Prevention Of Age-related Hearing Loss Research Articles

Genome-wide association study for age-related hearing loss in CFW mice.

Age-related hearing impairment is the most common cause of hearing loss and is one of the most prevalent conditions affecting the elderly globally. It is influenced by a combination of environmental and genetic factors. The mouse and human inner ears are functionally and genetically homologous. Investigating the genetic basis of age-related hearing loss (ARHL) in an outbred mouse model may lead to a better understanding of the molecular mechanisms of this condition. We used Carworth Farms White (CFW) outbred mice, because they are genetically diverse and exhibit variation in the onset and severity of ARHL. The goal of this study was to identify genetic loci involved in regulating ARHL. Hearing at a range of frequencies was measured using Auditory Brainstem Response (ABR) thresholds in 946 male and female CFW mice at the age of 1, 6, and 10 months. We obtained genotypes at 4.18 million single nucleotide polymorphisms (SNP) using low-coverage (mean coverage 0.27x) whole-genome sequencing followed by imputation using STITCH. To determine the accuracy of the genotypes we sequenced 8 samples at >30x coverage and used calls from those samples to estimate the discordance rate, which was 0.45%. We performed genetic analysis for the ABR thresholds for each frequency at each age, and for the time of onset of deafness for each frequency. The SNP heritability ranged from 0 to 42% for different traits. Genome-wide association analysis identified several regions associated with ARHL that contained potential candidate genes, including Dnah11, Rapgef5, Cpne4, Prkag2, and Nek11. We confirmed, using functional study, that Prkag2 deficiency causes age-related hearing loss at high frequency in mice; this makes Prkag2 a candidate gene for further studies. This work helps to identify genetic risk factors for ARHL and to define novel therapeutic targets for the treatment and prevention of ARHL.

Repair of noise-induced damage to stereocilia F-actin cores is facilitated by XIRP2 and its novel mechanosensor domain.

Prolonged exposure to loud noise has been shown to affect inner ear sensory hair cells in a variety of deleterious manners, including damaging the stereocilia core. The damaged sites can be visualized as 'gaps' in phalloidin staining of F-actin, and the enrichment of monomeric actin at these sites, along with an actin nucleator and crosslinker, suggests that localized remodeling occurs to repair the broken filaments. Herein, we show that gaps in mouse auditory hair cells are largely repaired within 1 week of traumatic noise exposure through the incorporation of newly synthesized actin. We provide evidence that Xin actin binding repeat containing 2 (XIRP2) is required for the repair process and facilitates the enrichment of monomeric γ-actin at gaps. Recruitment of XIRP2 to stereocilia gaps and stress fiber strain sites in fibroblasts is force-dependent, mediated by a novel mechanosensor domain located in the C-terminus of XIRP2. Our study describes a novel process by which hair cells can recover from sublethal hair bundle damage and which may contribute to recovery from temporary hearing threshold shifts and the prevention of age-related hearing loss.

Corticofugal and Brainstem Functions Associated With Medial Olivocochlear Cholinergic Transmission.

Cholinergic transmission is essential for survival and reproduction, as it is involved in several physiological responses. In the auditory system, both ascending and descending auditory pathways are modulated by cholinergic transmission, affecting the perception of sounds. The auditory efferent system is a neuronal network comprised of several feedback loops, including corticofugal and brainstem pathways to the cochlear receptor. The auditory efferent system’s -final and mandatory synapses that connect the brain with the cochlear receptor- involve medial olivocochlear neurons and outer hair cells. A unique cholinergic transmission mediates these synapses through α9/α10 nicotinic receptors. To study this receptor, it was generated a strain of mice carrying a null mutation of the Chrna9 gene (α9-KO mice), lacking cholinergic transmission between medial olivocochlear neurons and outer hair cells, providing a unique opportunity to study the role of medial olivocochlear cholinergic transmission in auditory and cognitive functions. In this article, we review behavioral and physiological studies carried out to research auditory efferent function in the context of audition, cognition, and hearing impairments. Auditory studies have shown that hearing thresholds in the α9-KO mice are normal, while more complex auditory functions, such as frequency selectivity and sound localization, are altered. The corticofugal pathways have been studied in α9-KO mice using behavioral tasks, evidencing a reduced capacity to suppress auditory distractors during visual selective attention. Finally, we discuss the evolutionary role of the auditory efferent system detecting vocalizations in noise and its role in auditory disorders, such as the prevention of age-related hearing loss.

