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NAD is a primary mediator of metabolic activity, so many studies consider the nature of NAD metabolism, the different metabolic pathways, and the impacts of different NAD precursors.

ARTICLE: What Are the Metabolic Pathways?


Here are the studies:

Feb 6, 2023

Metabolism - Heart / Vascular - NMN - Obesity

Journal of Clinical Endocrinology & Metabolism

Nicotinamide Adenine Dinucleotide Augmentation in Overweight or Obese Middle-Aged and Older Adults: A Physiologic Study

Pencina, Karol Mateusz


NMN 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.

Feb 3, 2023

Aging - Metabolism

International Journal of Molecular Sciences

The Central Role of the NAD+ Molecule in the Development of Aging and the Prevention of Chronic Age-Related Diseases: Strategies for NAD+ Modulation

Poljsak, Borut


This article reviews the NAD+ molecule in the development of aging and the prevention of chronic age-related diseases and discusses the strategies of NAD+ modulation for healthy aging and longevity.

Nov 17, 2022

Brain - Alzheimer's - Neuroinflammation - Metabolism - Diabetes

Scientific Reports

Sirt3 deficiency induced down regulation of insulin degrading enzyme in comorbid Alzheimer’s disease with metabolic syndrome

Tyagi, Alpna


Mitochondrial dysfunction, insulin resistance, metabolic dysregulation and neuroinflammation that contribute to cognitive decline in Alzheimer's Disease...The findings of this study suggest that SIRT3 is a potential therapeutic target for the treatment of AD. Sirtuins, including SIRT3, require NAD+ as a cosubstrate. Administration of NR, a precursor of NAD+, leads to increase in the cellular level of NAD+. In this study, we demonstrate that NR increases the levels of IDE as well as neprilysin and decreases the levels of BACE1 in vivo. Interestingly, NR also increases the levels of SIRT3, probably by autoregulation. NR has been reported to reverse insulin resistance and glucose intolerance in a mouse model for type 2 diabetes. NR has been shown to be effective in reducing neuroinflammation and improve cognition in Alzheimer’s mouse models. Therefore, NR-based treatment can be considered for the treatment of AD with comorbidities.

Oct 11, 2022

NMN - Metabolism - Gut Microbiota - Bioavailability


Nicotinamide mononucleotide (NMN) deamidation by host-microbiome interactions

Kim, Lynn-Jee


Ablation of the microbiome by antibiotic treatment increases the uptake and conversion of orally delivered NMN into the NAD metabolome, and that isotope labelled NMN overwhelmingly presents in intestinal tissue in the form of NR. Contrary to the assumption that exogenous NMN treatment raises NAD+ levels solely through its direct incorporation into the NAD metabolome, we show that treatment with isotope labelled NMN increases the levels of endogenous, unlabelled NAD metabolites....Given this evidence for the decomposition of NMN into free Nam prior to its uptake, a key question for the field is why downstream precursors in NAD+ synthesis such as NMN and NR lead to different outcomes compared to Nam alone...

Sep 20, 2022



Emerging Role of Nicotinamide Riboside in Health and Diseases

Sharma, Chiranjeev


Accumulating evidence unequivocally establish NR far ahead of other NAD+ precursors in improving human wellness. The future will reveal whether ample preclinical investigations can be translated into clinical applications.

Aug 22, 2022

Fat Metabolism

Frontiers in Cell and Developmental Biology

Nicotinamide-riboside shifts the differentiation of human primary white adipocytes to beige adipocytes impacting substrate preference and uncoupling respiration through SIRT1 activation and mitochondria-derived reactive species productio

Bai, Peter


Nicotinamide-riboside shifts the differentiation of human primary white adipocytes to beige adipocytes impacting substrate preference and uncoupling respiration through SIRT1 activation and mitochondria-derived reactive species production

Aug 15, 2022

Circadian Rhythm - Metabolism


Time-of-day defines the efficacy of NAD+ to treat diet-induced metabolic disease by adjusting oscillations of the hepatic circadian clock

Escalante-Covarrubias, Q


The circadian clock is a time-tracking endogenous system which anticipates and coordinates adaptation to daily environmental fluctuations. Circadian misalignment leads to obesity, which is accompanied by reduced levels of the clock-controlled metabolite NAD+. Concomitantly, increasing NAD+ levels is emerging as a therapy for diet-induced obesity and type 2 diabetes; however, the impact of daily fluctuations of NAD+ on these therapies remains unknown. Here, we demonstrate that time-of-day determines the efficacy of NAD+ as a therapy for diet-induced metabolic disease in mice...

