Functional, Morphological and Molecular Changes Reveal the Mechanisms Associated with Age-Related Vestibular Loss.

Age-related loss of vestibular function and hearing are common disorders that arise from the loss of function of the inner ear and significantly decrease quality of life. The underlying pathophysiological mechanisms are poorly understood and difficult to investigate in humans. Therefore, our study examined young (1.5-month-old) and old (24-month-old) C57BL/6 mice, utilizing physiological, histological, and transcriptomic methods. Vestibular sensory-evoked potentials revealed that older mice had reduced wave I amplitudes and delayed wave I latencies, indicating reduced vestibular function. Immunofluorescence and image analysis revealed that older mice exhibited a significant decline in type I sensory hair cell density, particularly in hair cells connected to dimorphic vestibular afferents. An analysis of gene expression in the isolated vestibule revealed the upregulation of immune-related genes and the downregulation of genes associated with ossification and nervous system development. A comparison with the isolated cochlear sensorineural structures showed similar changes in genes related to immune response, chondrocyte differentiation, and myelin formation. These findings suggest that age-related vestibular hypofunction is linked to diminished peripheral vestibular responses, likely due to the loss of a specific subpopulation of hair cells and calyceal afferents. The upregulation of immune- and inflammation-related genes implies that inflammation contributes to these functional and structural changes. Furthermore, the comparison of gene expression between the vestibule and cochlea indicates both shared and distinct mechanisms contributing to age-related vestibular and hearing impairments. Further research is necessary to understand the mechanistic connection between inflammation and age-related balance and hearing disorders and to translate these findings into clinical treatment strategies.

Age-related High-frequency Hearing Loss Is Not Associated With Horizontal Semicircular Canal Function.

OBJECTIVE: Investigate the association between age-related hearing loss and reduced peripheral vestibular function using paired assessments of high-frequency hearing and horizontal semicircular canal (HSC) function. We hypothesized that age-related high-frequency hearing loss would be correlated with reduced HSC function and, therefore, useful to predict age-related vestibular hypofunction. DESIGN: We conducted a single center, retrospective cross-sectional study in a tertiary/academic referral hospital. This study included 185 patients who were diagnosed with a cerebellopontine angle (CPA) tumor and referred to the academic hospital to evaluate treatment options. Data collected included pure-tone audiometry, caloric reflex test, video head-impulse test (vHIT), and medical history. High-frequency hearing loss was quantified by the high Fletcher index (hFI), and horizontal semicircular canal (HSC) function were quantified by the caloric reflex test and vHIT. RESULTS: We observed a significant association between age and high-frequency hearing loss that was significantly worse in men compared with women. In contrast, we observed no significant association between age and HSC function assessed by either the caloric reflex test or vHIT. We observed associations between HSC function and sex, with male sex predicting reduced HSC function by caloric reflex testing but enhanced HSC function by vHIT. High-frequency hearing loss did not predict HSC hypofunction. CONCLUSIONS: We found no evidence indicating age-related decline in HSC function or an association between age-related high-frequency hearing loss and age-related decline in HSC function. We did observe sex-specific differences in HSC function. Our study highlights the need for sex-specific normative values for identifying age-related reduced peripheral vestibular function and for future work linking comprehensive assessments of inner ear function with tests of balance and stability to understand the complex interactions underlying hearing loss and imbalance, especially in the elderly.

Transcriptome-Guided Identification of Drugs for Repurposing to Treat Age-Related Hearing Loss.

Age-related hearing loss (ARHL) or presbycusis is a prevalent condition associated with social isolation, cognitive impairment, and dementia. Age-related changes in the cochlea, the auditory portion of the inner ear, are the primary cause of ARHL. Unfortunately, there are currently no pharmaceutical approaches to treat ARHL. To examine the biological processes underlying age-related changes in the cochlea and identify candidate drugs for rapid repurposing to treat ARHL, we utilized bulk RNA sequencing to obtain transcriptomes from the functional substructures of the cochlea-the sensorineural structures, including the organ of Corti and spiral ganglion neurons (OC/SGN) and the stria vascularis and spiral ligament (SV/SL)-in young (6-week-old) and old (2-year-old) C57BL/6 mice. Transcriptomic analyses revealed both overlapping and unique patterns of gene expression and gene enrichment between substructures and with ageing. Based on these age-related transcriptional changes, we queried the protein products of genes differentially expressed with ageing in DrugBank and identified 27 FDA/EMA-approved drugs that are suitable to be repurposed to treat ARHL. These drugs target the protein products of genes that are differentially expressed with ageing uniquely in either the OC/SGN or SV/SL and that interrelate diverse biological processes. Further transcriptomic analyses revealed that most genes differentially expressed with ageing in both substructures encode protein products that are promising drug target candidates but are, nevertheless, not yet linked to approved drugs. Thus, with this study, we apply a novel approach to characterize the druggable genetic landscape for ARHL and propose a list of drugs to test in pre-clinical studies as potential treatment options for ARHL.

