Mechanisms Of Age-related Hearing Loss Research Articles

MiR-130b-3p involved in the pathogenesis of age-related hearing loss via targeting PPARγ and autophagy

The study focuses on the underlying regulatory mechanism of age-related hearing loss (ARHL), which results from autophagy dysregulation mediated by miR-130b-3p targeting PPARγ. We constructed miR-130b-3p knockout (antagomir) and PPARγ over-expression (OE-PPARγ) mice model by injecting mmu-miR-130b-3p antagomir and HBAAV2/Anc80-m-Pparg-T2A-mCHerry into the right ear’ round window of each mouse, respectively. In vitro, we introduced oxidative stress within HEI-OC1 cells by H2O2 and exogenously changed the miR-130b-3p and PPARγ levels. MiRNA level was detected by RT-qPCR, proteins by western blotting and immunohistochemistry. Morphology of autophagosomes was observed by electron microscopy. In vivo, the cochlea of aged mice showed higher miR-130b-3p expression and lower PPARγ expression, while exogenous inhibition of miR-130b-3p up-regulated PPARγ expression. Autophagy-related biomarkers expression (ATG5, Beclin-1 and LC3B II/I) decreased in aged mice, which reversely increased after the inhibition of miR-130b-3p. The elevation of PPARγ demonstrated similar effects. Contrarily, exogenous overexpression of miR-130b-3p resulted in the decrease of ATG5, Beclin-1 and LC3B II/I. We created oxidative stress within HEI-OC1 by H2O2, subsequently observed the formation of autophagosomes under electron microscope, so as the elevated cell apoptosis rate and weakened cell viability. MiR-130b-3p/PPARγ contributed to the premature senescence of these H2O2-induced HEI-OC1 cells. MiR-130b-3p regulated HEI-OC1 cell growth by targeting PPARγ, thus leading to ARHL.

Degradation of cochlear Connexin26 accelerate the development of age-related hearing loss.

The GJB2 gene, encoding Connexin26 (Cx26), is one of the most common causes of inherited deafness. Clinically, mutations in GJB2 cause congenital deafness or late-onset progressive hearing loss. Recently, it has been reported that Cx26 haploid deficiency accelerates the development of age-related hearing loss (ARHL). However, the roles of cochlear Cx26 in the hearing function of aged animals remain unclear. In this study, we revealed that the Cx26 expression was significantly reduced in the cochleae of aged mice, and further explored the underlying molecular mechanism for Cx26 degradation. Immunofluorescence co-localization results showed that Cx26 was internalized and degraded by lysosomes, which might be one of the important ways for Cx26 degradation in the cochlea of aged mice. Currently, whether the degradation of Cx26 in the cochlea leads directly to ARHL, as well as the mechanism of Cx26 degradation-related hearing loss are still unclear. To address these questions, we generated mice with Cx26 knockout in the adult cochlea as a model for the natural degradation of Cx26. Auditory brainstem response (ABR) results showed that Cx26 knockout mice exhibited high-frequency hearing loss, which gradually progressed over time. Pathological examination also revealed the degeneration of hair cells and spiral ganglions, which is similar to the phenotype of ARHL. In summary, our findings suggest that degradation of Cx26 in the cochlea accelerates the occurrence of ARHL, which may be a novel mechanism of ARHL.

Progress on mechanisms of age-related hearing loss.

Age-related hearing loss, or presbycusis, is a common cause of hearing loss in elderly people worldwide. It typically presents as progressive, irreversible, and usually affects the high frequencies of hearing, with a tremendous impact on the quality of life. Presbycusis is a complex multidimensional disorder, in addition to aging, multiple factors including exposure to noise, or ototoxic agents, genetic susceptibility, metabolic diseases and lifestyle can influence the onset and severity of presbycusis. With the aging of the body, its ability to clean up deleterious substances produced in the metabolic process is weakened, and the self-protection and repair function of the body is reduced, which in turn leads to irreversible damage to the cochlear tissue, resulting in the occurrence of presbycusis. Presently, oxidative stress (OS), mitochondrial DNA damage, low-grade inflammation, decreased immune function and stem cell depletion have been demonstrated to play a critical role in developing presbycusis. The purpose of this review is to illuminate the various mechanisms underlying this age-related hearing loss, with the goal of advancing our understanding, prevention, and treatment of presbycusis.

