{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T22:16:57Z","timestamp":1773094617283,"version":"3.50.1"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T00:00:00Z","timestamp":1617667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["16K20257, 17K16928"],"award-info":[{"award-number":["16K20257, 17K16928"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>Age-related hearing loss (ARHL) is the most common form of hearing loss and the predominant neurodegenerative disease associated with aging. <jats:italic>Sirtuin 1 (SIRT1)<\/jats:italic> is associated with the most complex physiological processes, including metabolism, cancer onset, and aging. SIRT1 protein levels are enhanced by the conversion of nicotinamide to N<jats:sup>1<\/jats:sup>-methylnicotinamide (MNAM), independent of its mRNA levels. Moreover, MNAM has implications in increased longevity achieved through its mitohormetic effects. Nicotinamide N-methyltransferase (Nnmt) is an enzyme involved in MNAM metabolism, and its level increases under caloric restriction (CR) conditions. The CR condition has implications in delaying ARHL onset. In this study, we aimed to determine the relationship between diet, hearing function, SIRT1 and SIRT3 expression levels in the inner ear, and cochlear morphology. Mice fed with a high-fat diet (HFD), HFD + 1% MNAM, and low-fat diet (LFD) were monitored for age-related auditory-evoked brainstem responses, and changes in cochlear histology, metabolism, and protein and mRNA expressions were analyzed. Our results revealed that the HFD- and aging-mediated downregulated expression of SIRT1 and SIRT3 promoted hearing loss that was obfuscated by MNAM supplementation-induced upregulated expression of cochlear SIRT1 and SIRT3. Thus, our results suggest that MNAM can be used as a therapeutic agent for preventing ARHL.<\/jats:p>","DOI":"10.3389\/fncel.2021.634868","type":"journal-article","created":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T04:35:28Z","timestamp":1617683728000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Protective Effects of N1-Methylnicotinamide Against High-Fat Diet- and Age-Induced Hearing Loss via Moderate Overexpression of Sirtuin 1 Protein"],"prefix":"10.3389","volume":"15","author":[{"given":"Toru","family":"Miwa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1512","DOI":"10.1161\/01.RES.0000267723.65696.4a","article-title":"Sirt1 regulates aging and resistance to oxidative stress in the heart","volume":"100","author":"Alcendor","year":"2007","journal-title":"Circ. Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1515\/cclm-2021-0170","article-title":"The Preyer reflex\u2013an easy estimate of hearing function in guinea pigs","volume":"106","author":"B\u00f6hmer","year":"1988","journal-title":"Acta Otolaryngol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1016\/j.cmet.2014.11.003","article-title":"Activation of Sirt3 by the NAD+ precursor nicotinamide riboside protects from noise-induced hearing loss","volume":"20","author":"Brown","year":"2014","journal-title":"Cell Metab."},{"key":"B4","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.cmet.2012.07.003","article-title":"High-fat diet triggers inflammation-induced cleavage of Sirt1 in adipose tissue to promote metabolic dysfunction","volume":"16","author":"Chalkiadaki","year":"2012","journal-title":"Cell Metab."},{"key":"B5","doi-asserted-by":"publisher","first-page":"10794","DOI":"10.1073\/pnas.1934713100","article-title":"Developmental defects and p53 hyperacetylation in Sir2 homolog (Sirt1)-deficient mice","volume":"100","author":"Cheng","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"B6","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1002\/emmm.201302451","article-title":"Sirt1 and Sirt2: emerging targets in neurodegeneration","volume":"5","author":"Donmez","year":"2013","journal-title":"EMBO Mol. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.heares.2012.04.012","article-title":"A long-term high-fat diet increases oxidative stress, mitochondrial damage and apoptosis in the inner ear of D-galactose-induced aging rats","volume":"287","author":"Du","year":"2012","journal-title":"Hear. Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1038\/nature08197","article-title":"Recent progress in the biology and physiology of Sirtuins","volume":"460","author":"Finkel","year":"2009","journal-title":"Nature"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e0117547","DOI":"10.1371\/journal.pone.0117547","article-title":"A high-fat diet delays age-related hearing loss progression in C57BL\/6J mice","volume":"10","author":"Fujita","year":"2015","journal-title":"PLoS One"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.1016\/S0140-6736(05)67423-5","article-title":"Presbycusis","volume":"366","author":"Gates","year":"2005","journal-title":"Lancet"},{"key":"B11","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1146\/annurev.pathol.4.110807.092250","article-title":"Mammalian sirtuins: biological insights and disease relevance","volume":"5","author":"Haigis","year":"2010","journal-title":"Annu. Rev. Pathol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.neurobiolaging.2016.03.023","article-title":"Sirt1 deficiency protects cochlear cells and delays the early onset of age-related hearing loss in C57BL\/6 mice","volume":"43","author":"Han","year":"2016","journal-title":"Neurobiol. Aging"},{"key":"B13","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1016\/j.otohns.2010.04.266","article-title":"A combination antioxidant therapy prevents age-related hearing loss in C57BL\/6 mice","volume":"143","author":"Heman-Ackah","year":"2010","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"B14","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1038\/nm.3882","article-title":"Nicotinamide N-methyltransferase regulates hepatic nutrient metabolism through Sirt1 protein stabilization","volume":"21","author":"Hong","year":"2015","journal-title":"Nat. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"e60730","DOI":"10.1371\/journal.pone.0060730","article-title":"Diet-induced obesity exacerbates auditory degeneration via hypoxia, inflammation, and apoptosis signaling pathways in CD\/1 mice","volume":"8","author":"Hwang","year":"2013","journal-title":"PLoS One"},{"key":"B16","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.freeradbiomed.2014.03.035","article-title":"Natural forms of vitamin E: metabolism, antioxidant and anti-inflammatory activities and their role in disease prevention and therapy","volume":"72","author":"Jiang","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1007\/s00125-014-3490-7","article-title":"Association of nicotinamide-N-methyltransferase mRNA expression in human adipose tissue and the plasma concentration of its product, 1-methylnicotinamide, with insulin resistance","volume":"58","author":"Kannt","year":"2015","journal-title":"Diabetologia"},{"key":"B18","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/S0378-5955(03)00365-4","article-title":"Age-related hearing loss and the ahl locus in mice","volume":"188","author":"Keithley","year":"2004","journal-title":"Hear. Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1038\/nature13198","article-title":"Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity","volume":"508","author":"Kraus","year":"2014","journal-title":"Nature"},{"key":"B20","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.trsl.2011.02.006","article-title":"Nutrient-enhanced diet reduces noise-induced damage to the inner ear and hearing loss","volume":"158","author":"Le Prell","year":"2011","journal-title":"Transl. Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.cmet.2008.05.004","article-title":"Sirt1 inhibition reduces IGF-I\/IRS-2\/Ras\/ERK1\/2 signaling and protects neurons","volume":"8","author":"Li","year":"2008","journal-title":"Cell Metab."},{"key":"B22","doi-asserted-by":"publisher","first-page":"bio043612","DOI":"10.1242\/bio.043612","article-title":"Role of Dach1 revealed using a novel inner ear-specific Dach1-knockdown mouse model","volume":"8","author":"Miwa","year":"2019","journal-title":"Biol. Open"},{"key":"B23","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s13041-020-00570-z","article-title":"Tsukushi is essential for the development of the inner ear","volume":"13","author":"Miwa","year":"2020","journal-title":"Mol. Brain"},{"key":"B24","doi-asserted-by":"publisher","first-page":"E186","DOI":"10.3390\/metabo10050186","article-title":"MetaboAnalystR 3.0: toward an optimized workflow for global metabolomics","volume":"10","author":"Pang","year":"2020","journal-title":"Metabolites"},{"key":"B25","doi-asserted-by":"publisher","first-page":"9793","DOI":"10.1073\/pnas.0802917105","article-title":"Sirt1 protects against high-fat diet-induced metabolic damage","volume":"105","author":"Pfluger","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"B26","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1016\/j.tibs.2012.12.004","article-title":"The ways and means that fine tune Sirt1 activity","volume":"38","author":"Revollo","year":"2013","journal-title":"Trends Biochem. Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1038\/nchembio.1352","article-title":"Role of Sirtuins in lifespan regulation is linked to methylation of nicotinamide","volume":"9","author":"Schmeisser","year":"2013","journal-title":"Nat. Chem. Biol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"19432","DOI":"10.1073\/pnas.0908786106","article-title":"Age-related hearing loss in C57BL\/6J mice is mediated by Bak-dependent mitochondrial apoptosis","volume":"106","author":"Someya","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"B29","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1016\/j.cell.2010.10.002","article-title":"Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction","volume":"143","author":"Someya","year":"2010","journal-title":"Cell"},{"key":"B30","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.heares.2009.01.007","article-title":"Interactions of hearing loss and diabetes mellitus in the middle age CBA\/CaJ mouse model of presbycusis","volume":"249","author":"Vasilyeva","year":"2009","journal-title":"Hear. Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"4477","DOI":"10.1172\/JCI46243","article-title":"Hepatic Sirt1 deficiency in mice impairs mTorc2\/Akt signaling and results in hyperglycemia, oxidative damage and insulin resistance","volume":"121","author":"Wang","year":"2011","journal-title":"J. Clin. Invest."},{"key":"B32","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.exger.2013.12.006","article-title":"Sirt1 expression in the cochlea and auditory cortex of a mouse model of age-related hearing loss","volume":"51","author":"Xiong","year":"2014","journal-title":"Exp. Gerontol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1692","DOI":"10.1016\/j.neurobiolaging.2014.12.034","article-title":"Activation of miR-34a\/Sirt1\/p53 signaling contributes to cochlear hair cell apoptosis: implications for age-related hearing loss","volume":"36","author":"Xiong","year":"2015","journal-title":"Neurobiol. Aging"},{"key":"B34","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.neulet.2014.10.001","article-title":"Neurogenesis of the spiral ganglion cells in the cochlea requires the transcriptional cofactor TIS21","volume":"584","author":"Yamada","year":"2015","journal-title":"Neurosci. Lett."},{"key":"B35","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.heares.2013.01.021","article-title":"Current concepts in age-related hearing loss: epidemiology and mechanistic pathways","volume":"303","author":"Yamasoba","year":"2013","journal-title":"Hear. Res."}],"container-title":["Frontiers in Cellular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2021.634868\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T04:35:31Z","timestamp":1617683731000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2021.634868\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,6]]},"references-count":35,"alternative-id":["10.3389\/fncel.2021.634868"],"URL":"https:\/\/doi.org\/10.3389\/fncel.2021.634868","relation":{},"ISSN":["1662-5102"],"issn-type":[{"value":"1662-5102","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,6]]},"article-number":"634868"}}