation in isolated aortas increased NAD(+) threefold and manganese superoxide dismutase (MnSOD) by 50%. NMN supplementation may represent a novel therapy to restore SIRT1 activity and reverse age-related arterial dysfunction by decreasing oxidative stress., (© 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

As the aging population continues to grow rapidly, age-related diseases are becoming an increasing burden on the healthcare system and a major concern for the well-being of elderly individuals. While aging is an inevitable process for all humans, it can be slowed down and age-related diseases can be treated or alleviated. Nicotinamide adenine dinucleotide (NAD) is a critical coenzyme or cofactor that plays a central role in metabolism and is involved in various cellular processes including the maintenance of metabolic homeostasis, post-translational protein modifications, DNA repair, and immune responses. As individuals age, their NAD levels decline, and this decrease has been suggested to be a contributing factor to the development of numerous age-related diseases, such as cancer, diabetes, cardiovascular diseases, and neurodegenerative diseases. In pursuit of healthy aging, researchers have investigated approaches to boost or maintain NAD levels. Here, we provide an overview of NAD metabolism and the role of NAD in age-related diseases and summarize recent progress in the development of strategies that target NAD metabolism for the treatment of age-related diseases, particularly neurodegenerative diseases., (© 2023. The Author(s).)

The biological clocks of the circadian timing system coordinate cellular and physiological processes and synchronize them with daily cycles. While the central clock in the suprachiasmatic nucleus (SCN) is mainly synchronized by the light/dark cycles, the peripheral clocks react to other stimuli, including the feeding/fasting state, nutrients, sleep-wake cycles, and physical activity. During the disruption of circadian rhythms due to genetic mutations or social and occupational obligations, incorrect arrangement between the internal clock system and environmental rhythms leads to the development of obesity. Desynchronization between the central and peripheral clocks by altered timing of food intake and diet composition leads to uncoupling of the peripheral clocks from the central pacemaker and to the development of metabolic disorders. The strong coupling of the SCN to the light-dark cycle creates a situation of misalignment when food is ingested during the "wrong" time of day. Food-anticipatory activity is mediated by a self-sustained circadian timing, and its principal component is a food-entrainable oscillator. Modifying the time of feeding alone greatly affects body weight, whereas ketogenic diet (KD) influences circadian biology, through the modulation of clock gene expression. Night-eating behavior is one of the causes of circadian disruption, and night eaters have compulsive and uncontrolled eating with severe obesity. By contrast, time-restricted eating (TRE) restores circadian rhythms through maintaining an appropriate daily rhythm of the eating-fasting cycle. The hypothalamus has a crucial role in the regulation of energy balance rather than food intake. While circadian locomotor output cycles kaput (CLOCK) expression levels increase with high-fat diet-induced obesity, peroxisome proliferator-activated receptor-alpha (PPARα) increases the transcriptional level of brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like 1 (BMAL1) in obese subjects. In this context, effective timing of chronotherapies aiming to correct SCN-driven rhythms depends on an accurate assessment of the SCN phase. In fact, in a multi-oscillator system, local rhythmicity and its disruption reflects the disruption of either local clocks or central clocks, thus imposing rhythmicity on those local tissues, whereas misalignment of peripheral oscillators is due to exosome-based intercellular communication.Consequently, disruption of clock genes results in dyslipidemia, insulin resistance, and obesity, while light exposure during the daytime, food intake during the daytime, and sleeping during the biological night promote circadian alignment between the central and peripheral clocks. Thus, shift work is associated with an increased risk of obesity, diabetes, and cardiovascular diseases because of unusual eating times as well as unusual light exposure and disruption of the circadian rhythm., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The NAD + -dependent protein deacetylase SIRT1 regulates energy metabolism, responses to stress, and aging by deacetylating many different proteins, including histones and transcription factors. The mechanisms controlling SIRT1 enzymatic activity are complex and incompletely characterized, yet essential for understanding how to develop therapeutics that target SIRT1. Here, we demonstrate that the N-terminal domain of SIRT1 (NTERM) can trans-activate deacetylation activity by physically interacting with endogenous SIRT1 and promoting its association with the deacetylation substrate NF-κB p65. Two motifs within the NTERM domain contribute to activation of SIRT1-dependent activities, and expression of one of these motifs in mice is sufficient to lower fasting glucose levels and improve glucose tolerance in a manner similar to overexpression of SIRT1. Our results provide insights into the regulation of SIRT1 activity and a rationale for pharmacological control of SIRT1-dependent activities., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

