Association between BCL11B gene polymorphisms and age-related hearing loss in the elderly: A case-control study in Qingdao, China.

Age-related hearing loss is a complex disease caused by a combination of genetic and environmental factors, and a study have conducted animal experiments to explore the association between BCL11B heterozygosity and age-related hearing loss. The present study used established genetic models to examine the association between BCL11B gene polymorphisms and age-related hearing loss. A total of 410 older adults from two communities in Qingdao, China, participated in this study. The case group comprised individuals aged ≥ 60 years with age-related hearing loss, and the control group comprised individuals without age-related hearing loss from the same communities. The groups were matched 1:1 for age and sex. The individual characteristics of the participants were analyzed descriptively using the Mann-Whitney U test and the chi-square test. To explore the association between BCL11B gene polymorphisms and age-related hearing loss, conditional logistic regression was performed to construct genetic models for two single-nucleotide-polymorphisms (SNPs) of BCL11B, and haplotype analysis was conducted to construct their haplotype domains. Two SNP sites of the BCL11B gene, four genetic models of rs1152781 (additive, dominant, recessive, and codominant), and five genetic models of rs1152783 (additive, dominant, recessive, codominant, and over dominant) were significantly associated with age-related hearing loss in the models both unadjusted and adjusted for all covariates (P < 0.05). Additionally, a linkage disequilibrium between rs1152781 and rs1152783 was revealed through haplotype analysis. Our study revealed that BCL11B gene polymorphisms were significantly associated with age-related hearing loss.

Aberrant auditory metabolite levels and topological properties are associated with cognitive decline in presbycusis patients.

Presbycusis has been reported as related to cognitive decline, but its underlying neurophysiological mechanism is still unclear. This study aimed to investigate the relationship between metabolite levels, cognitive function, and node characteristics in presbycusis based on graph theory methods. Eighty-four elderly individuals with presbycusis and 63 age-matched normal hearing controls underwent magnetic resonance spectroscopy, functional magnetic resonance imaging scans, audiological assessment, and cognitive assessment. Compared with the normal hearing group, presbycusis patients exhibited reduced gamma-aminobutyric acid and glutamate levels in the auditory region, increased nodal characteristics in the temporal lobe and precuneus, as well as decreased nodal characteristics in the superior occipital gyrus and medial orbital. The right gamma-aminobutyric acid levels were negatively correlated with the degree centrality in the right precuneus and the executive function. Degree centrality in the right precuneus exhibited significant correlations with information processing speed and executive function, while degree centrality in the left medial orbital demonstrated a negative association with speech recognition ability. The degree centrality and node efficiency in the superior occipital gyrus exhibited a negative association with hearing loss and speech recognition ability, respectively. These observed changes indicate alterations in metabolite levels and reorganization patterns at the brain network level after auditory deprivation.

PARP1 inhibition prevents oxidative stress in age-related hearing loss via PAR-Ca2+-AIF axis in cochlear strial marginal cells.

Studies have highlighted oxidative damage in the inner ear as a critical pathological basis for sensorineural hearing loss, especially the presbycusis. Poly(ADP-ribose) polymerase-1 (PARP1) activation responds to oxidative stress-induced DNA damage with pro-repair and pro-death effects resembling two sides of the same coin. PARP1-related cell death, known as parthanatos, whose underlying mechanisms are attractive research hotspots but remain to be clarified. In this study, we observed that aged rats showed stria vascularis degeneration and oxidative damage, and PARP1-dependent cell death was prominent in age-related cochlear disorganization and dysfunction. Based on oxidative stress model of primary cultured stria marginal cells (MCs), we revealed that upregulated PARP1 and PAR (Poly(ADP-ribose)) polymers are responsible for MCs oxidative death with high mitochondrial permeability transition pore (mPTP) opening and mitochondrial membrane potential (MMP) collapse, while inhibition of PARP1 ameliorated the adverse outcomes. Importantly, the PARylation of apoptosis-inducing factor (AIF) is essential for its conformational change and translocation, which subsequently causes DNA break and cell death. Concretely, the interaction of PAR and truncated AIF (tAIF) is the mainstream in the parthanatos pathway. We also found that the effects of AIF cleavage and release were achieved through calpain activity and mPTP opening, both of which could be regulated by PARP1 via mediation of mitochondria Ca2+ concentration. In conclusion, the PAR-Ca2+-tAIF signaling pathway in parthanatos contributes to the oxidative stress damage observed in MCs. Targeting PAR-Ca2+-tAIF might be a potential therapeutic strategy for the early intervention of presbycusis and other oxidative stress-associated sensorineural deafness.

