Roles of Sirtuins in Hearing Protection
"> Figure 1
<p>Flow diagram representing the screening process for articles investigating sirtuins in hearing loss. Created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p> "> Figure 2
<p>Sirtuin and hearing loss research over time by the number of publications in each sirtuin paralog * Up to May 2024.</p> "> Figure 3
<p>Potential roles of sirtuins in hearing loss. SIRT1 and SIRT3 can modulate ROS in the pathologies leading to hearing loss, evidenced by studies in cell cultures and animal models. The major mechanism is the inhibition of intrinsic apoptosis pathway in IHCs, OHCs, and SGNs. Autophagy and mitophagy, which are triggered by pathways involving SIRT1 and SIRT3, can keep the cells under the threshold of caspase-3 activity sufficient for triggering apoptosis, providing protective roles. Inhibition of SIRT2 may be beneficial in NIHL. It is unclear if SIRT4, SIRT5, and SIRT6 are involved in hearing loss or hearing protection. Created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p> ">
Abstract
:1. Introduction
2. Selection of Studies
2.1. Literature Review Eligibility Criteria
2.2. Identifying Bias and Heterogeneus Results
2.3. Effect Measures in Selected Papers
3. Literature Review
4. Discussion
4.1. SIRT1 in ARHL
4.2. SIRT1 in NIHL
4.3. SIRT1 in DIHL
4.4. SIRT3 in ARHL
4.5. SIRT3 in NIHL
4.6. SIRT3 in DIHL
4.7. SIRT2 in Hearing Loss
4.8. SIRT7 in Hearing Loss
4.9. SIRT4, SIRT5, and SIRT6
5. Summary
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Study Model * | Treatment | Sirtuin | Relevance to Sirtuins in Hearing Loss |
---|---|---|---|
Alzheimer’s mouse model (TgAD) with EOHR (2024) [44] | None | Sirt3 | Sirt3 mRNA decreased in male mice (p < 0.05) |
Dominant optic atrophy mouse model (Opa1delTTAG) with ARHL (2024) [45] | None | Sirt3 | SIRT3 (western blot) expression increased in heterozygote KO (p < 0.001) |
HEI-OC1 cells with senescence induced by D-gal (2024) [46] | Kaempferol; a SIRT3 activator | Sirt3 | Kaempferol increased SIRT3 expression (p < 0.001) |
24-month-old Sirt3−/− mouse model (2024) [47] | None | Sirt3 | Mitochondrial structural damage occurred in Sirt3−/−. Sirt3−/− genotype resulted in hearing loss at 5~32 kHz (p < 0.05) assessed by ABRs |
Ménière’s disease biomarker study in clinics (2023) [48] | Coriolus mushroom; an antioxidant | Sirt1 | A small increase in SIRT1 in Ménière’s disease patients, a further increase after 6 months Coriolus treatment |
OC1 cells (2023) [49] | METTL3, a methyltransferase | Sirt1 | METTL3 KO decreased SIRT1 expression and increased apoptosis (p < 0.05) |
Senescent HEI-OC1, OC-k3, SV-k1 cells treated with H2O2 (2023) [50] | Cocoa polyphenols extract | Sirt1 Sirt3 | Cocoa polyphenols extract increased SIRT1 and SIRT3 expression (ELISA) in all three types of auditory cells (p < 0.05) |
Senescence induced by D-gal in strial marginal cells (SMCs) (2023) [51] | Adenovirus-Sirt1 | Sirt1 | Adenovirus-Sirt1 returned the expression of SOD2 to the level before D-gal induction (p < 0.05) |
Guinea pigs exposed to helicopter noise (2023) [52] | Ginsenoside RD | Sirt1 | Noise exposure decreased SIRT1 expression in the cochlea (p < 0.05) |
Rats exposed to noise (2023) [53] | None | Sirt1 | Sirt1 mRNA decreased in noise-exposed rats (p < 0.05) |
Cochlea basilar membrane cells (2022) [54] | H2O2 | Sirt3 | NR reduced H2O2-induced apoptosis of hair cells and IHC synapses due to H2O2 possibly through SIRT3 expression |
