Progression Of Age-related Hearing Loss Research Articles

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.

Long-term NAD+ supplementation prevents the progression of age-related hearing loss in mice.

Age-related hearing loss (ARHL) is the most common sensory disability associated with human aging. Yet, there are no approved measures for preventing or treating this debilitating condition. With its slow progression, continuous and safe approaches are critical for ARHL treatment. Nicotinamide Riboside (NR), a NAD+ precursor, is well tolerated even for long-term use and is already shown effective in various disease models including Alzheimer's and Parkinson's disease. It has also been beneficial against noise-induced hearing loss and in hearing loss associated with premature aging. However, its beneficial impact on ARHL is not known. Using two different wild-type mouse strains, we show that long-term NR administration prevents the progression of ARHL. Through transcriptomic and biochemical analysis, we find that NR administration restores age-associated reduction in cochlear NAD+ levels, upregulates biological pathways associated with synaptic transmission and PPAR signaling, and reduces the number of orphan ribbon synapses between afferent auditory neurons and inner hair cells. We also find that NR targets a novel pathway of lipid droplets in the cochlea by inducing the expression of CIDEC and PLIN1 proteins that are downstream of PPAR signaling and are key for lipid droplet growth. Taken together, our results demonstrate the therapeutic potential of NR treatment for ARHL and provide novel insights into its mechanism of action.

Inoculation of lymphocytes from young mice prevents progression of age-related hearing loss in a senescence-associated mouse model

Despite the increase in age-related hearing loss (ARHL) prevalence owing to increased population aging, preventive measures against ARHL have not yet been established. The immune system becomes one of the most dysfunctional systems upon aging, and immunosenescence greatly affects homeostasis and promotes systemic aging along with chronic inflammation and oxidative stress. This study aimed to determine whether immuno-rejuvenation procedures can prevent ARHL and have clinical applications as well as to analyze the communication mechanisms between the systemic immune system and the cochlea using a murine model. Lymphocytes from young mice inhibited the progression of ARHL. The method of cryopreserving these lymphocytes and inoculating them at the onset of ARHL suggests their clinical application. Mice that were administered this treatment not only maintained auditory threshold but also avoided spinal ganglion degeneration, cellular immune aging, and nitric oxide production, which causes age-related tissue damage. These findings coincide with our previous strategies against immunosenescence and neuronal aging. Therefore, the manipulation of systemic immune function may contribute not only to the prevention of ARHL but also to the development of novel anti-aging clinical measures, paving the way to healthy longevity with preserved organ function.

A Narrative Review of Lifestyle Risk Factors and the Role of Oxidative Stress in Age-Related Hearing Loss.

Age-related hearing loss affects a significant proportion of adults aged 60 years and above, with a prevalence of 65%. This condition has a negative impact on both physical and mental well-being, and while hearing interventions can help alleviate the effects of hearing loss, they cannot completely restore normal hearing or halt the progression of age-related hearing loss. Oxidative stress and inflammation have been identified as potential contributors to this condition. By addressing modifiable lifestyle risk factors that exacerbate oxidative stress, there may be an opportunity to prevent hearing loss. Therefore, this narrative review provides an overview of the major modifiable lifestyle risk factors associated with age-related hearing loss, that is, exposure to noise and ototoxic chemicals, smoking, diet, physical activity, and the presence of chronic lifestyle diseases, and offers an overview of the role of oxidative stress in the pathophysiology of this condition.

Two Loci Contribute to Age-Related Hearing Loss Resistance in the Japanese Wild-Derived Inbred MSM/Ms Mice

An MSM/Ms strain was established using Japanese wild mice, which exhibit resistance to several phenotypes associated with aging, such as obesity, inflammation, and tumorigenesis, compared to common inbred mouse strains. MSM/Ms strain is resistant to age-related hearing loss, and their auditory abilities are sustained for long durations. The age-related hearing loss 3 (ahl3) locus contributes to age-related hearing in MSM/Ms strain. We generated ahl3 congenic strains by transferring a genomic region on chromosome 17 from MSM/Ms mice into C57BL/6J mice. Although C57BL/6J mice develop age-related hearing loss because of the ahl allele of the cadherin 23 gene, the development of middle- to high-frequency hearing loss was significantly delayed in an ahl3 congenic strain. Moreover, the novel age-related hearing loss 10 (ahl10) locus associated with age-related hearing resistance in MSM/Ms strain was mapped to chromosome 12. Although the resistance effects in ahl10 congenic strain were slightly weaker than those in ahl3 congenic strain, slow progression of age-related hearing loss was confirmed in ahl10 congenic strain despite harboring the ahl allele of cadherin 23. These results suggest that causative genes and polymorphisms of the ahl3 and ahl10 loci are important targets for the prevention and treatment of age-related hearing loss.