The complex relationship between the gut microbiome and host metabolic health has been an emerging research area. Several recent studies have highlighted the potential effects of the microbiome's diversity, composition and metabolic production capabilities on Body Mass Index (BMI), liver health, glucose homeostasis and Type-2 Diabetes (T2D). The majority of these studies were constrained by relatively small cohorts, mostly focusing on individuals with metabolic disorders, limiting a comprehensive understanding of the microbiome's role in metabolic health. Leveraging a large-scale, comprehensive cohort of nearly 9000 individuals, measured using Continuous Glucose Monitoring (CGM), Dual-energy X-ray absorptiometry (DXA) scan and liver Ultrasound (US) we examined the functional profile of the gut microbiome, and its relation to 38 metabolic health measures. We identified 145 unique bacterial pathways significantly correlated with metabolic health measures, with 86.9% of these showing significant associations with more than one metabolic health measure. Furthermore, 87,678 unique bacterial gene families were found to be significantly associated with at least one metabolic health measure. Notably, "key" bacterial pathways such as purine ribonucleosides degradation and anaerobic energy metabolism demonstrated multiple robust associations across various metabolic health measures, highlighting their potential roles in regulating metabolic processes. Our results remained largely unchanged after adjustments for nutritional habits and for BMI they were replicated in a geographically independent cohort. These insights pave the way for future research and potentially the development of microbiome-targeted interventions to enhance metabolic health. Here, employing a large cohort of nearly 9000 individuals, the authors reveal associations between gut microbiome functions and metabolic measures, highlighting bacterial gene families and pathways affecting host metabolic health. [ABSTRACT FROM AUTHOR]

NADH and NAD+ act as electron donors and acceptors and NAD+ was shown to stimulate mitochondrial biogenesis and metabolic health. We here develop a non-invasive Phosphorous Magnetic Resonance Spectroscopy (31P-MRS) method to quantify these metabolites in human skeletal muscle on a clinical 3 T MRI scanner. This new MR-sequence enables NADH and NAD+ quantification by suppressing α-ATP signal, normally overlapping with NADH and NAD+. The sequence is based on a double spin echo in combination with a modified z-Filter achieving strong α-ATP suppression with little effect on NAD+ and NADH. Here we test and validate it in phantoms and in humans by measuring reproducibility and detecting a physiological decrease in NAD+ and increase in NADH induced by ischemia. Furthermore, the 31P-MRS outcomes are compared to analysis in biopsies. Additionally, we show higher NAD+ and lower NADH content in physically active older adults compared to sedentary individuals, reflecting increased metabolic health. NADH and NAD+ act as electron donors and acceptors and NAD+ was shown to stimulate mitochondrial biogenesis and metabolic health. Here, the researchers developed and validated a non-invasive Phosphorous Magnetic Resonance Spectroscopy method to non-invasively quantify NAD+ and NADH in muscle on a clinical 3 T MRI scanner. [ABSTRACT FROM AUTHOR]

Chemotherapy induced ovarian failure and infertility is an important concern in female cancer patients of reproductive age or younger, and non-invasive, pharmacological approaches to maintain ovarian function are urgently needed. Given the role of reduced nicotinamide adenine dinucleotide phosphate (NADPH) as an essential cofactor for drug detoxification, we sought to test whether boosting the NAD(P)+ metabolome could protect ovarian function. We show that pharmacological or transgenic strategies to replenish the NAD+ metabolome ameliorates chemotherapy induced female infertility in mice, as measured by oocyte yield, follicle health, and functional breeding trials. Importantly, treatment of a triple-negative breast cancer mouse model with the NAD+ precursor nicotinamide mononucleotide (NMN) reduced tumour growth and did not impair the efficacy of chemotherapy drugs in vivo or in diverse cancer cell lines. Overall, these findings raise the possibility that NAD+ precursors could be a non-invasive strategy for maintaining ovarian function in cancer patients, with potential benefits in cancer therapy. Synopsis: Female fertility is impaired by chemotherapy in cancer patients. Fertility preservation relies on timely freezing of reproductive material prior to treatment, which is not always feasible. As chemo-induced infertility resembles ovarian ageing, we tested an agent that overcomes reproductive ageing. Boosting the nicotinamide adenine dinucleotide (NAD+) metabolome protected against chemotherapy-induced ovarian toxicity and female infertility. Effects on fertility were long-lasting, indicating long-term protection of the ovarian reserve. The efficacy of chemotherapy against tumour growth in mice was not impaired, indicating that ovarian function protection might not come at the cost of impaired cancer treatment. Female fertility is impaired by chemotherapy in cancer patients. Fertility preservation relies on timely freezing of reproductive material prior to treatment, which is not always feasible. As chemo-induced infertility resembles ovarian ageing, we tested an agent that overcomes reproductive ageing. [ABSTRACT FROM AUTHOR]

