Decreased Modulation of Population Correlations in Auditory Cortex Is Associated with Decreased Auditory Detection Performance in Old Mice.

Age-related hearing loss (presbycusis) affects one-third of the world's population. One hallmark of presbycusis is difficulty hearing in noisy environments. Presbycusis can be separated into two components: the aging ear and the aging brain. To date, the role of the aging brain in presbycusis is not well understood. Activity in the primary auditory cortex (A1) during a behavioral task is because of a combination of responses representing the acoustic stimuli, attentional gain, and behavioral choice. Disruptions in any of these aspects can lead to decreased auditory processing. To investigate how these distinct components are disrupted in aging, we performed in vivo 2-photon Ca2+ imaging in both male and female mice (Thy1-GCaMP6s × CBA/CaJ mice) that retain peripheral hearing into old age. We imaged A1 neurons of young adult (2-6 months) and old mice (16-24 months) during a tone detection task in broadband noise. While young mice performed well, old mice performed worse at low signal-to-noise ratios. Calcium imaging showed that old animals have increased prestimulus activity, reduced attentional gain, and increased noise correlations. Increased correlations in old animals exist regardless of cell tuning and behavioral outcome, and these correlated networks exist over a much larger portion of cortical space. Neural decoding techniques suggest that this prestimulus activity is predictive of old animals making early responses. Together, our results suggest a model in which old animals have higher and more correlated prestimulus activity and cannot fully suppress this activity, leading to the decreased representation of targets among distracting stimuli.SIGNIFICANCE STATEMENT Aging inhibits the ability to hear clearly in noisy environments. We show that the aging auditory cortex is unable to fully suppress its responses to background noise. During an auditory behavior, fewer neurons were suppressed in the old relative to young animals, which leads to higher prestimulus activity and more false alarms. We show that this excess activity additionally leads to increased correlations between neurons, reducing the amount of relevant stimulus information in the auditory cortex. Future work identifying the lost circuits that are responsible for proper background suppression could provide new targets for therapeutic strategies to preserve auditory processing ability into old age.

Age-Related Hearing Loss: The Link between Inflammaging, Immunosenescence, and Gut Dysbiosis.

This article provides a theoretical overview of the association between age-related hearing loss (ARHL), immune system ageing (immunosenescence), and chronic inflammation. ARHL, or presbyacusis, is the most common sensory disability that significantly reduces the quality of life and has a high economic impact. This disorder is linked to genetic risk factors but is also influenced by a lifelong cumulative effect of environmental stressors, such as noise, otological diseases, or ototoxic drugs. Age-related hearing loss and other age-related disorders share common mechanisms which often converge on low-grade chronic inflammation known as "inflammaging". Various stimuli can sustain inflammaging, including pathogens, cell debris, nutrients, and gut microbiota. As a result of ageing, the immune system can become defective, leading to the accumulation of unresolved inflammatory processes in the body. Gut microbiota plays a central role in inflammaging because it can release inflammatory mediators and crosstalk with other organ systems. A proinflammatory gut environment associated with ageing could result in a leaky gut and the translocation of bacterial metabolites and inflammatory mediators to distant organs via the systemic circulation. Here, we postulate that inflammaging, as a result of immunosenescence and gut dysbiosis, accelerates age-related cochlear degeneration, contributing to the development of ARHL. Age-dependent gut dysbiosis was included as a hypothetical link that should receive more attention in future studies.

Age-Related Hearing Loss Is Dominated by Damage to Inner Ear Sensory Cells, Not the Cellular Battery That Powers Them.