Bases genéticas, moleculares y bioquímicas del envejecimiento auditivo ¿Qué nos enseñan los modelos experimentales

Age-related hearing loss (ARHL) affects one in three people older than 65 years and is the most prevalent sensorineural deficit. This type of hearing loss precedes and accelerates the onset of cognitive impairment and is associated with an increased risk for neurodegenerative diseases such as dementia and Alzheimer disease. The onset and progression of ARHL is influenced by genetic factors, which are still poorly understood, and environmental factors, which in particular include exposure to excessive noise and ototoxic substances. At present, no effective drug treatments are available for ARHL prevention or treatment, and therefore research in this field is a priority. In the research field, animal models offer a crucial tool for i) identifying new genes associated with ARHL, ii) understanding the cellular and molecular basis of auditory ageing and iii) defining new therapeutic targets and evaluating candidate treatments.

4 Key Post-pandemic Trends for Marketing Hearing Care to Baby Boomers

The COVID-19 pandemic has created permanent changes throughout society, including the health care landscape. As society inches towards reopening, audiologists would benefit from updating their understanding of patients’ needs for hearing health care. An ongoing study conducted by Auditory Insight identified four post-pandemic trends that impact how audiologists may best market their practices.1FigureFigure 1: Baby Boomers’ Growing Interest in Telehealth. (Sources: 2019 Accenture survey, 2021 HIMSS survey)Table 1: Recommended Marketing Programs for Baby Boomers Based on Four.We conceive of the marketing function in broad, strategic terms. Marketing includes not only marketing messages and promotional campaigns, but also product selection and place, i.e., the retail experience audiologists create for their patients. Our recommendations reflect this perspective. BABY BOOMERS & HEALTH CARE For most audiologists, their core patient constituency is the baby boomer generation, currently 57 to 75 years old. In addition to this demographic's purchasing power—baby boomers hold 53% of the wealth in the US—their sheer numbers could fuel demand for hearing aids.2 About 20 million baby boomers in the United States have hearing loss, with the prevalence of hearing loss exceeding 50% among those aged 70 to 79, according to Auditory Insight research.3 The pandemic has not completely upended baby boomers’ health care needs. They will continue to sign up for Medicare, manage chronic health conditions, and require access to prescriptions. However, the pandemic has brought into relief four key trends for this generation. TREND #1: GROWING INTEREST IN TELEHEALTH Continuing to serve baby boomers in a post-pandemic world requires understanding their growing interest in telehealth. More than one-quarter of baby boomers report post pandemic that they prefer video visits for primary care, according to an HIMSS March 2021 survey on telehealth (see Fig. 1).4 Most patients who prefer telehealth for primary care would also do so for routine hearing aid appointments. Patients who view hearing aids as consumer products, as opposed to medical devices, may be even more willing to seek virtual care with an audiologist. During the pandemic, baby boomers increased their online spending by almost 50%, having adapted to and embraced services like grocery delivery and Amazon Prime.5 Will baby boomers’ interest in telehealth dwindle now that about 80% of them are fully vaccinated?6 Our research forecasts that at least one-fifth of baby boomers will continue to prefer telehealth for audiological care. The telehealth genie is out of the bottle: Baby boomers have experienced the convenience and flexibility of connecting with a provider while in the comfort of their homes. Recommendation #1: Offer Telehealth Options. In order to respond to baby boomers who prefer telehealth, audiologists may conduct hearing aid fine tuning and troubleshooting over video calls. Audiologists would benefit from teaching this demographic how to change wires and domes over video calls. Telehealth companies such as Lexie Hearing and Listen Lively routinely coach patients through these processes. In addition, audiologists may consider a hybrid customer service model, conducting otoscopy, a full audiometric assessment, device selection, and real-ear measurement in a single appointment. The key is to use trial hearing aids or aids in stock during this appointment, later shipping the programmed, new hearing aids directly to the patient, as state regulations allow. Phonak US, for example, has created a best practice model for their hearing care professionals leveraging this approach.7 For new patients or those needing an upgrade, audiologists may recommend hearing aid models with Bluetooth connectivity and remote programming apps that permit virtual care. Audiologists would also benefit from displaying telehealth options prominently on their websites. When patients book appointments, ask about and record their telehealth preferences. TREND #2: HEALTH & FITNESS TRACKING IN APPS & WEARABLES Baby boomers have learned to track their health and fitness using wearables and smartphone