Factors associated with Self Rated Health in persons with tinnitus from the general population.

OBJECTIVES: Tinnitus, the perception of a sound without a corresponding external source, may be associated with decreased Self-Rated Health (SRH). Most research on tinnitus has been done in clinical populations. We aimed to study factors associated with SRH in individuals reporting tinnitus from the general population. METHODS: In this cross-sectional study, we used data of participants of the Lifelines population-based cohort who answered the question: "Do you hear soughing or whistling in your ear or ears?" (N=124,490). SRH was assessed using the RAND-36 item on SRH. Linear regression was used to study associations between SRH and impairment of hearing, physical and mental health, lifestyle, personality, and demographic features, in the group reporting always tinnitus (N=8,011). Models were also run in the entire study cohort, to test whether tinnitus was associated with SRH after adjustment for these variables. RESULTS: Of all participants, 6.4% reported always hearing tinnitus, with 83.7% of these reporting good to excellent SRH. The strongest positive associations with SRH in the group reporting always tinnitus were found for younger age, higher education levels, good sleep quality, more social contacts, absence of irritable bowel syndrome and fibromyalgia, high competence, and low impulsivity. In the total population, tinnitus was negatively associated with SRH, while adjusting for demographic features, physical and mental health history, lifestyle, and personality. CONCLUSION: Our findings contribute to increased understanding of resilience towards the negative consequences of tinnitus. In their early encounters with tinnitus patients, clinicians could focus on self-help regarding sleep hygiene and stimulate social activities.

A retrospective cross-sectional study on tinnitus prevalence and disease associations in the Dutch population-based cohort Lifelines.

Tinnitus is a highly prevalent disorder with heterogenous presentation and limited treatment options. Better understanding of its prevalence and disease and lifestyle risk factor associations in the general population is necessary to identify the underlying mechanisms. To this end, we quantified the prevalence of tinnitus and identified disease and lifestyle risk factors associated with tinnitus within a general population cohort. For this study, we used the Lifelines population-based cohort study to perform a retrospective cross-sectional study. Lifelines is a large, multi-generational, prospective cohort study that includes over 167,000 participants (or 10% of the population) from the northern Netherlands. For this study, conducted between 2018 and 2021, data from the Lifelines population-based cohort study was used to perform a cross-sectional study. Adult participants (age ≥ 18 years) with data on tinnitus perception (collected once between 2011 and 2015) were included in this study. An elastic-net regression analysis was performed with tinnitus as the dependent variable and parameters of diseases and lifestyle risk factors (collected once between 2006 and 2014)-including hearing problems, cardiovascular disease, metabolic disorders, psychiatric disorders, thyroid disease, inflammatory disease, and functional somatic syndromes-as the independent variables. Among 124,609 participants, N = 8,011 (6.4%) reported perceiving tinnitus constantly (CT: constant tinnitus) and N = 39,625 (31.8%) reported perceiving tinnitus constantly or occasionally (AT: any tinnitus). Our analysis identified 38 parameters that were associated with AT and 48 parameters that were associated with CT. Our study identified established disease associates with tinnitus, including problems with hearing (OR 8.570 with CT), arrythmia (OR 1.742 with CT), transient ischemic attack (OR 1.284 with AT), diabetes mellitus (OR 1.014 with AT) and psychiatric disorders, including major depressive disorder (OR 1.506 with CT). Factors related to lifestyle associated with tinnitus included waist-hip ratio (OR 1.061 with CT) and smoking (OR 1.028 with AT). Novel disease associates with CT were identified for inflammatory diseases, including rheumatoid arthritis (OR 1.297) and ulcerative colitis (OR 1.588), thyroid disease (as evidenced by the use of thyroid medication) (OR 1.298), and functional somatic syndromes, including chronic fatigue syndrome (OR 1.568). In addition to validating established disease associates in a general population cohort, this study identified novel associations with tinnitus and several disease categories, including functional somatic syndromes, inflammatory diseases, and thyroid disease. Future work will be necessary to identify whether (common) mechanisms underly tinnitus and these associated disorders. Lifelines is an important new resource available for future studies investigating tinnitus in the general population.