Age-related hearing loss arises from irreversible damage in the inner ear, where sound is transduced into electrical signals. Prior human studies suggested that sensory-cell loss is rarely the cause; correspondingly, animal work has implicated the stria vascularis, the cellular "battery" driving the amplification of sound by hair cell "motors." Here, quantitative microscopic analysis of hair cells, auditory nerve fibers, and strial tissues in 120 human inner ears obtained at autopsy, most of whom had recent audiograms in their medical records, shows that the degree of hearing loss is well predicted from the amount of hair cell loss and that inclusion of strial damage does not improve the prediction. Although many aging ears showed significant strial degeneration throughout the cochlea, our statistical models suggest that, by the time strial tissues are lost, hair cell death is so extensive that the loss of battery is no longer important to pure-tone thresholds and that audiogram slope is not diagnostic for strial degeneration. These data comprise the first quantitative survey of hair cell death in normal-aging human cochleas, and reveal unexpectedly severe hair cell loss in low-frequency cochlear regions, and dramatically greater loss in high-frequency regions than seen in any aging animal model. Comparison of normal-aging ears to an age-matched group with acoustic-overexposure history suggests that a lifetime of acoustic overexposure is to blame.SIGNIFICANCE STATEMENT This report upends dogma about the causes of age-related hearing loss. Our analysis of over 120 autopsy specimens shows that inner-ear sensory cell loss can largely explain the audiometric patterns in aging, with minimal contribution from the stria vascularis, the "battery" that powers the inner ear, previously viewed as the major locus of age-related hearing dysfunction. Predicting inner ear damage from the audiogram is critical, now that clinical trials of therapeutics designed to regrow hair cells are underway. Our data also show that hair cell degeneration in aging humans is dramatically worse than that in aging animals, suggesting that the high-frequency hearing losses that define human presbycusis reflect avoidable contributions of chronic ear abuse to which aging animals are not exposed.

Age-related hearing loss: Why we need to think about sex as a biological variable.

It has long been known that age-related hearing loss (ARHL) is more common, more severe, and with an earlier onset in men compared to women. Even in the absence of confounding factors such as noise exposure, these sexdifferences in susceptibility to ARHL remain. In the last decade, insight into the pleiotrophic nature by which estrogen signaling can impact multiple signaling mechanisms to mediate downstream changes in gene expression and/or elicit rapid changes in cellular function has rapidly gathered pace, and a role for estrogen signaling in the biological pathways that confer neuroprotection is becoming undeniable. Here I review the evidence why we need to consider sex as a biological variable (SABV) when investigating the etiology of ARHL. Loss of auditory function with aging is frequency-specific and modulated by SABV. Evidence also suggests that differences in cochlear physiology between women and men are already present from birth. Understanding the molecular basis of these sex differences in ARHL will accelerate the development of precision medicine therapies for ARHL.

Tinnitus, hearing loss and inflammatory processes in an older Portuguese population.

Objective: Tinnitus is associated with various conditions such as presbycusis, infectious, autoimmune and many other diseases. Our study aims to identify an association between inflammatory markers and the presence of tinnitus or hearing loss (HL).Design: Exploratory study including a structured interview, complete ENT observation, audiological and inflammatory markers evaluation.Study Sample: Sixty women and 54 men (55 to 75 years) from the Portuguese population, with or without sensory presbycusis and/or tinnitus.Results: IL10 levels were significantly lower in participants with tinnitus than in those without tinnitus. Moreover, TGF-ß was lower in older participants (p = 0.034), IL1α was higher in participants with tonal tinnitus (p = 0.033), and IL2 was lower in participants who reported partial or complete residual inhibition (p = 0.019). Additionally, we observed a negative correlation between tinnitus duration and IL10 levels (r= -.281), and between HSP70 levels and tinnitus loudness (r= -.377). TNF-α and HSP70 levels appears to be sensitive to the time when samples were collected (morning or afternoon).Conclusions: The results of our study showing fluctuations in inflammatory markers along the hearing loss process, reinforce the idea that inflammatory mechanisms are involved in hearing loss pathogenesis but also in tinnitus. IL10 levels appear significantly altered in tinnitus but not in hearing loss.

Age-related hearing decline in individuals with and without occupational noise exposure.

This study was conducted to compare the pattern of age-related hearing decline in individuals with and without self-reported previous occupational noise exposure. This was a prospective, population-based, longitudinal study of individuals aged 70-75 years, from an epidemiological investigation, comprising three age cohorts. In total there were 1013 subjects (432 men and 581 women). Participants were tested with pure tone audiometry, and they answered a questionnaire to provide information regarding number of years of occupational noise exposure. There were no significant differences in hearing decline, at any frequency, for those aged 70-75 years between the noise-exposed (N= 62 men, 22 women) and the nonexposed groups (N = 96 men, 158 women). This study supports the additive model of noise-induced hearing loss (NIHL) and age-related hearing loss (ARHL). The concept of different patterns of hearing decline between persons exposed and not exposed to noise could not be verified.