The Stria Vascularis: Renewed Attention on a Key Player in Age-Related Hearing Loss.

Age-related hearing loss (HL), or presbycusis, is a complex and heterogeneous condition, affecting a significant portion of older adults and involving various interacting mechanisms. Metabolic presbycusis, a type of age-related HL, is characterized by the dysfunction of the stria vascularis, which is crucial for maintaining the endocochlear potential necessary for hearing. Although attention on metabolic presbycusis has waned in recent years, research continues to identify strial pathology as a key factor in age-related HL. This narrative review integrates past and recent research, bridging findings from animal models and human studies, to examine the contributions of the stria vascularis to age-related HL. It provides a brief overview of the structure and function of the stria vascularis and then examines mechanisms contributing to age-related strial dysfunction, including altered ion transport, changes in pigmentation, inflammatory responses, and vascular atrophy. Importantly, this review outlines the contribution of metabolic mechanisms to age-related HL, highlighting areas for future research. It emphasizes the complex interdependence of metabolic and sensorineural mechanisms in the pathology of age-related HL and highlights the importance of animal models in understanding the underlying mechanisms. The comprehensive and mechanistic investigation of all factors contributing to age-related HL, including cochlear metabolic dysfunction, remains crucial to identifying the underlying mechanisms and developing personalized, protective, and restorative treatments.

Design and Methods of the Early Age-Related Hearing Loss Investigation Randomized Controlled Trial.

OBJECTIVE: Hearing loss has been identified as a major modifiable risk factor for cognitive decline. The Early Age-Related Hearing Loss Investigation (EARHLI) study will assess the mechanisms linking early age-related hearing loss (ARHL) and cognitive impairment. STUDY DESIGN: Randomized, controlled, single-site, early phase II, superiority trial. SETTING: Tertiary academic medical center. PARTICIPANTS: One hundred fifty participants aged 55 to 75 years with early ARHL (severity defined as borderline to moderate) and amnestic mild cognitive impairment will be included. INTERVENTIONS: Participants will be randomized 1:1 to a best practice hearing intervention or a health education control. MAIN OUTCOME MEASURES: The primary study outcome is cognition measured by the Alzheimer Disease Cooperative Study-Preclinical Alzheimer Cognitive Composite. Secondary outcomes include additional measures of cognition, social engagement, and brain organization/connectivity. RESULTS: Trial enrollment will begin in early 2024. CONCLUSIONS: After its completion in 2028, the EARHLI trial should offer evidence on the effect of hearing treatment versus a health education control on cognitive performance, social engagement, and brain organization/connectivity in 55- to 75-year-old community-dwelling adults with early ARHL and amnestic mild cognitive impairment.

Hearing loss-related altered neuronal activity in the inferior colliculus.

Hearing loss is well known to cause plastic changes in the central auditory system and pathological changes such as tinnitus and hyperacusis. Impairment of inner ear functions is the main cause of hearing loss. In aged individuals, not only inner ear dysfunction but also senescence of the central nervous system is the cause of malfunction of the auditory system. In most cases of hearing loss, the activity of the auditory nerve is reduced, but that of the successive auditory centers is increased in a compensatory way. It has been reported that activity changes occur in the inferior colliculus (IC), a critical nexus of the auditory pathway. The IC integrates the inputs from the brainstem and drives the higher auditory centers. Since abnormal activity in the IC is likely to affect auditory perception, it is crucial to elucidate the neuronal mechanism to induce the activity changes of IC neurons with hearing loss. This review outlines recent findings on hearing-loss-induced plastic changes in the IC and brainstem auditory neuronal circuits and discusses what neuronal mechanisms underlie hearing-loss-induced changes in the activity of IC neurons. Considering the different causes of hearing loss, we discuss age-related hearing loss separately from other forms of hearing loss (non-age-related hearing loss). In general, the main plastic change of IC neurons caused by both age-related and non-age-related hearing loss is increased central gain. However, plastic changes in the IC caused by age-related hearing loss seem to be more complex than those caused by non-age-related hearing loss.

