Age-Related Hearing Loss and Its Cellular and Molecular Bases (original) (raw)
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Central Asian Scientific Press (CAS-Press), 2022
• ARHL is characterized by increasing age and hearing loss from low to high frequencies. • Factors involved in ARHL are divided into two genetic and nongenetic categories. • Inflammation, apoptosis, and oxidative stress are three main mechanisms of ARHL. Age-related hearing loss (ARHL) is a type of bilateral hearing loss that progresses from low frequencies to high frequencies with age. This disorder is classified as a multifactorial disease. Factors involved in ARHL pathology are divided into two categories of genetic and non-genetic factors. The genes involved in this disorder include three categories of genes involved in cochlear structure and function, genes correlated with oxidative stress, and mitochondrial-dependent genes. Oxidative stress, apoptosis, and inflammation are the three main causes of ARHL. Damage to hair cells induces intrinsic and extrinsic apoptosis and can therefore accelerate ARHL. Some process in cells leads to the production of high amounts of reactive oxygen species including hydrogen peroxide (H 2 O 2), anion superoxide (O 2-), and hydroxyl radical (OH). Reactive oxygen species or ROS can generally have several sources including nitric oxide synthase, NADPH oxidase, microsomal, mitochondrial, and proxisomal pathways. In typical conditions, ROS is produced and neutralized by antioxidant enzymes such as superoxide dismutase, catalase, and glutathione, balancing cell homeostasis. Though, the process of aging, drug treatment, and some other factors upset this homeostasis, and this causes oxidative stress and induction of ARHL in the cells of the auditory system. The aim of this study was to describe the cellular and molecular mechanisms involved in ARHL with a focus on oxidative stress.
Molecular mechanisms of age-related hearing loss
Ageing research reviews, 2002
Age-related hearing loss, known as presbyacusis, is characterized by the progressive deterioration of auditory sensitivity associated with aging and is the most common cause of adult auditory deficiency in the United States. Presbyacusis is defined as a progressive, bilateral, high-frequency hearing loss that is manifested on audiometric assessment by a moderately sloping pure tone audiogram. This condition affects approximately 23% of the population between 65 and 75 years of age and 40% of the population older than 75 years of age. In 1980, it was estimated that 11% of the population was 76 years or older and this number is expected to nearly double by the year 2030 [Gates et al., 1986, Otolaryngol. Head Neck Surg. 100, 262]. When coupled with the fact that the population over 65 years of age is experiencing the most rapid progression of hearing loss, the potential socioeconomic ramifications are staggering. Interestingly, presbyacusis varies in its frequency across differing societies. This discrepancy has been attributed to many factors such as genetics, diet, socioeconomic factors, and environmental variables [
Frontiers in Genetics
Age-related hearing loss (ARHL) is the most common sensory impairment in the elderly affecting millions of people worldwide. To shed light on the genetics of ARHL, a large cohort of 464 Italian patients has been deeply characterized at clinical and molecular level. In particular, 46 candidate genes, selected on the basis of genomewide association studies (GWAS), animal models and literature updates, were analyzed by targeted re-sequencing. After filtering and prioritization steps, SLC9A3R1 has been identified as a strong candidate and then validated by "in vitro" and "in vivo" studies. Briefly, a rare (MAF: 2.886e-5) missense variant c.539G > A, p.(R180Q) was detected in two unrelated male patients affected by ARHL characterized by a severe to profound high-frequency hearing loss. The variant, predicted as damaging, was not present in healthy matched controls. Protein modeling confirmed the pathogenic effect of p.(R180Q) variant on protein's structure leading to a change in the total number of hydrogen bonds. In situ hybridization showed slc9a3r1 expression in zebrafish inner ear. A zebrafish knock-in model, generated by CRISPR-Cas9 technology, revealed a reduced auditory response at all frequencies in slc9a3r1 R180Q/R180Q mutants compared to slc9a3r1 +/+ and slc9a3r1 +/R180Q animals. Moreover, a significant reduction (5.8%) in the total volume of the saccular otolith (which is responsible for sound detection) was observed in slc9a3r1 R180Q/R180Q compared to slc9a3r1 +/+ (P = 0.0014), while the utricular otolith, necessary for balance, was not affected in agreement with the human phenotype. Overall, these data strongly support the role of SLC9A3R1 gene in the pathogenesis of ARHL opening new perspectives in terms of diagnosis, prevention and treatment.