Rats exposed to noise (2022) [55] | SODZIF8; superoxide dismutase nanoparticle | Sirt3 | SIRT3 expression decreased after noise exposure, but SODZIF8 counteracted this effect as shown in a quantitative western blot (p < 0.05) |
Mice ototoxicity induced by aminoglycosides (2022) [56] | dihydronicotinamide riboside (NRH); a reduced form of NR | Sirt1 | SIRT1 expression increased in kanamycin-treated mice after NRH IP injection (p < 0.01), and the injection lowered hearing thresholds (p < 0.01) |
Guinea pigs exposed to noise (2022) [57] | Resveratrol | Sirt1 | Resveratrol increased SIRT1 expression in noise-exposed guinea pigs (western blot), but unclear hearing threshold change |
HEI-OC1 cells given oxidative stress by H2O2 (2022) [58] | H19; an LncRNA which is downregulated in old mouse cochleae | Sirt1 | H2O2 increased H19 and SIRT1 expression (p < 0.05). H19 overexpression under H2O2 increased SIRT1 expression and reduced ROS (p < 0.05) |
OC cells treated with H2O2 (2022) [59] | 3-TYP; a SIRT3 inhibitor | Sirt3 | H2O2 induced loss of synapses and hair cells (p < 0.01) and 3-TYP further induced loss of OHCs only (p < 0.05) |
74-week-old rats using NAD+ level to measure sirtuins (2021) [60] | Environmental enrichment with plastic toys | Sirt1 | Sirt1 activity was higher in the enrichment group, and the ABR click threshold was lower in the enrichment group |
8-month-old C57BL/6J mice (2021) [40] | Thymoquinone; an antioxidant | Sirt3 | Thymoquinone lowered hearing thresholds (8, 16, 22 kHz), increased SIRT1 expression (p < 0.001), and reduced Bak1 expression (p < 0.001) |
HEI-OC1 cells treated with H2O2 (2021) [61] | Luteolin; an antioxidant flavonoid | Sirt1 | Luteolin reduced H2O2-induced senescence (p < 0.05) via upregulating SIRT1 (p < 0.05) |
OC explants extracted from C57BL/6 mice treated with cisplatin (2021) [62] | TES-1025; a promoter of NAD+ | Sirt1 | Cisplatin treatment with TES-1025 increased SIRT3 expression compared to cisplatin-only (p < 0.05), and antibody staining showed that TES-1025 protected hair cells |
Sirt3 KO mice cochlear explants exposed to ototoxic herbicide (2021) [63] | Paraquat; a superoxide generator | Sirt3 | Paraquat destroyed hair cells, but different Sirt3 genotypes did not cause any difference |
3-month-old male B6 mice (2021) [64] | MNAM; a possible SIRT1 inducer | Sirt1 | High-fat diet reduced SIRT1 expression (p < 0.01), but MNAM returned it to the control level (p < 0.01) |
Mice exposed to noise (2021) [65] | Apelin-13; a neuroprotective agent | Sirt1 | Apelin-13 increased SIRT1 expression in noise-exposed cochlea (p < 0.001) |
Mice exposed to cisplatin (2020) [66] | Honokiol | Sirt3 | Honokiol protected hearing as shown through reduced threshold elevations in ABR (p < 0.01) and reduced amplitudes in DPOAE (p < 0.01). Antibody staining showed increased SIRT3 expression in OHCs in honokiol-treated mice (p < 0.01) |
Gentamicin-treated HEI-OC1 cells and cochlear explants (2020) [67] | Dihydromyricetin | Sirt3 | Gentamicin reduced SIRT3 expression which returned to normal upon dihydromyricetin induction (p < 0.001) |
Male guinea pigs exposed to a loudspeaker (2020) [68] | Ginsenoside RD | Sirt1 | Noise exposure decreased SIRT1 expression in the cochlea (p < 0.001), but GSRd returned it to the normal level (p < 0.01) |
