Development Of Age-related Hearing Loss Research Articles

D-galactose-induced mitochondrial DNA oxidative damage in the auditory cortex of rats

Chronic administration of D-galactose (D-gal) is a useful method for establishing a model of natural aging in the auditory system. Previous studies have demonstrated that NADPH oxidases (NOXs) may be an important source of reactive oxygen species (ROS) in the peripheral auditory system (PAS) and cause an increase in mitochondrial DNA (mtDNA) common deletion (CD) levels in the PAS and central auditory system (CAS) of rats with D-gal-induced aging. However, the source of the ROS in the CAS and the mechanisms of age-related hearing loss (ARHL) have yet to be elucidated. In the present study, male Sprague Dawley rats were administered a daily injection of D-gal (150, 300 and 500 mg/kg, respectively) for eight weeks. All three doses of D-gal caused a significant increase in the expression of NOX2, 8-hydroxy-2-deoxyguanosine, a biomarker of DNA oxidative damage, and uncoupling protein 2, together with a decrease in the mitochondrial total antioxidant capabilities in the auditory cortex, as compared with the control rats (injected daily with the same volume of 0.9% saline for eight weeks). The levels of the mtDNA CD were also increased in the auditory cortex of the D-gal-induced aging rats. These findings suggest that both NOX- and mitochondria-associated ROS generation may contribute to mtDNA oxidative damage in the auditory cortex of the CAS of D-gal-induced aging rats. This study may provide novel insight into the development of ARHL.

Age-related hearing loss patterns in Fischer 344/NHsd rats with cisplatin-induced hearing loss

The current study was undertaken to explore the impact of cisplatin ototoxicity at a young adult age on the development of age-related hearing loss, both in terms of age of onset and severity of the hearing loss. For the study, 21 Fischer 344/NHsd rats were tested. All rats were tested for auditory brainstem responses (ABRs) at age 7 months and then 15 of the rats were exposed to 7 mg/kg cisplatin by intra-peritoneal infusion. The other 6 rats received saline infusions to serve as controls. Seven of the cisplatin rats were euthanized after an ABR test 7 days after cisplatin exposure to assess acute damage. The other 14 rats were tested monthly until age 18 months. Cisplatin caused acute ABR threshold shift at 30 and 40 kHz, but that acute hearing loss led to less age-related hearing loss at those frequencies. Cisplatin exposure led to a primarily additive interaction with age-related hearing loss at 20 kHz, with some exacerbation of hearing loss at age 16–18 months, along with a larger lesion of missing outer hair cells in the corresponding region of the cochlea. ABR P1 amplitude input–output functions were not significantly affected by the cisplatin exposure when controlling for threshold shift. Results indicate that cisplatin ototoxicity and age-related hearing loss interact antagonistically in the cochlear region damaged by cisplatin, and primarily show an additive interaction in the frequencies lower than the focus of the cisplatin damage.

Age-related cochlear cytokine gene expression in the BALB/cJ mouse with systemic versus intratympanic dosing of steroid drugs

Conclusion: Age-related differences in the expression of inflammatory cytokines in the inner ear may contribute to the development of age-related hearing loss (ARHL). Objectives: ARHL is characterized by tissue remodeling, ischemia, ion homeostasis, and inflammation. Steroid therapy is an otoprotective strategy that likely acts by reducing inflammation. We examined age-related changes in cytokine gene expression in the cochlea of the BALB/cJ mouse model of premature ARHL after systemic or intratympanic steroid delivery. Methods: ‘Young' (2.5–3 months) and ‘Old' (5–9 months) mice were treated with dexamethasone or fludrocortisone administered either orally or intratympanically. Cytokine gene expression in cochlear RNA was analyzed using prefabricated cDNA arrays. Old groups were compared to Young groups to identify age-related changes. Results: Down-regulation of a cytokine associated with bone remodeling (SPP1) was observed in the untreated Old group. Numerous genes were up- or down-regulated by more than twofold by steroid treatment, including proinflammatory interleukins (IL-16) and anti-inflammatory cytokines.