apps. During the pandemic, the general adoption of wearables, such as the Apple Watch, skyrocketed 10 percentage points across all generations.8Mobiquity specifically estimates that 42% of baby boomers now use a smartwatch or wearable to monitor their health.9 The robust Mobiquity estimate may stem from a survey population that skews towards upper-income respondents; however, patients who purchase premium hearing aids also generally have higher purchasing power. These polls evince this generation's perspective that knowledge is power when it comes to staying on top of personal health. Recommendation #2: Market the Importance of Exercise. Audiologists would benefit from determining which of their baby boomer patients are interested in physical fitness. Long-term exercise delays the progression of age-related hearing loss.10 Audiologists may use this information to counsel patients and also as a positive marketing message on their website and in other communications. For patients specifically interested in health and fitness tracking, the Starkey Livio AI11 is capable of counting steps, eliminating the need for a separate step counter such as the Fitbit. TREND #3: THE ONGOING ATTRACTION OF TV ENTERTAINMENT Despite baby boomers’ desire to stay healthy, they spend more time in front of the TV than exercising by a whopping factor of 15. Prior to the pandemic, they averaged at least three hours of television every day.12 The pandemic has only increased screen time across generations.13 In addition to counseling that exercise promotes whole-body health, audiologists benefit from acknowledging and addressing many patients’ interest in watching TV. These patients need to be able to hear programs without blaring the volume, creating discomfort for others. Recommendation #3: Demonstrate How To Improve Leisure Time. On websites and in other communications, audiologists may promote that they help patients hear better across all aspects of their lifestyle, including watching TV. Offer to instruct patients on how closed captioning works on streaming platforms. Audiologists may also point patients in the direction of specific devices like the Nuheara IQstream TV or Oticon ConnectLine that, in conjunction with those company's hearing devices, amplify TV audio.14, 15 TREND #4: WORKFORCE PARTICIPATION AND JOB HUNTING Auditory Insight's research demonstrates that hearing better at work is the primary catalyst for people under 65 to seek treatment for hearing loss.16 Professional office workers struggle to hear over Zoom calls while front-line workers such as ride-sharing drivers strain to hear passengers in the back seat. Prior to the pandemic, more than half of baby boomers were still in the civilian labor force, employed in full- or part-time jobs.17 COVID-19 forced a higher rate of retirement in people aged 65 and older but did not impact the retirement rate for baby boomers aged 57-64.18 For these younger baby boomers, the pandemic has shifted the distribution of jobs in the economy toward those requiring new training or fluency with digital tools.19 Workers as a result are reevaluating their functional roles and industry choices. For people who are interviewing for new jobs, the act of hearing is essential. Baby boomers in the workforce are understandably sensitive to the societal stigma surrounding hearing loss and hearing aids. Stereotypes, portraying people with hearing loss as “out of touch,” “old,” or even “crippled” are antithetical to the personas that people need to project at work.20 Recommendation #4: Prioritize Patients’ Schedules and Make On-Balance Suggestions. To adapt to working patients’ busy lives, audiologists may offer flexible office hours. Evening hours on Thursdays or a Wednesday-Sunday office schedule is an investment that signals a practice values patients’ time. To further attract these younger boomers, include messaging about the importance for patients of hearing well at work. For patients concerned about stigma, recommend a discreet hearing aid. Fully in the ear canal, the Phonak Virto B-Titanium is a highly-rated, nearly invisible hearing aid.21, 22 The device's inconspicuousness may outweigh certain inconveniences, like the need to create a custom-fit mold and the lack of rechargeable batteries or Bluetooth streaming. The Signia Active Pro takes a completely different approach in that this fully featured hearing aid camouflages as an earbud.23 Designed for people with mild to moderate hearing loss, these hearing aids are ready to wear and offer rechargeability and direct Bluetooth streaming on iOS devices. The aids look sleek, in colors like white and rose gold. ADDRESSING BABY BOOMERs' POST-PANDEMIC HEARING HEALTH NEEDS COVID-19 caused unprecedented societal upheaval that has worked its way to the provision of hearing health. To stay relevant, audiologists would benefit from upgrading their full marketing mix—from product selection to marketing messages to the retail experience—to reflect patients’ current priorities and lifestyle (see Table 1 for a summary of recommendations). Recognizing the growing importance of telehealth and fitness tracking, the ongoing attraction of TV entertainment, and the changing nature of work will enable audiologists to maximize their marketing efforts.