Sirt3 KO Mice exposed to noise (2020) [69] | None | Sirt3 | Sirt3 loss does not affect recovery from temporary threshold shift or synaptic loss but may affect the pre-noise exposure threshold |
Ménière’s disease patients with SNHL (2019) [70] | Coriolus mushroom; an antioxidant | Sirt1 | Increase in SIRT1 in Ménière’s disease patients after Coriolus treatment (p < 0.05) |
24 months old C57BL/6J mice with ARHL (2019) [71] | β-lapachone; an anti-cancer drug | Sirt1 Sirt3 | β-lapachone restored SIRT1 activity to the control level in 24 months old mice (p < 0.05) and partially restored SIRT3 activity (p < 0.05) and reduced hearing thresholds at 4, 8, 16, 32 kHz (p < 0.05) |
12 months old C57BL/6 mice with less SIRT1 due to age (2019) [72] | Resveratrol dietary supplement, SIRT1 siRNA | Sirt1 | 12-month-old mice had a lower SIRT1 expression (p < 0.001), and lower autophagy markers (LC3-II and p62) than 2-month-old mice (p < 0.001). Resveratrol reduced ABR threshold elevations in the aging mice (p < 0.05) |
10 months old C57BL/6 mice (2019) [73] | Resveratrol supplement | Sirt1 | Resveratrol reduced ABR threshold elevations at 8, 16, and 32 kHz (p < 0.001) |
HEI-OC1 cells treated with cisplatin (2019) [74] | SRT1720; SIRT1 inducer 3-MA; autophagy inhibitor | Sirt1 | Cisplatin increased SIRT1 expression (p < 0.01), and SRT1720 increased LC3-11 (p < 0.05) but decreased p62 expression (p < 0.05). Autophagy inhibition prevented SRT1720-mediated cell survival (p < 0.005) |
Zebrafish lateral line hair cells treated with cisplatin (2019) [74] | SRT1720 increased the number of lateral line cells after 24 h of cisplatin treatment compared to controls (p < 0.005) | ||
C57BL/6 mice treated with cisplatin (2019) [74] | SRT1720 reduced cisplatin-induced ABR threshold elevations at 4, 8, 16, and 32 kHz (p < 0.01) and reduced hair cell loss | ||
C57BL/6J mice exposed to noise (2019) [41] | AK-7 (SIRT2 inhibitor) IP injection 1 day before noise exposure | Sirt2 | SIRT2 inhibition resulted in IHC protection (p < 0.01) and reduced ABR threshold elevations at 8, 16, 24, and 32 kHz (p < 0.05) |
Sprague Dawley rats with hearing loss induced by 3-NP (2018) [75] | EGb 761; otoprotective leaf extract | Sirt1 | EGb 761 reduced ABR threshold elevations at 8, 16, and 32 kHz. EGb 761 preserved the number of SIRT1-positive type II fibrocytes compared to controls |
C57BL/6 mice exposed to noise (2017) [76] | Resveratrol dietary supplement before noise exposure | Sirt1 | Resveratrol attenuated cochlear SIRT1 decrease upon noise exposure |
Diabetic db/db mice (obese) versus db/m mice (lean) (2017) [77] | miR-34a inhibitor | Sirt1 | SIRT1 expression was lower and HIF-1α was higher in db/db mice (p < 0.05). MiR-34a inhibition increased SIRT1 expression (p < 0.05). db/db mice showed higher threshold shifts between 0.5 and 32 kHz (p < 0.05) |
C57BL/6. Young mice (<2 months old) and old mice (12< months old) (2016) [78] | miR-29b inhibitor | Sirt1 | Old mice showed decreased SIRT1 and increased miR-29B expression (p < 0.05). miR-34a inhibition restored SIRT1 expression to the control level (p < 0.05) |
Sirt1+/− mice (2016) [42] | None | Sirt1 | Sirt1 deficiency delayed AR at 8, 16, and 32 kHz (p < 0.05) and protects hair cells and SGNs |
Male C57BL/6 mice with the Nqo1−/− genoype treated with cisplatin (2016) [79] | Dunnione; an NAD+ inducer acting via NQO1 | Sirt1 | Dunnione restored SIRT1 expression previously decreased by cisplatin treatment (p < 0.05), but not in Nqo1−/− mice |
