The ototoxic drug cisplatin localises to stress granules altering their dynamics and composition.

Cisplatin is an effective platinum-based chemotherapeutic with several side effects, including ototoxicity. Cochlear cells have low rates of proliferation yet are highly susceptible to cisplatin. We hypothesised that cisplatin ototoxicity might be caused by cisplatin-protein interactions rather than cisplatin-DNA interactions. Two known cisplatin-binding proteins are involved in the stress granule (SG) response. SGs are a pro-survival mechanism involving formation of transient ribonucleoprotein complexes during stress. We examined the effects of cisplatin on SG dynamics and composition in cell lines derived from the cochlea and retinal pigment epithelium. Cisplatin-induced SGs are significantly diminished in size and quantity compared to arsenite-induced SGs and are persistent after 24 h recovery. Additionally, cisplatin pre-treated cells were unable to form a typical SG response to subsequent arsenite stress. Cisplatin-induced SGs had significant reductions in the sequestration of eIF4G and the proteins RACK1 and DDX3X. Live-cell imaging of Texas Red-conjugated cisplatin revealed its localisation to SGs and retention for at least 24 h. We show cisplatin-induced SGs have impaired assembly, altered composition and are persistent, providing evidence of an alternate mechanism for cisplatin-induced ototoxicity via an impaired SG response.

GWAS Identifies 44 Independent Associated Genomic Loci for Self-Reported Adult Hearing Difficulty in UK Biobank.

Age-related hearing impairment (ARHI) is the most common sensory impairment in the aging population; a third of individuals are affected by disabling hearing loss by the age of 65. It causes social isolation and depression and has recently been identified as a risk factor for dementia. The genetic risk factors and underlying pathology of ARHI are largely unknown, meaning that targets for new therapies remain elusive, yet heritability estimates range between 35% and 55%. We performed genome-wide association studies (GWASs) for two self-reported hearing phenotypes, using more than 250,000 UK Biobank (UKBB) volunteers aged between 40 and 69 years. Forty-four independent genome-wide significant loci (p < 5E-08) were identified, considerably increasing the number of established trait loci. Thirty-four loci are novel associations with hearing loss of any form, and only one of the ten known hearing loci has a previously reported association with an ARHI-related trait. Gene sets from these loci are enriched in auditory processes such as synaptic activities, nervous system processes, inner ear morphology, and cognition, while genetic correlation analysis revealed strong positive correlations with multiple personality and psychological traits for the first time. Immunohistochemistry for protein localization in adult mouse cochlea implicate metabolic, sensory, and neuronal functions for NID2, CLRN2, and ARHGEF28. These results provide insight into the genetic landscape underlying ARHI, opening up novel therapeutic targets for further investigation. In a wider context, our study also highlights the viability of using self-report phenotypes for genetic discovery in very large samples when deep phenotyping is unavailable.

Mouse screen reveals multiple new genes underlying mouse and human hearing loss.

Adult-onset hearing loss is very common, but we know little about the underlying molecular pathogenesis impeding the development of therapies. We took a genetic approach to identify new molecules involved in hearing loss by screening a large cohort of newly generated mouse mutants using a sensitive electrophysiological test, the auditory brainstem response (ABR). We review here the findings from this screen. Thirty-eight unexpected genes associated with raised thresholds were detected from our unbiased sample of 1,211 genes tested, suggesting extreme genetic heterogeneity. A wide range of auditory pathophysiologies was found, and some mutant lines showed normal development followed by deterioration of responses, revealing new molecular pathways involved in progressive hearing loss. Several of the genes were associated with the range of hearing thresholds in the human population and one, SPNS2, was involved in childhood deafness. The new pathways required for maintenance of hearing discovered by this screen present new therapeutic opportunities.

Disruption of SorCS2 reveals differences in the regulation of stereociliary bundle formation between hair cell types in the inner ear.