Efficiency of resveratrol in the prevention and treatment of age-related hearing loss.

Age-related hearing loss (ARHL) is a major public health concern, which is characterized by gradual, progressive sensorineural hearing loss and deterioration of sound localization, with no effective treatment available to date. The aim of the present study was to evaluate the efficacy of resveratrol to prevent and treat ARHL. For this purpose, 32 male C57BL/6 mice were assigned to four groups: Early treatment, late treatment, control and sham control. The experiment lasted for 15 months. Treatment was started at three months of age in the early treatment group and at sixth months in the late treatment group. The auditory brainstem response test was performed once every three months. At the end of the study period, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, NF-κB, Bcl-2, Bcl-xL, Bax, Bcl-2 homologous antagonist/killer (Bak), caspase-3 and caspase-9 levels in the cochlear tissues of the animals were analyzed by reverse transcription-quantitative PCR. Hearing thresholds of the mice in the early treatment group were better than those in the other groups (P<0.001) at the end of the study. However, hearing levels in the late treatment group were not significantly different from those in the control groups (P>0.05), although mean thresholds were lower. The threshold shift in the early treatment group was significantly lower at all frequencies when compared with those in the control groups (P<0.001). The mRNA expression levels of pro-apoptotic genes Bax and Bak were lower (P<0.05), anti-apoptotic genes Bcl-2 and Bcl-xL were higher (P<0.05), NF-κB, COX-2 and iNOS as genes that have a role in inflammation and caspase-3 and caspase-9 as genes with a vital role in apoptosis were lower (P<0.05) in the early treatment group when compared with the late treatment and control groups. These results suggested that resveratrol is effective in the prevention of ARHL, particularly when started prior to the beginning of hearing loss.

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.

Role of melatonin in prevention of age-related hearing loss.

IntroductionAge-related hearing loss (ARHL) is a consequence of aging of the auditory system. The best known mechanism of cell death in ARHL is apoptosis due to increased production of reactive oxygen species. In this context, it is hypothesized that melatonin, owing to its high antioxidant potential and its action in the mitochondria, helps prevent or delay outer hair cell dysfunction (HCD).AimsTo evaluate the effect of melatonin on the prevention of HCD dysfunction in the ARHL process in a susceptible murine C57BL/6J model.MethodC57BL/6J animals were divided into two groups: control (CG) and melatonin (MG). The CG received a saline and ethanol solution and the MG, melatonin (10 mg/kg/day). The solutions were offered daily (50 μl) orally over a 10-month period. Distortion Product Otoacoustic Emissions (DPOAE) measurements were conducted once a month.ResultsThere was a decrease in DPOAE values in both groups over time and a differentiation between them from the 10th month of life onwards. At 10 months, the MG maintained higher DPOAE values than the CG at all frequencies tested.ConclusionThe use of melatonin has otoprotective effects on HCD in the ARHL process in the C57BL/6J model.

Prevention of Age-Related Hearing Loss by Oral Intake of Heat-Killed Bacteria in Mice

Prevention of Age-Related Hearing Loss by Oral Intake of Heat-Killed Bacteria in Mice

Protection and Prevention of Age-Related Hearing Loss.

Presbycusis is a sensorineural hearing loss caused by hearing system aging and degeneration. The clinical manifestations are progressive bilateral symmetrical hearing loss, and the hearing curve is mostly slope-shaped with high-frequency reduction, sometimes flat. The results of the second national sample survey of disabled persons (2006) showed that the total number of hearing and speech disability in China was 27.8 million, accounting for 34% of the total number of disabled people in China. Among them are people over 60years old. There are 20.4541 million people with hearing disabilities. There are 9.49 million senile deaf patients, accounting for 34.1% of the total number of hearing disabilities. As society gradually becomes aging, the incidence of presbycusis is getting higher and higher. The study of its pathogenesis is of great significance for the diagnosis, treatment, and prevention of presbycusis. The rapid progress of molecular biology experimental technology has provided us with a new opportunity to fully understand and reveal the presbycusis. In the near future, early diagnosis of presbycusis-related genes and early prevention or delay of the occurrence and development of presbycusis will become a reality.

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.

Role of antioxidants in prevention of age-related hearing loss: a review of literature.

