NAD+ and sirtuins in aging and disease
Open accessAbstract
Nicotinamide adenine dinucleotide (NAD(+)) is a classical coenzyme mediating many redox reactions. NAD(+) also plays an important role in the regulation of NAD(+)-consuming enzymes, including sirtuins, poly-ADP-ribose polymerases (PARPs), and CD38/157 ectoenzymes. NAD(+) biosynthesis, particularly mediated by nicotinamide phosphoribosyltransferase (NAMPT), and SIRT1 function together to regulate metabolism and circadian rhythm. NAD(+) levels decline during the aging process and may be an Achilles' heel, causing defects in nuclear and mitochondrial functions and resulting in many age-associated pathologies. Restoring NAD(+) by supplementing NAD(+) intermediates can dramatically ameliorate these age-associated functional defects, counteracting many diseases of aging, including neurodegenerative diseases. Thus, the combination of sirtuin activation and NAD(+) intermediate supplementation may be an effective antiaging intervention, providing hope to aging societies worldwide.
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NAMPT protein and NAD+ levels decrease significantly in white adipose tissue and skeletal muscle of old mice, affecting NAD-dependent enzymes such as sirtuins.
“The NAMPT (nicotinamide phosphoribosyltransferase) protein and NAD+ levels decreased significantly in organs, such as white adipose tissue and skeletal muscle in old mice [13] affecting the activity of NAD+ -dependent enzymes such as sirtuins [15, 98].”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [15]
The sections “NAD+ declines with aging” and “Possible mechanisms for how NAD+ levels decline in aging” report lower NAD+ in aged mouse skeletal muscle and some evidence that NAMPT declines with age. They also link declining NAD+ to reduced sirtuin activity. The copy does not establish a significant decline in both NAMPT protein and NAD+ in white adipose tissue and skeletal muscle of old mice. (LLM, conf=0.85)
Experimental — accuracy not yet measuredDuring aging, DNA damage accumulates in the cell nucleus, causing PARP activation and reducing both NAD+ levels and SIRT1 activity.
“During the aging process, DNA damage accumulates in the cell nucleus causing PARPs activation and reducing both NAD+ levels and SIRT1 activity [15].”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [15]
In “Possible mechanisms for how NAD+ levels decline in aging” (page not provided), the paper reports chronic PARP activation in aging animals alongside reduced NAD+ and evidence of lower SIRT1 activity. It presents accumulated nuclear DNA damage as a possible explanation for PARP-mediated NAD+ depletion, not as an established cause of the entire chain stated in the claim. (LLM, conf=0.87)
Experimental — accuracy not yet measuredInhibiting PARP1 can raise cellular NAD+ by reducing its degradation.
“several studies have proposed that PARP1 inhibition can be used to promote increases in cellular levels of NAD+ by decreasing its degradation”
From A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline (2018) · cites this paper as Imai and Guarente, 2014
PARP1 is the main PARP enzyme in mammalian tissues and consumes NAD+ during catalysis.
“PARP1 is the main PARP enzyme in mammalian tissues and utilize NAD+ during its catalysis”
From A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline (2018) · cites this paper as Imai and Guarente, 2014
Sirtuins have been linked to regulation of chromosomal integrity, DNA damage repair, metabolism, aging, health span, and longevity.
“have been implicated in the regulation of chromosomal integrity, DNA damage repair, metabolism, aging, health span, and longevity”
From A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline (2018) · cites this paper as Imai and Guarente, 2014
Sirtuins are enzymes that remove covalent modifications such as acetylation, malonylation, and succinylation from lysine residues in proteins.
“Sirtuins are enzymes that remove specific covalent modification in lysine residues, such as acetylation, malonylation, and succinylation, in several proteins”
From A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline (2018) · cites this paper as Imai and Guarente, 2014
Sirtuin activity and NAD levels both decline with age.
“Sirtuin activity and NAD levels both decline with age116,117.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [116]
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- Authors
- Imai, S.-I., & Guarente, L.
- Affiliations
- Washington University in St. Louis (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- Corresponding author
- Imai, Shin-ichiro
- Guarente, Leonard
- Venue
- Trends in Cell Biology
- Publisher
- Elsevier BV
- Published
- 2014-08
- Volume
- 24
- Issue
- 8
- Pages
- 464-471
- ISSN
- 0962-8924 (ISSN-L)
- PMC
- PMC4112140
- OpenAlex
- W1989674299
- Cited by
- 1,481
- References
- 71
- Citations by year
- 2026: 210 · 2025: 157 · 2024: 134 · 2023: 138 · 2022: 147 · 2021: 118 · 2020: 140 · 2019: 90 · 2018: 112 · 2017: 105 · 2016: 62 · 2015: 59 · 2014: 8
- FWCI
- 6.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Trends in Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- PMC
- Funders
- Glenn Foundation for Medical Research
- National Institutes of Health
- National Institute on Aging (R01AG024150, AG037457, R01AG037457, R01AG015339, AG024150, R01AG011119)
- 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
- NAD+, sirtuins, aging, NAD biosynthesis, visfatin, SIRT1, poly(ADP-ribose) polymerase, NAD+ precursors, anti-aging interventions, neurodegenerative diseases, mitochondrial function, circadian rhythm, metabolism
- MeSH terms
- Aging, Animals, Circadian Rhythm, Disease, Humans, Mitochondria, NAD, Sirtuins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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