Activation of SIRT3 by the NAD(+) precursor nicotinamide riboside protects from noise-induced hearing loss
Open accessAbstract
Intense noise exposure causes hearing loss by inducing degeneration of spiral ganglia neurites that innervate cochlear hair cells. Nicotinamide adenine dinucleotide (NAD(+)) exhibits axon-protective effects in cultured neurons; however, its ability to block degeneration in vivo has been difficult to establish due to its poor cell permeability and serum instability. Here, we describe a strategy to increase cochlear NAD(+) levels in mice by administering nicotinamide riboside (NR), a recently described NAD(+) precursor. We find that administration of NR, even after noise exposure, prevents noise-induced hearing loss (NIHL) and spiral ganglia neurite degeneration. These effects are mediated by the NAD(+)-dependent mitochondrial sirtuin, SIRT3, since SIRT3-overexpressing mice are resistant to NIHL and SIRT3 deletion abrogates the protective effects of NR and expression of NAD(+) biosynthetic enzymes. These findings reveal that administration of NR activates a NAD(+)-SIRT3 pathway that reduces neurite degeneration caused by noise exposure.
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In neurons, SIRT3 mediates adaptive responses to exercise, intermittent fasting, and excitatory challenges and helps prevent noise-induced hearing loss and spiral ganglia neurite degeneration.
“In neurons, SIRT3 mediates the adaptive responses of neurons to exercise, intermittent fasting, and excitatory challenges and helps prevent noise-induced hearing loss and spiral ganglia neurite degeneration (Brown et al., 2014; Cheng et al., 2016; Liu et al., 2019).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Brown et al., 2014
Wlds mouse studies largely show the neuroprotective function of NMNAT1, NMNAT2 and NMNAT3 and their protective role in several neurodegenerative disorders, including Parkinson disease.
“Overall, Wlds mouse studies largely show the neuro protective function of the biosynthetic enzymes NMNAT1, NMNAT2 and NMNAT3 (REFS142,150–152) and their protective role in several neurodegenerative disorders, including Parkinson disease153–155.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [155]
The protective effects of nicotinamide riboside on noise-induced hearing loss appear to be mediated in mitochondria because SIRT3-overexpressing mice are resistant and SIRT3 deletion abrogates the protection.
“These effects appear to be mediated in the mitochondria because SIRT3-overexpressing mice are resistant to noise-induced hearing loss and SIRT3 deletion abrogates the protective effects of nicotinamide riboside ((Brown et al. 2014))”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Brown et al. 2014
Administering the NAD precursor nicotinamide riboside prevents noise-induced hearing loss and degeneration of spiral ganglia neurites.
“Administering the NAD precursor nicotinamide riboside prevents noise-induced hearing loss and degeneration of spiral ganglia neurite degeneration.”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Brown et al. 2014
SIRT3 protects against hearing loss in response to intense noise exposure.
“SIRT3 also protects against hearing loss in response to intense noise exposure (Brown et al. 2014).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Brown et al. 2014
The protective effects of nicotinamide riboside against noise-induced hearing loss depend on SIRT3, since SIRT3 overexpression confers resistance and SIRT3 deletion abrogates protection.
“These effects are dependent on SIRT3, since SIRT3-overexpressing mice are resistant to noise-induced hearing loss and SIRT3 deletion abrogates the protective effects of NR.”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Brown et al. 2014
Cochlear NAD+ levels increased in mice after administering nicotinamide riboside and prevented noise-induced hearing loss.
“Cochlear NAD(+) levels increased in mice after administering nicotinamide riboside, a precursor to NAD(+) and prevented noise-induced hearing loss.”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Brown et al. 2014
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- Authors
- Brown, K. D., Maqsood, S., Huang, J.-Y., Pan, Y., Harkcom, W., Li, W., Sauve, A., Verdin, E., & Jaffrey, S. R.
- Affiliations
- Cornell University (US)
- Gladstone Institutes (US)
- Corresponding author
- Brown, Kevin D.
- Verdin, Eric
- Jaffrey, Samie R.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 20
- Issue
- 6
- Pages
- 1059-1068
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4940130
- OpenAlex
- W2044697772
- Cited by
- 277
- References
- 55
- Citations by year
- 2026: 9 · 2025: 16 · 2024: 17 · 2023: 24 · 2022: 33 · 2021: 26 · 2020: 29 · 2019: 27 · 2018: 30 · 2017: 26 · 2016: 24 · 2015: 14 · 2014: 2
- FWCI
- 11.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- New York State Department of Health
- National Institutes of Health
- Weill Cornell Medical College
- National Cancer Institute (R21CA176638, CA176638)
- National Institute of Neurological Disorders and Stroke (NS56306, R01NS056306)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Neuroscience › Sensory Systems › Hearing, Cochlea, Tinnitus, Genetics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Hearing Loss and Rehabilitation
- Keywords
- noise-induced hearing loss, nicotinamide riboside, SIRT3, NAD+, spiral ganglion neurons, neurite degeneration, cochlear hair cells, mitochondrial sirtuins, NAD biosynthesis, axon protection, neuroprotection
- MeSH terms
- Animals, Female, Hearing Loss, Noise-Induced, Male, NAD, Niacinamide, Pyridinium Compounds, Mice, Sirtuin 3
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