Oocytes play a crucial role in transmitting maternal mitochondrial DNA (mtDNA), essential for the continuation of species. However, the effects of mitochondrial reactive oxygen species (ROS) on mammalian oocyte maturation and mtDNA maintenance remain unclear. We investigated this by conditionally knocking out the Sod2 gene in primordial follicles, elevating mitochondrial matrix ROS levels from early oocyte stages. Our data indicates that reproductive aging in Sod2 conditional knockout females begins at 6 months, with oxidative stress impairing oocyte quality, particularly affecting OXPHOS complex II and mtDNA-encoded mRNA levels. Despite unchanged mtDNA mutation load, mtDNA copy numbers exhibited significant variations. Strikingly, reducing mtDNA copy numbers by reducing mtSSB protein, crucial for mtDNA replication, accelerated reproductive aging onset to three months, underscoring the critical role of mtDNA copy number maintenance under oxidative stress conditions. This research provides new insights into the relationship among mitochondrial ROS, mtDNA, and reproductive aging, offering potential strategies for delaying aging-related fertility decline. Elevating mitochondrial ROS induces female reproductive aging without increasing maternal mtDNA mutation load where deducing mtDNA copy numbers accelerates this phenomenon, highlighting the importance of maintaining mtDNA quantity under oxidative stress. [ABSTRACT FROM AUTHOR]

Noninvasive pharmacological strategies like nicotinamide mononucleotide (NMN) supplementation can effectively address age‐related ovarian infertility by maintaining or enhancing oocyte quality and quantity. This study revealed that ovarian nicotinamide adenine dinucleotide levels decline with age, but NMN administration significantly restores these levels, preventing ovarian atrophy and enhancing the quality and quantity of ovulated oocytes. Improvements in serum hormone secretion and antioxidant factors, along with decreased expression of proinflammatory factors, were observed. Additionally, a significant increase in the number of ovarian follicles in aging individuals was noted. Scanning electron microscopy data indicated that NMN significantly alters the density and morphology of lipid droplets and mitochondria in granulosa cells, suggesting potential targets and mechanisms. Transcriptomic analysis and validation experiments collectively suggested that the beneficial effects of NMN on aging ovaries are mediated through enhanced mitochondrial function, improved energy metabolism, and reduced inflammation levels. Our results suggest that NMN supplementation could improve the health status of aging ovaries and enhance ovarian reserve, offering new insights into addressing fertility challenges in older women through assisted reproductive technology. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular diseases (CVDs) are the leading cause of death worldwide, and the prevalence of CVDs increases markedly with age. Due to the high energetic demand, the heart is highly sensitive to mitochondrial dysfunction. The complexity of the cardiac mitochondrial proteome hinders the development of effective strategies that target mitochondrial dysfunction in CVDs. Mammalian mitochondria are composed of over 1000 proteins, most of which can undergo post-translational modifications (PTMs). Top-down proteomics is a powerful technique for characterizing and quantifying proteoform sequence variations and PTMs. However, there are still knowledge gaps in the study of age-related mitochondrial proteoform changes using this technique. In this study, we used top-down proteomics to identify intact mitochondrial proteoforms in young and old hearts and determined changes in protein abundance and PTMs in cardiac aging. Methods: Intact mitochondria were isolated from the hearts of young (4-month-old) and old (24-25-month-old) mice. The mitochondria were lysed, and mitochondrial lysates were subjected to denaturation, reduction, and alkylation. For quantitative top-down analysis, there were 12 runs in total arising from 3 biological replicates in two conditions, with technical duplicates for each sample. The collected top-down datasets were deconvoluted and quantified, and then the proteoforms were identified. Results: From a total of 12 LC-MS/MS runs, we identified 134 unique mitochondrial proteins in the different sub-mitochondrial compartments (OMM, IMS, IMM, matrix). 823 unique proteoforms in different mass ranges were identified. Compared to cardiac mitochondria of young mice, 7 proteoforms exhibited increased abundance and 13 proteoforms exhibited decreased abundance in cardiac mitochondria of old mice. Our analysis also detected PTMs of mitochondrial proteoforms, including N-terminal acetylation, lysine succinylation, lysine acetylation, oxidation, and phosphorylation. Data are available via ProteomeXchange with the identifier PXD051505. Conclusion: By combining mitochondrial protein enrichment using mitochondrial fractionation with quantitative top-down analysis using ultrahigh-pressure liquid chromatography (UPLC)-MS and label-free quantitation, we successfully identified and quantified intact proteoforms in the complex mitochondrial proteome. Using this approach, we detected age-related changes in abundance and PTMs of mitochondrial proteoforms in the heart. [ABSTRACT FROM AUTHOR]

Visfatin is an adipokine involved in energy metabolism, insulin resistance, inflammation, and female reproduction. Due to limited data about its action in the human placenta, the aims of our studies included the analysis of visfatin expression and immunolocalization in trophoblast cell lines JEG-3 and BeWo as well as in human placentas from normal and pathological pregnancies. Moreover, we also checked the hormonal regulation of visfatin levels and the molecular mechanism of observed changes in JEG-3 cells. Cell culture and placental fragments collection along with statistical analysis were performed using standard laboratory procedures also described in our previous papers. We demonstrated an increased gene and protein expression of visfatin in JEG-3, BeWo cells, while variable expression in maternal and fetal parts of normal/ pathological pregnancy placentas. In addition, the immunolocalization of visfatin was observed in the cytoplasm of both cell lines, the capillary epithelium of the maternal part and syncytiotrophoblasts of the placental fetal part; in all tested pathologies, the signal was also detected in decidual cells. Furthermore, we demonstrated that hormones: progesterone, estradiol, human chorionic gonadotropin, and insulin increased the visfatin levels in JEG-3 cells with the involvement of specific signaling pathways. Taken together, differences in the expression and localization of visfatin between normal and pathological placentas suggested that visfatin may be a potential marker for the diagnosis of pregnancy disorders. In addition, we found that placental levels of visfatin can be regulated by hormones known to modulate the function of placental cells. [ABSTRACT FROM AUTHOR]