Adenosine kinase inhibition in the cochlea delays the onset of age-related hearing loss

This study was undertaken to determine the role of adenosine signalling in the development of age-related hearing loss (ARHL). We and others have shown previously that adenosine signalling via A 1 receptors is involved in cochlear protection from noise-induced cochlear injury. Here we demonstrate that enhanced adenosine signalling in the cochlea provides partial protection from ARHL in C57BL/6J mice. We targeted adenosine kinase (ADK), the key enzyme in adenosine metabolism, using a treatment regime with the selective ADK inhibitor ABT-702 (1.5 mg/kg intraperitoneally twice a week) commencing at the age of three months or six months. This treatment, intended to increase free adenosine levels in the cochlea, was maintained until the age of nine months and hearing thresholds were evaluated monthly using auditory brainstem responses (ABR). At nine months, when C57BL/6J mice normally exhibit significant ARHL, both groups treated with ABT-702 showed lower ABR threshold shifts at 10 and 16 kHz compared to control animals receiving the vehicle solution. The better thresholds of the ABT-702-treated mice at these frequencies were supported by increased survival of hair cells in the apical region of the cochlea. This study provides the first evidence that ARHL can be mitigated by enhancing adenosine signalling in the cochlea.

Hearing Sensitivity in Older Adults: Associations with Cardiovascular Risk Factors in the Health, Aging and Body Composition Study

To examine the association between cardiovascular disease (CVD) and its risk factors and age-associated hearing loss in a cohort of older black and white adults. Cross-sectional cohort study. The Health, Aging, and Body Composition (Health ABC) Study, a community-based cohort study of older adults from Pittsburgh, Pennsylvania, and Memphis, Tennessee. Two thousand forty-nine well-functioning adults (mean age 77.5; 37% black). Pure-tone audiometry measurement and history of clinical CVD were obtained at the fourth annual follow-up visit. Pure-tone averages in decibels reflecting low (250, 500, and 1,000 Hz), middle (500, 1,000, and 2,000 Hz), and high (2,000, 4,000, and 8,000 Hz) frequencies were calculated for each ear. CVD risk factors, aortic pulse-wave velocity (PWV), and ankle-arm index (AAI) were obtained at study baseline. In sex-stratified models, after adjustment for age, race, study site, and occupational noise exposure, risk factors associated with poorer hearing sensitivity in men included high triglyceride levels, high resting heart rate, and history of smoking. In women, poor hearing sensitivity was associated with high body mass index, high resting heart rate, fast PWV, and low AAI. Modifiable risk factors for CVD may play a role in the development of age-related hearing loss.

Dietary Glycemic Load Is a Predictor of Age-Related Hearing Loss in Older Adults ,

Age-related hearing loss is a frequent disability in older adults and nutrition could play a role in the development of this condition. Carbohydrate nutrition [including dietary glycemic index (GI) and load (GL)] may be linked to hearing loss. We aimed to determine the association between carbohydrate nutrition (including mean dietary GI and GL, and the dietary intakes of carbohydrate and sugar), starch, cereal and total fiber, and age-related hearing loss. The Blue Mountains Hearing Study is a population-based survey of age-related hearing loss (1997–1999 to 2002–2004). Hearing loss was measured in 2956 participants (aged ≥50 y) and was defined as the pure-tone average of frequencies 0.5, 1.0, 2.0, and 4.0 kHz > 25 dB hearing level. Dietary data were collected in a semiquantitative FFQ. A purpose-built database based on Australian GI values was used to calculate the mean GI. A higher mean dietary GI was associated with an increased prevalence of any hearing loss, comparing quintiles 1 (lowest) and 5 (highest), [multivariable-adjusted odds ratio = 1.41 (95% CI = 1.01–1.97)]. Participants in the highest quartile of mean dietary GL intake compared with those in the lowest quartile had a 76% greater risk of developing incident hearing loss (P-trend = 0.04). Higher carbohydrate and sugar intakes were associated with incident hearing loss (P-trend = 0.03 and P-trend = 0.05, respectively). In summary, a high-GL diet was a predictor of incident hearing loss, as was higher intake of total carbohydrate. Hence, high postprandial glycemia might be a potential underlying biological mechanism in the development of age-related hearing loss.

