N1-methylnicotinamide promotes age-related cochlear damage via the overexpression of SIRT1
Age-related hearing loss (ARHL) is a complex condition with genetic, aging, and environmental influences. Sirtuins, particularly SIRT1, are NAD-dependent protein deacetylases critical to aging and stress responses. SIRT1 is modulated by nicotinamide N-methyltransferase (NNMT) and its product, N1-met...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2025.1542164/full |
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| author | Toru Miwa Toru Miwa Akihito Tarui Akihito Tarui Teppei Kouga Yasunori Asai Yasunori Asai Hideaki Ogita Hideaki Ogita Taro Fujikawa Nobuhiro Hakuba Nobuhiro Hakuba |
| author_facet | Toru Miwa Toru Miwa Akihito Tarui Akihito Tarui Teppei Kouga Yasunori Asai Yasunori Asai Hideaki Ogita Hideaki Ogita Taro Fujikawa Nobuhiro Hakuba Nobuhiro Hakuba |
| author_sort | Toru Miwa |
| collection | DOAJ |
| description | Age-related hearing loss (ARHL) is a complex condition with genetic, aging, and environmental influences. Sirtuins, particularly SIRT1, are NAD-dependent protein deacetylases critical to aging and stress responses. SIRT1 is modulated by nicotinamide N-methyltransferase (NNMT) and its product, N1-methylnicotinamide (MNAM), which influence ARHL progression. While SIRT1 is protective under certain conditions, its overexpression may paradoxically exacerbate hearing loss. This study examines MNAM supplementation’s impact on SIRT1 expression and ARHL in low-fat diet (LFD)-fed B6 and CBA mice. Mice were divided into LFD and LFD + MNAM groups and evaluated for auditory function, cochlear morphology, metabolic profiles, and SIRT1 expression at 3, 6, and 12 months of age. MNAM supplementation accelerated ARHL in both strains, with B6 mice showing more pronounced and earlier disease progression. Auditory brainstem response (ABR) thresholds were significantly elevated, and distortion-product otoacoustic emissions (DPOAE) indicated outer hair cell dysfunction. Cochlear histology revealed reduced hair cell and spiral ganglion cell counts, as well as decreased Na+/K+-ATPase α1 expression and endocochlear potential. MNAM increased SIRT1 protein levels in the cochlea without altering Sirt1 mRNA, suggesting post-transcriptional regulation. Metabolomic analysis revealed disrupted mitochondrial and oxidative pathways, including fatty acid oxidation and gluconeogenesis. Tricarboxylic acid (TCA) cycle dysregulation was evident, particularly in B6 mice, with elevated pyruvate, fumarate, and lactate levels. Despite similar metabolic trends in CBA mice, their slower aging profiles mitigated ARHL progression. These results suggest that while moderate SIRT1 expression protects against ARHL, overexpression disrupts metabolic homeostasis, accelerating cochlear aging and dysfunction. The dual role of SIRT1 emphasizes the need for precise modulation of its expression for effective therapeutic interventions. Future research should explore mechanisms underlying SIRT1-induced cochlear damage and strategies to maintain balanced SIRT1 expression. This study highlights MNAM’s detrimental effects on ARHL, underscoring its significance for developing targeted approaches to delay ARHL onset and preserve auditory function. |
| format | Article |
| id | doaj-art-280ef52c85ee4f6cbc7baaa68157e67d |
| institution | Kabale University |
| issn | 1662-5102 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cellular Neuroscience |
| spelling | doaj-art-280ef52c85ee4f6cbc7baaa68157e67d2025-01-31T06:40:09ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022025-01-011910.3389/fncel.2025.15421641542164N1-methylnicotinamide promotes age-related cochlear damage via the overexpression of SIRT1Toru Miwa0Toru Miwa1Akihito Tarui2Akihito Tarui3Teppei Kouga4Yasunori Asai5Yasunori Asai6Hideaki Ogita7Hideaki Ogita8Taro Fujikawa9Nobuhiro Hakuba10Nobuhiro Hakuba11Department of Otolaryngology, Teikyo University Hospital, Mizonokuchi, Kawasaki, JapanDepartment of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Otolaryngology, Teikyo University Hospital, Mizonokuchi, Kawasaki, JapanDepartment of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Otolaryngology, Osaka Metropolitan University, Osaka, JapanDepartment of Otolaryngology, Teikyo University