Behavioural anomalies suggesting an inner ear disorder were observed in a colony of transgenic mice. Affected animals were profoundly deaf. Severe hair bundle defects were identified in all outer and inner hair cells (OHC, IHC) in the cochlea and in hair cells of vestibular macular organs, but hair cells in cristae were essentially unaffected. Evidence suggested the disorder was likely due to gene disruption by a randomly inserted transgene construct. Whole-genome sequencing identified interruption of the SorCS2 (Sortilin-related VPS-10 domain containing protein) locus. Real-time-qPCR demonstrated disrupted expression of SorCS2 RNA in cochlear tissue from affected mice and this was confirmed by SorCS2 immuno-labelling. In all affected hair cells, stereocilia were shorter than normal, but abnormalities of bundle morphology and organisation differed between hair cell types. Bundles on OHC were grossly misshapen with significantly fewer stereocilia than normal. However, stereocilia were organised in rows of increasing height. Bundles on IHC contained significantly more stereocilia than normal with some longer stereocilia towards the centre, or with minimal height differentials. In early postnatal mice, kinocilia (primary cilia) of IHC and of OHC were initially located towards the lateral edge of the hair cell surface but often became surrounded by stereocilia as bundle shape and apical surface contour changed. In macular organs the kinocilium was positioned in the centre of the cell surface throughout maturation. There was disruption of the signalling pathway controlling intrinsic hair cell apical asymmetry. LGN and Gαi3 were largely absent, and atypical Protein Kinase C (aPKC) lost its asymmetric distribution. The results suggest that SorCS2 plays a role upstream of the intrinsic polarity pathway and that there are differences between hair cell types in the deployment of the machinery that generates a precisely organised hair bundle.

Mutations and altered expression of SERPINF1 in patients with familial otosclerosis.

Otosclerosis is a relatively common heterogenous condition, characterized by abnormal bone remodelling in the otic capsule leading to fixation of the stapedial footplate and an associated conductive hearing loss. Although familial linkage and candidate gene association studies have been performed in recent years, little progress has been made in identifying disease-causing genes. Here, we used whole-exome sequencing in four families exhibiting dominantly inherited otosclerosis to identify 23 candidate variants (reduced to 9 after segregation analysis) for further investigation in a secondary cohort of 84 familial cases. Multiple mutations were found in the SERPINF1 (Serpin Peptidase Inhibitor, Clade F) gene which encodes PEDF (pigment epithelium-derived factor), a potent inhibitor of angiogenesis and known regulator of bone density. Six rare heterozygous SERPINF1 variants were found in seven patients in our familial otosclerosis cohort; three are missense mutations predicted to be deleterious to protein function. The other three variants are all located in the 5'-untranslated region (UTR) of an alternative spliced transcript SERPINF1-012 RNA-seq analysis demonstrated that this is the major SERPINF1 transcript in human stapes bone. Analysis of stapes from two patients with the 5'-UTR mutations showed that they had reduced expression of SERPINF1-012 All three 5'-UTR mutations are predicted to occur within transcription factor binding sites and reporter gene assays confirmed that they affect gene expression levels. Furthermore, RT-qPCR analysis of stapes bone cDNA showed that SERPINF1-012 expression is reduced in otosclerosis patients with and without SERPINF1 mutations, suggesting that it may be a common pathogenic pathway in the disease.

Evidence of distinct RELN and TGFB1 genetic associations in familial and non-familial otosclerosis in a British population.

Otosclerosis is a common form of hearing loss which typically presents in young adults. The disease has a familial, monogenic form and a non-familial form with a more complex aetiology. A previous genome wide association study identified evidence that variants within RELN are associated with the condition. Other genes in which an association has been reported include BMP2, COL1A1, FGF2, PPP2R5B and TGFB1. However, follow up studies have often failed to replicate initial positive results. The aim of this study was to establish if an association exists between eight single nucleotide polymorphisms (SNPs) in these six previously implicated genes and otosclerosis in a British case-control cohort (n = 748). Evidence of an association between rs1800472 in TGFB1 and otosclerosis was found (p = 0.034), this association was strongest amongst non-familial cases (p = 0.011). No evidence of an association was detected with variants in COL1A1, FGF2, BMP2, and PPP2R5B. No association between variation in RELN and otosclerosis was observed in the whole cohort. However, a significant association (p = 0.0057) was detected between one RELN SNP (rs39399) and otosclerosis in familial patients. Additionally, we identify expression of one RELN transcript in 51 of 81 human stapes tested, clarifying previous conflicting data as to whether RELN is expressed in the affected tissue. Our findings strengthen the association of TGFB1 (rs1800472) with otosclerosis and support a relationship between RELN and familial otosclerosis only, which may explain previous variable replications.

The mouse as a model for age-related hearing loss - a mini-review.

