内耳疾患の治療をめざして―基礎研究の最前線―加齢による内耳変性老人性難聴の予防に向けて―

Abstract

Mitochondrial DNA (mtDNA) mutations/deletions and decline of mitochondrial function are considered to be associated with the development of age-related hearing loss (AHL). First, we examined age-related changes in gene expression profile in the cochlea of DBA/2J mouse. This mouse exhibited mild hearing loss at 2 months of age and became deaf by 8 months. Comprehensive gene expression analysis identified significant expression changes correlated with AHL in over 4000 cochlear genes. When compared to 2 month old mice, approximately 2,200 genes were downregulated and approximately 1,900 genes were upregulated in the cochlea of 8 month old mice. AHL-correlated genes in the cochlea of 8-month-old DBA/2J mice were statistically associated with 15 mitochondrial process categories, suggesting that AHL is associated with profound down-regulation of genes involved in the mitochondrial function in the cochlea of aged DBA/2J mice. Next, we assessed the role of accumulation of mtDNA mutations in the development of AHL using Polg (D257A) knock-in mouse, which exhibited increased spontaneous mtDNA mutation rates during aging and showed accelerated aging. They exhibited moderate hearing loss and degeneration and apoptosis in the cochlea by 9 month of age, while wild-type animals did not. MtDNA mutations were associated with transcriptional alterations consistent with impairment of energy metabolism, induction of apoptosis, and hearing dysfunction in the cochlea of aged mitochondrial mutator mice. Lastly, we examined if 26% calorie restriction (CR) could prevent AHL in C57BL/6 mice. CR mice retained normal hearing and showed no cochlear degeneration by 15 months of age, whereas control mice developed moderate hearing loss and cochlear degeneration due to increased apoptosis at 15 months of age. CR mice also showed a significant reduction in the number of TUNEL-positive cells and cleaved caspase-3-positive cells. Microarray analysis revealed that CR upregulated the expression of genes involved in mitochondrial and hearing function and downregulated that of apoptotic genes. Taken together, these findings suggest that accumulation of mtDNA mutations during aging leads to mitochondrial dysfunction and induces an apoptotic program, thereby causing AHL.