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.

Characteristics of spatial protein expression in the mouse cochlear sensory epithelia: Implications for age-related hearing loss.

Hair cells in the cochlear sensory epithelia serve as mechanosensory receptors, converting sound into neuronal signals. The basal sensory epithelia are responsible for transducing high-frequency sounds, while the apex handles low-frequency sounds. Age-related hearing loss predominantly affects hearing at high frequencies and is indicative of damage to the basal sensory epithelia. However, the precise mechanism underlying this site-selective injury remains unclear. In this study, we employed a microscale proteomics approach to examine and compare protein expression in different regions of the cochlear sensory epithelia (upper half and lower half) in 1.5-month-old (normal hearing) and 6-month-old (severe high-frequency hearing loss without hair cell loss) C57BL/6J mice. A total of 2,386 proteins were detected, and no significant differences in protein expression were detected in the upper half of the cochlear sensory epithelia between the two age groups. The expression of 20 proteins in the lower half of the cochlear sensory epithelia significantly differed between the two age groups (e.g., MATN1, MATN4, and AQP1). Moreover, there were 311 and 226 differentially expressed proteins between the upper and lower halves of the cochlear sensory epithelia in 1.5-month-old and 6-month-old mice, respectively. The expression levels of selected proteins were validated by Western blotting. These findings suggest that the spatial differences in protein expression within the cochlear sensory epithelia may play a role in determining the susceptibility of cells at different sites of the cochlea to age-related damage.

Electrocochleographic frequency-following responses as a potential marker of age-related cochlear neural degeneration.

Auditory nerve (AN) fibers that innervate inner hair cells in the cochlea degenerate with advancing age. It has been proposed that age-related reductions in brainstem frequency-following responses (FFR) to the carrier of low-frequency, high-intensity pure tones may partially reflect this neural loss in the cochlea (Märcher-Rørsted et al., 2022). If the loss of AN fibers is the primary factor contributing to age-related changes in the brainstem FFR, then the FFR could serve as an indicator of cochlear neural degeneration. In this study, we employed electrocochleography (ECochG) to investigate the effects of age on frequency-following neurophonic potentials, i.e., neural responses phase-locked to the carrier frequency of the tone stimulus. We compared these findings to the brainstem-generated FFRs obtained simultaneously using the same stimulation. We conducted recordings in young and older individuals with normal hearing. Responses to pure tones (250 ms, 516 and 1086 Hz, 85 dB SPL) and clicks were recorded using both ECochG at the tympanic membrane and traditional scalp electroencephalographic (EEG) recordings of the FFR. Distortion product otoacoustic emissions (DPOAE) were also collected. In the ECochG recordings, sustained AN neurophonic (ANN) responses to tonal stimulation, as well as the click-evoked compound action potential (CAP) of the AN, were significantly reduced in the older listeners compared to young controls, despite normal audiometric thresholds. In the EEG recordings, brainstem FFRs to the same tone stimulation were also diminished in the older participants. Unlike the reduced AN CAP response, the transient-evoked wave-V remained unaffected. These findings could indicate that a decreased number of AN fibers contributes to the response in the older participants. The results suggest that the scalp-recorded FFR, as opposed to the clinical standard wave-V of the auditory brainstem response, may serve as a more reliable indicator of age-related cochlear neural degeneration.

L-Ergothioneine slows the progression of age-related hearing loss in CBA/CaJ mice.