The most common form of sensory disability is age-related hearing loss (ARHL), also referred to as presbycusis. ARHL is a complex disorder with a mixture of genetic and environmental components, a combination that leads to a progressive decline in hearing function with increased age. In the last 15 years, there has been a vast increase in our knowledge of the genes that underlie congenital deafness and the critical components of hearing. In contrast, knowledge of the pathological processes involved in ARHL remains very limited. The mouse has proved an essential tool in the identification of early-onset deafness genes and in revealing the basic mechanisms of hearing. As focus is now turning toward elucidating the most common form of hearing loss, ARHL, the mouse will again play a fundamental role in this research. Here, we review the need for an animal model and discuss the suitability of the mouse as an ARHL model. Finally, we outline the ways in which hearing researchers are utilising the mouse in the investigation of ARHL and provide perspectives on the need for these data to be integrated with the results of human genetic studies.

A new mutation of Sgms1 causes gradual hearing loss associated with a reduced endocochlear potential.

Sgms1 encodes sphingomyelin synthase 1, an enzyme in the sphingosine-1-phosphate signalling pathway, and was previously reported to underlie hearing impairment in the mouse. A new mouse allele, Sgms1tm1a, unexpectedly showed normal Auditory Brainstem Response thresholds. We found that the Sgms1tm1a mutation led to incomplete knockdown of transcript to 20 % of normal values, which was enough to support normal hearing. The Sgms1tm1b allele was generated by knocking out exon 7, leading to a complete lack of detectable transcript in the inner ear. Sgms1tm1b homozygotes showed largely normal auditory brainstem response thresholds at first, followed by progressive loss of sensitivity until they showed severe impairment at 6 months old. The endocochlear potential was consistently reduced in Sgms1tm1b mutants at 3, 4 and 8 weeks old, to around 80 mV compared with around 120 mV in control littermates. The stria vascularis showed a characteristic irregularity of marginal cell surfaces and patchy loss of Kcnq1 expression at their apical membrane, and expression analysis of the lateral wall suggested that marginal cells were the most likely initial site of dysfunction in the mutants. Finally, significant association of auditory thresholds with DNA markers within and close to the human SGMS1 gene were found in the 1958 Birth Cohort, suggesting that SGMS1 variants may play a role in the range of hearing abilities in the human population.

Caprin-1 is a target of the deafness gene Pou4f3 and is recruited to stress granules in cochlear hair cells in response to ototoxic damage.

The POU4 family of transcription factors are required for survival of specific cell types in different sensory systems. Pou4f3 is essential for the survival of auditory sensory hair cells and several mutations in human POU4F3 cause hearing loss. Thus, genes regulated by Pou4f3 are likely to be essential for hair cell survival. We performed a subtractive hybridisation screen in an inner-ear-derived cell line to find genes with differential expression in response to changes in Pou4f3 levels. The screen identified the stress-granule-associated protein Caprin-1 as being downregulated by Pou4f3. We demonstrated that this regulation occurs through the direct interaction of Pou4f3 with binding sites in the Caprin-1 5' flanking sequence, and describe the expression pattern of Caprin-1 mRNA and protein in the cochlea. Moreover, we found Caprin-1-containing stress granules are induced in cochlear hair cells following aminoglycoside-induced damage. This is the first report of stress granule formation in mammalian hair cells and suggests that the formation of Caprin-1-containing stress granules is a key damage response to a clinically relevant ototoxic agent. Our results have implications for the understanding of aminoglycoside-induced hearing loss and provide further evidence that stress granule formation is a fundamental cellular stress response.

The future role of genetic screening to detect newborns at risk of childhood-onset hearing loss.

OBJECTIVE: To explore the future potential of genetic screening to detect newborns at risk of childhood-onset hearing loss. DESIGN: An expert led discussion of current and future developments in genetic technology and the knowledge base of genetic hearing loss to determine the viability of genetic screening and the implications for screening policy. RESULTS AND DISCUSSION: Despite increasing pressure to adopt genetic technologies, a major barrier for genetic screening in hearing loss is the uncertain clinical significance of the identified mutations and their interactions. Only when a reliable estimate of the future risk of hearing loss can be made at a reasonable cost, will genetic screening become viable. Given the speed of technological advancement this may be within the next 10 years. Decision-makers should start to consider how genetic screening could augment current screening programmes as well as the associated data processing and storage requirements. CONCLUSION: In the interim, we suggest that decision makers consider the benefits of (1) genetically testing all newborns and children with hearing loss, to determine aetiology and to increase knowledge of the genetic causes of hearing loss, and (2) consider screening pregnant women for the m.1555A> G mutation to reduce the risk of aminoglycoside antibiotic-associated hearing loss.