Background: Atmospheric particulate matter (PM) exposure-induced neuroinflammation is critical in mediating nervous system impairment. However, effective intervention is yet to be developed. Results: In this study, we examine the effect of β-nicotinamide mononucleotide (NMN) supplementation on nervous system damage upon PM exposure and the mechanism of spatial regulation of lipid metabolism. 120 C57BL/6 male mice were exposed to real ambient PM for 11 days (subacute) or 16 weeks (sub-chronic). NMN supplementation boosted the level of nicotinamide adenine dinucleotide (NAD+) in the mouse brain by 2.04 times. This augmentation effectively reduced neuroinflammation, as evidenced by a marked decrease in activated microglia levels across various brain regions, ranging from 29.29 to 85.96%. Whole brain lipidomics analysis revealed that NMN intervention resulted in an less increased levels of ceramide (Cer) and lysophospholipid in the brain following subacute PM exposure, and reversed triglyceride (TG) and glycerophospholipids (GP) following sub-chronic PM exposure, which conferred mice with anti-neuroinflammation response, improved immune function, and enhanced membrane stability. In addition, we demonstrated that the hippocampus and hypothalamus might be the most sensitive brain regions in response to PM exposure and NMN supplementation. Particularly, the alteration of TG (60:10, 56:2, 60:7), diacylglycerol (DG, 42:6), and lysophosphatidylcholine (LPC, 18:3) are the most profound, which correlated with the changes in functional annotation and perturbation of pathways including oxidative stress, inflammation, and membrane instability unveiled by spatial transcriptomic analysis. Conclusions: This study demonstrates that NMN intervention effectively reduces neuroinflammation in the hippocampus and hypothalamus after PM exposure by modulating spatial lipid metabolism. Strategies targeting the improvement of lipid homeostasis may provide significant protection against brain injury associated with air pollutant exposure. [ABSTRACT FROM AUTHOR]

Objective: Nicotinamide mononucleotide (NMN) is extensively utilized as an anti-aging agent and possesses anti-inflammatory properties. Lipopolysaccharide (LPS) activates Toll-like receptor 4, a process modulated by intracellular signaling pathways such as the Wnt/β-catenin pathway. This study investigated the impact of NMN on osteogenesis in the presence of LPS. Methods: To elucidate the role of NMN in osteogenesis in the context of Gram-negative bacterial infection after LPS treatment, we cultured a mouse pre-osteoblast cell line (MC3T3-E1) and subsequently incubated it with NMN and/or LPS. We then evaluated osteogenic activity by measuring alkaline phosphatase activity, assessing gene expression and protein levels, and performing Alizarin Red S staining and immunocytochemistry. Results: MC3T3-E1 cells underwent successful differentiation into osteoblasts following treatment with osteogenic induction medium. LPS diminished features related to osteogenic differentiation, which were subsequently partially reversed by treatment with NMN. The restorative effects of NMN on LPS-exposed MC3T3-E1 cells were further substantiated by elucidating the role of Wnt/β-catenin signaling, as confirmed through immunocytochemistry. Conclusion: This study showed that infection with Gram-negative bacteria disrupted the osteogenic differentiation of MC3T3-E1 cells. This adverse effect was partially reversed by administering a high-dose of NMN. Drawing on these results, we propose that NMN could serve as a viable therapeutic strategy to preserve bone homeostasis in elderly and immunocompromised patients. [ABSTRACT FROM AUTHOR]

Objective: We analyzed NAD + metabolism in patients with rheumatoid arthritis (RA), its association with disease activity and clinical outcomes of RA, and the therapeutic potential of pharmacologic NAD + boosting., Methods: Our study included 253 participants. In the first cohort, comprising 153 RA patients and 56 healthy donors, we assessed NAD + levels and NAD + -related gene pathways. We analyzed 92 inflammatory molecules by proximity extension assay. In the second cohort, comprising 44 RA patients starting anti-tumor necrosis factor (anti-TNF) drugs, we evaluated changes in NAD + levels and their association with clinical response after 3 months. Mechanistic studies were performed ex vivo on peripheral blood mononuclear cells (PBMCs) from patients with RA to test the beneficial effects of NAD + boosters, such as nicotinamide and nicotinamide riboside., Results: Reduced NAD + levels were found in RA samples, in line with altered activity and expression of genes involved in NAD + consumption (sirtuins, poly[ADP-ribose] polymerase, CD38), transport (connexin 43), and biosynthesis (NAMPT, NMNATs). Unsupervised clustering analysis identified a group of RA patients with the highest inflammatory profile, the lowest NAD + levels, and the highest disease activity (as shown by the Disease Activity Score in 28 joints). NAD + levels were modulated by anti-TNF therapy in parallel with the clinical response. In vitro studies using PBMCs from RA patients showed that nicotinamide riboside and nicotinamide increased NAD + levels via NAMPT and NMNAT and reduced their prooxidative, proapoptotic, and proinflammatory status., Conclusion: RA patients display altered NAD + metabolism, directly linked to their inflammatory and disease activity status, which was reverted by anti-TNF therapy. The preclinical beneficial effects of NAD + boosters, as shown in leukocytes from RA patients, along with their proven clinical safety, might pave the way for the development of clinical trials using these compounds., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