The naturally occurring amino acid, l-ergothioneine (EGT), has immense potential as a therapeutic, having shown promise in the treatment of other disease models, including neurological disorders. EGT is naturally uptaken into cells via its specific receptor, OCTN1, to be utilized by cells as an antioxidant and anti-inflammatory. In our current study, EGT was administered over a period of 6 months to 25-26-month-old CBA/CaJ mice as a possible treatment for age-related hearing loss (ARHL), since presbycusis has been linked to higher levels of cochlear oxidative stress, apoptosis, and chronic inflammation. Results from the current study indicate that EGT can prevent aging declines of some key features of ARHL. However, we found a distinct sex difference for the response to the treatments, for hearing - Auditory Brainstem Responses (ABRs) and Distortion Product Otoacoustic Emissions (DPOAEs). Males exhibited lower threshold declines in both low dose (LD) and high dose (HD) test groups throughout the testing period and did not display some of the characteristic aging declines in hearing seen in Control animals. In contrast, female mice did not show any therapeutic effects with either treatment dose. Further confirming this sex difference, EGT levels in whole blood sampling throughout the testing period showed greater uptake of EGT in males compared to females. Additionally, RT-PCR results from three tissue types of the inner ear confirmed EGT activity in the cochlea in both males and females. Males and females exhibited significant differences in biomarkers related to apoptosis (Cas-3), inflammation (TNF-a), oxidative stress (SOD2), and mitochondrial health (PGC1a).These changes were more prominent in males as compared to females, especially in stria vascularis tissue. Taken together, these findings suggest that EGT has the potential to be a naturally derived therapeutic for slowing down the progression of ARHL, and possibly other neurodegenerative diseases. EGT, while effective in the treatment of some features of presbycusis in aging males, could also be modified into a general prophylaxis for other age-related disorders where treatment protocols would include eating a larger proportion of EGT-rich foods or supplements. Lastly, the sex difference discovered here, needs further investigation to see if therapeutic conditions can be developed where aging females show better responsiveness to EGT.

Surface electrical stimulation of the auditory cortex preserves efferent medial olivocochlear neurons and reduces cochlear traits of age-related hearing loss.

The auditory cortex is the source of descending connections providing contextual feedback for auditory signal processing at almost all levels of the lemniscal auditory pathway. Such feedback is essential for cognitive processing. It is likely that corticofugal pathways are degraded with aging, becoming important players in age-related hearing loss and, by extension, in cognitive decline. We are testing the hypothesis that surface, epidural stimulation of the auditory cortex during aging may regulate the activity of corticofugal pathways, resulting in modulation of central and peripheral traits of auditory aging. Increased auditory thresholds during ongoing age-related hearing loss in the rat are attenuated after two weeks of epidural stimulation with direct current applied to the surface of the auditory cortex for two weeks in alternate days (Fernández del Campo et al., 2024). Here we report that the same cortical electrical stimulation protocol induces structural and cytochemical changes in the aging cochlea and auditory brainstem, which may underlie recovery of age-degraded auditory sensitivity. Specifically, we found that in 18 month-old rats after two weeks of cortical electrical stimulation there is, relative to age-matched non-stimulated rats: a) a larger number of choline acetyltransferase immunoreactive neuronal cell body profiles in the ventral nucleus of the trapezoid body, originating the medial olivocochlear system.; b) a reduction of age-related dystrophic changes in the stria vascularis; c) diminished immunoreactivity for the pro-inflammatory cytokine TNFα in the stria vascularis and spiral ligament. d) diminished immunoreactivity for Iba1 and changes in the morphology of Iba1 immunoreactive cells in the lateral wall, suggesting reduced activation of macrophage/microglia; d) Increased immunoreactivity levels for calretinin in spiral ganglion neurons, suggesting excitability modulation by corticofugal stimulation. Altogether, these findings support that non-invasive neuromodulation of the auditory cortex during aging preserves the cochlear efferent system and ameliorates cochlear aging traits, including stria vascularis dystrophy, dysregulated inflammation and altered excitability in primary auditory neurons.

Clinical Practice Guideline: Age-Related Hearing Loss.