Two distinct types of nodes of Ranvier support auditory nerve function in the mouse cochlea.

The auditory nerve (AN) of the inner ear is the primary conveyor of acoustic information from sensory hair cells to the brainstem. Approximately 95% of peripheral AN fibers are myelinated by glial cells. The integrity of myelin and the glial-associated paranodal structures at the node of Ranvier is critical for normal AN activity and axonal survival and function in the central auditory nervous system. However, little is known about the node of Ranvier's spatiotemporal development in the AN, how the aging process (or injury) affects the activity of myelinating glial cells, and how downstream alterations in myelin and paranodal structure contribute to AN degeneration and sensorineural hearing loss. Here, we characterized two types of Ranvier nodes-the axonal node and the ganglion node-in the mouse peripheral AN, and found that they are distinct in several features of postnatal myelination and age-related degeneration. Cellular, molecular, and structure-function correlations revealed that the two node types are each critical for different aspects of peripheral AN function. Neural processing speed and synchrony is associated with the length of the axonal node, while stimulus level-dependent amplitude growth and action potentials are associated with the ganglion node. Moreover, our data indicate that dysregulation of glial cells (e.g., satellite cells) and degeneration of the ganglion node structure are an important new mechanism of age-related hearing loss.

Redox activation of excitatory pathways in auditory neurons as mechanism of age-related hearing loss

Age-related hearing (ARHL) loss affects a large part of the human population with a major impact on our aging societies. Yet, underlying mechanisms are not understood, and no validated therapy or prevention exists. NADPH oxidases (NOX), are important sources of reactive oxygen species (ROS) in the cochlea and might therefore be involved in the pathogenesis of ARHL. Here we investigate ARHL in a mouse model. Wild type mice showed early loss of hearing and cochlear integrity, while animals deficient in the NOX subunit p22phox remained unaffected up to six months. Genes of the excitatory pathway were down-regulated in p22phox-deficient auditory neurons. Our results demonstrate that NOX activity leads to upregulation of genes of the excitatory pathway, to excitotoxic cochlear damage, and ultimately to ARHL. In the absence of functional NOXs, aging mice conserve hearing and cochlear morphology. Our study offers new insights into pathomechanisms and future therapeutic targets of ARHL.

Hearing loss through apoptosis of the spiral ganglion neurons in apolipoprotein E knockout mice fed with a western diet

Age-related hearing loss (ARHL) is a neurodegenerative disease associated with an aged population. ARHL is influenced by biological factors such as aging, sex difference, and atherosclerosis. The mechanisms of ARHL caused by atherosclerosis have not been previously determined in apolipoprotein E knockout (ApoE KO) male mice. To investigate the onset and cause of the hearing loss, ApoE KO male mice were treated with a western diet (ApoE KO-WD) for 16 weeks. The lipid profile, atherosclerotic plaques throughout the aorta, and auditory brainstem response (ABR) thresholds were measured in the ApoE KO-WD male mice. The expression of S100 calcium-binding protein B (S100B), a neuronal damage biomarker, was also observed. Reactive oxygen species (ROS) and apoptosis rates were detected in the cochlea of the ApoE KO male mice. Atherosclerotic plaques on the aorta and ABR thresholds were significantly increased in the ApoE KO-WD male mice at 24 weeks of age. ABR thresholds had a statistically significant positive correlation with the area of atherosclerotic plaques (r = 0.783, p = 0.013) in male mice at 24 weeks of age. S100B protein expression and the dihydroethidium (DHE) reaction to ROS in the cochlear spiral ganglion neurons (SGNs) were significantly increased in the ApoE KO and ApoE KO-WD male mice. Cells positive for active caspase-3 and terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) in the SGNs were significantly increased in ApoE KO-WD male mice indicating an increased rate of cellular apoptosis. In conclusion, ROS in the SGNs were activated by increased S100B expression in ApoE KO-WD male mice, and this resulted in an increased apoptosis rate. Thus, hearing loss began at 16 weeks in ApoE KO-WD male mice. Our results suggest that the ApoE KO-WD male mice are a suitable animal model for studying ARHL associated with exacerbated atherosclerosis.