The nicotinamide adenine dinucleotide (NAD + ) precursor nicotinamide mononucleotide (NMN) is a proposed therapy for age-related disease, whereby it is assumed that NMN is incorporated into NAD + through the canonical recycling pathway. During oral delivery, NMN is exposed to the gut microbiome, which could modify the NAD + metabolome through enzyme activities not present in the mammalian host. We show that orally delivered NMN can undergo deamidation and incorporation in mammalian tissue via the de novo pathway, which is reduced in animals treated with antibiotics to ablate the gut microbiome. Antibiotics increased the availability of NAD + metabolites, suggesting the microbiome could be in competition with the host for dietary NAD + precursors. These findings highlight new interactions between NMN and the gut microbiome., (© 2023 Federation of European Biochemical Societies.)

Type 2 diabetes (T2D) has become epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD(+) biosynthesis, and the NAD(+)-dependent protein deacetylase SIRT1. Here, we show that NAMPT-mediated NAD(+) biosynthesis is severely compromised in metabolic organs by high-fat diet (HFD). Strikingly, nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a key NAD(+) intermediate, ameliorates glucose intolerance by restoring NAD(+) levels in HFD-induced T2D mice. NMN also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD(+) and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide critical insights into a potential nutriceutical intervention against diet- and age-induced T2D., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Nicotinamide mononucleotide (NMN), a naturally occurring biologically active nucleotide, mainly functions via mediating the biosynthesis of NAD + . In recent years, its excellent pharmacological activities including anti-aging, treating neurodegenerative diseases, and protecting the heart have attracted increasing attention from scholars and entrepreneurs for production of a wide range of formulations, including functional food ingredients, health care products, active pharmaceuticals, and pharmaceutical intermediates. Presently, the synthesis methods of NMN mainly include two categories: chemical synthesis and biosynthesis. With the development of biocatalyst engineering and synthetic biology strategies, bio-preparation has proven to be efficient, economical, and sustainable methods. This review summarizes the chemical synthesis and biosynthetic pathways of NMN and provides an in-depth investigation on the mining and modification of enzyme resources during NMN biosynthesis, as well as the screening of hosts and optimization of chassis cells via metabolic engineering, which provide effective strategies for efficient production of NMN. In addition, an overview of the significant physiological functions and activities of NMN is elaborated. Finally, future research on technical approaches to further enhance NMN synthesis and strengthen clinical studies of NMN are prospected, which would lay the foundation for further promoting the application of NMN in nutrition, healthy food, and medicine in the future. KEY POINTS: • NMN supplementation effectively increases the level of NAD + . • The chemical and biological synthesis of NMN are comprehensively reviewed. • The impact of NMN on the treatment of various diseases is summarized., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Obesity is caused by an imbalance between calorie intake and energy expenditure, leading to excessive adipose tissue accumulation. Nicotinamide adenine dinucleotide (NAD + ) is an important molecule in energy and signal transduction, and NAD + supplementation therapy is a new treatment for obesity in recent years. Liver kinase B1 (LKB1) is an energy metabolism regulator. The relationship between NAD + and LKB1 has only been studied in the heart and has not yet been reported in obesity. Nicotinamide mononucleotide (NMN), as a direct precursor of NAD + , can effectively enhance the level of NAD + . In the current study, we showed that NMN intervention altered body composition in obese mice, characterized by a reduction in fat mass and an increase in lean mass. NMN reversed high-fat diet-induced blood lipid levels then contributed to reducing hepatic steatosis. NMN also improved glucose tolerance and alleviated adipose tissue inflammation. Moreover, our data suggested that NMN supplementation may be depends on the NAD + /SIRT6/LKB1 pathway to regulate brown adipose metabolism. These results provided new evidence for NMN in obesity treatment., (© 2023 International Union of Biochemistry and Molecular Biology.)