Cellular correlates of progressive hearing loss in 129S6/SvEv mice
The Journal of Comparative Neurology, 2004
Several strains of mice hear well initially but show progressive sensorineural hearing loss. Affected cochlear cell types include all those known to be affected in human age-related hearing loss (ARHL), or presbycusis. Thus these mice have been offered as models of human ARHL. At present, however, few mouse ARHL models are sufficiently well described to serve as the basis for specific hypotheses about human ARHL. We examined 1-month-old and 15-month-old 129S6/SvEv (129S6) mice and compared them with BALB/cJ and CBA/J mice. Age-related elevation of compound action potential thresholds was interpreted in the light of endocochlear potentials and changes in hair cells, afferent neurons, fibrocytes in spiral limbus and ligament, and supporting cells within the organ of Corti. Aging in 129S6 mice was associated with high-frequency hearing loss. Four components of age-related cochlear degeneration emerged from quantitative analyses, including 1) basal loss of outer hair cells; 2) basal loss of type IV fibrocytes in the spiral ligament; 3) apical loss of fibrocytes in spiral limbus, and 4) anomalies of supporting cells in the cochlear base. Although neuronal loss was not consistently found, two mice showed loss of afferent dendrites and cell bodies in the cochlear apex without inner hair cell loss. Despite multifaceted degeneration, hearing loss in 129S6 mice appears to be best explained by degenerative changes in outer hair cells and in the organ of Corti, conforming to human sensory ARHL. Age-related changes in the apical spiral limbus may promote pathology of the medial organ of Corti and eventual loss of afferent neurons, with possible implications for human neural ARHL.
Age-related hearing loss: Is it a preventable condition?
Hearing Research, 2010
Numerous techniques have been tested to attempt to prevent the onset or progression of age-related hearing loss (ARHL): raising the animals in an augmented acoustic environment (used successfully in mouse and rat models), enhancing the antioxidant defenses with exogenous antioxidant treatments (used with mixed results in mouse and rat models), raising the animals with a calorie restricted diet (used successfully in mouse and rat models), restoring lost endocochlear potential voltage with exogenous electrical stimulation (used successfully in the Mongolian gerbil model), and hypothetical enhancement of outer hair cell electromotility with salicylate therapy. Studies of human ARHL have revealed a set of unique hearing loss configurations with unique underlying pathologies. Animal research has developed models for the different forms of age-related peripheral pathology. Using the animal models, different techniques for prevention of ARHL have been developed and tested. The current review discusses ARHL patterns in humans and animal models, followed by discussions of the different prevention techniques.
Biological Bases of Age-Related Hearing Loss
2010
The goal of the present chapter is to present some novel findings and insights related to biologicallybased changes in the auditory inner ear and brain that might underlie some of the performance limitations of contemporary hearing aids designed for elderly clients. Specifically, at the cochlear level, age-related cell loss occurs for both sensory hair cells, supporting cells and auditory nerve fibers, resulting in a loss of auditory sensitivity. Peripheral cell loss can induce plastic changes in the parts of the brain used for hearing, due to declining inputs from the ear with age. Aging can also directly affect the brain, resulting in declines in the efferent feedback system from the brainstem to the cochlear hair cells, which can even start in middle age in humans and lab animals. Aging can also result in auditory temporal processing deficits at the level of the brainstem, which are related to suprathreshold speech comprehension deficits in aged listeners. There is also new evide...