Age-related hearing loss (ARHL), also known as presbycusis, is one of the most prevalent chronic degenerative conditions. It is characterized by a decline in auditory function. ARHL is caused by the interaction of multiple factors, including cochlear aging, environment, genetic predisposition, and health comorbidities. The primary pathology of ARHL includes the hair cells loss, stria vascularis atrophy, and loss of spiral ganglion neurons as well as the changes in central auditory pathways. The research to date suggests that oxidative stress and mitochondrial DNA deletion (mtDNA) play a major role in pathophysiology of ARHL. Therefore, similar to other otological conditions, several studies have also showed that antioxidants can slow ARHL, but some also indicate that antioxidant therapy is not a magic elixir that will prevent or treat hearing loss associated with aging completely, but why? All availableclinical trials, including animal and human studies, in English language that examined the protective effects of antioxidantsagainst ARHL were reviewed. Materials were obtained by searching ELSEVIER, PubMed, Scopus, Web of knowledge, Google Scholar databases, Clinical trials, and Cochrane database of systematic reviews. Although ARHL has been shown to be slowed by supplementation with antioxidants, particularly in laboratory animals, a few studies have investigated the effect of interventions against ARHL in humans. High-quality clinical trials are needed to investigate if ARHL can be delayed or prevented in humans. However, it seems that targeting several cell-death pathways is better than targeting the only oxidative stress pathway.

SIRT3 Protein Deacetylates Isocitrate Dehydrogenase 2 (IDH2) and Regulates Mitochondrial Redox Status

Mitochondria play a central role in oxidative energy metabolism and age-related diseases such as cancer. Accumulation of spurious oxidative damage can cause cellular dysfunction. Antioxidant pathways that rely on NADPH are needed for the reduction of glutathione and maintenance of proper redox status. The mitochondrial matrix protein isocitrate dehydrogenase 2 (IDH2) is a major source of NADPH. Previously, we demonstrated that the NAD(+)-dependent deacetylase SIRT3 was essential for the prevention of age-related hearing loss in mice fed a calorically restricted diet. Here we provide direct biochemical and biological evidence establishing an exquisite regulatory relationship between IDH2 and SIRT3 under acute and chronic caloric restriction. The regulated site of acetylation was mapped to Lys-413, an evolutionarily invariant residue. Site-specific, genetic incorporation of N(ε)-acetyllysine into position 413 of IDH2 revealed that acetylated IDH2 displays a dramatic 44-fold loss in activity. Deacetylation by SIRT3 fully restored maximum IDH2 activity. The ability of SIRT3 to protect cells from oxidative stress was dependent on IDH2, and the deacetylated mimic, IDH2(K413R) variant was able to protect Sirt3(-/-) mouse embryonic fibroblasts from oxidative stress through increased reduced glutathione levels. Together these results uncover a previously unknown mechanism by which SIRT3 regulates IDH2 under dietary restriction. Recent findings demonstrate that IDH2 activities are a major factor in cancer, and as such, these results implicate SIRT3 as a potential regulator of IDH2-dependent functions in cancer cell metabolism.

Correlation of PDCD5 and apoptosis in hair cells and spiral ganglion neurons of different age of C57BL/6J mice

This study examined the expression pattern of programmed cell death 5 (PDCD5) in cochlear hair cells and spiral ganglion neurons (SGNs) and its association with age-related hearing loss in mice. Sixty C57BL/6J (C57) mice at different ages were divided into four groups (3, 6, 9 or 12 months). PDCD5 expression was detected by using immunohistochemistry, real-time PCR and Western blot. Morphological change of the cochleae was also evaluated by using immunoassay. The results showed that the expression of PDCD5 had a gradual increase with ageing in both protein and RNA levels in C57 mice, as well as gradually increased apoptosis of cochlear hair cells and SGNs. In addition, we also found that caspase-3 activity was enhanced and its expression was enhanced with ageing. It is implied that overexpression of PDCD5 causes the increase in caspase-3 activity and the subsequent increase of apoptosis in cochlear hair cells and SGNs, and thereby plays a role in the pathogenesis of presbycusis. Thus, PDCD5 may be a new target site for the treatment and prevention of age-related hearing loss.