Rare disease gene association discovery from burden analysis of the 100,000 Genomes Project data.

To discover rare disease-gene associations, we developed a gene burden analytical framework and applied it to rare, protein-coding variants from whole genome sequencing of 35,008 cases with rare diseases and their family members recruited to the 100,000 Genomes Project (100KGP). Following in silico triaging of the results, 88 novel associations were identified including 38 with existing experimental evidence. We have published the confirmation of one of these associations, hereditary ataxia with UCHL1 , and independent confirmatory evidence has recently been published for four more. We highlight a further seven compelling associations: hypertrophic cardiomyopathy with DYSF and SLC4A3 where both genes show high/specific heart expression and existing associations to skeletal dystrophies or short QT syndrome respectively; monogenic diabetes with UNC13A with a known role in the regulation of ß cells and a mouse model with impaired glucose tolerance; epilepsy with KCNQ1 where a mouse model shows seizures and the existing long QT syndrome association may be linked; early onset Parkinson's disease with RYR1 with existing links to tremor pathophysiology and a mouse model with neurological phenotypes; anterior segment ocular abnormalities associated with POMK showing expression in corneal cells and with a zebrafish model with developmental ocular abnormalities; and cystic kidney disease with COL4A3 showing high renal expression and prior evidence for a digenic or modifying role in renal disease. Confirmation of all 88 associations would lead to potential diagnoses in 456 molecularly undiagnosed cases within the 100KGP, as well as other rare disease patients worldwide, highlighting the clinical impact of a large-scale statistical approach to rare disease gene discovery.

An emerging role for stress granules in neurodegenerative disease and hearing loss.

Stress granules (SGs) are membrane-less cytosolic assemblies that form in response to stress (e.g., heat, oxidative stress, hypoxia, viral infection and UV). Composed of mRNA, RNA binding proteins and signalling proteins, SGs minimise stress-related damage and promote cell survival. Recent research has shown that the stress granule response is vital to the cochlea's response to stress. However, emerging evidence suggests stress granule dysfunction plays a key role in the pathophysiology of multiple neurodegenerative diseases, several of which present with hearing loss as a symptom. Hearing loss has been identified as the largest potentially modifiable risk factor for dementia. The underlying reason for the link between hearing loss and dementia remains to be established. However, several possible mechanisms have been proposed including a common pathological mechanism. Here we will review the role of SGs in the pathophysiology of neurodegenerative diseases and explore possible links and emerging evidence that they may play an important role in maintenance of hearing and may be a common mechanism underlying age-related hearing loss and dementia.

Targeted deletion of the RNA-binding protein Caprin1 leads to progressive hearing loss and impairs recovery from noise exposure in mice.

Cell cycle associated protein 1 (Caprin1) is an RNA-binding protein that can regulate the cellular post-transcriptional response to stress. It is a component of both stress granules and neuronal RNA granules and is implicated in neurodegenerative disease, synaptic plasticity and long-term memory formation. Our previous work suggested that Caprin1 also plays a role in the response of the cochlea to stress. Here, targeted inner ear-deletion of Caprin1 in mice leads to an early onset, progressive hearing loss. Auditory brainstem responses from Caprin1-deficient mice show reduced thresholds, with a significant reduction in wave-I amplitudes compared to wildtype. Whilst hair cell structure and numbers were normal, the inner hair cell-spiral ganglion neuron (IHC-SGN) synapse revealed abnormally large post-synaptic GluA2 receptor puncta, a defect consistent with the observed wave-I reduction. Unlike wildtype mice, mild-noise-induced hearing threshold shifts in Caprin1-deficient mice did not recover. Oxidative stress triggered TIA-1/HuR-positive stress granule formation in ex-vivo cochlear explants from Caprin1-deficient mice, showing that stress granules could still be induced. Taken together, these findings suggest that Caprin1 plays a key role in maintenance of auditory function, where it regulates the normal status of the IHC-SGN synapse.

Aminoglycoside antibiotics cochleotoxicity in paediatric cystic fibrosis (CF) patients: A study using extended high-frequency audiometry and distortion product otoacoustic emissions.