Auditory Dysfunction in Aging: Prospects for Stem Cell Therapy

Age-related hearing loss is the most common cause of adult auditory dysfunction. It is characterized by bilateral, progressive auditory deterioration associated with the aging process. There currently are limited options for the treatment as hearing aids or cochlear implants. To establish novel strategies for the treatment of this entity, it is crucial to elucidate the mechanisms of age-related hearing loss. Its etiology is believed to be multifactorial including both intrinsic and extrinsic factors. Oxidative damage, as seen in other aging organs systems, may play an essential role in the pathogenesis of the age-related hearing loss. Studies on animal models and human temporal bones have indicated a close relationship between degeneration of the cochlear lateral wall and hearing loss. Additional therapies that may prove beneficial in the treatment of age-related hearing loss include stem cell therapy, which we intend to review in this manuscript.

Tuberous sclerosis complex-mediated mTORC1 overactivation promotes age-related hearing loss.

The underlying molecular mechanisms of age-related hearing loss (ARHL) in humans and many strains of mice have not been fully characterized. This common age-related disorder is assumed to be closely associated with oxidative stress. Here, we demonstrate that mTORC1 signaling is highly and specifically activated in the cochlear neurosensory epithelium (NSE) in aging mice, and rapamycin injection prevents ARHL. To further examine the specific role of mTORC1 signaling in ARHL, we generated murine models with NSE-specific deletions of Raptor or Tsc1, regulators of mTORC1 signaling. Raptor-cKO mice developed hearing loss considerably more slowly than WT littermates. Conversely, Tsc1 loss led to the early-onset death of cochlear hair cells and consequently accelerated hearing loss. Tsc1-cKO cochleae showed features of oxidative stress and impaired antioxidant defenses. Treatment with rapamycin and the antioxidant N-acetylcysteine rescued Tsc1-cKO hair cells from injury in vivo. In addition, we identified the peroxisome as the initial signaling organelle involved in the regulation of mTORC1 signaling in cochlear hair cells. In summary, our findings identify overactive mTORC1 signaling as one of the critical causes of ARHL and suggest that reduction of mTORC1 activity in cochlear hair cells may be a potential strategy to prevent ARHL.

Role of MiR-34a/Bcl-2 apoptotic pathway in age-related hearing loss of mouse model

Objective To explore the possible mechanism of miR-34a/Bcl-2 apoptotic pathway in the mouse model of age-related hearing loss. Methods A C57BL/6 mouse model of age-related hearing loss was conducted, and 4-week-old and 12-month-old mice were considered as the objects. The auditory brainstem response (ABR) was used to test the hearing function. The TdT-mediated dUTP nick end labeling (TUNEL) was used to observe the apoptosis of neuron in auditory cortex. The mRNA and protein levels of miR-34a, Bcl-2 and caspase 3 were detected by real-time PCR and Western bloting, respectively. Results The ABR showed that the hearing threshold level at 4, 8, 16, 32 kHz were higher in 12-month-old mice than in 4-week-old mice〔(80.0±2.5) dBHL vs. (32.0±4.5) dBHL, (74.0±3.5) dBHL vs. (51.0±1.2) dBHL, (86.0±4.6) dBHL vs. (51.0±3.5) dBHL, (87.0±6.6) dBHL vs. (56.0±1.5) dBHL, all P<0.05〕. Compared with 4-week-old mice, the total number of neurons in auditory cortex was decreased, the number of apoptosis neurons was increased, the expressions of miR-34a (t=6.02, P=0.001), Bax (t=6.51, P=0.012) and Caspase-3 (P=0.023) rised, and the expression of Bcl-2 (t=7.12, P=0.032) declined in 12-month-old mice. Conclusions The activation of miR-34a/Bcl-2 apoptotic pathway may be one of the mechanisms of age-related hearing loss. Key words: Presbycusis; Apoptosis

Recognition and Control of the Progression of Age-Related Hearing Loss

Recent breakthroughs have provided notable insights into both the pathogenesis and therapeutic strategies for age-related hearing loss (ARHL). Simultaneously, these breakthroughs enhance our knowledge about this neurodegenerative disease and raise the question of whether the disorder is preventable or even treatable. Discoveries relating to ARHL have revealed a unique link between ARHL and the underlying pathologies. Therefore, we need to better understand the pathogenesis or the mechanism of ARHL and learn how to take full advantage of various therapeutic strategies to prevent the progression of ARHL.