The Sir2 (silent information regulator 2) family of NAD-dependent deacetylases regulates aging and longevity across a wide variety of organisms, including yeast, worms, and flies. In mammals, the Sir2 ortholog Sirt1 promotes fat mobilization, fatty acid oxidation, glucose production, and insulin secretion in response to nutrient availability. We previously reported that an increased dosage of Sirt1 in pancreatic beta cells enhances glucose-stimulated insulin secretion (GSIS) and improves glucose tolerance in beta cell-specific Sirt1-overexpressing (BESTO) transgenic mice at 3 and 8 months of age. Here, we report that as this same cohort of BESTO mice reaches 18-24 months of age, the GSIS regulated by Sirt1 through repression of Ucp2 is blunted. Increased body weight and hyperlipidemia alone, which are observed in aged males and also induced by a Western-style high-fat diet, are not enough to abolish the positive effects of Sirt1 on beta cell function. Interestingly, plasma levels of nicotinamide mononucleotide (NMN), an important metabolite for the maintenance of normal NAD biosynthesis and GSIS in beta cells, are significantly reduced in aged BESTO mice. Furthermore, NMN administration restores enhanced GSIS and improved glucose tolerance in the aged BESTO females, suggesting that Sirt1 activity decreases with advanced age due to a decline in systemic NAD biosynthesis. These findings provide insight into the age-dependent regulation of Sirt1 activity and suggest that enhancement of systemic NAD biosynthesis and Sirt1 activity in tissues such as beta cells may be an effective therapeutic intervention for age-associated metabolic disorders such as type 2 diabetes.

Intracellular nicotinamide phosphoribosyltransferase (iNampt) is an essential enzyme in the NAD biosynthetic pathway. An extracellular form of this protein (eNampt) has been reported to act as a cytokine named PBEF or an insulin-mimetic hormone named visfatin, but its physiological relevance remains controversial. Here we show that eNampt does not exert insulin-mimetic effects in vitro or in vivo but rather exhibits robust NAD biosynthetic activity. Haplodeficiency and chemical inhibition of Nampt cause defects in NAD biosynthesis and glucose-stimulated insulin secretion in pancreatic islets in vivo and in vitro. These defects are corrected by administration of nicotinamide mononucleotide (NMN), a product of the Nampt reaction. A high concentration of NMN is present in mouse plasma, and plasma eNampt and NMN levels are reduced in Nampt heterozygous females. Our results demonstrate that Nampt-mediated systemic NAD biosynthesis is critical for beta cell function, suggesting a vital framework for the regulation of glucose homeostasis.

Nicotinamide mononucleotide (NMN), a crucial intermediate in NAD + synthesis, can rapidly transform into NAD + within the body after ingestion. NMN plays a pivotal role in several important biological processes, including energy metabolism, cellular aging, circadian rhythm regulation, DNA repair, chromatin remodeling, immunity, and inflammation. NMN has emerged as a key focus of research in the fields of biomedicine, health care, and food science. Recent years have witnessed extensive preclinical studies on NMN, offering valuable insights into the pathogenesis of age- and aging-related diseases. Given the sustained global research interest in NMN and the substantial market expectations for the future, here, we comprehensively review the milestones in research on NMN biotherapy over the past 10 years. Additionally, we highlight the current research on NMN in the field of digestive system diseases, identifying existing problems and challenges in the field of NMN research. The overarching aim of this review is to provide references and insights for the further exploration of NMN within the spectrum of digestive system diseases. [ABSTRACT FROM AUTHOR]

Oocyte aging is a key constraint on oocyte quality, leading to fertilization failure and abnormal embryonic development. In addition, it is likely to generate unfavorable assisted reproductive technology (ART) outcomes. SCM-198, a synthetic form of leonurine, was found to rescue the rate of oocyte fragmentation caused by postovulatory aging. Therefore, the aim of this study was to conduct a more in-depth investigation of SCM-198 by exploring its relationship with aged oocytes after ovulation or maternal aging and clarifying whether it affects cell quality. The results indicate that, compared to the postovulatory aged group, the 50 µM SCM-198 group significantly improved sperm-egg binding and increased fertilization of aged oocytes, restoring the spindle apparatus/chromosome structure, cortical granule distribution, and ovastacin and Juno protein distribution. The 50 µM SCM-198 group showed significantly normal mitochondrial distribution, low levels of reactive oxygen species (ROS), and a small quantity of early oocyte apoptosis compared to the postovulatory aged group. Above all, in vivo supplementation with SCM-198 effectively eliminated excess ROS and reduced the spindle/chromosome structural defects in aged mouse oocytes. In summary, these findings indicate that SCM-198 inhibits excessive oxidative stress in oocytes and alters oocyte quality both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Adipose tissue, both intricate and fundamental to physiological functions, comprises cell types, including adipocytes, pivotal in secreting bioactive peptides known as 'adipokines.' Apelin (APLN), Visfatin (VSFTN), and Irisin (IRSN) are novel adipokines involved in regulating energy, carbohydrate, protein, and lipid metabolism. APLN acts as an endogenous ligand for G-protein-coupled receptors, VSFTN is essential in nicotinamide adenine dinucleotide (NAD) biosynthesis, and IRSN is released from skeletal muscle and adipose tissues. Their influence spans various physiological domains, including insulin resistance and sensitivity, cardiovascular functions, angiogenesis, and reproductive systems. This review focuses on the potential roles of APLN, VSFTN, and IRSN in energy regulation mechanisms related to farm animal production. Despite accumulating evidence of their significance, comprehensive understanding is still emerging, with most studies based on model organisms. Thus, there's a pressing need for targeted research on farm animals. Addressing these knowledge gaps could pave the way for improved health strategies, reproductive efficiency, and productivity in farm animals. Future research should focus on understanding the multifaceted interactions of these adipokines and their implications for promoting sustainable and effective animal production. [ABSTRACT FROM AUTHOR]

