scholarly journals Nicotinamide mononucleotide (NMN) deamidation by the gut microbiome and evidence for indirect upregulation of the NAD+ metabolome

2020 ◽  
Author(s):  
Lynn-Jee Kim ◽  
Timothy J. Chalmers ◽  
Greg C. Smith ◽  
Abhirup Das ◽  
Eric Wing Keung Poon ◽  
...  
Keyword(s):  
Nicotinic Acid ◽  
Gut Microbiome ◽  
Nicotinamide Adenine Dinucleotide ◽  
Fold Increase ◽  
Health It ◽  
Isotope Labelling ◽  
Nicotinamide Mononucleotide ◽  
Age Related ◽  
Recycling Pathway ◽  
Direct Incorporation

ABSTRACTTreatment with nicotinamide mononucleotide (NMN) is a prominent strategy to address the age-related decline in nicotinamide adenine dinucleotide (NAD+) levels for maintaining aspects of late-life health. It is assumed that exogenous NMN is directly incorporated into NAD+ in mammals by the canonical recycling pathway, however the need for NAD+ is conserved across evolution, including bacteria in the gut microbiome, which can deamidate NMN to nicotinic acid mononucleotide (NaMN). Here, we use strategic isotope labelling studies to demonstrate a role for the gut microbiome in deamidating orally delivered NMN into NaMN prior to its uptake and incorporation in mammals. Microbiome depletion increased the overall abundance of NAD metabolites, suggesting a competition relationship. Strikingly, treatment with labelled NMN increased the production of unlabelled NAD precursors, with a greater than 3-fold increase in endogenous NR levels in the gut of antibiotics treated animals upon labelled NMN treatment. These data suggest that exogenous NMN impacts the NAD metabolome through indirect means, rather than through its direct incorporation, including through the production of endogenous NR via an as-yet unidentified pathway, and demonstrate an important role for the gut microbiome in the assimilation of orally delivered NMN.

Nicotinamide mononucleotide (NMN) deamidation and indirect regulation of the NAD metabolome

2020 ◽  
Author(s):  
Lynn-Jee Kim ◽  
Timothy Chalmers ◽  
Greg Smith ◽  
Catherine Li ◽  
Abhirup Das ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Metabolic Flux ◽  
De Novo ◽  
Health It ◽  
Nicotinamide Riboside ◽  
Endogenous Production ◽  
Nicotinamide Mononucleotide ◽  
Age Related ◽  
Recycling Pathway ◽  
Direct Incorporation

Abstract Treatment with nicotinamide mononucleotide (NMN) is a prominent strategy to address the age-related decline in nicotinamide adenine dinucleotide (NAD+) levels for maintaining aspects of late-life health. It is assumed that exogenous NMN is directly incorporated into the NAD+ metabolome in mammals via the canonical recycling pathway. Here, we show that NMN can undergo direct deamidation and incorporation via the de novo pathway, which is in part mediated by the gut microbiome. Surprisingly, isotope labelling studies revealed that exogenous NMN treatment potently increased the endogenous production of unlabelled NAD metabolites, suggesting that exogenous NMN impacts the NAD metabolome through indirect means, rather than through its direct incorporation. This included a striking increase in endogenous production of the metabolites nicotinic acid riboside (NaR) and nicotinamide riboside (NR) which was amplified in antibiotics treated animals, suggesting the production of endogenous NaR/NR through altered metabolic flux, enzyme kinetics and/or an as-yet unidentified pathway that interacts with the gut microbiome.

scholarly journals NAD precursors cycle between host tissues and the gut microbiome

2021 ◽  
Author(s):  
Karthikeyani Chellappa ◽  
Melanie R McReynolds ◽  
Wenyun Lu ◽  
Xianfeng Zeng ◽  
Mikhail Makarov ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Nicotinic Acid ◽  
Gut Microbiome ◽  
Nicotinamide Adenine Dinucleotide ◽  
Proximal Part ◽  
Main Route ◽  
Nicotinamide Riboside ◽  
Dietary Consumption ◽  
Nad Synthesis ◽  
Host Tissues

Nicotinamide adenine dinucleotide (NAD) is an essential redox cofactor in both mammals and microbes. Here we use isotope tracing to investigate the precursors supporting NAD synthesis in the gut microbiome. We find that preferred dietary NAD precursors are absorbed in the proximal part of the gastrointestinal tract and not available to microbes in the distal gut. Instead, circulating host nicotinamide enters the gut lumen and supports gut microbiome NAD synthesis. In addition, the microbiome converts nicotinamide, originating from the host circulation, into nicotinic acid. Host tissues uptake and utilize this microbiome-derived nicotinic acid for NAD synthesis, maintaining circulating nicotinic acid levels even in the absence of dietary consumption. Moreover, 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.

