title: Sirt1 deficiency protects cochlear cells and delays the early onset of age-related hearing loss in C57BL/6 mice.
abstract: Hearing gradually declines with age in both animals and humans, and this condition is known as age-related hearing loss (AHL). Here, we investigated the effects of deficiency of Sirt1, a member of the mammalian sirtuin family, on age-related cochlear pathology and associated hearing loss in C57BL/6 mice, a mouse model of early-onset AHL. Sirt1 deficiency reduced age-related oxidative damage of cochlear hair cells and spiral ganglion neurons and delayed the early onset of AHL. In cultured mouse inner ear cell lines, Sirt1 knockdown increased cell viability under oxidative stress conditions, induced nuclear translocation of Foxo3a, and increased acetylation status of Foxo3a. This resulted in increased activity of the antioxidant enzyme catalase. In young wild-type mice, both Sirt1 and Foxo3a proteins resided in the cytoplasm of the supporting cells within the organ of Corti of the cochlea. Therefore, our findings suggest that SIRT1 promotes early-onset AHL through suppressing FOXO3a-mediated oxidative stress resistance in the cochlea of C57BL/6 mice.
authors.affiliation: Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA.
authors.forename: Chul
authors.initials: C
authors.lastname: Han
authors.affiliation: Whitney Laboratory, University of Florida, St Augustine, FL, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Linser
authors.affiliation: Department of Neurology, University of Florida, Gainesville, FL, USA.
authors.forename: Hyo-Jin
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA.
authors.forename: Mi-Jung
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA.
authors.forename: Karessa
authors.initials: K
authors.lastname: White
authors.affiliation: Department of Genetics, University of Wisconsin, Madison, WI, USA; Department of Medical Genetics, University of Wisconsin, Madison, WI, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Vann
authors.affiliation: Center for Hearing and Deafness, State University of New York at Buffalo, NY, USA.
authors.forename: Dalian
authors.initials: D
authors.lastname: Ding
authors.affiliation: Department of Genetics, University of Wisconsin, Madison, WI, USA; Department of Medical Genetics, University of Wisconsin, Madison, WI, USA.
authors.forename: Tomas A
authors.initials: TA
authors.lastname: Prolla
authors.affiliation: Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA. Electronic address: someya@ufl.edu.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Someya
mesh_terms: D000107:Acetylation; D000375:Aging / Q000473:pathology* / Q000502:physiology*; D000818:Animals; D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D004195:Disease Models, Animal; D007758:Ear, Inner / Q000166:cytology / Q000378:metabolism; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006198:Hair Cells, Auditory / Q000473:pathology*; D034381:Hearing Loss / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D056564:Sirtuin 1 / Q000172:deficiency* / Q000502:physiology*
chemical_list: D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; D002374:Catalase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Aging; Hearing loss; Inner ear; Oxidative stress; Sirtuin