Treg and IL-1 receptor type 2-expressing CD4+ T cell-deleted CD4+ T cell fraction prevents the progression of age-related hearing loss in a mouse model

We investigated the association between cellular immunity and age-related hearing loss (ARHL) development using three CD4+ T cell fractions, namely, naturally occurring regulatory T cells (Treg), interleukin 1 receptor type 2-expressing T cells (I1R2), and non-Treg non-I1R2 (nTnI) cells, which comprised Treg and I1R2-deleted CD4+ T cells. Inoculation of the nTnI fraction into a ARHL murine model, not only prevented the development of ARHL and the degeneration of spiral ganglion neurons, but also suppressed serum nitric oxide, a source of oxidative stress. Further investigations on CD4+ T cell fractions could provide novel insights into the prevention of aging, including presbycusis.

Food hardness influences the progression of age-related hearing loss in mice.

C57BL/6J and DBA/2J mice are often used for hearing research because of their early onset and progression of age-related hearing loss (AHL). Here, we report that the hardness of the diet affects the progression of AHL in these mice. When C57BL/6J mice and DBA/2J mice were fed a pellet-type or powder-type standard AIN93M diet, the pellet diet significantly promoted AHL. AHL promotion was eliminated by crushing the pellet diet to a powder. Subsequently, when C57BL/6J mice were fed the pellet-type AIN93M diet obtained from three different manufacturers, two of them significantly promoted AHL. The hardness of the diets was measured, and it was found that the two diets that promoted AHL were significantly harder than the other diet. Next, we attempted to reduce diet hardness by replacing some nutritional ingredients with dried eggs or phosphatidylcholine (PC), and we succeeded in obtaining brittle diets with lower hardness values. Then, C57BL/6J mice were bred with brittle diets for 6months and the promotion of AHL was suppressed to the equivalent level as the powder diet. Furthermore, when senescence-accelerated mice, SAMP8, were fed a brittle diet for one year, the progression of AHL was also suppressed; however, it did not affect other aging indexes, such as mental and physical performance. We also confirmed that a high-fat pellet diet, which is soft even in pellet form, did not promote AHL. Time-restricted feeding (tRF), which is a chrono-nutritional method to delay aging, ameliorated the promotion of AHL by the hard AIN93M pellets in C57BL/6J mice. These results indicate that the physical form and hardness of diets affect the progression of AHL in mouse models.

Activation of the NRF2 pathway in Keap1-knockdown mice attenuates progression of age-related hearing loss

Age-related hearing loss (AHL) is a progressive sensorineural hearing loss in elderly people. Although no prevention or treatments have been established for AHL, recent studies have demonstrated that oxidative stress is closely related to pathogenesis of AHL, suggesting that suppression of oxidative stress leads to inhibition of AHL progression. NRF2 is a master transcription factor that regulates various antioxidant proteins and cytoprotection factors. To examine whether NRF2 pathway activation prevents AHL, we used Keap1-knockdown (Keap1FA/FA) mice, in which KEAP1, a negative regulator of NRF2, is decreased, resulting in the elevation of NRF2 activity. We compared 12-month-old Keap1FA/FA mice with age-matched wild-type (WT) mice in the same breeding colony. In the Keap1FA/FA mice, the expression levels of multiple NRF2 target genes were verified to be significantly higher than the expression levels of these genes in the WT mice. Histological analysis showed that cochlear degeneration at the apical and middle turns was ameliorated in the Keap1FA/FA mice. Auditory brainstem response (ABR) thresholds in the Keap1FA/FA mice were significantly lower than those in the WT mice, in particular at low–mid frequencies. Immunohistochemical detection of oxidative stress markers suggested that oxidative stress accumulation was attenuated in the Keap1FA/FA cochlea. Thus, we concluded that NRF2 pathway activation protects the cochlea from oxidative damage during aging, in particular at the apical and middle turns. KEAP1-inhibiting drugs and phytochemicals are expected to be effective in the prevention of AHL.

Biophysical and morphological changes in inner hair cells and their efferent innervation in the ageing mouse cochlea.