Aug 2, 2022

Metabolism - Bioavailability

Cellular and Molecular Life Sciences

Balancing NAD+ deficits with nicotinamide riboside: therapeutic possibilities and limitations

Circillieux, Angelique


Alterations in cellular nicotinamide adenine dinucleotide (NAD+) levels have been observed in multiple lifestyle and age-related medical conditions. This has led to the hypothesis that dietary supplementation with NAD+ precursors, or vitamin B3s, could exert health benefits. Among the different molecules that can act as NAD+ precursors, Nicotinamide Riboside (NR) has gained most attention due to its success in alleviating and treating disease conditions at the pre-clinical level. However, the clinical outcomes for NR supplementation strategies have not yet met the expectations generated in mouse models. In this review we aim to provide a comprehensive view on NAD+ biology, what causes NAD+ deficits and the journey of NR from its discovery to its clinical development...

Jul 15, 2022

Metabolism - Cancer - Niacin


Structure-Based Identification and Biological Characterization of New NAPRT Inhibitors

Franco, Jorge


NAPRT displays marked tissue [specificity] and is mostly present in several catabolic healthy mammalian tissues including the heart, kidney, liver, and small intestine. In tissues that express the NAPRT protein, NA is the preferred precursor of NAD.

Jul 9, 2022

Metabolism - Bioavailability


NAD+ Precursors: A Questionable Redundancy

Canto, Carles


The last decade has seen a strong proliferation of therapeutic strategies for the treatment of metabolic and age-related diseases based on increasing cellular NAD+ bioavailability. Among them, the dietary supplementation with NAD+ precursors—classically known as vitamin B3—has received most of the attention. Multiple molecules can act as NAD+ precursors through independent biosynthetic routes. Interestingly, eukaryote organisms have conserved a remarkable ability to utilize all of these different molecules, even if some of them are scarcely found in nature. Here, we discuss the possibility that the conservation of all of these biosynthetic pathways through evolution occurred because the different NAD+ precursors might serve specialized purposes.

Jul 1, 2022

Metabolism - Bioavailability - NRH - NARH


Nicotinamide Riboside and Dihydronicotinic Acid Riboside Synergistically Increase Intracellular NAD+ by Generating Dihydronicotinamide Riboside

Ciarlo, Eleonora


This work demonstrates for the first time that NARH can act as a NAD+ precursor in mammalian cells and how different NAD+ precursors can interact and influence each other when co-administered...NARH achieved synergistic effects with NR in increasing NAD+ levels, but not with any of the other NAD+ precursors tested...The effect was remarkable, given the fact that NR or NARH had limited effects on NAD+ levels in these two cell lines when used as single treatments...The synergistic action of NR and NARH could be confirmed in vivo...NR degradation to NAM was not a critical step, as NAM and NARH did not lead to cooperative increases in NAD+ levels...The vigorous increase in NAD+ levels observed when combining NR and NARH was reminiscent of the effects of NRH...The simplest explanation for this would be that the combination of NR and NARH led to the production of NRH...The results showed that, when used together, NR and NARH increased the intracellular levels of NRH...Simply adding the two molecules to a vial of water at room temperature was enough to generate NRH

May 22, 2022

NAM - Metabolism


A Combination of Nicotinamide and D-Ribose (RiaGev) Is Safe and Effective to Increase NAD+ Metabolome in Healthy Middle-Aged Adults: A Randomized, Triple-Blind, Placebo-Controlled, Cross-Over Pilot Clinical Trial

Xue, Yongquan


...This randomized, triple-blind, placebo-controlled, crossover pilot study assessed the efficacy and safety of a combination of nicotinamide with D-ribose (RiaGev) for NAD metabolome enhancement and related benefits in healthy middle-aged adults...

Apr 11, 2022

NMN - Metabolism

Frontiers in Nutrition

Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects

Okabe, Keisuke


...Previous mouse models showed that NMN administration can increase NAD+ in various organs and ameliorate aging-related diseases, such as obesity, diabetes, heart failure, stroke, kidney failure, and Alzheimer’s disease through NAD+-mediated pathways. However, evidence of its effect on humans is still scarce. In this study, we conducted a placebo-controlled, randomized, double blind, parallel-group trial to investigate the safety of orally administered NMN and its efficacy to increase NAD+ levels in thirty healthy subjects...Oral supplementation of NMN for 12 weeks caused no abnormalities in physiological and laboratory tests, and no obvious adverse effects were observed. NAD+ levels in whole blood were significantly increased after NMN administration. We also observed the significant rise in nicotinic acid mononucleotide (NAMN) levels, but not in NMN...These results suggest that oral administration of NMN is a safe and practical strategy to boost NAD+ levels in humans.