Polyamines are molecules with multiple amino groups that are essential for cellular function. The major polyamines are putrescine, spermidine, spermine, and cadaverine. Polyamines are important for posttranscriptional regulation, autophagy, programmed cell death, proliferation, redox homeostasis, and ion channel function. Their levels are tightly controlled. High levels of polyamines are associated with proliferative pathologies such as cancer, whereas low polyamine levels are observed in aging, and elevated polyamine turnover enhances oxidative stress. Polyamine metabolism is implicated in several pathophysiological processes in the nervous, immune, and cardiovascular systems. Currently, manipulating polyamine levels is under investigation as a potential preventive treatment for several pathologies, including aging, ischemia/reperfusion injury, pulmonary hypertension, and cancer. Although polyamines have been implicated in many intracellular mechanisms, our understanding of these processes remains incomplete and is a topic of ongoing investigation. Here, we discuss the regulation and cellular functions of polyamines, their role in physiology and pathology, and emphasize the current gaps in knowledge and potential future research directions. [ABSTRACT FROM AUTHOR]

Aging leads to progressive deterioration of the structure and function of arteries, which eventually contributes to the development of vascular aging-related diseases. N6 -methyladenosine (m6A) is the most prevalent modification in eukaryotic RNAs. This reversible m6A RNA modification is dynamically regulated by writers, erasers, and readers, playing a critical role in various physiological and pathological conditions by affecting almost all stages of the RNA life cycle. Recent studies have highlighted the involvement of m6A in vascular aging and related diseases, shedding light on its potential clinical significance. In this paper, we comprehensively discuss the current understanding of m6A in vascular aging and its clinical implications. We discuss the molecular insights into m6A and its association with clinical realities, emphasizing its significance in unraveling the mechanisms underlying vascular aging. Furthermore, we explore the possibility of m6A and its regulators as clinical indicators for early diagnosis and prognosis prediction and investigate the therapeutic potential of m6A-associated anti-aging approaches. We also examine the challenges and future directions in this field and highlight the necessity of integrating m6A knowledge into patient-centered care. Finally, we emphasize the need for multidisciplinary collaboration to advance the field of m6A research and its clinical application. [ABSTRACT FROM AUTHOR]

Introduction: It is well-established that obesity plays a significant role in the development of metabolic syndrome. Visfatin is a novel adipocytokine predominantly secreted in adipose tissue, associated with a wide range of biological effects including glucose and lipid metabolism. Visfatin levels are significantly linked to inflammation and the development of obesity-related metabolic disorders. Unfortunately, the roles of visfatin in obesity, particularly in the Indian population, are scarce. Aim: To study the role of serum visfatin in diagnosing metabolic syndrome in overweight and obese adults. Materials and Methods: A comparative cross-sectional study was conducted at the Department of Biochemistry, Tomo Riba Institute of Health and Medical Sciences, Naharlagun, Arunachal Pradesh, India, between September 2022 and October 2023. A total of 200 subjects (50 controls, 50 overweight individuals, 50 obese individuals without metabolic syndrome, and 50 obese individuals with metabolic syndrome), aged 20-70 years, were enrolled as study participants. Anthropometric parameters, lipid profiles, and fasting glucose were analysed using an auto analyser. Serum visfatin levels were measured by Enzymelinked Immunosorbent Assay (ELISA). Statistical analysis was performed using the t-test, and categorical data were analysed using the Chi-square test. Correlation analysis was done by Pearson’s correlation at a significance level of 5%. Results: The control group consisted of 17 males and 33 females with a mean age of 41.5±13.4 years, the overweight group consisted of 13 males and 37 females with a mean age of 37.1±10.9 years, the obese without metabolic syndrome group consists of 16 males and 34 females with a mean age of 40.6±12.7 years, and obese with metabolic syndrome group had 23 males and 27 females with a mean age of 42.0±9.2 years. Serum visfatin levels (ng/mL) were significantly elevated in the overweight (1.7±0.3), obese without metabolic syndrome (4.3±3.2), and obese with metabolic syndrome (10.9±6.6) groups compared to the controls (1.0±0.2). Serum visfatin levels were positively correlated with Body Mass Index (BMI) (r=0.51, p<0.001), Waist to Hip Ratio (WHR) (r=0.41, p<0.001), Neck Circumference (NC) (r=0.50, p<0.001), Fasting glucose (r=0.44, p<0.001), Total Cholesterol (TC) (r=0.41, p<0.001), Triglycerides (TG) (r=0.39, p<0.001), LowDensity Lipoprotein-cholesterol (LDL-c) (r=0.39, p<0.001), Very Low-Density Lipoprotein (VLDL) (VLDL) (r=0.39, p<0.001), Systolic Blood Pressure (SBP) (r=0.52, p<0.001), and Diastolic Blood Pressure (DBP) (r=0.45, p<0.001), and negatively correlated with High-Density Lipoprotein-cholesterol (HDL-c) (r=-0.20, p<0.002). Conclusion: The present study revealed a good relationship between serum visfatin and the anthropometric and biochemical parameters. The current data belief is that visfatin may be a promising biomarker for predicting metabolic syndrome and its associated disorders particularly in overweight and obese adults. [ABSTRACT FROM AUTHOR]