Age-related hearing loss is a progressive hearing loss involving environmental and genetic factors, leading to a decrease in hearing sensitivity, threshold and speech discrimination. We compared age-related changes in inner hair cells (IHCs) between four mouse strains with different levels of progressive hearing loss. The surface area of apical coil IHCs (9-12kHz cochlear region) decreases by about 30-40% with age. The number of BK channels progressively decreases with age in the IHCs from most mouse strains, but the basolateral membrane current profile remains unchanged. The mechanoelectrical transducer current is smaller in mice harbouring the hypomorphic Cdh23 allele Cdh23ahl (C57BL/6J; C57BL/6NTac), but not in Cdh23-repaired mice (C57BL/6NTacCdh23+ ), indicating that it could contribute to the different progression of hearing loss among mouse strains. The degree of efferent rewiring onto aged IHCs, most likely coming from the lateral olivocochlea fibres, was correlated with hearing loss in the different mouse strains. Inner hair cells (IHCs) are the primary sensory receptors of the mammalian cochlea, transducing acoustic information into electrical signals that are relayed to the afferent neurons. Functional changes in IHCs are a potential cause of age-related hearing loss. Here, we have investigated the functional characteristics of IHCs from early-onset hearing loss mice harbouring the allele Cdh23ahl (C57BL/6J and C57BL/6NTac), from late-onset hearing loss mice (C3H/HeJ), and from mice corrected for the Cdh23ahl mutation (C57BL/6NTacCdh23+ ) with an intermediate hearing phenotype. There was no significant loss of IHCs in the 9-12kHz cochlear region up to at least 15months of age, but their surface area decreased progressively by 30-40% starting from ∼6months of age. Although the size of the BK current decreased with age, IHCs retained a normal KCNQ4 current and resting membrane potential. These basolateral membrane changes were most severe for C57BL/6J and C57BL/6NTac, less so for C57BL/6NTacCdh23+ and minimal or absent in C3H/HeJ mice. We also found that lateral olivocochlear (LOC) efferent fibres re-form functional axon-somatic connections with aged IHCs, but this was seen only sporadically in C3H/HeJ mice. The efferent post-synaptic SK2 channels appear prior to the establishment of the efferent contacts, suggesting that IHCs may play a direct role in re-establishing the LOC-IHC synapses. Finally, we showed that the size of the mechanoelectrical transducer (MET) current from IHCs decreased significantly with age in mice harbouring the Cdh23ahl allele but not in C57BL/6NTacCdh23+ mice, indicating that the MET apparatus directly contributes to the progression of age-related hearing loss.

Ninjinyoeito Has a Protective Effect on the Auditory Nerve and Suppresses the Progression of Age-Related Hearing Loss in Mice.

Currently, there are limited reports available regarding the treatment and prevention of progressive age-related hearing loss. This is because age-related hearing loss is not a critical disease with direct fatalities and has several well-established countermeasures such as hearing aids and cochlear implants. This study evaluated the efficacy of Ninjinyoeito (NYT) in the treatment of age-related hearing loss. C57BL/6J mice were divided into three groups: baseline group, untreated group, and NYT-treated group, with the latter receiving NYT treatment for 2 months. The mice were fed with NYT extract mixed with 4% mouse normal chow. Hearing loss was confirmed by a reduction in intact cell density of the auditory nerve from the age of 5–7 months. The suppression of hearing loss with aging and decrease in the intact cell density of the auditory nerve were significant in mice fed with NYT for 2 months. NYT has been reported to improve blood flow and enhance mitochondrial activity and may exert its protective effects on spiral neurons through these mechanisms. There was no decrease in the size of the stria vascularis from the age of 5–7 months in C57BL/6J mice. The present model failed to reveal the effect of NYT on atrophy of the stria vascularis of the cochlear duct. In conclusion, NYT appears to have a protective effect on the auditory nerve and suppress the progression of age-related hearing loss by reducing age-related auditory nerve degeneration.

Pathophysiological changes in inner hair cell ribbon synapses in the ageing mammalian cochlea.