Consumption of omega-3 fatty acids and fish and risk of age-related hearing loss

Identification of modifiable risk factors that could prevent or slow the development of age-related hearing loss (presbycusis) would be valuable. Dietary polyunsaturated fatty acid (PUFA) intake may be related to age-related hearing loss. We aimed to determine the association between dietary intakes of omega-3 (n-3) PUFAs and fish and the risk of presbycusis. The Blue Mountains Hearing Study is a population-based survey of age-related hearing loss (1997-1999 to 2002-2004). We collected dietary data by using a semiquantitative food-frequency questionnaire and calculated PUFA and fish intakes. In 2956 participants (aged > or =50 y), we measured presbycusis, which we defined as the pure-tone average of frequencies 0.5, 1.0, 2.0, and 4.0 kHz >25 decibels of hearing loss. There was an inverse association between total n-3 PUFA intake and prevalent hearing loss [odds ratio (OR) per SD increase in energy-adjusted n-3 PUFAs: 0.89; 95% CI: 0.81, 0.99]. There was an inverse association between long-chain n-3 PUFAs and incident hearing loss (OR per SD increase in long-chain n-3 PUFAs: 0.76; 95% CI: 0.60, 0.97). Participants who had > or =2 servings of fish/wk compared with participants who had <1 serving of fish/wk had a significantly reduced risk (42%) of developing presbycusis at follow-up (multivariate-adjusted OR: 0.58; 95% CI: 0.35, 0.95). There was an association between consumption of > or =1 to <2 servings/wk of fish and a reduced risk of a progression of hearing loss (OR: 0.53; 95% CI: 0.32, 0.88). There was an inverse association between higher intakes of long-chain n-3 PUFAs and regular weekly consumption of fish and hearing loss. Dietary intervention with n-3 PUFAs could prevent or delay the development of age-related hearing loss.

Cumulative lead exposure and age-related hearing loss: The VA Normative Aging Study

Although lead has been associated with hearing loss in occupational settings and in children, little epidemiologic research has been conducted on the impact of cumulative lead exposure on age-related hearing loss in the general population. We determined whether bone lead levels, a marker of cumulative lead exposure, are associated with decreased hearing ability in 448 men from the Normative Aging Study, seen between 1962 and 1996 (2264 total observations). Air conduction hearing thresholds were measured at 0.25–8 kHz and pure-tone averages (PTA) (mean of 0.5, 1, 2 and 4 kHz) were computed. Tibia and patella lead levels were measured using K X-ray fluorescence between 1991 and 1996. In cross-sectional analyses, after adjusting for potential confounders including occupational noise, patella lead levels were significantly associated with poorer hearing thresholds at 2, 3, 4, 6 and 8 kHz and PTA. The odds of hearing loss significantly increased with patella lead levels. We also found significant positive associations between tibia lead and the rate change in hearing thresholds at 1, 2, and 8 kHz and PTA in longitudinal analyses. Our results suggest that chronic low-level lead exposure may be an important risk factor for age-related hearing loss and reduction of lead exposure could help prevent or delay development of age-related hearing loss.

The Effects of Smoking and Alcohol Consumption on Age-Related Hearing Loss: The Blue Mountains Hearing Study

We aimed to investigate the temporal association between smoking or alcohol consumption and hearing loss, and to confirm previously published cross-sectional associations. The Blue Mountains Hearing Study is a population-based survey of age-related hearing loss conducted in a defined suburban area, west of Sydney. Hearing loss was measured in 2956 participants (aged 50+ yrs) and was defined as the pure-tone average of frequencies 0.5, 1.0, 2.0, and 4.0 kHz >25 dB HL in the better ear (bilateral hearing loss). Alcohol consumption and smoking status were measured using an interviewer-administered questionnaire. Logistic regression was used to obtain odds ratios (OR) with 95% confidence intervals (95% CI) that compared the chances of having hearing loss in participants who did or did not smoke or consume alcohol, after adjusting for other factors previously reported to be associated with hearing loss. The prevalence of hearing loss at baseline was 33.0% (N = 929) and the 5-year incidence of hearing loss was 17.9% (N = 156). Cross-sectional analysis demonstrated a significant protective association between the moderate consumption of alcohol (>1 but < or =2 drinks/day) and hearing function in older adults (compared with nondrinkers), OR 0.75 (95% CI, 0.57 to 0.98). Current smokers not exposed to occupational noise had a significantly higher likelihood of hearing loss after adjusting for multiple variables, OR 1.63 (95% CI, 1.01 to 2.64). A formal likelihood ratio test demonstrated that the interaction between smoking and noise exposure was not significant (p = 0.23). When the joint effects of alcohol consumption and smoking on hearing were explored, there was a trend for alcohol to have a protective relationship with hearing loss in smokers, but this was not statistically significant. However, the 5-year incidence of hearing loss was not predicted by either smoking or alcohol consumption. This study confirms previously reported associations between alcohol consumption or smoking and prevalent hearing loss, but these were not demonstrated in temporal data. Other risk factors could confer greater vulnerability or cause the initial damage to hearing. Future large population-based studies, exploring the influence of other risk factors on the development of age-related hearing loss are warranted.