OBJECTIVE: Age-related hearing loss (ARHL) is a prevalent but often underdiagnosed and undertreated condition among individuals aged 50 and above. It is associated with various sociodemographic factors and health risks including dementia, depression, cardiovascular disease, and falls. While the causes of ARHL and its downstream effects are well defined, there is a lack of priority placed by clinicians as well as guidance regarding the identification, education, and management of this condition. PURPOSE: The purpose of this clinical practice guideline is to identify quality improvement opportunities and provide clinicians trustworthy, evidence-based recommendations regarding the identification and management of ARHL. These opportunities are communicated through clear actionable statements with explanation of the support in the literature, evaluation of the quality of the evidence, and recommendations on implementation. The target patients for the guideline are any individuals aged 50 years and older. The target audience is all clinicians in all care settings. This guideline is intended to focus on evidence-based quality improvement opportunities judged most important by the guideline development group (GDG). It is not intended to be a comprehensive, general guide regarding the management of ARHL. The statements in this guideline are not intended to limit or restrict care provided by clinicians based on their experience and assessment of individual patients. ACTION STATEMENTS: The GDG made strong recommendations for the following key action statements (KASs): (KAS 4) If screening suggests hearing loss, clinicians should obtain or refer to a clinician who can obtain an audiogram. (KAS 8) Clinicians should offer, or refer to a clinician who can offer, appropriately fit amplification to patients with ARHL. (KAS 9) Clinicians should refer patients for an evaluation of cochlear implantation candidacy when patients have appropriately fit amplification and persistent hearing difficulty with poor speech understanding. The GDG made recommendations for the following KASs: (KAS 1) Clinicians should screen patients aged 50 years and older for hearing loss at the time of a health care encounter. (KAS 2) If screening suggests hearing loss, clinicians should examine the ear canal and tympanic membrane with otoscopy or refer to a clinician who can examine the ears for cerumen impaction, infection, or other abnormalities. (KAS 3) If screening suggests hearing loss, clinicians should identify sociodemographic factors and patient preferences that influence access to and utilization of hearing health care. (KAS 5) Clinicians should evaluate and treat or refer to a clinician who can evaluate and treat patients with significant asymmetric hearing loss, conductive or mixed hearing loss, or poor word recognition on diagnostic testing. (KAS 6) Clinicians should educate and counsel patients with hearing loss and their family/care partner(s) about the impact of hearing loss on their communication, safety, function, cognition, and quality of life (QOL). (KAS 7) Clinicians should counsel patients with hearing loss on communication strategies and assistive listening devices. (KAS 10) For patients with hearing loss, clinicians should assess if communication goals have been met and if there has been improvement in hearing-related QOL at a subsequent health care encounter or within 1 year. The GDG offered the following KAS as an option: (KAS 11) Clinicians should assess hearing at least every 3 years in patients with known hearing loss or with reported concern for changes in hearing.

Relationship Between Serum Brain-Derived Neurotrophic Factor and Neurotrophin-3 Levels and Hearing Thresholds in Patients With Age-Related Hearing Loss.

BACKGROUND: Age-related hearing loss (ARHL) is a general term used to describe the sensorineural type of hearing loss occurring in both ears in older adults. Neurotrophins are the most promising candidates for supporting the auditory nerve by increasing neuronal survival. This study aimed to help elucidate the pathophysiology of ARHL by determining whether any relationship exists between brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) levels in serum samples from patients diagnosed with ARHL. MATERIALS AND METHOD: Seventy-seven individuals, a study group of 41 patients diagnosed with ARHL, and a control group of 36 participants without hearing loss were evaluated. Serum samples were collected and used to measure serum BDNF and NT-3 levels with the new Nepenthe enzyme-linked immunosorbent assay method. RESULTS: Median pure-tone average results in the 2000, 4000, and 6000 Hz ranges were 52.5 (44.3-67.3) dB HL in the ARHL group and 13.5 (11.1-17.1) dB HL in the control group. The difference was statistically significant (p = .001). Although NT-3 and BDNF levels were both lower in ARHL patients than in participants without hearing loss, only the BDNF levels were significantly (p = .002) lower. Mean left and right ear word recognition scores were also lower in ARHL patients than in control groups. The ARHL group was further divided into two subgroups based on word recognition scores to evaluate significant differences in BDNF and NT-3 levels. No statistically significant difference was observed in BDNF and NT-3 levels between these subgroups. However, there was a significant difference in word recognition scores. CONCLUSIONS: Low BDNF levels in the ARHL group suggest that BDNF may play a role in the pathogenesis of ARHL. Patients with low (ARHL1) and high (ARHL2) word recognition scores were compared for the first time in the literature in terms of BDNF and NT-3 levels. However, the results were not statistically significant. This article is a preliminary study and was written to provide guidance for our next comprehensive project.

Central Auditory Changes Associated with Age-related Hearing Loss.

