Abstract
MicroRNAs (miRNAs), a class of short non-coding RNAs that regulate the expression of mRNA targets, are important regulators of cellular senescence and aging. We questioned which miRNAs are involved in age-related degeneration of the organ of Corti (OC), the auditory sensory epithelium that transduces mechanical stimuli to electrical activity in the inner ear. Degeneration of the OC is generally accepted as the main cause of age-related hearing loss (ARHL), a progressive loss of hearing in individuals as they grow older. To determine which miRNAs are involved in the onset and progression of ARHL, miRNA gene expression in the OC of two mouse strains, C57BL/6J and CBA/J, was compared at three different ages using GeneChip miRNA microarray and was validated by real-time PCR. We showed that 111 and 71 miRNAs exhibited differential expression in the C57 and CBA mice, respectively, and that downregulated miRNAs substantially outnumbered upregulated miRNAs during aging. miRNAs that had approximately 2-fold upregulation included members of miR-29 family and miR-34 family, which are known regulators of pro-apoptotic pathways. In contrast, miRNAs that were downregulated by about 2-fold were members of the miR-181 family and miR-183 family, which are known to be important for proliferation and differentiation, respectively. The shift of miRNA expression favoring apoptosis occurred earlier than detectable hearing threshold elevation and hair cell loss. Our study suggests that changes in miRNA expression precede morphological and functional changes, and that upregulation of pro-apoptotic miRNAs and downregulation of miRNAs promoting proliferation and differentiation are both involved in age-related degeneration of the OC.
Highlights
Age-related hearing loss (ARHL), known as presbycusis, is a progressive sensorineural hearing loss that occurs as people get older
The C57 strain possesses a mutation in the Ahl gene that leads to deficiencies in the cadherin 23 protein [27,28], an important component of the transduction apparatus in the stereocilia of hair cells [29,30,31]
The ABR audiogram indicates that C57 mice displayed an onset and rapid progression of hearing loss starting from high frequencies as early as 3 months after birth, whereas CBA mice exhibit minimal hearing loss even at 16 m
Summary
Age-related hearing loss (ARHL), known as presbycusis, is a progressive sensorineural hearing loss that occurs as people get older. It has been reported that as many as 35% to 50% of the population aged between 65 and 75 have ARHL [1,2]. MiRNAs are a vital part of genetic regulation and exhibit a wide range of biological functions including cell differentiation, proliferation, apoptosis, metabolism, and self-renewal [4]. Recent studies have established a direct correlation between miRNA regulation and aging in worms (Caenorhabditis elegans), mice, and humans [5,6]. A number of other miRNAs including the miR29 family, miR-34 family, miR-15/16, miR-17-92 cluster, miR146a/b, and miR-200 family are all known to be involved in networks regulating cell senescence and death [8,9,10]
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