Introduction:
Research on NAD+ biology has gained significant momentum, shedding light on age-associated decline and diseases. Two key NAD+ intermediates, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), have been extensively studied and offer exciting prospects for preventive and therapeutic interventions.
Unraveling NAD+ Metabolism:
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Historical Background:
NAD+ was discovered in 1906 and its role in redox reactions and NAD+ biosynthesis was gradually uncovered.
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Key Discoveries:
The discovery of NMN and NMNAT in the 1960s and 2000s, respectively, led to further research in NAD+ biology.
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Dietary Sources:
NR and NMN are present in daily foods and human milk.
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Age-Related NAD+ Decline:
NAD+ levels decline with age and contribute to age-associated pathophysiologies.
Therapeutic Potential of NR and NMN:
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Pharmacokinetics and Metabolic Fate:
The pharmacokinetics and metabolic fates of NMN and NR are still being investigated.
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Tissue-Specific Behavior:
NMN and NR exhibit distinct behavior, and their fates depend on tissue distribution and expression levels of NAD+ biosynthetic enzymes, nucleotidases, and transporters.
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Proposed Concept:
A comprehensive concept connecting NAD+ metabolism to aging and longevity in mammals has been proposed.
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Translation to Human Health:
The stage is set to test whether the promising preclinical results can be translated to improve human health.
Therapeutic Efficacy of NMN:
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Administration and Effects:
NMN administration improves age-associated pathophysiologies in various tissues and shows efficacy in diseases such as diabetes, neurodegenerative disorders, and kidney injury.
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Safety and Tolerance:
Long-term oral administration of NMN has shown to be safe and well-tolerated in mice.
Therapeutic Efficacy of NR:
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Supplementation Impact:
NR boosts NAD+ levels beyond conventional B vitamin metabolism.
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Metabolic Benefits:
NR supplementation has shown efficacy in improving metabolic health, muscle disorders, liver health, and nervous system function.
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Therapeutic Potential:
NR holds promise as a therapeutic strategy for overall health improvement and treatment of various conditions.
Comparing NMN and NR:
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Benchmarks Yet to be Conducted:
Head-to-head comparisons between NMN and NR effects across pathophysiological conditions have not been conducted.
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Unknown Mechanisms:
The downstream mechanisms mediating the beneficial effects of NAD+ supplementation are still unclear.
Pharmacokinetics of NMN and NR:
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NMN Uptake and Distribution:
NMN rapidly appears in plasma and target tissues after administration, with unclear cellular uptake mechanisms.
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NR Metabolism:
NR is likely converted into nicotinamide before tissue uptake.
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Distinct Behavior:
NMN and NR exhibit different in vivo behavior and kinetics, requiring further investigation.
The NAD World Concept and Beyond:
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Systemic Regulatory Mechanism:
The "NAD World" concept proposes a systemic regulatory mechanism for aging and longevity control, with NMN and NR as key components.
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Revisiting Subcellular Compartments:
The compartmentalization of NAD+ biosynthesis is being questioned, with potential distinct machinery in different subcellular compartments.
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Towards Breakthroughs:
Exciting developments in NAD+ biology offer new opportunities for breakthroughs and effective interventions in humans.
Conclusion:
The research on NAD+ biology and its intermediates NR and NMN provides promising avenues for combating age-associated decline and diseases. With ongoing investigations and clinical trials, potential therapeutic applications of NMN and NR are being explored, bringing hope for improved human health in the future.
Note: The manuscript is still undergoing editing and proofreading before final publication. The authors have stated that they have no competing financial interests.
Title of paper: NAD(+) Intermediates: The Biology and Therapeutic Potential of NMN and NR
Author(s): Yoshino J, Baur JA, Imai SI.
Year published: 2018
Published in: Cell Metab
Original article can be found here.