Objective. This study aimed to investigate age-related changes in cortical auditory evoked potentials (CAEPs) while considering three crucial factors: aging, high-frequency hearing loss and sensation level of the CAEP stimulus. Method. The electrophysiological and audiometric data of 71 elderly participants were analyzed using multiple regression analysis to investigate the association of CAEPs with the factors of aging, high-frequency hearing loss and sensation level of the CAEP test stimulus. Results. Aging was significantly associated with prolonged N1 and P2 latencies and reduced P2 amplitude. Elevated thresholds related to the sensation level of the CAEP stimulus were significantly associated with increased N1 and P2 amplitudes and decreased N1 latency. A significant relationship was detected between high-frequency hearing thresholds and the shortening of P2 latencies and the reduction of P2 amplitudes. Conclusion. The results of this study highlight the complex interplay of aging, high-frequency hearing loss and the sensation level of the CAEP stimulus on CAEP components in elderly people. These factors should be considered in future research using CAEPs to enhance overall understanding of auditory processing in the aging population.

Plain Language Summary: Age-Related Hearing Loss.

The plain language summary explains age-related hearing loss to patients, families, and care partners. The summary is for any patient aged 50 years and older, families, and care partners. It is based on the 2024 "Clinical Practice Guideline: Age-Related Hearing Loss." This plain language summary is a companion publication to the full guideline, which provides greater detail for clinicians. Guidelines and their recommendations may not apply to every patient, but they can be used to find best practices and quality improvement opportunities.

Clinical Practice Guideline: Age-Related Hearing Loss Executive Summary.

OBJECTIVE: Age-related hearing loss (ARHL) is a prevalent but often underdiagnosed and undertreated condition among individuals aged 50 and above. It is associated with various sociodemographic factors and health risks including dementia, depression, cardiovascular disease, and falls. While the causes of ARHL and its downstream effects are well defined, there is a lack of priority placed by clinicians as well as guidance regarding the identification, education, and management of this condition. PURPOSE: The purpose of this clinical practice guideline is to identify quality improvement opportunities and provide clinicians trustworthy, evidence-based recommendations regarding the identification and management of ARHL. These opportunities are communicated through clear actionable statements with an explanation of the support in the literature, the evaluation of the quality of the evidence, and recommendations on implementation. The target patients for the guideline are any individuals aged 50 years and older. The target audience is all clinicians in all care settings. This guideline is intended to focus on evidence-based quality improvement opportunities judged most important by the Guideline Development Group (GDG). It is not intended to be a comprehensive, general guide regarding the management of ARHL. The statements in this guideline are not intended to limit or restrict care provided by clinicians based on their experience and assessment of individual patients. ACTION STATEMENTS: The GDG made strong recommendations for the following key action statements (KASs): (KAS 4) If screening suggests hearing loss, clinicians should obtain or refer to a clinician who can obtain an audiogram. (KAS 8) Clinicians should offer, or refer to a clinician who can offer, appropriately fit amplification to patients with ARHL. (KAS 9) Clinicians should refer patients for an evaluation of cochlear implantation candidacy when patients have appropriately fit amplification and persistent hearing difficulty with poor speech understanding. The GDG made recommendations for the following KASs: (KAS 1) Clinicians should screen patients aged 50 years and older for hearing loss at the time of a health care encounter. (KAS 2) If screening suggests hearing loss, clinicians should examine the ear canal and tympanic membrane with otoscopy or refer to a clinician who can examine the ears for cerumen impaction, infection, or other abnormalities. (KAS 3) If screening suggests hearing loss, clinicians should identify sociodemographic factors and patient preferences that influence access to and utilization of hearing health care. (KAS 5) Clinicians should evaluate and treat or refer to a clinician who can evaluate and treat patients with significant asymmetric hearing loss, conductive or mixed hearing loss, or poor word recognition on diagnostic testing. (KAS 6) Clinicians should educate and counsel patients with hearing loss and their family/care partner(s) about the impact of hearing loss on their communication, safety, function, cognition, and quality of life. (KAS 7) Clinicians should counsel patients with hearing loss on communication strategies and assistive listening devices. (KAS 10) For patients with hearing loss, clinicians should assess if communication goals have been met and if there has been improvement in hearing-related quality of life at a subsequent health care encounter or within 1 year. The GDG offered the following KAS as an option: (KAS 11) Clinicians should assess hearing at least every 3 years in patients with known hearing loss or with reported concern for changes in hearing.