Genetics of progressive hearing loss: a link between hearing impairment and dysfunction of mechanosensory hair cells

Genetics of progressive hearing loss: a link between hearing impairment and dysfunction of mechanosensory hair cells

内耳疾患の治療をめざして―基礎研究の最前線―加齢による内耳変性老人性難聴の予防に向けて―

Mitochondrial DNA (mtDNA) mutations/deletions and decline of mitochondrial function are considered to be associated with the development of age-related hearing loss (AHL). First, we examined age-related changes in gene expression profile in the cochlea of DBA/2J mouse. This mouse exhibited mild hearing loss at 2 months of age and became deaf by 8 months. Comprehensive gene expression analysis identified significant expression changes correlated with AHL in over 4000 cochlear genes. When compared to 2 month old mice, approximately 2,200 genes were downregulated and approximately 1,900 genes were upregulated in the cochlea of 8 month old mice. AHL-correlated genes in the cochlea of 8-month-old DBA/2J mice were statistically associated with 15 mitochondrial process categories, suggesting that AHL is associated with profound down-regulation of genes involved in the mitochondrial function in the cochlea of aged DBA/2J mice. Next, we assessed the role of accumulation of mtDNA mutations in the development of AHL using Polg (D257A) knock-in mouse, which exhibited increased spontaneous mtDNA mutation rates during aging and showed accelerated aging. They exhibited moderate hearing loss and degeneration and apoptosis in the cochlea by 9 month of age, while wild-type animals did not. MtDNA mutations were associated with transcriptional alterations consistent with impairment of energy metabolism, induction of apoptosis, and hearing dysfunction in the cochlea of aged mitochondrial mutator mice. Lastly, we examined if 26% calorie restriction (CR) could prevent AHL in C57BL/6 mice. CR mice retained normal hearing and showed no cochlear degeneration by 15 months of age, whereas control mice developed moderate hearing loss and cochlear degeneration due to increased apoptosis at 15 months of age. CR mice also showed a significant reduction in the number of TUNEL-positive cells and cleaved caspase-3-positive cells. Microarray analysis revealed that CR upregulated the expression of genes involved in mitochondrial and hearing function and downregulated that of apoptotic genes. Taken together, these findings suggest that accumulation of mtDNA mutations during aging leads to mitochondrial dysfunction and induces an apoptotic program, thereby causing AHL.

Role of mitochondrial dysfunction and mitochondrial DNA mutations in age-related hearing loss

Mitochondrial DNA (mtDNA) mutations/deletions are considered to be associated with the development of age-related hearing loss (AHL). We assessed the role of accumulation of mtDNA mutations in the development of AHL using Polg D257A knock-in mouse, which exhibited increased spontaneous mtDNA mutation rates during aging and showed accelerated aging primarily due to increased apoptosis. They exhibited moderate hearing loss and degeneration of the hair cells, spiral ganglion cells and stria vascularis by 9 month of age, while wild-type animals did not. We next examined if mitochondrial damage induced by systemic application of germanium dioxide caused progressive hearing loss and cochlear damage. Guinea pigs and mice given germanium dioxide exhibited degeneration of the muscles and kidney and developed hearing loss due to degeneration of cochlear tissues, including the stria vascularis. Calorie restriction, which causes a metabolic shift toward increased energy metabolism in some organs, has been shown to attenuate AHL and age-related cochlear degeneration and to lower quantity of mtDNA deletions in the cochlea of mammals. Together these findings indicate that decreased energy metabolism due to accumulation of mtDNA mutations/deletions and decline of respiratory chain function play an important role in the manifestation of AHL.