Cited by 1,481Sirtuins and Resveratrol in MedicineBiochemical and Molecular ResearchGenetics, Aging, and Longevity in Model Organisms

NAD+ and sirtuins in aging and disease

Open access
Imai, Shin-ichiro, Guarente, Leonard·2014·Trends in Cell Biology

Abstract

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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Crossref · 10.1016/j.tcb.2014.04.002

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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 measured
  • During 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 measured
  • Inhibiting 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”
  • 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”
  • 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”

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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)
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
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

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