[Inner Ear Hearing Loss]. / Innenohrschwerhörigkeit.

Hearing loss is one of the most dominant handicaps in modern societies, which additionally very often is not realized or not admitted. About one quarter of the general population suffers from inner ear hearing loss and is therefore restricted in communicational skills. Demographic factors like increasing age play an important role as well as environmental influences and an increasing sound and noise exposure especially in leisure activities. Thus borders between a "classical" presbyacusis - if it ever existed - and envirionmentally induced hearing loss disappear. Today restrictions in hearing ability develop earlier in age but at the same time they are detected and diagnosed earlier. This paper can eventually enlighten the wide field of inner ear hearing loss only fragmentarily; therefore mainly new research, findings and developments are reviewed. The first part discusses new aspects of diagnostics of inner ear hearing loss and different etiologies.

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.

Noise and age-related hearing loss: a study of 40 123 gold miners in South Africa.

OBJECTIVE AND DESIGN: This retrospective cohort study aimed to describe the differential effect of noise exposure and age-related hearing loss in a large sample of gold miners in South Africa. STUDY SAMPLE: Audiological data of 40 123 South African mine workers were investigated. Data of a non-noise-exposed control group (n = 6162) and group exposed to underground noise (≥ 85 dB A (TWA) (n = 33 961) were included. Within these two larger noise-exposed groups two homogenous exposure groups (HEG) were also selected for analyses, namely the driller group (n = 4399) and the administration group (administrative workers) (n = 2211). Participants were categorized in terms of noise exposure, age, and race. RESULTS: Significantly different thresholds (worse for underground noise group) with respect to the median for all frequencies after adjusting for age was evident between the noise-exposed and control groups (ANCOVA). The largest differences in hearing thresholds between the noise-exposed and control groups were observed at 3 and 4 kHz in the age group 36 to 45 years. Administration and driller group differed significantly (driller group worse results) with respect to the mean LFA512 and HFA346 after adjusting for age (ANCOVA). Black males had significantly better high-frequency hearing compared with white male counterparts but significantly worse low-frequency hearing. CONCLUSION: Age was the most important influence on hearing thresholds for the noise and control groups. Race was shown to be a very significant factor determining susceptibility to NIHL and ARHL.

Stumbling Blocks in the Investigation of the Relationship Between Age-Related Hearing Loss and Cognitive Impairment.

The relationship between age-related hearing loss (ARHL) and cognitive impairment (CI) remains intricate. However, there is no robust evidence from experimental or clinical studies to elucidate their relationship. The key unaddressed questions are (a) whether there is a causal effect of ARHL on CI and (b) whether efficacious treatment of ARHL (such as hearing-aid use) ameliorates CI and dementia-related behavioral symptoms. Because of several methodological and systematic flaws/challenges, rigorous verification has not been conducted. Addressing these stumbling blocks is essential to unraveling the relationship between ARHL and CI, which motivated us to undertake this review. Here, we discuss the methodological problems from the perspectives of potential confounding bias, assessments of CI and ARHL, hearing-aid use, functional-imaging studies, and animal models based on the latest information and our experiences. We also identify potential solutions for each problem from the viewpoints of clinical epidemiology. We believe that "objectivity," specifically the use of more objective behavioral assessments and new computerized technologies, may be the key to improving experimental designs for studying the relationship between ARHL and CI.

Plasma Levels of Interleukin 2 (IL-2) Associated with Hearing Loss Evaluation in the Elderly.