UNLABELLED: Despite known ototoxic effects of aminoglycoside (AG) antibiotics, audiological assessment is not routinely undertaken in UK CF patients. Consequently, the incidence of hearing loss is not well established. OBJECTIVE: To document the incidence of hearing loss in cystic fibrosis (CF) children. DESIGN: Hearing function of 45 children from Great Ormond Street Hospital was assessed using pure-tone audiometry up to 20kHz and DPOAEs up to 8kHz. STUDY SAMPLE: 39/45 of participants had received intravenous (IV) AGs, 23 of which received repeated IV AGs every 3 months. RESULTS: In this high exposure group, 8 (21%) had clear signs of ototoxicity; average 8-20kHz thresholds were elevated by ∼50dB and DPOAE amplitudes were >10dB lower at f2 3.2-6.3 kHz. The remaining 31/39 (79%) of AG exposed patients had normal, even exceptionally good hearing. The 21% incidence of ototoxicity we observed is substantial and higher than previously reported. However, our finding of normal hearing in children with equal AG exposure strongly suggests that other unknown factors, possibly genetic susceptibility, influence this outcome. CONCLUSIONS: We recommend comparable auditory testing in all CF patients with high AG exposures. Genetic analysis may help explain the dichotomy in response to AGs found.

Differential regulation of mammalian and avian ATOH1 by E2F1 and its implication for hair cell regeneration in the inner ear.

The mammalian inner ear has a limited capacity to regenerate its mechanosensory hair cells. This lack of regenerative capacity underlies the high incidence of age-related hearing loss in humans. In contrast, non-mammalian vertebrates can form new hair cells when damage occurs, a mechanism that depends on re-activation of expression of the pro-hair cell transcription factor Atoh1. Here, we show that members of the E2F transcription factor family, known to play a key role in cell cycle progression, regulate the expression of Atoh1. E2F1 activates chicken Atoh1 by directly interacting with a cis-regulatory region distal to the avian Atoh1 gene. E2F does not activate mouse Atoh1 gene expression, since this regulatory element is absent in mammals. We also show that E2F1 expression changes dynamically in the chicken auditory epithelium during ototoxic damage and hair cell regeneration. Therefore, we propose a model in which the mitotic regeneration of non-mammalian hair cells is due to E2F1-mediated activation of Atoh1 expression, a mechanism which has been lost in mammals.

Hearing difficulty is linked to Alzheimer's disease by common genetic vulnerability, not shared genetic architecture.

Age-related hearing loss was recently established as the largest modifiable risk factor for Alzheimer's disease (AD), however, the reasons for this link remain unclear. We investigate shared underlying genetic associations using results from recent large genome-wide association studies (GWAS) on adult hearing difficulty and AD. Genetic correlation and Mendelian randomization (MR) analysis do not support a genetic correlation between the disorders, but suggest a direct causal link from AD genetic risk to hearing difficulty, driven by APOE. Systematic MR analyses on the effect of other traits revealed shared effects of glutamine, gamma-glutamylglutamine, and citrate levels on reduced risk of both hearing difficulty and AD. In addition, pathway analysis on GWAS risk variants suggests shared function in neuronal signalling pathways as well as etiology of diabetes and cardiovascular disease. However, after multiple testing corrections, neither analysis led to statistically significant associations. Altogether, our genetic-driven analysis suggests hearing difficulty and AD are linked by a shared vulnerability in molecular pathways rather than by a shared genetic architecture.

Glucose hypometabolism in the Auditory Pathway in Age Related Hearing Loss in the ADNI cohort.