Microarray analysis on Cmah KO mice, which are linked to ARHL (2015) [80] | None | Sirt3 | SIRT3, SIRT4, SIRT5, Hif1α, SOD2 expressions were reduced in Cmah KO mice |
Cochlear explant cultures treated with gentamicin (2015) [81] | Adjudin | Sirt3 | Adjudin increased SIRT3 expression (p < 0.05) |
C57BL/6. Young mice (<2 months old) and old mice (12< months old) (2015) [82] | Resveratrol | Sirt1 | Aging increased miR-34a and p53, decreased SIRT1 (p < 0.05) |
WldSTg+/−Sirt3−/− mice (overexpression of NAD+ with Sirt3 deletion) exposed to noise (2014) [83] | NR | Sirt3 | WldSTg+/− mice are protected from NIHL (p < 0.001), but Sirt3−/− genotype abolishes the protection (p < 0.001) at 8, 16, and 32 kHz. NR reduces NIHL depending on Sirt3−/− genotype at 8, 16, 32 kHz (p < 0.005). NR prevents neurite degeneration |
Sirt7−/− mice (2014) [84] | None | Sirt7 | Sirt7−/− mice showed hearing loss at 4, 8, 16, and 32 kHz at 33 weeks compared to Sirt7+/+ mice (p < 0.05)—no difference at 8 weeks |
HEI-OC1 cells NQO1 KO mice (2014) [85] | β-lapachone | Sirt1 | Cisplatin decreased SIRT1 expression (p < 0.05), while β-lapachone restored the SIRT1 expression (p < 0.05) in cells. β-lapachone restored hearing thresholds at 4, 8, 16, and 32 kHz to pre-cisplatin treatment level in mice (p < 0.05), but this was not seen in NQO1 KO mice |
C57BL/6 mice which are young (1–2 months) and old (12–16 months) (2014) [32] | None | Sirt1 | Hearing loss occurs in old mice at 4, 8, 16, and 32 kHz (p < 0.01) and hair cell loss is seen in immunostaining (p < 0.05). SIRT1 expression was lower in cochlea (p < 0.05), but not expressed in auditory cortex |
SAMP1/Sku Slc mice (develop ARHL) were treated from young (1 month), middle (7 months), and old (13 months) (2014) [31] | Ubiquinol-10 (CoQ10) | Sirt1 Sirt3 | SIRT1 (p < 0.01) and SIRT3 (p < 0.01) expression increased in 7-month-old mice which had been given CoQ10 supplement since they were 1 month old. CoQ10 also reduced hearing thresholds at 32 kHz when the mice were 7 (p < 0.05) and 13 months (p < 0.05) old |
C57BL/6J Sirt3+/− mice backcrossed 4 times (~94% congenic), 2 months or 12 months old (2010) [33] | Caloric restriction, 25% reduction from the original | Sirt3 | In 12-month-old Sirt3+/+ mice, caloric restriction lowered thresholds at 8, 16, and 32 kHz (p < 0.05). In 12 months old Sirt3−/− mice, there was no significant change |
Drug Name * | Identity | Sirtuin | Mechanism | Drug Target | Subject Tested | Ref |
---|---|---|---|---|---|---|
Kaempferol | Polyphenol | Sirt3 | OPA1 deacetylation and SIRT3 activation | ARHL | Cells | [46] |
Cocoa polyphenol extract | Polyphenol | Sirt1 Sirt3 | Inhibits auditory cell senescence through increasing SIRT1, SIRT3 | ARHL | Cells | [50] |
Adenovirus-Sirt1 | Drug vector | Sirt1 | Releasing DNA, which translocates to the nucleus | ARHL | Cells | [51] |
NR | Nucleoside | Sirt3 | Reduction of hair cell apoptosis via increasing SIRT3 | ARHL | Cells, mice | [54,83] |
H19 | LncRNA | Sirt1 | Inhibition of ROS via inhibition of miR-653-5p and increase in SIRT1 | ARHL | Cells | [58] |
Thymoquinone | Natural quinone product | Sirt3 | Increase in SIRT3 and decrease in Bak1-mediated apoptosis in cochleae | ARHL | Mice | [40] |
Luteolin | Polyphenol | Sirt1 | Reducing cellular senescence via an increase in SIRT1 and inhibition of p53 | ARHL | Cells | [61] |