CONTEXT: Presbycusis can be mediated by the effects of inflammatory processes on the auditory system, and these aging biological mechanisms remain poorly studied. AIMS: The aim of this study was to determine whether plasma biomarkers are associated with hearing disorders caused by aging in the elderly. SETTINGS AND DESIGN: Cross-sectional study with 106 participants in the Active Aging Project, 93 (88%) females and 13 (12%) males, with an average age of 70 years. METHODS AND MATERIAL: Audiological evaluation was performed with pure tone audiometry and collection of peripheral blood for the measurement of plasma levels of interleukins 2, 4, 6, and 10, tumor necrosis factor-α, and interferon-γ by means of flow cytometry. STATISTICAL ANALYSIS USED: The SPSS (v.0, SPSS Inc., Chicago, USA) was used for the analysis of the data obtained. For all data analyzed, the significance level adopted was P < 0.05 and 95% confidence interval. RESULTS: There were statistically significant correlations between male and IL-2 (P = 0.031; rs = 0.210), mean II of the right ear (P = 0.004; rs = 0.279), longer in years (P = 0.002; rs = 0.307) and in hours (P = 0.004; rs = 0.281) of noise exposure also in males. CONCLUSIONS: In the present study, there was an association between the male gender and higher plasma levels of IL-2, an increase in the average hearing in the right ear, and greater time in years and hours of exposure to noise. There was a predominance of mild sensorineural hearing loss and worsening of hearing related to age, characteristics of presbycusis.

Recent advances in the study of age-related hearing loss: a mini-review.

Hearing loss is a common age-associated affliction that can result from the loss of hair cells and spiral ganglion neurons (SGNs) in the cochlea. Although hair cells and SGNs are typically lost in the same cochlea, recent analysis suggests that they can occur independently, via unique mechanisms. Research has identified both environmental and genetic factors that contribute to degeneration of cochlear cells. Additionally, molecular analysis has identified multiple cell-signaling mechanisms that likely contribute to pathological changes that result in hearing deficiencies. These analyses should serve as useful primers for future work, including genomic and proteomic analysis, to elucidate the mechanisms driving cell loss in the aging cochlea. Significant progress in this field has occurred in the past decade. As our understanding of aging-induced cochlear changes continues to improve, our ability to offer medical intervention will surely benefit the growing elderly population.

Age related changes in gene expression within the cochlea of C57BL/6J mice.

BACKGROUND AND AIMS: Hearing loss as a unique symptom is highly prevalent in the elderly and while there exists several pathologies that would result in age related hearing loss (ARHL), most agree it is multifactorial with environmental, metabolic and genetic components. However, no research to date has discovered a definitive genetic cause. This paper describes the use of microarray to address this issue. METHODS: The left cochlea of laboratory aged C57BL6J mice at 4, 15 and 45 weeks was extracted from pooled, agematched animals and the RNA extracted for use in microarray analysis. The contralateral cochlea was also removed and used for immunohistochemical analysis. RESULTS: Microarray revealed 116 genes to be up or down regulated between young and old animals, the most prominent being prolactin (108.2 fold increase) and growth hormone (43.94 fold increase). The prolactin inhibitor calcitonin was also down regulated over 2 fold. Immunohistochemistry revealed prolactin to be weakly expressed within the spiral ganglion, whilst its receptor was widely distributed throughout the cochlea. CONCLUSION: This is the first study demonstrating the cochlea as a site for extrapituitary prolactin expression and that this expression is related to age. Combined with the widespread distribution of prolactin receptor, there may be implications for prolactin's role in ARHL.

Temporal acuity is preserved in the auditory midbrain of aged mice.

Impaired temporal resolution of the central auditory system has long been suggested to contribute to speech understanding deficits in the elderly. However, it has been difficult to differentiate between direct age-related central deficits and indirect effects of confounding peripheral age-related hearing loss on temporal resolution. To differentiate this, we measured temporal acuity in the inferior colliculus (IC) of aged CBA/J and C57BL/6 mice, as a model of aging with and without concomitant hearing loss. We used two common measures of auditory temporal processing: gap detection as a measure of temporal fine structure and amplitude-modulated noise as a measure of envelope sensitivity. Importantly, auditory temporal acuity remained precise in the IC of old CBA/J mice when no or only minimal age-related hearing loss was present. In contrast, temporal acuity was only indirectly reduced by the presence of age-related hearing loss in aged C57BL/6 mice, not by affecting the brainstem precision, but by affecting the signal-to-noise ratio of the neuronal activity in the IC. This demonstrates that indirect effects of age-related peripheral hearing loss likely remain an important factor for temporal processing in aging in comparison to 'pure' central auditory decline itself. It also draws attention to the issue that the threshold difference between 'nearly normal' or 'clinically normal' hearing aging subjects in comparison to normal hearing young subjects still can have indirect effects on central auditory neural representations of temporal processing.