Nicotinamide adenine dinucleotide metabolism in plants. I. Intermediates of biosynthesis in wheat leaves and the effect of benzimidazole

1970 ◽  
Vol 48 (12) ◽  
pp. 2267-2278 ◽  
Author(s):  
H. R. Godavari ◽  
E. R. Waygood
Keyword(s):  
Nicotinic Acid ◽  
Nicotinamide Adenine Dinucleotide ◽  
Triticum Aestivum L ◽  
Total Radioactivity ◽  
Significant Loss ◽  
Nicotinamide Adenine ◽  
Nad Metabolism ◽  
Nicotinamide Riboside ◽  
Nicotinamide Mononucleotide ◽  
Wheat Leaves

Leaves of wheat (Triticum aestivum L. var. Selkirk) were incubated with nicotinic acid-7-14C and nicotinamide-7-14C for varying time periods from 5 min to 12 h. Aliquots of alcoholic extracts of leaves were subjected to paper chromatography and radioautography to isolate the intermediates of the synthesis and breakdown of nicotinamide adenine dinucleotide. Nine compounds were isolated quantitatively and identified as intermediates in the pathway of NAD metabolism. All the intermediates were labeled rapidly and the rapidity of labeling became a problem in rigorously proving the sequential operation of the pathway. The results indicate that the Preiss-Handler pathway: nicotinic acid→nicotinic acid mononucleotide→nicotinic acid adenine dinucleotide→NAD operates in wheat leaves. The degradation of NAD proceeded from NAD→nicotinamide mononucleotide→nicotinamide riboside→nicotinamide. Deamidation of the nicotinamide to nicotinic acid initiated a fresh cycle of biosynthesis. The total radioactivity recovered in the intermediates indicates that no measurable amount was lost to other metabolic pathways. Nicotinamide is recovered without significant loss and recycled. The rapid appearance of labeled nicotinamide indicates a possible interconversion of nicotinic acid and nicotinamide. About 80% of the radioactivity accumulated was present in trigonelline which is considered, on the basis of other evidence, to be a non-toxic form of nicotinic acid. Benzimidazole treatment of the leaves increased the incorporation of 14C into NADP.

scholarly journals Nicotinamide Phosphoribosyltransferase as a Key Molecule of the Aging/Senescence Process

2021 ◽  
Vol 22 (7) ◽  
pp. 3709
Author(s):  
Fiqri D. Khaidizar ◽  
Yasumasa Bessho ◽  
Yasukazu Nakahata
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
The Elderly ◽  
Cellular Level ◽  
Salvage Pathway ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Nicotinamide Riboside ◽  
Nicotinamide Mononucleotide ◽  
Age Related ◽  
Rate Limiting ◽  
Over Time

Aging is a phenomenon underlined by complex molecular and biochemical changes that occur over time. One of the metabolites that is gaining strong research interest is nicotinamide adenine dinucleotide, NAD+, whose cellular level has been shown to decrease with age in various tissues of model animals and humans. Administration of NAD+ precursors, nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), to supplement NAD+ production through the NAD+ salvage pathway has been demonstrated to slow down aging processes in mice. Therefore, NAD+ is a critical metabolite now understood to mitigate age-related tissue function decline and prevent age-related diseases in aging animals. In human clinical trials, administration of NAD+ precursors to the elderly is being used to address systemic age-associated physiological decline. Among NAD+ biosynthesis pathways in mammals, the NAD+ salvage pathway is the dominant pathway in most of tissues, and NAMPT is the rate limiting enzyme of this pathway. However, only a few activators of NAMPT, which are supposed to increase NAD+, have been developed so far. In this review, we will focus on the importance of NAD+ and the possible application of an activator of NAMPT to promote successive aging.

scholarly journals Oral Administration of Nicotinamide Mononucleotide Increases Nicotinamide Adenine Dinucleotide Level in an Animal Brain

Nutrients ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 300
Author(s):  
Chidambaram Ramanathan ◽  
Thomas Lackie ◽  
Drake H. Williams ◽  
Paul S. Simone ◽  
Yufeng Zhang ◽  
...  
Keyword(s):  
Oral Administration ◽  
Neurodegenerative Diseases ◽  
Nicotinamide Adenine Dinucleotide ◽  
Nicotinamide Adenine ◽  
Disease States ◽  
Nicotinamide Mononucleotide ◽  
Age Related ◽  
Mice Brain ◽  
The Brain

