NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR
Open accessAbstract
Research on the biology of NAD+ has been gaining momentum, providing many critical insights into the pathogenesis of age-associated functional decline and diseases. In particular, two key NAD+ intermediates, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), have been extensively studied over the past several years. Supplementing these NAD+ intermediates has shown preventive and therapeutic effects, ameliorating age-associated pathophysiologies and disease conditions. Although the pharmacokinetics and metabolic fates of NMN and NR are still under intensive investigation, these NAD+ intermediates can exhibit distinct behavior, and their fates appear to depend on the tissue distribution and expression levels of NAD+ biosynthetic enzymes, nucleotidases, and presumptive transporters for each. A comprehensive concept that connects NAD+ metabolism to the control of aging and longevity in mammals has been proposed, and the stage is now set to test whether these exciting preclinical results can be translated to improve human health.
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Boosting or restoring NAD+ levels exhibits benefits against physiological aging and its associated disorders, including obesity, muscle degeneration, and neurodegeneration.
“Thus, boosting or restoring NAD+ levels exhibits benefits against physiological aging and its associated disorders, including obesity, muscle degeneration, and neurodegeneration (4–8).”
From Nicotinamide riboside and nicotinamide mononucleotide facilitate NAD <sup>+</sup> synthesis via enterohepatic circulation (2025) · cites this paper as [4]
Tissue NAD levels progressively decline with ageing in rodents and humans across multiple tissues.
“Recently, a progressive decrease in NAD levels during ageing in both rodents and humans has been documented in multiple tissues2.”
From Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages (2020) · cites this paper as [2]
NAD precursor supplementation with NR, NAM, NA, and NMN mitigates several age-associated diseases.
“restoration of NAD levels with the NAD precursor vitamins nicotinamide riboside (NR), nicotinamide (NAM) and nicotinic acid (NA), in addition to the biosynthetic NAD precursor nicotinamide mononucleotide (NMN), appears to mitigate several age-associated diseases2-4.”
From Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages (2020) · cites this paper as [2]
Preclinical studies in C. elegans, D. melanogaster, rodents and human primary cells have established an age-dependent decline of NAD+ levels ranging from 10% to 65%, depending on organ and age.
“Preclinical studies in different animal models, such as Caenorhabditis elegans, D. melanogaster, rodents and human primary cells, have firmly established that there is an age-dependent decline of NAD+ levels, which ranges from 10% to 65%, depending on different organs and age130.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [130]
NR and NMN have a protective effect in a number of age-related disease models, by increasing the pool of precursors and thus NAD+ levels in the body.
“According to reports, NR and NMN have a protective effect in a number of age-related disease models, by increasing the pool of precursors and thus NAD+ levels in the body, both of which have been tested in murine and invertebrate aging studies [195, 197, 199].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [197]
NAD+ declines in many tissues during the aging process, including adipose tissue, skeletal muscle, brain, liver, pancreas, heart, spleen, kidney, and lungs, leading to various age-related pathophysiology developments.
“Much of the literature suggests that NAD+ declines in many tissues during the aging process, including adipose tissue, skeletal muscle, brain, liver, pancreas, heart, spleen, kidney, and lungs, leading to various age-related pathophysiology developments [195–197].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [197]
Administration of NAD precursors, in particular nicotinamide riboside and nicotinamide mononucleotide, has shown benefits in terms of healthspan and lifespan.
“The administration of NAD precursors, in particular nicotinamide riboside and nicotinamide mononucleotide, has shown benefits in terms of healthspan219 and lifespan39.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [219]
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References 126 · Cited by 1,061
- Authors
- Yoshino, J., Baur, J. A., & Imai, S.-I.
- Affiliations
- Washington University in St. Louis (US)
- University of Pennsylvania (US)
- Corresponding author
- Yoshino, Jun
- Baur, Joseph A.
- Imai, Shin-ichiro
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 27
- Issue
- 3
- Pages
- 513-528
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5842119
- OpenAlex
- W2775008495
- Cited by
- 1,061
- References
- 126
- Citations by year
- 2026: 157 · 2025: 155 · 2024: 154 · 2023: 137 · 2022: 132 · 2021: 110 · 2020: 99 · 2019: 74 · 2018: 42
- FWCI
- 6.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIDDK (DK104995, DK098656)
- Longer Life Foundation
- NIA (AG043483, AG037457, AG047902)
- American Federation for Aging Research
- Tanaka Fund
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- nicotinamide mononucleotide, nicotinamide riboside, NAD+ metabolism, aging, longevity, NAD+ precursors, therapeutic potential
- MeSH terms
- Aging, Animals, Humans, NAD, Niacinamide, Nicotinamide Mononucleotide, Pyridinium Compounds
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