Metabolic and Sensory Components of Age-Related Hearing Loss.

Age-related hearing loss is a multifactorial condition with effects of aging and environmental exposures that contribute to cochlear pathologies. Metabolic hearing loss involves declines in the endocochlear potential, which broadly reduce cochlear amplification of low-level sounds. Sensory hearing loss involves damage to outer hair cells that may eliminate amplification, especially for high-frequency sounds. A novel approach was developed to estimate the extent of metabolic and sensory components (in dB) for an individual, by combining hearing loss profiles to optimally approximate their hearing thresholds (audiogram). This approach was validated using estimates of metabolic and sensory hearing loss from retrospective datasets including gerbils, cross-sectional and longitudinal audiograms from older adults, a measure of speech recognition in noise, and histopathology case reports. Simulation results showed that well-approximated audiograms can produce accurate metabolic and sensory estimates. Estimates of metabolic and sensory components of age-related hearing loss differentiated gerbils with known strial and/or sensory pathologies based on age and exposures. For older adults, metabolic estimates consistently increased with age and were associated with poorer speech recognition in noise, while sensory estimates were related to sex and noise exposure differences. Histopathology case reports (with audiograms) that described strial and outer hair cell pathology in temporal bones from older donors showed significant differences in metabolic and sensory estimates, respectively. The results support the view that audiograms include information that can be used to estimate the metabolic and sensory components of age-related hearing loss.

A BK channel-targeted peptide induces age-dependent improvement in behavioral and neural sound representation.

Recent evidence suggests that modulation of the large-conductance, calcium-activated potassium (BK) channel regulates auditory processing in the brain. Because ion channel expression often changes during aging, this could be a factor in age-related hearing loss. The current study explored how the novel BK channel modulator LS3 shapes central auditory processing in young and old adult mice. In vivo extracellular recordings in the auditory midbrain demonstrated that LS3 differentially modulates neural processing along the tonotopic axis. Though sound-evoked activity was reduced in the mid and ventral tonotopic regions, LS3 enhanced excitatory drive and sound-evoked responses for some neurons in the dorsal, low-frequency region. Behavioral assessment using acoustic reflex modification audiometry indicated improved tone salience following systemic LS3 administration. Moderation of these responses with aging correlated with an age-related decline in BK channel expression. These findings suggest that targeting the BK channel enhances responsivity to tonal sounds, providing the potential to improve hearing acuity and treat hearing loss.

Early subclinical cochlear dysfunction in myotonic dystrophy type 1.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is an autosomal-dominant inherited disorder clinically characterized by variable systemic manifestations. Among clinical features of the disease, 'precocious presbyacusis' has been previously reported. The underlying mechanism of this auditory impairment remains still poorly understood. Hearing is an active process located in the cochlea, where the outer hair cells (OHCs) play an important role in sound perception through a 'contractile' like movement resembling skeletal muscle fibers dynamics. OHCs status has not yet been investigated in DM1 patients. OHCs integrity can be assessed by measuring transient-evoked otoacoustic emissions (TEOAE), a non-invasive, repeatable, and objective quantitative tool. METHODS: We recruited 25 patients with a genetically confirmed diagnosis of DM1, and 28 age-matched control subjects. All of them underwent a routine audiological evaluation and TEOAE recordings. RESULTS: We detected a high prevalence of sensorineural high-frequency hearing loss (HFHL) in DM1 patients, significantly different if compared to control subjects. Interestingly, the accurate analysis of DM1 recorded data showed a marked impairment of TEOAE both in HFHL+ and unexpectedly in HFHL- group. Cochlear dysfunction was restricted to frequencies above 2000 Hz in the HFHL- group, but it extended to 1000 Hz in HFHL+ DM1 patients. CONCLUSIONS: Our study indicates that cochlear impairment in DM1 is present, even in patients without evidence of hearing loss at a standard audiometric analysis. Hence, in the current clinical practice, an assessment of cochlear function by TEOAE recording may be useful in DM1 patients to identify precocious signs of cochlear dysfunction.

