Identifying microRNAs involved in the onset and progression of age-related hearing loss

Age-related hearing loss (ARHL) is a progressive sensorineural hearing loss that occurs as people get older. It is generally accepted that degeneration of the organ of Corti and atrophy of the stria vascularis in the inner ear are the two primary causes of ARHL. MicroRNAs (miRNAs), a class of short non-coding RNAs that regulate the expression of mRNA/protein targets, are important regulators of cellular senescence and aging. I examined miRNA gene expression profiles in the organ of Corti (OC) and stria vascularis (SV) of C57BL/6J and CBA/J mice at three different ages using microarray analysis, and hair cell and strial morphology and auditory function using immunocytochemistry and electrophysiology. One hundred eleven and 71 miRNAs exhibited differential expression in the OV of C57 and CBA mice, respectively, while 95 and 59 miRNAs were differentially expressed, respectively, in the SV of these mice. Downregulated miRNAs substantially outnumbered upregulated miRNAs during aging. The changes in the miRNA expression occurred well before morphological and functional changes were detected. Further experiments using quantitative real-time PCR (qPCR) and in situ hybridization showed that four separate subsets of miRNAs in the OC and SV were positively expressed in different areas in the cochlea. The changes were consistent with their presumptive roles in regulating growth and apoptosis. The potential targets of several apoptosis-related miRNAs were further explored using an apoptosis-related gene microarray technique and bioinformatic analyses. It appears that the underlying process and regulatory mechanisms of aging in the OC and SV involve repression of miRNAs important for proliferation and differentiation and enhancement of miRNAs that promote apoptosis. The present work is the first step in an effort to elucidate the roles of miRNAs and their regulatory networks in age-related degeneration of the inner ear. It lays the groundwork for future experiments that can explore whether suppression or overexpression of certain specific miRNAs can slow the onset and progression of ARHL.