Identification of mRNA expression profiles and their characterization in age-related hearing loss.

Age-related hearing loss (ARHL), is a pervasive health problem worldwide. ARHL seriously affects the quality of life and reportedly leads to social isolation and dementia in the elderly. ARHL is caused by the degeneration or disorders of cochlear hair cells and auditory neurons. Numerous studies have verified that genetic factors contributed to this impairment, however, the mechanism behind remains unclear. In this study, we analyzed an mRNA expression dataset (GSE49543) from the GEO database. Differentially expressed genes (DEGs) between young control mice and presbycusis mice were analyzed using limma in R and weighted gene co-expression network analysis (WGCNA) methods. Functional enrichment analyses of the DEGs were conducted with the clusterProfiler R package and the results were visualized using ggplot2 R package. The STRING database was used for the construction of the protein-protein interaction (PPI) network of the screened DEGs. Two machine learning algorithms LASSO and SVM-RFE were used to screen the hub genes. We identified 54 DEGs in presbycusis using limma and WGCNA. DEGs were associated with the synaptic vesicle cycle, distal axon, neurotransmitter transmembrane transporter activity in GO analysis, and alcoholic liver disease, pertussis, lysosome pathway according to KEGG analyses. PPI network analysis identified three significant modules. Five hub genes (CLEC4D, MS4A7, CTSS, LAPTM5, ALOX5AP) were screened by LASSO and SVM-RFE. These hub genes were highly expressed in presbycusis mice compared with young control mice. We screened DEGs and identified hub genes involved in ARHL development, which might provide novel clues to understanding the molecular basis of ARHL.

The crucial role of diverse animal models to investigate cochlear aging and hearing loss.

Age-related hearing loss affects a large and growing segment of the population, with profound impacts on quality of life. Age-related pathology of the cochlea-the mammalian hearing organ-underlies age-related hearing loss. Because investigating age-related changes in the cochlea in humans is challenging and often impossible, animal models are indispensable to investigate these mechanisms as well as the complex consequences of age-related hearing loss on the brain and behavior. In this review, we advocate for a comparative and interdisciplinary approach while also addressing the challenges of comparing age-related hearing loss across species with varying lifespans. We describe the experimental advantages and limitations as well as areas for future research in well-established models of age-related hearing loss, including mice, rats, gerbils, chinchillas, and birds. We also indicate the need to expand characterization of age-related hearing loss in other established animal models, especially guinea pigs, cats, and non-human primates, in which auditory function is well characterized but age-related cochlear pathology is understudied. Finally, we highlight the potential of emerging animal models for advancing our understanding of age-related hearing loss, including deer mice, with their notably extended lifespans and preserved hearing, naked mole rats, with their exceptional longevity and extensive vocal communications, as well as zebrafish, which offer genetic tractability and suitability for drug screening. Ultimately, a comparative and interdisciplinary approach in auditory research, combining insights from various animal models with human studies, is key to robust and reliable research outcomes that better advance our understanding and treatment of age-related hearing loss.

Endoplasmic reticulum stress-induced necroptosis promotes cochlear inflammation: Implications for age-related hearing loss.

Age-related hearing loss (ARHL) is the most common sensory disorder associated with human aging. Chronic inflammation is supposed to be an important contributor to ARHL. Yet, the underlying mechanisms of developing cochlear inflammation are still not well understood. In this study, we found that the inflammation, endoplasmic reticulum (ER) stress and necroptosis signalings are activated in the cochlea of aged C57BL/6 mice. ER stress activator tunicamycin (TM) induced necroptosis in cochlear HEI-OC1 cells and cochlear explants, while necroptosis inhibitors protected cochlear cells from ER stress-induced cell death. The antioxidants inhibited necroptosis and protected HEI-OC1 cells from TM insults. Necroptotic HEI-OC1 cells promoted the activation of the co-cultured macrophages via Myd88 signaling. Moreover, necroptosis inhibitor protected from TM-induced hearing loss, and inhibited inflammation in C57BL/6 mice. These findings suggest that ER stress-induced necroptosis promotes cochlear inflammation and hearing loss. Targeting necroptosis serves as a potential approach for the treatment of cochlear inflammation and ARHL.