MNAM | Metabolized NAM | Sirt1 | Possible SIRT1 inducer | ARHL | Mice | [64] |
β-lapachone | Natural quinone product | Sirt1 Sirt3 | Increase in NAD+ through SIRT1, SIRT3 | ARHL | Cells, mice | [71,85] |
siRNA SIRT1 | siRNA drug | Sirt1 | RNAi | ARHL | Mice | [72] |
miR-34a | miRNA | Sirt1 | Binding to mRNA to repress translation | ARHL | Mice | [73] |
miR-29b inhibitor | Oligo-nucleotide | Sirt1 | Antisense oligonucleotides complementary to their targets, binding target miRNA which then are unable to bind their original target | ARHL | Mice | [78] |
Ubiquinol-10 (CoQ10) | Coenzyme produced in the body | Sirt1 Sirt3 | Involved in the mitochondrial electron transport chain | ARHL | Mice | [31] |
Ginsenoside RD | Polyphenol | Sirt1 | Upregulation of SIRT1 and SOD2 | NIHL | G. pigs | [52,68] |
SODZIF8 (superoxide dismutase nanoparticle) | Superoxide dismutase mimic | Sirt3 | Increase in SIRT3 via SODZIF8 and reducing ROS | NIHL | Rats | [55] |
Resveratrol | Polyphenol | Sirt1 Sirt3 | Reduces ROS in NIHR and DIHL through SIRT1 and SIRT3 pathways | NIHL | G. pigs, mice | [57,76,81] |
Apelin-13 | Oligopeptide | Sirt1 | Decreasing caspase-3 and BAX via increasing SIRT1 | NIHL | Mice | [65] |
AK-7 | Small molecule drug | Sirt2 | SIRT2 inhibitor | NIHL | Mice | [41] |
NRH | Reduced form of nicotinamide riboside | Sirt1 | Sirt1 activation and protection against drug ototoxicity | DIHL | Mice | [56] |
TES-1025 | Pyrimidine derivative | Sirt1 | ACMSD inhibitor which promotes NAD+ via SIRT1 | DIHL | Mice | [62] |
Honokiol | Polyphenol | Sirt3 | SIRT3 activation, causing IDH2 deacetylation and ROS reduction | DIHL | Mice | [66] |
Dihydromyricetin | Polyphenol | Sirt3 | Protection against ototoxicity via PGC-1a/SIRT3 signaling | DIHL | Cells | [67] |
β-lapachone | Natural quinone product | Sirt1 Sirt3 | Increase in NAD+ through SIRT1 and SIRT3 expressions | DIHL | Cells, mice | [71,85] |
SRT1720 | Small molecule drug | Sirt1 | SIRT1 inducer | DIHL | Cells, mice | [74] |
3-MA | Adenine drug | Sirt1 | Autophagy inhibitor | DIHL | ||
EGb 761 | Leaf extract | Sirt1 | Antioxidant | DIHL | Rats | [75] |
Dunnione | Leaf extract | Sirt1 | NAD+ inducer via NQO1 | DIHL | Mice | [79] |
Adjudin | Indazole-carboxylic acid | Sirt3 | Reversible germ cell loss | DIHL | Mice cochlear explant | [81] |
METTL3 | Methyl-transferase | Sirt1 | Decreasing ROS and apoptosis through increasing SIRT1 | EOHL | Cells | [49] |
Coriolus mushroom | Poly-saccharide | Sirt1 | Increasing SIRT1 and neuron protection | Ménière’s disease | Clinical | [48,70] |
miR-34a inhibitor | Oligo-nucleotide | Sirt1 | Antisense oligonucleotides complementary to their targets, binding target miRNA which then are unable to bind their original target | Diabetes Type 2 | Mice | [77] |
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Koo, C.; Richter, C.-P.; Tan, X. Roles of Sirtuins in Hearing Protection. Pharmaceuticals 2024, 17, 998. https://doi.org/10.3390/ph17080998
Koo C, Richter C-P, Tan X. Roles of Sirtuins in Hearing Protection. Pharmaceuticals. 2024; 17(8):998. https://doi.org/10.3390/ph17080998
Chicago/Turabian StyleKoo, Chail, Claus-Peter Richter, and Xiaodong Tan. 2024. "Roles of Sirtuins in Hearing Protection" Pharmaceuticals 17, no. 8: 998. https://doi.org/10.3390/ph17080998
APA StyleKoo, C., Richter, C. -P., & Tan, X. (2024). Roles of Sirtuins in Hearing Protection. Pharmaceuticals, 17(8), 998. https://doi.org/10.3390/ph17080998