Aging, 2016
Age-related hearing loss (ARHL) -presbycusis - is the most prevalent neurodegenerative disease and number one communication disorder of our aged population; and affects hundreds of millions of people worldwide. Its prevalence is close to that of cardiovascular disease and arthritis, and can be a precursor to dementia. The auditory perceptual dysfunction is well understood, but knowledge of the biological bases of ARHL is still somewhat lacking. Surprisingly, there are no FDA-approved drugs for treatment. Based on our previous studies of human subjects, where we discovered relations between serum aldosterone levels and the severity of ARHL, we treated middle age mice with aldosterone, which normally declines with age in all mammals. We found that hearing thresholds and suprathreshold responses significantly improved in the aldosterone-treated mice compared to the non-treatment group. In terms of cellular and molecular mechanisms underlying this therapeutic effect, additional experime...
Scientific Reports
Presbycusis or age-related hearing loss (ARHL) is the most common sensory deficit in the human population. A substantial component of the etiology stems from pathological changes in sensory and non-sensory cells in the cochlea. Using a non-obese diabetic (noD) mouse model, we have characterized changes in both hair cells and spiral ganglion neurons that may be relevant for early signs of age-related hearing loss (ARHL). We demonstrate that hair cell loss is preceded by, or in parallel with altered primary auditory neuron functions, and latent neurite retraction at the hair cell-auditory neuron synapse. The results were observed first in afferent inner hair cell synapse of type I neurites, followed by type ii neuronal cell-body degeneration. Reduced membrane excitability and loss of postsynaptic densities were some of the inaugural events before any outward manifestation of hair bundle disarray and hair cell loss. We have identified profound alterations in type I neuronal membrane properties, including a reduction in membrane input resistance, prolonged action potential latency, and a decrease in membrane excitability. the resting membrane potential of aging type i neurons in the noD, ARHL model, was significantly hyperpolarized, and analyses of the underlying membrane conductance showed a significant increase in K + currents. We propose that attempts to alleviate some forms of ARHL should include early targeted primary latent neural degeneration for effective positive outcomes. Age-related hearing loss (ARHL) is the prevalent form of sensory deficit worldwide. The disease remains less understood, owing to the apparent late-onset phenotype and confounding factors, such as ototoxic drugs, noise trauma, and genetic predispositions 1-3. Although the frequency ranges in which mice (~1-90 kHz) and humans (~0.60-20 kHz) hear are distinct, similarities between the anatomy and physiology of the cochlea make the mouse a compelling animal model to study the mechanisms for ARHL in humans 1,4-6. Previous studies of mutations linked to deafness in mice have provided important insights into human congenital deafness-associated genes 7-10. Additionally, several inbred mouse strains exhibit progressive non-syndromic hearing loss that is expressed phenotypically at advanced ages, which mirrors ARHL in humans 11,12. However, some of the missing mechanistic information for ARHL models is the detailed characterization of early events that occur in the cochlea. Previous studies have described several ARHL mouse models. The ahl locus on chromosome 10 is the hub for the cadherin 23 (Cdh23) gene 12,13 , identified as a major contributor to ARHL in several mouse strains 14. Mutations of two alleles, Cdh23 ahl and ahl2, are responsible for hair cell (HC) loss and an unidentified inner ear pathology, respectively 14-16. These studies have provided a detailed characterization of the pathology of the cochlea in ARHL, but the functional neural mechanisms remain largely unknown. One of the prevailing views is that
Progress and prospects in human genetic research into age-related hearing impairment
BioMed research international, 2014
Age-related hearing impairment (ARHI) is a complex, multifactorial disorder that is attributable to confounding intrinsic and extrinsic factors. The degree of impairment shows substantial variation between individuals, as is also observed in the senescence of other functions. This individual variation would seem to refute the stereotypical view that hearing deterioration with age is inevitable and may indicate that there is ample scope for preventive intervention. Genetic predisposition could account for a sizable proportion of interindividual variation. Over the past decade or so, tremendous progress has been made through research into the genetics of various forms of hearing impairment, including ARHI and our knowledge of the complex mechanisms of auditory function has increased substantially. Here, we give an overview of recent investigations aimed at identifying the genetic risk factors involved in ARHI and of what we currently know about its pathophysiology. This review is divi...