Age-related hearing loss (ARHL) is associated with the loss of inner hair cell (IHC) ribbon synapses, lower hearing sensitivity and decreased ability to understand speech, especially in a noisy environment. Little is known about the age-related physiological and morphological changes that occur at ribbon synapses. We show that the differing degrees of ARHL in four selected mouse stains is correlated with the loss of ribbon synapses, being most severe for the strains C57BL/6NTac and C57BL/6J, less so for C57BL/6NTacCdh23+ -Repaired and lowest for C3H/HeJ. Despite the loss of ribbon synapses with age, the volume of the remaining ribbons increased and the size and kinetics of Ca2+ -dependent exocytosis in IHCs was unaffected, indicating the presence of a previously unknown degree of functional compensation at ribbon synapses. Although the age-related morphological changes at IHC ribbon synapses contribute to the different progression of ARHL, without the observed functional compensation hearing loss could be greater. Mammalian cochlear inner hair cells (IHCs) are specialized sensory receptors able to provide dynamic coding of sound signals. This ability is largely conferred by their ribbon synapses, which tether a large number of vesicles at the IHC's presynaptic active zones, allowing high rates of sustained synaptic transmission onto the afferent fibres. How the physiological and morphological properties of ribbon synapses change with age remains largely unknown. Here, we have investigated the biophysical and morphological properties of IHC ribbon synapses in the ageing cochlea (9-12kHz region) of four mouse strains commonly used in hearing research: early-onset progressive hearing loss (C57BL/6J and C57BL/6NTac) and 'good hearing' strains (C57BL/6NTacCdh23+ and C3H/HeJ). We found that with age, both modiolar and pillar sides of the IHC exhibited a loss of ribbons, but there was an increased volume of those that remained. These morphological changes, which only occurred after 6months of age, were correlated with the level of hearing loss in the different mouse strains, being most severe for C57BL/6NTac and C57BL/6J, less so for C57BL/6NTacCdh23+ and absent for C3H/HeJ strains. Despite the age-related reduction in ribbon number in three of the four strains, the size and kinetics of Ca2+ -dependent exocytosis, as well as the replenishment of synaptic vesicles, in IHCs was not affected. The degree of vesicle release at the fewer, but larger, individual remaining ribbon synapses colocalized with the post-synaptic afferent terminals is likely to increase, indicating the presence of a previously unknown degree of functional compensation in the ageing mouse cochlea.

Age-related changes in the biophysical and morphological characteristics of mouse cochlear outer hair cells.

Age-related hearing loss (ARHL) is a very heterogeneous disease, resulting from cellular senescence, genetic predisposition and environmental factors (e.g. noise exposure). Currently, we know very little about age-related changes occurring in the auditory sensory cells, including those associated with the outer hair cells (OHCs). Using different mouse strains, we show that OHCs undergo several morphological and biophysical changes in the ageing cochlea. Ageing OHCs also exhibited the progressive loss of afferent and efferent synapses. We also provide evidence that the size of the mechanoelectrical transducer current is reduced in ageing OHCs, highlighting its possible contribution in cochlear ageing. Outer hair cells (OHCs) are electromotile sensory receptors that provide sound amplification within the mammalian cochlea. Although OHCs appear susceptible to ageing, the progression of the pathophysiological changes in these cells is still poorly understood. By using mouse strains with a different progression of hearing loss (C57BL/6J, C57BL/6NTac, C57BL/6NTacCdh23+ , C3H/HeJ), we have identified morphological, physiological and molecular changes in ageing OHCs (9-12kHz cochlear region). We show that by 6months of age, OHCs from all strains underwent a reduction in surface area, which was not a sign of degeneration. Although the ageing OHCs retained a normal basolateral membrane protein profile, they showed a reduction in the size of the K+ current and non-linear capacitance, a readout of prestin-dependent electromotility. Despite these changes, OHCs have a normal Vm and retain the ability to amplify sound, as distortion product otoacoustic emission thresholds were not affected in aged, good-hearing mice (C3H/HeJ, C57BL/6NTacCdh23+ ). The loss of afferent synapses was present in all strains at 15months. The number of efferent synapses per OHCs, defined as postsynaptic SK2 puncta, was reduced in aged OHCs of all strains apart from C3H mice. Several of the identified changes occurred in aged OHCs from all mouse strains, thus representing a general trait in the pathophysiological progression of age-related hearing loss, possibly aimed at preserving functionality. We have also shown that the mechanoelectrical transduction (MET) current from OHCs of mice harbouring the Cdh23ahl allele is reduced with age, highlighting the possibility that changes in the MET apparatus could play a role in cochlear ageing.