Experience restores innate female preference for male ultrasonic vocalizations

Mouse models are increasingly contributing to our understanding of the neural genetics of sensory processing and memory. For example, strain differences have helped elucidate basic mechanisms of age-related hearing loss and auditory fear conditioning. Assessing sensory differences arising in acoustic communication contexts is also important for understanding natural audition. While this topic has not been well studied, it is currently being addressed through auditory neuroethological studies in the CBA/CaJ strain, where insights will help lay a foundation for future neural genetic studies. Here, we focus on the responses of adult females to ultrasonic vocalizations of males. We tested a group of female mice in a place-preference paradigm before and after auditory and olfactory experience with a male. A control group was housed with other female cagemates between trials. All females showed an initial preference for male calls that rapidly decayed over the course of a trial. However, only females that had been pair-housed with a male during the inter-trial interval displayed a reinstated interest in male vocalizations, suggesting possible group differences in the assessment of the calls' behavioral relevance. These findings provide a timeframe during which auditory processing of male ultrasounds might be expected to show a difference depending on behavioral relevance, and also suggest an importance of social interactions in maintaining call recognition.

Attenuation of progressive hearing loss in a model of age-related hearing loss by a heat shock protein inducer, geranylgeranylacetone

Mechanisms of age-related hearing loss (ARHL) have not been elucidated as aging processes are extremely complex. Although oxidative stress and apoptotic cell death are involved in progression of ARHL, number of trial to treat ARHL is limited. Heat shock response is characterized by induction of heat shock proteins (HSPs) in response to stresses such as heat shock, which diminishes during aging. HSPs act as molecular chaperones, and some HSPs also inhibit apoptotic pathways. Here, we examined age-related expression of HSPs in the cochlea of ARHL model DBA/2J mice and control CBA/N mice. Western blot assay revealed that CBA/N mice showed constant expression of Hsp70 and Hsp110 with age, but not in DBA/2J mice. The result suggests that pharmacological upregulation of HSPs might attenuate ARHL. We administered DBA/2J mice with food containing geranylgeranylacetone (GGA) that induces HSPs in the cochlea, and found that its administration suppresses ARHL examined by ABR test and histological examination though protection is specific for the apical part of the cochlea. These results demonstrate that dietary supplementation of GGA could be an effective therapeutic strategy for treatment of ARHL.

Mechanisms of Age-Related Hearing Loss

Mechanisms of Age-Related Hearing Loss

Effects of age on the distortion product otoacoustic emission growth functions

Age-related hearing loss (presbycusis) is thought to result from age-related degeneration (aging) of the cochlea plus the cumulative effects of extrinsic damage (noise and other ototoxic agents) and intrinsic disorders (e.g. systemic diseases). Previous studies have implicated dysfunction of the hair cells (sensory presbycusis) as the principal mechanism of age-related hearing loss. However, recent evidence from quiet-reared gerbils suggests that cochlear aging results primarily from atrophy of the stria vascularis, which is associated with diminished endocochlear potential (EP), spiral ganglion atrophy, and a relatively flat audiometric loss, termed metabolic presbycusis. Because it is not currently possible to measure EP directly in the clinical setting, we wondered if cochlear metabolic dysfunction might be evidenced indirectly from existing clinical tests, specifically, the input–output (IO) growth function of the distortion product (DP) otoacoustic emissions in relation to behavioral hearing threshold levels (HTL). We anticipated finding discordance between the IO functions and HTL with either a greater decline with age in HTL than in IO functions if an age-related metabolic dysfunction of the cochlea was operant, or a greater loss of IO function than HTL if outer hair cell dysfunction was the dominant pathology. To address this supposition we analyzed existing auditory data from a large cohort of adults to determine the change with age in three aspects of the DP IO function: area under the curve, threshold, and slope. The analyses demonstrated a greater effect of age on HTL than on the DP IO measures. This effect supports the hypothesis that strial dysfunction is a substantive factor in cochlear aging. The etiology and mechanisms for this dysfunction are conjectural at present.