Age-Related Changes in the Cochlea and Vestibule: Shared Patterns and Processes.

Both age-related hearing loss (ARHL) and age-related loss in vestibular function (ARVL) are prevalent conditions with deleterious consequences on the health and quality of life. Age-related changes in the inner ear are key contributors to both conditions. The auditory and vestibular systems rely on a shared sensory organ - the inner ear - and, like other sensory organs, the inner ear is susceptible to the effects of aging. Despite involvement of the same sensory structure, ARHL and ARVL are often considered separately. Insight essential for the development of improved diagnostics and treatments for both ARHL and ARVL can be gained by careful examination of their shared and unique pathophysiology in the auditory and vestibular end organs of the inner ear. To this end, this review begins by comparing the prevalence patterns of ARHL and ARVL. Next, the normal and age-related changes in the structure and function of the auditory and vestibular end organs are compared. Then, the contributions of various molecular mechanisms, notably inflammaging, oxidative stress, and genetic factors, are evaluated as possible common culprits that interrelate pathophysiology in the cochlea and vestibular end organs as part of ARHL and ARVL. A careful comparison of these changes reveals that the patterns of pathophysiology show similarities but also differences both between the cochlea and vestibular end organs and among the vestibular end organs. Future progress will depend on the development and application of new research strategies and the integrated investigation of ARHL and ARVL using both clinical and animal models.

Sodium-activated potassium channels shape peripheral auditory function and activity of the primary auditory neurons in mice.

Potassium (K+) channels shape the response properties of neurons. Although enormous progress has been made to characterize K+ channels in the primary auditory neurons, the molecular identities of many of these channels and their contributions to hearing in vivo remain unknown. Using a combination of RNA sequencing and single molecule fluorescent in situ hybridization, we localized expression of transcripts encoding the sodium-activated potassium channels KNa1.1 (SLO2.2/Slack) and KNa1.2 (SLO2.1/Slick) to the primary auditory neurons (spiral ganglion neurons, SGNs). To examine the contribution of these channels to function of the SGNs in vivo, we measured auditory brainstem responses in KNa1.1/1.2 double knockout (DKO) mice. Although auditory brainstem response (wave I) thresholds were not altered, the amplitudes of suprathreshold responses were reduced in DKO mice. This reduction in amplitude occurred despite normal numbers and molecular architecture of the SGNs and their synapses with the inner hair cells. Patch clamp electrophysiology of SGNs isolated from DKO mice displayed altered membrane properties, including reduced action potential thresholds and amplitudes. These findings show that KNa1 channel activity is essential for normal cochlear function and suggest that early forms of hearing loss may result from physiological changes in the activity of the primary auditory neurons.

Changes in spontaneous movement in response to silent gaps are not robust enough to indicate the perception of tinnitus in mice.

Approaches to identify the perception of tinnitus in various animal models have been difficult to apply to mouse. As a result, mice have been underutilized to investigate the cellular, molecular, and genetic mechanisms underlying tinnitus. A recent study in guinea pigs identified a novel spontaneous behavior (unconditioned response), changes in movement during silent gaps, that identified a subgroup of animals presumably with tinnitus. Guinea pigs identified with tinnitus failed to "freeze" in response to silent gaps in sound. In the hope of developing a rapid and reliable assay for mice, we used a similar approach. C57BL/6J mice underwent three trials in which spontaneous movement was video recorded in the presence of white noise interrupted with six silent gaps. Movement metrics included velocity and body movement. Before the third trial, mice underwent either sham or noise exposure to induce hearing loss and tinnitus. Auditory brainstem responses before and after noise trauma confirmed normal hearing in sham-treated animals and hearing loss in the noise-exposed cohort. No differences in the various movement metrics were detected during the silent gaps either before or after sham/noise exposure. Variability in spontaneous movement both before and after sham/noise exposure was substantially greater in mice compared to guinea pigs. Thus, this assay is not sufficiently statistically powerful to identify changes in movement that might indicate tinnitus perception in mice. Previous observations also reported increased movement overall in guinea pigs identified as suffering tinnitus. In contrast, mice showed no statistically significant differences in movement between the three trials. Despite our results, other unconditioned (as well as conditioned) behaviors should be examined in mice to test their utility to detect changes that indicate the perception of tinnitus. Such assays are essential to accelerate the use of mouse models in tinnitus research.