PURPOSE: Hearing loss (HL) is one of the most common age-related diseases. Here, we investigate the central auditory correlates of HL in people with normal cognition and mild cognitive impairment (MCI) and test their association with genetic markers with the aim of revealing pathogenic mechanisms. METHODS: Brain glucose metabolism based on FDG-PET, self-reported HL status, and genetic data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. FDG-PET data was analysed from 742 control subjects (non-HL with normal cognition or MCI) and 162 cases (HL with normal cognition or MCI) with age ranges of 72.2 ± 7.1 and 77.4 ± 6.4, respectively. Voxel-wise statistics of FDG uptake differences between cases and controls were computed using the generalised linear model in SPM12. An additional 1515 FDG-PET scans of 618 participants were analysed using linear mixed effect models to assess longitudinal HL effects. Furthermore, a quantitative trait genome-wide association study (GWAS) was conducted on the glucose uptake within regions of interest (ROIs), which were defined by the voxel-wise comparison, using genotyping data with 5,082,878 variants available for HL cases and HL controls (N = 817). RESULTS: The HL group exhibited hypometabolism in the bilateral Heschl's gyrus (kleft = 323; kright = 151; Tleft = 4.55; Tright = 4.14; peak Puncorr < 0.001), the inferior colliculus (k = 219;T = 3.53; peak Puncorr < 0.001) and cochlear nucleus (k = 18;T = 3.55; peak Puncorr < 0.001) after age correction and using a cluster forming height threshold P < 0.005 (FWE-uncorrected). Moreover, in an age-matched subset, the cluster comprising the left Heschl's gyrus survived the FWE-correction (kleft = 1903; Tleft = 4.39; cluster PFWE-corr = 0.001). The quantitative trait GWAS identified no genome-wide significant locus in the three HL ROIs. However, various loci were associated at the suggestive threshold (p < 1e-05). CONCLUSION: Compared to the non-HL group, glucose metabolism in the HL group was lower in the auditory cortex, the inferior colliculus, and the cochlear nucleus although the effect sizes were small. The GWAS identified candidate genes that might influence FDG uptake in these regions. However, the specific biological pathway(s) underlying the role of these genes in FDG-hypometabolism in the auditory pathway requires further investigation.

Genome-wide association study suggests that variation at the RCOR1 locus is associated with tinnitus in UK Biobank.

Tinnitus is a prevalent condition in which perception of sound occurs without an external stimulus. It is often associated with pre-existing hearing loss or noise-induced damage to the auditory system. In some individuals it occurs frequently or even continuously and leads to considerable distress and difficulty sleeping. There is little knowledge of the molecular mechanisms involved in tinnitus which has hindered the development of treatments. Evidence suggests that tinnitus has a heritable component although previous genetic studies have not established specific risk factors. From a total of 172,608 UK Biobank participants who answered questions on tinnitus we performed a case-control genome-wide association study for self-reported tinnitus. Final sample size used in association analysis was N = 91,424. Three variants in close proximity to the RCOR1 gene reached genome wide significance: rs4906228 (p = 1.7E-08), rs4900545 (p = 1.8E-08) and 14:103042287_CT_C (p = 3.50E-08). RCOR1 encodes REST Corepressor 1, a component of a co-repressor complex involved in repressing neuronal gene expression in non-neuronal cells. Eleven other independent genetic loci reached a suggestive significance threshold of p < 1E-06.

Self-reported hearing loss questions provide a good measure for genetic studies: a polygenic risk score analysis from UK Biobank.

Age-related hearing impairment (ARHI) is very common in older adults and has major impact on quality of life. The heritability of ARHI has been estimated to be around 50%. The present study aimed to estimate heritability and environmental contributions to liability of ARHI and the extent to which a polygenic risk score (PRS) derived from a recent genome-wide association study of questionnaire items regarding hearing loss using the UK Biobank is predictive of hearing loss in other samples. We examined (1) a sample from TwinsUK who have had hearing ability measured by pure-tone audiogram and the speech-to-noise ratio test as well as questionnaire measures that are comparable with the UK Biobank questionnaire items and (2) European and non-European samples from the UK Biobank which were not part of the original GWAS. Results indicated that the questionnaire items were over 50% heritable in TwinsUK and comparable with the objective hearing measures. In addition, we found very high genetic correlation (0.30-0.84) between the questionnaire responses and objective hearing measures in the TwinsUK sample. Finally, PRS computed from weighted UK Biobank GWAS results were predictive of both questionnaire and objective measures of hearing loss in the TwinsUK sample, as well as questionnaire-measured hearing loss in Europeans but not non-European subpopulations. These results demonstrate the utility of questionnaire-based methods in genetic association studies of hearing loss in adults and highlight the differences in genetic predisposition to ARHI by ethnic background.

Age-Related Hearing Loss.

Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly. This progressive hearing impairment leads to social isolation and is also associated with comorbidities, such as frailty, falls, and late-onset depression. Moreover, there is a growing evidence linking it with cognitive decline and increased risk of dementia. Given the large social and welfare burden that results from ARHL, and because ARHL is potentially a modifiable risk factor for dementia, there is an urgent need for therapeutic interventions to ameliorate age-related auditory decline. However, a prerequisite for design of therapies is knowledge of the underlying molecular mechanisms. Currently, our understanding of ARHL is very limited. Here, we review recent findings from research into ARHL from both human and animal studies and discuss future prospects for advances in our understanding of genetic susceptibility, pathology, and potential therapeutic approaches in ARHL.