Hospital, Mizonokuchi, Kawasaki, JapanDepartment of Otolaryngology-Head and Neck Surgery, Fujita Health University, Toyoake, JapanDepartment of Otolaryngology, Teikyo University Hospital, Mizonokuchi, Kawasaki, JapanDepartment of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Otolaryngology, Teikyo University Hospital, Mizonokuchi, Kawasaki, JapanDepartment of Otolaryngology, Teikyo University Hospital, Mizonokuchi, Kawasaki, JapanDepartment of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, JapanAge-related hearing loss (ARHL) is a complex condition with genetic, aging, and environmental influences. Sirtuins, particularly SIRT1, are NAD-dependent protein deacetylases critical to aging and stress responses. SIRT1 is modulated by nicotinamide N-methyltransferase (NNMT) and its product, N1-methylnicotinamide (MNAM), which influence ARHL progression. While SIRT1 is protective under certain conditions, its overexpression may paradoxically exacerbate hearing loss. This study examines MNAM supplementation’s impact on SIRT1 expression and ARHL in low-fat diet (LFD)-fed B6 and CBA mice. Mice were divided into LFD and LFD + MNAM groups and evaluated for auditory function, cochlear morphology, metabolic profiles, and SIRT1 expression at 3, 6, and 12 months of age. MNAM supplementation accelerated ARHL in both strains, with B6 mice showing more pronounced and earlier disease progression. Auditory brainstem response (ABR) thresholds were significantly elevated, and distortion-product otoacoustic emissions (DPOAE) indicated outer hair cell dysfunction. Cochlear histology revealed reduced hair cell and spiral ganglion cell counts, as well as decreased Na+/K+-ATPase α1 expression and endocochlear potential. MNAM increased SIRT1 protein levels in the cochlea without altering Sirt1 mRNA, suggesting post-transcriptional regulation. Metabolomic analysis revealed disrupted mitochondrial and oxidative pathways, including fatty acid oxidation and gluconeogenesis. Tricarboxylic acid (TCA) cycle dysregulation was evident, particularly in B6 mice, with elevated pyruvate, fumarate, and lactate levels. Despite similar metabolic trends in CBA mice, their slower aging profiles mitigated ARHL progression. These results suggest that while moderate SIRT1 expression protects against ARHL, overexpression disrupts metabolic homeostasis, accelerating cochlear aging and dysfunction. The dual role of SIRT1 emphasizes the need for precise modulation of its expression for effective therapeutic interventions. Future research should explore mechanisms underlying SIRT1-induced cochlear damage and strategies to maintain balanced SIRT1 expression. This study highlights MNAM’s detrimental effects on ARHL, underscoring its significance for developing targeted approaches to delay ARHL onset and preserve auditory function.https://www.frontiersin.org/articles/10.3389/fncel.2025.1542164/fullage related hearing lossSirtuin 1N1-methylnicotinamidespiral ligamentmetabolomeauditory brainstem responses |
| spellingShingle | Toru Miwa Toru Miwa Akihito Tarui Akihito Tarui Teppei Kouga Yasunori Asai Yasunori Asai Hideaki Ogita Hideaki Ogita Taro Fujikawa Nobuhiro Hakuba Nobuhiro Hakuba N1-methylnicotinamide promotes age-related cochlear damage via the overexpression of SIRT1 Frontiers in Cellular Neuroscience age related hearing loss Sirtuin 1 N1-methylnicotinamide spiral ligament metabolome auditory brainstem responses |
| title | N1-methylnicotinamide promotes age-related cochlear damage via the overexpression of SIRT1 |
| title_full | N1-methylnicotinamide promotes age-related cochlear damage via the overexpression of SIRT1 |
| title_fullStr | N1-methylnicotinamide promotes age-related cochlear damage via the overexpression of SIRT1 |
| title_full_unstemmed | N1-methylnicotinamide promotes age-related cochlear damage via the overexpression of SIRT1 |
| title_short | N1-methylnicotinamide promotes age-related cochlear damage via the overexpression of SIRT1 |
| title_sort | n1 methylnicotinamide promotes age related cochlear damage via the overexpression of sirt1 |
| topic | age related hearing loss Sirtuin 1 N1-methylnicotinamide spiral ligament metabolome auditory brainstem responses |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2025.1542164/full |
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