Prevention of age-related hearing loss under caloric restriction

Prevention of age-related hearing loss under caloric restriction

Sirt3 Mediates Reduction of Oxidative Damage and Prevention of Age-Related Hearing Loss under Caloric Restriction

Caloric restriction (CR) extends the life span and health span of a variety of species and slows the progression of age-related hearing loss (AHL), a common age-related disorder associated with oxidative stress. Here, we report that CR reduces oxidative DNA damage in multiple tissues and prevents AHL in wild-type mice but fails to modify these phenotypes in mice lacking the mitochondrial deacetylase Sirt3, a member of the sirtuin family. In response to CR, Sirt3 directly deacetylates and activates mitochondrial isocitrate dehydrogenase 2 (Idh2), leading to increased NADPH levels and an increased ratio of reduced-to-oxidized glutathione in mitochondria. In cultured cells, overexpression of Sirt3 and/or Idh2 increases NADPH levels and protects from oxidative stress-induced cell death. Therefore, our findings identify Sirt3 as an essential player in enhancing the mitochondrial glutathione antioxidant defense system during CR and suggest that Sirt3-dependent mitochondrial adaptations may be a central mechanism of aging retardation in mammals.

Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis

Age-related hearing loss (AHL), known as presbycusis, is a universal feature of mammalian aging and is the most common sensory disorder in the elderly population. The molecular mechanisms underlying AHL are unknown, and currently there is no treatment for the disorder. Here we report that C57BL/6J mice with a deletion of the mitochondrial pro-apoptotic gene Bak exhibit reduced age-related apoptotic cell death of spiral ganglion neurons and hair cells in the cochlea, and prevention of AHL. Oxidative stress induces Bak expression in primary cochlear cells, and Bak deficiency prevents apoptotic cell death. Furthermore, a mitochondrially targeted catalase transgene suppresses Bak expression in the cochlea, reduces cochlear cell death, and prevents AHL. Oral supplementation with the mitochondrial antioxidants alpha-lipoic acid and coenzyme Q(10) also suppresses Bak expression in the cochlea, reduces cochlear cell death, and prevents AHL. Thus, induction of a Bak-dependent mitochondrial apoptosis program in response to oxidative stress is a key mechanism of AHL in C57BL/6J mice.

Inner ear pathology and loss of hearing in estrogen receptor-β deficient mice

There are well known differences between males and females in hearing. In the present study, the role of estrogen receptor-beta (ER-beta; listed as ESR2 in the MGI Database) in hearing was investigated by comparing hearing and morphology of the inner ear in ER-beta knock-out mice (ER-beta(-/-)) with that of wild-type (WT) littermates. Hearing was analyzed with auditory brainstem response audiometry at 3 and 12 months. The ER-beta(-/-) mice were deaf at 1 year of age, and the morphological analysis showed absence of hair cells and loss of the whole organ of Corti initiated in the basal turn of the cochlea. Furthermore, in ER-beta(-/-), but not in WT mice, the spiral ganglion was lacking many of its neurons. Immunostaining showed the presence of both ER-alpha (listed as ESR1 in the MGI Database) and ER-beta in the nuclei of some neurons in the inner ear in WT mice, but no ER-beta was found in the ER-beta(-/-) mice as expected. ER-alpha staining was predominant in the nuclei of large neurons and ER-beta in nuclei of small neurons and fibroblasts. These results reveal that both ERs are present in the inner ear at specific localizations suggesting subtype-specific functions. It is concluded that ER-beta is important for the prevention of age-related hearing loss. These findings strengthen the hypothesis that estrogen has a direct effect on hearing functions.

Smoking and drinking habits as risk factors for hearing loss in the elderly: epidemiological study of subjects undergoing routine health checks in Aichi, Japan

In order to determine the risk factors for hearing loss in the elderly, a total of 496 subjects with bilateral hearing loss and 2807 age-matched persons without hearing disturbance were recruited from the participants in an automated multiphasic health screening examination, and their lifestyle and medical data were analysed. Current smokers showed a significantly increased risk of hearing loss compared with non-smokers (odds ratio after adjustment for sex, age, and potential confounders=2.10 (1.53–2.89)), while heavy drinkers did not show an increased risk compared to non-drinkers. Our findings might provide some clues for the primary prevention of age-related hearing loss. Public Health (2001) 115, 192–196.

Smoking and drinking habits as risk factors for hearing loss in the elderly epidemiological study of subjects undergoing routine health checks in Aichi, Japan

In order to determine the risk factors for hearing loss in the elderly, a total of 496 subjects with bilateral hearing loss and 2807 age-matched persons without hearing disturbance were recruited from the participants in an automated multiphasic health screening examination, and their lifestyle and medical data were analysed. Current smokers showed a significantly increased risk of hearing loss compared with non-smokers (odds ratio after adjustment for sex, age, and potential confounders=2.10 (1.53–2.89)), while heavy drinkers did not show an increased risk compared to non-drinkers. Our findings might provide some clues for the primary prevention of age-related hearing loss. Public Health (2001) 115 , 192–196.