A neural basis of speech-in-noise perception in older adults.

OBJECTIVE: We investigated a neural basis of speech-in-noise perception in older adults. Hearing loss, the third most common chronic condition in older adults, is most often manifested by difficulty understanding speech in background noise. This trouble with understanding speech in noise, which occurs even in individuals who have normal-hearing thresholds, may arise, in part, from age-related declines in central auditory processing of the temporal and spectral components of speech. We hypothesized that older adults with poorer speech-in-noise (SIN) perception demonstrate impairments in the subcortical representation of speech. DESIGN: In all participants (28 adults, age 60-73 yr), average hearing thresholds calculated from 500 to 4000 Hz were ≤ 25 dB HL. The participants were evaluated behaviorally with the Hearing in Noise Test (HINT) and neurophysiologically using speech-evoked auditory brainstem responses recorded in quiet and in background noise. The participants were divided based on their HINT scores into top and bottom performing groups that were matched for audiometric thresholds and intelligent quotient. We compared brainstem responses in the two groups, specifically, the average spectral magnitudes of the neural response and the degree to which background noise affected response morphology. RESULTS: In the quiet condition, the bottom SIN group had reduced neural representation of the fundamental frequency of the speech stimulus and an overall reduction in response magnitude. In the noise condition, the bottom SIN group demonstrated greater disruption in noise, reflecting reduction in neural synchrony. The role of brainstem timing is particularly evident in the strong relationship between SIN perception and quiet-to-noise response correlations. All physiologic measures correlated with SIN perception. CONCLUSION: Adults in the bottom SIN group differed from the audiometrically matched top SIN group in how speech was neurally encoded. The strength of subcortical encoding of the fundamental frequency appears to be a factor in successful speech-in-noise perception in older adults. Given the limitations of amplification, our results suggest the need for inclusion of auditory training to strengthen central auditory processing in older adults with SIN perception difficulties.

[Socio-presbyacusis: definition and prevention]. / La sociopresbiacusia: cos'è e come si previene.

Socio-presbyacusis is a hot topic with an increasing incidence and high social costs. The main etiological factors are: genetics, smoking and drinking habits, diet, metabolic syndrome, chronic otitis and noise exposure (professional, environmental and recreative). Despite its multifactorial origin, the pathogenetic mechanism of cochlear damage is based on the increased production of Reactive Oxygen Species (ROS). The clinical characteristic feature of socio-presbyacusis is represented by slow cochlear degeneration causing a reduction of central hearing inputs. The result is a gradual social isolation of the deaf patient with a worsening of his Quality of Life. The main target of the management of socio-presbyacusis is the early diagnosis and prosthetic remediation in order to avoid patient's isolation. New preventive and remediative strategies are represented by antioxidant drugs.

Heat Shock Factor 1 Prevents Age-Related Hearing Loss by Decreasing Endoplasmic Reticulum Stress.

Endoplasmic reticulum (ER) stress is a common stress factor during the aging process. Heat shock factor 1 (HSF1) plays a critical role in ER stress; however, its exact function in age-related hearing loss (ARHL) has not been fully elucidated. The purpose of the present study was to identify the role of HSF1 in ARHL. In this study, we demonstrated that the loss of inner and outer hair cells and their supporting cells was predominant in the high-frequency region (basal turn, 32 kHz) in ARHL cochleae. In the aging cochlea, levels of the ER stress marker proteins p-eIF2α and CHOP increased as HSF1 protein levels decreased. The levels of various heat shock proteins (HSPs) also decreased, including HSP70 and HSP40, which were markedly downregulated, and the expression levels of Bax and cleaved caspase-3 apoptosis-related proteins were increased. However, HSF1 overexpression showed significant hearing protection effects in the high-frequency region (basal turn, 32 kHz) by decreasing CHOP and cleaved caspase-3 and increasing the HSP40 and HSP70 proteins. These findings were confirmed by HSF1 functional studies using an auditory cell model. Therefore, we propose that HSF1 can function as a mediator to prevent ARHL by decreasing ER stress-dependent apoptosis in the aging cochlea.