Mar 1, 2022

CD38 - Metabolism

American Journal of Physiology - Cell Physiology

The CD38 glycohydrolase and the NAD sink: implications for pathological conditions

Zeidler, Julianna


Nicotinamide adenine dinucleotide (NAD) acts as a cofactor in several oxidation-reduction (redox) reactions and is a substrate for a number of nonredox enzymes. NAD is fundamental to a variety of cellular processes including energy metabolism, cell signaling, and epigenetics. NAD homeostasis appears to be of paramount importance to health span and longevity, and its dysregulation is associated with multiple diseases. NAD metabolism is dynamic and maintained by synthesis and degradation. The enzyme CD38, one of the main NAD-consuming enzymes, is a key component of NAD homeostasis. The majority of CD38 is localized in the plasma membrane with its catalytic domain facing the extracellular environment, likely for the purpose of controlling systemic levels of NAD. Several cell types express CD38, but its expression predominates on endothelial cells and immune cells capable of infiltrating organs and tissues. Here we review potential roles of CD38 in health and disease and postulate ways in which CD38 dysregulation causes changes in NAD homeostasis and contributes to the pathophysiology of multiple conditions. Indeed, in animal models the development of infectious diseases, autoimmune disorders, fibrosis, metabolic diseases, and age-associated diseases including cancer, heart disease, and neurodegeneration are associated with altered CD38 enzymatic activity. Many of these conditions are modified in CD38-deficient mice or by blocking CD38 NADase activity. In diseases in which CD38 appears to play a role, CD38-dependent NAD decline is often a common denominator of pathophysiology. Thus, understanding dysregulation of NAD homeostasis by CD38 may open new avenues for the treatment of human diseases.

Jan 25, 2022

Metabolism - Gut Microbiome


Metabolic Disease, NAD Metabolism, Nicotinamide Riboside, and the Gut Microbiome: Connecting the Dots from the Gut to Physiology

Suave, Anthony


...The involvement of the gut microbiome as a factor in NR effects is linked to changes to the gut microbiome and its activity to transform NR and downstream catabolites. This commentary draws attention to these findings and focuses on some puzzling aspects of NAD+ boosters, exploring the still murky interactions between NAD+ metabolism, energy homeostasis, and the gut microbiome.

Dec 1, 2021


Aging and Disease

Pharmacology and Potential Implications of Nicotinamide Adenine Dinucleotide Precursors

She, Jing


Compared with other precursors, NR is gradually becoming a preferred candidate precursor because of its high bioavailability, safety, and ability to increase NAD+ levels. It offers many potential health benefits in diseases such as cardiovascular diseases, neurodegenerative diseases, and metabolic diseases. In summary, NR is a more effective precursor for synthesizing NAD+ and increasing the activity of NAD+-dependent enzymes than NA and NAM...

Nov 19, 2021

Metabolism - Bioavailability - Gut Microbiota

Cell Metabolism

NAD precursors cycle between host tissues and the gut microbiome

Chellappa, Karthikeyani


...The main route from oral nicotinamide riboside, a widely used nutraceutical, to host NAD is via conversion into nicotinic acid by the gut microbiome. Thus, NAD precursors cycle between the host and gut microbiome to maintain NAD homeostasis.

Nov 19, 2021

Metabolism - Bioavailability - Gut Microbiota

Nature Communications

BST1 regulates nicotinamide riboside metabolism via its glycohydrolase and base-exchange activities

Yaku, Keisuke


The present study demonstrated that orally administered NR increased NAD+ levels in a diphasic manner. First, in the early phase (within 1 h after administration), NR was directly taken up by the small intestine and utilized for NAD+ synthesis via the NR salvage pathway. In the late phase (~3 h after administration), NR increased NAD+ levels in a manner dependent on gut microbiota.

Oct 1, 2021

Aging - Metabolism

Mechanisms of Ageing and Development

The balance between NAD+ biosynthesis and consumption in ageing

Strømland, Øyvind


The progression of some age-related diseases can be halted or reversed by therapeutic augmentation of NAD+ levels. NAD+ metabolism has therefore emerged as a potential target to ameliorate age-related diseases. The present review explores how ageing affects NAD+ metabolism and current approaches to reverse the age-dependent decline of NAD+...As NAD+ is constantly consumed in these reactions, there is a need for continuous NAD+ biosynthesis. Imbalances between these NAD+ consumption and NAD + biosynthesis may result in insufficient NAD+ supply, which has been linked to several diseases, such as neuropathy, autoimmune diseases, and cancer.

Sep 23, 2021

Metabolism - Bioavailability

Cell Systems

NAD+ flux is maintained in aged mice despite lower tissue concentrations

McReynolds, Melanie


NAD+ is an essential coenzyme for all living cells. NAD+ concentrations decline with age, but whether this reflects impaired production or accelerated consumption remains unclear. We employed isotope tracing and mass spectrometry to probe age-related changes in NAD+ metabolism across tissues. In aged mice, we observed modest tissue NAD+ depletion (median decrease ∼30%). Circulating NAD+ precursors were not significantly changed, and isotope tracing showed the unimpaired synthesis of nicotinamide from tryptophan. In most tissues of aged mice, turnover of the smaller tissue NAD+ pool was modestly faster such that absolute NAD+ biosynthetic flux was maintained, consistent with more active NAD+-consuming enzymes. Calorie restriction partially mitigated age-associated NAD+ decline by decreasing consumption. Acute inflammatory stress induced by LPS decreased NAD+ by impairing synthesis in both young and aged mice. Thus, the decline in NAD+ with normal aging is relatively subtle and occurs despite maintained NAD+ production, likely due to increased consumption.

NAD Research - Metabolism

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