As a redox-sensitive coenzyme, nicotinamide adenine dinucleotide (NAD+) plays a central role in cellular energy metabolism and homeostasis. Low NAD+ levels are linked to multiple disease states, including age-related diseases, such as metabolic and neurodegenerative diseases. Consequently, restoring/increasing NAD+ levels in vivo has emerged as an important intervention targeting age-related neurodegenerative diseases. One of the widely studied approaches to increase NAD+ levels in vivo is accomplished by using NAD+ precursors, such as nicotinamide mononucleotide (NMN). Oral administration of NMN has been shown to successfully increase NAD+ levels in a variety of tissues; however, it remains unclear whether NMN can cross the blood–brain barrier to increase brain NAD+ levels. This study evaluated the effects of oral NMN administration on NAD+ levels in C57/B6J mice brain tissues. Our results demonstrate that oral gavage of 400 mg/kg NMN successfully increases brain NAD+ levels in mice after 45 min. These findings provide evidence that NMN may be used as an intervention to increase NAD+ levels in the brain.

Metabolism and Degradation of Nicotinic Acid in Parsley (Petroselinum hortense) Cell Suspension Cultures and Seedlings

1986 ◽  
Vol 41 (1-2) ◽  
pp. 148-157 ◽  
Author(s):  
Ludger Schwenen ◽  
Dieter Komoßa ◽  
Wolfgang Barz
Keyword(s):  
Nicotinic Acid ◽  
Cell Suspension ◽  
Nicotinamide Adenine Dinucleotide ◽  
Cell Suspension Cultures ◽  
Pyridine Nucleotide ◽  
Suspension Cultures ◽  
Glucose Ester ◽  
Nicotinamide Mononucleotide ◽  
Pyridine Nucleotide Cycle ◽  
Unknown Structure

Abstract Application of [6-14C]-or [7-14C]nicotinic acid to parsley cell suspension cultures led to the accumulation of labelled nicotinamide mononucleotide, nicotinamide adenine dinucleotide, nicotinamide N-riboside, nicotinamide and nicotinic acid, indicating the operation of the pyridine nucleotide cycle in these cells. As main conjugates, nicotinic acid N-glucoside and nicotinic acid glucose ester were found. For nicotinic acid degradation the following sequence is suggested: nicotinic acid → 6-hydroxynicotinic acid → 2,5-dihydroxypyridine → a C4/C3 unit of unknown structure → CO2. In aseptically grown parsley seedlings nicotinic acid is also degraded to CO2

scholarly journals Creating enzymes and self-sufficient cells for biosynthesis of the non-natural cofactor nicotinamide cytosine dinucleotide

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xueying Wang ◽  
Yanbin Feng ◽  
Xiaojia Guo ◽  
Qian Wang ◽  
Siyang Ning ◽  
...  
Keyword(s):  
Biological Sciences ◽  
Escherichia Coli ◽  
Nicotinamide Adenine Dinucleotide ◽  
Chemical Biology ◽  
Reduced Form ◽  
Redox Transformations ◽  
Nicotinamide Mononucleotide ◽  
Self Sufficiency ◽  
Binding Pockets ◽  
Pathway Regulation

AbstractNicotinamide adenine dinucleotide (NAD) and its reduced form are indispensable cofactors in life. Diverse NAD mimics have been developed for applications in chemical and biological sciences. Nicotinamide cytosine dinucleotide (NCD) has emerged as a non-natural cofactor to mediate redox transformations, while cells are fed with chemically synthesized NCD. Here, we create NCD synthetase (NcdS) by reprograming the substrate binding pockets of nicotinic acid mononucleotide (NaMN) adenylyltransferase to favor cytidine triphosphate and nicotinamide mononucleotide over their regular substrates ATP and NaMN, respectively. Overexpression of NcdS alone in the model host Escherichia coli facilitated intracellular production of NCD, and higher NCD levels up to 5.0 mM were achieved upon further pathway regulation. Finally, the non-natural cofactor self-sufficiency was confirmed by mediating an NCD-linked metabolic circuit to convert L-malate into D-lactate. NcdS together with NCD-linked enzymes offer unique tools and opportunities for intriguing studies in chemical biology and synthetic biology.

Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle motility in healthy old men

2021 ◽  
Author(s):  
Masaki Igarashi ◽  
Masaomi Miura ◽  
Yoshiko Nakagawa-Nagahama ◽  
Keisuke Yaku ◽  
Kosuke Kashiwabara ◽  
...  
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
Nicotinamide Adenine ◽  
Double Blind ◽  
Oral Supplementation ◽  
Healthy Elderly ◽  
Nicotinamide Mononucleotide ◽  
Parallel Group ◽  
And Performance ◽  
Old Men ◽  
Parallel Group Trial

Abstract Preclinical studies have revealed that the elevation of nicotinamide adenine dinucleotide (NAD+) levels on administration of an NAD+ precursor, nicotinamide mononucleotide (NMN), can mitigate aging-related disorders; however, human data are sparse. Therefore, we aimed to investigate whether the chronic oral supplementation of NMN can elevate blood NAD+ levels and alter physiological dysfunctions, including muscle weakness, in healthy elderly participants. We administered 250 mg NMN per day to aged men for 6 or 12 weeks (n=21 for 6 weeks, n=10 for 12 weeks) in a placebo-controlled, randomized, double blind, parallel-group trial. Chronic supplementation with NMN was well tolerated and did not cause any significant deleterious effect. Metabolomic analysis of whole blood demonstrated that the oral supplementation of NMN significantly increased the concentrations of NAD+ and NAD+ metabolites. Moreover, NMN significantly improved muscle strength and performance, which were evaluated using the 30-second chair stand test, walking speed, and grip strength, and it showed no significant effect on body composition. Thus, our evidence indicates that chronic oral NMN supplementation can be an efficient NAD+ booster for preventing aging-related muscle dysfunctions in humans.

scholarly journals NAD+Metabolism in Aging and Cancer

2019 ◽  
Vol 3 (1) ◽  
pp. 105-130 ◽  
Author(s):  
Tyler G. Demarest ◽  
Mansi Babbar ◽  
Mustafa N. Okur ◽  
Xiuli Dan ◽  
Deborah L. Croteau ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Redox Homeostasis ◽  
Accelerated Aging ◽  
Cancer Therapies ◽  
Nad Metabolism ◽  
Cellular Processes ◽  
Cancer Pathogenesis ◽  
Nicotinamide Mononucleotide ◽  
Age Related

Aging is a major risk factor for many types of cancer, and the molecular mechanisms implicated in aging, progeria syndromes, and cancer pathogenesis display considerable similarities. Maintaining redox homeostasis, efficient signal transduction, and mitochondrial metabolism is essential for genome integrity and for preventing progression to cellular senescence or tumorigenesis. NAD+is a central signaling molecule involved in these and other cellular processes implicated in age-related diseases and cancer. Growing evidence implicates NAD+decline as a major feature of accelerated aging progeria syndromes and normal aging. Administration of NAD+precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) offer promising therapeutic strategies to improve health, progeria comorbidities, and cancer therapies. This review summarizes insights from the study of aging and progeria syndromes and discusses the implications and therapeutic potential of the underlying molecular mechanisms involved in aging and how they may contribute to tumorigenesis.

scholarly journals The Gut Microbiota and Healthy Aging: A Mini-Review

Gerontology ◽  
2018 ◽  
Vol 64 (6) ◽  
pp. 513-520 ◽  
Author(s):  
Sangkyu Kim ◽  
S. Michal Jazwinski
Keyword(s):  
Gut Microbiota ◽  
Individual Variation ◽  
Gut Microbiome ◽  
Chronological Age ◽  
Low Grade ◽  
Beneficial Effects ◽  
Gut Dysbiosis ◽  
Age Related ◽  
Host Health ◽  
Nutrient Signaling

The gut microbiota shows a wide inter-individual variation, but its within-individual variation is relatively stable over time. A functional core microbiome, provided by abundant bacterial taxa, seems to be common to various human hosts regardless of their gender, geographic location, and age. With advancing chronological age, the gut microbiota becomes more diverse and variable. However, when measures of biological age are used with adjustment for chronological age, overall richness decreases, while a certain group of bacteria associated with frailty increases. This highlights the importance of considering biological or functional measures of aging. Studies using model organisms indicate that age-related gut dysbiosis may contribute to unhealthy aging and reduced longevity. The gut microbiome depends on the host nutrient signaling pathways for its beneficial effects on host health and lifespan, and gut dysbiosis disrupting the interdependence may diminish the beneficial effects or even have reverse effects. Gut dysbiosis can trigger the innate immune response and chronic low-grade inflammation, leading to many age-related degenerative pathologies and unhealthy aging. The gut microbiota communicates with the host through various biomolecules, nutrient signaling-independent pathways, and epigenetic mechanisms. Disturbance of these communications by age-related gut dysbiosis can affect the host health and lifespan. This may explain the impact of the gut microbiome on health and aging.

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