Suppressed expression of LDHB promotes age-related hearing loss via aerobic glycolysis

Age-dependent decrease of mitochondrial energy production and cellular redox imbalance play significant roles in age-related hearing loss (ARHL). Lactate dehydrogenase B (LDHB) is a key glycolytic enzyme that catalyzes the interconversion of pyruvate and lactate. LDH activity and isoenzyme patterns are known to be changed with aging, but the role of LDHB in ARHL has not been studied yet. Here, we found that LDHB knockout mice showed hearing loss at high frequencies, which is the typical feature of ARHL. LDHB knockdown caused downregulation of mitochondrial functions in auditory cell line, University of Bristol/organ of Corti 1 (UB/OC1) with decreased NAD+ and increased hypoxia inducing factor-1α. LDHB knockdown also enhanced the death of UB/OC1 cells with ototoxic gentamicin treatment. On the contrary, the induction of LDHB expression caused enhanced mitochondrial functions, including changes in mitochondrial respiratory subunits, mitochondrial membrane potentials, ATP, and the NAD+/NADH ratio. Thus, we concluded that suppression of LDHB activity may be closely related with the early onset or progression of ARHL.

Guanylyl Cyclase A/cGMP Signaling Slows Hidden, Age- and Acoustic Trauma-Induced Hearing Loss.

In the inner ear, cyclic guanosine monophosphate (cGMP) signaling has been described as facilitating otoprotection, which was previously observed through elevated cGMP levels achieved by phosphodiesterase 5 inhibition. However, to date, the upstream guanylyl cyclase (GC) subtype eliciting cGMP production is unknown. Here, we show that mice with a genetic disruption of the gene encoding the cGMP generator GC-A, the receptor for atrial and B-type natriuretic peptides, display a greater vulnerability of hair cells to hidden hearing loss and noise- and age-dependent hearing loss. This vulnerability was associated with GC-A expression in spiral ganglia and outer hair cells (OHCs) but not in inner hair cells (IHCs). GC-A knockout mice exhibited elevated hearing thresholds, most pronounced for the detection of high-frequency tones. Deficits in OHC input–output functions in high-frequency regions were already present in young GC-A-deficient mice, with no signs of an accelerated progression of age-related hearing loss or higher vulnerability to acoustic trauma. OHCs in these frequency regions in young GC-A knockout mice exhibited diminished levels of KCNQ4 expression, which is the dominant K+ channel in OHCs, and decreased activation of poly (ADP-ribose) polymerase-1, an enzyme involved in DNA repair. Further, GC-A knockout mice had IHC synapse impairments and reduced amplitudes of auditory brainstem responses that progressed with age and with acoustic trauma, in contrast to OHCs, when compared to GC-A wild-type littermates. We conclude that GC-A/cGMP-dependent signaling pathways have otoprotective functions and GC-A gene disruption differentially contributes to hair-cell damage in a healthy, aged, or injured system. Thus, augmentation of natriuretic peptide GC-A signaling likely has potential to overcome hidden and noise-induced hearing loss, as well as presbycusis.

Age-Related Hearing Loss Is Accelerated by Repeated Short-Duration Loud Sound Stimulation.

Both age-related hearing loss (ARHL) and noise-induced hearing loss (NIHL) may share pathophysiological mechanisms in that they are associated with excess free radical formation and cochlear blood flow reduction, leading to cochlear damage. Therefore, it is possible that short, but repeated exposures to relatively loud noise during extended time periods, like in leisure (i.e., musical devices and concerts) or occupational noise exposures, may add to cochlear aging mechanisms, having an impact on the onset and/or progression of ARHL. Consequently, the aim of the present study was to determine if repeated short-duration overexposure to a long-term noise could accelerate permanent auditory threshold shifts associated with auditory aging in an animal model of ARHL. Toward this goal, young adult, 3-month-old Wistar rats were divided into two groups: one exposed (E) and the other non-exposed (NE) to noise overstimulation. The stimulation protocol consisted of 1 h continuous white noise at 110 dB sound pressure level (SPL), 5 days a week, allowing 2 days for threshold recovery before initiating another stimulation round, until the animals reached an age of 18 months. Auditory brainstem response (ABR) recordings at 0.5, 1, 2, 4, 8, 16, and 32 kHz were performed at 3, 6, 12, and 18 months of age. The results demonstrate that in the E group there were significant increases in auditory thresholds at all tested frequencies starting already at 6 months of age, which extended at 12 and 18 months. However, in NE animals threshold shifts were not evident until 12 months, extending to 18 months of age. Threshold shifts observed in the E animals at 6 and 12 months were significantly larger than those observed in the NE group at the same ages. Threshold shifts at 6 and 12 months in E animals resembled those at 12 and 18 months in NE animals, respectively. This suggests that repeated noise overstimulation in short-duration episodes accelerates the time-course of hearing loss in this animal model of ARHL.

Protective Effects of Silymarin Against Age-Related Hearing Loss in an Aging Rat Model.