Nicotinamide adenine dinucleotide (NAD+) is a universal coenzyme regulating cellular energy metabolism in many cell types. Recent studies have demonstrated the close relationships between defective NAD+ metabolism and aging and age-associated metabolic diseases. The major purpose of the present study was to test the hypothesis that NAD+ biosynthesis, mediated by a rate-limiting NAD+ biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT), is essential for maintaining normal adipose tissue function and whole body metabolic health during the aging process. To this end, we provided in-depth and comprehensive metabolic assessments for female adipocyte-specific Nampt knockout (ANKO) mice during aging. We first evaluated body fat mass in young (<4-mo-old), middle aged (10-14-mo-old), and old (≥18-mo-old) mice. Intriguingly, adipocyte-specific Nampt deletion protected against age-induced obesity without changing energy balance. However, data obtained from the hyperinsulinemic-euglycemic clamp procedure (HECP) demonstrated that, despite the lean phenotype, old ANKO mice had severe insulin resistance in skeletal muscle, heart, and white adipose tissue (WAT). Old ANKO mice also exhibited hyperinsulinemia and hypoadiponectinemia. Mechanistically, loss of Nampt caused marked decreases in WAT gene expression of lipogenic targets of peroxisome proliferator-activated receptor gamma (PPAR-γ) in an age-dependent manner. In addition, administration of a PPAR-γ agonist rosiglitazone restored fat mass and improved metabolic abnormalities in old ANKO mice. In conclusion, these findings highlight the importance of the NAMPT-NAD+-PPAR-γ axis in maintaining functional integrity and quantity of adipose tissue, and whole body metabolic function in female mice during aging. NEW & NOTEWORTHY Defective NAD+ metabolism is associated with aging and age-associated metabolic diseases. In the present study, we provided in-depth metabolic assessments in female mice with adipocyte-specific inactivation of a key NAD+ biosynthetic enzyme NAMPT and revealed an unexpected role of adipose tissue NAMPT-NAD+-PPAR-γ axis in maintaining functional integrity and quantity of adipose tissue and whole body metabolic health during the aging process. [ABSTRACT FROM AUTHOR]

Background: There are contradictory effects regarding the effect of NAD + precursor on glucose metabolism and liver enzymes. In order to obtain a better viewpoint from them, this study aimed to comprehensively investigate the effects of NAD + precursor supplementation on glucose metabolism, C-reactive protein (CRP), and liver enzymes. Methods: PubMed/MEDLINE, Web of Science, SCOPUS, and Embase databases were searched using standard keywords to identify all controlled trials investigating the glucose metabolism, CRP, and liver enzymes effects of NAD + precursor. Pooled weighted mean difference (WMD) and 95% confidence intervals (95% CI) were achieved by random-effects model analysis for the best estimation of outcomes. Results: Forty-five articles with 9256 participants' were included in this article. The pooled findings showed that NAD + precursor supplementation had a significant increase in glucose (WMD: 2.17 mg/dL, 95% CI: 0.68, 3.66, P = 0.004) and HbA1c (WMD: 0.11, 95% CI: 0.06, 0.16, P < 0.001) as well as a significant decrease in CRP (WMD: -0.93 mg/l, 95% CI -1.47 to -0.40, P < 0.001) compared with control group, and was not statistically significant with respect to insulin and homeostasis model assessment of insulin resistance (HOMA-IR). However, we found no systemic changes in aspartate transaminase (AST), alanine transaminase (ALT), or alkaline phosphatase (ALP) levels after NAD + precursor supplementation. The results of the subgroup analysis showed that the intake of NAD + precursor during the intervention of more than 12 weeks caused a greater increase in the glucose level. Furthermore, Nicotinic acid supplementation (NA) causes a greater increase in glucose and HbA1c levels than nicotinamide (NE) supplementation. Conclusions: Overall, these findings suggest that NAD + precursor supplementation might have an increase effect on glucose metabolism as well as a decrease in CRP. [ABSTRACT FROM AUTHOR]