Age-related hearing loss (ARHL) is one of the most common chronic degenerative disorders. Several studies have indicated that supplementation with some antioxidants can slow down the progression of ARHL. Despite several lines of evidence about the potent antioxidant and anti-aging effects of silymarin, its protective effect against ARHL has not evaluated yet. The aim of the current study was to investigate the effects of silymarin in prevention of ARHL in a d-Galactose-induced aging rat model for the first time. 45 male wistar rats aged 3-month old were divided into 5 groups: group 1, 2 and 3 received 500mg/kg/day d-Gal plus 100, 200 and 300mg/kg/day silymarin respectively for 8weeks, placebo group received 500mg/kg/day d-Gal plus propylene glycol as placebo, and control group received normal saline during this period of time. Auditory brainstem responses were measured at several frequencies (4, 6, 8, 12 and 16kHz) before and after the intervention. Placebo group and group 3 showed significant ABR threshold increase across frequencies of 4, 6, 16kHz compared with the other groups (P < 0.05). However, rats treated with silymarin 100 and 200 mg/kg/day plus d-Gal did not show any significant ABR threshold shifts. Similarly, ABR amplitude of P2 at 4, 8kHz and P1, P4 at 4kHz in the placebo group and group 3 were decreased significantly compared with other groups (P < 0.05). However, no significant differences are found in ABR absolute and inter-peak latencies between groups (P > 0.05). The findings indicates that silymarin with doses of 100 and 200mg/kg/day has protective effect against ARHL and it can be supplemented into the diet of older people to slow down the progression of age-related hearing loss.

The Role of Insulin-Like Growth Factor 1 in the Progression of Age-Related Hearing Loss.

Aging is associated with impairment of sensorial functions and with the onset of neurodegenerative diseases. As pari passu circulating insulin-like growth factor 1 (IGF-1) bioavailability progressively decreases, we see a direct correlation with sensory impairment and cognitive performance in older humans. Age-related sensory loss is typically caused by the irreversible death of highly differentiated neurons and sensory receptor cells. Among sensory deficits, age-related hearing loss (ARHL), also named presbycusis, affects one third of the population over 65 years of age and is a major factor in the progression of cognitive problems in the elderly. The genetic and molecular bases of ARHL are largely unknown and only a few genes related to susceptibility to oxidative stress, excitotoxicity, and cell death have been identified. IGF-1 is known to be a neuroprotective agent that maintains cellular metabolism, activates growth, proliferation and differentiation, and limits cell death. Inborn IGF-1 deficiency leads to profound sensorineural hearing loss both in humans and mice. IGF-1 haploinsufficiency has also been shown to correlate with ARHL. There is not much information available on the effect of IGF-1 deficiency on other human sensory systems, but experimental models show a long-term impact on the retina. A secondary action of IGF-1 is the control of oxidative stress and inflammation, thus helping to resolve damage situations, acute or made chronic by aging. Here we will review the primary actions of IGF-1 in the auditory system and the underlying molecular mechanisms.

Long-term treatment with aldosterone slows the progression of age-related hearing loss

Age-related hearing loss (ARHL), clinically referred to as presbycusis, is one of the three most prevalent chronic medical conditions of our elderly, with the majority of persons over the age of 60 suffering from some degree of ARHL. The progressive loss of auditory sensitivity and perceptual capability results in significant declines in workplace productivity, quality of life, cognition and abilities to communicate effectively. Aldosterone is a mineralocorticoid hormone produced in the adrenal glands and plays a role in the maintenance of key ion pumps, including the Na-K+-Cl co-transporter 1 or NKCC1, which is involved in homeostatic maintenance of the endocochlear potential. Previously we reported that aldosterone (1 μM) increases NKCC1 protein expression in vitro and that this up-regulation of NKCC1 was not dose-dependent (dosing range from 1 nM to 100 μM). In the current study we measured behavioral and electrophysiological hearing function in middle-aged mice following long-term systemic treatment with aldosterone. We also confirmed that blood pressure remained stable during treatment and that NKCC1 protein expression was upregulated. Pre-pulse inhibition of the acoustic startle response was used as a functional measure of hearing, and the auditory brainstem response was used as an objective measure of peripheral sensitivity. Long-term treatment with aldosterone improved both behavioral and physiological measures of hearing (ABR thresholds). These results are the first to demonstrate a protective effect of aldosterone on age-related hearing loss and pave the way for translational drug development, using aldosterone as a key component to prevent or slow down the progression of ARHL.