Age-Related Hearing Loss and Its Cellular and Molecular Bases (original) (raw)
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...
Primary Neural Degeneration in the Human Cochlea: Evidence for Hidden Hearing Loss in the Aging Ear
The noise-induced and age-related loss of synaptic connections between auditory-nerve fibers and cochlear hair cells is well-established from histopathology in several mammalian species; however, its prevalence in humans, as inferred from electrophysiological measures, remains controversial. Here we look for cochlear neuropathy in a temporal-bone study of ''normal-aging" humans, using autopsy material from 20 subjects aged 0-89 yrs, with no history of otologic disease. Cochleas were immunostained to allow accurate quantification of surviving hair cells in the organ Corti and peripheral axons of auditory-nerve fibers. Mean loss of outer hair cells was 30-40% throughout the audiometric frequency range (0.25-8.0 kHz) in subjects over 60 yrs, with even greater losses at both apical (low-frequency) and basal (high-frequency) ends. In contrast, mean inner hair cell loss across audiometric frequencies was rarely >15%, at any age. Neural loss greatly exceeded inner hair cell loss, with 7/11 subjects over 60 yrs showing >60% loss of peripheral axons re the youngest subjects, and with the age-related slope of axonal loss outstripping the age-related loss of inner hair cells by almost 3:1. The results suggest that a large number of auditory neurons in the aging ear are disconnected from their hair cell targets. This primary neural degeneration would not affect the audiogram, but likely contributes to age-related hearing impairment, especially in noisy environments. Thus, therapies designed to regrow peripheral axons could provide clinically meaningful improvement in the aged ear. Ó 2018 The Author(s). Published by Elsevier Ltd on behalf of IBRO. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Human Cochlear Histopathology Reflects Clinical Signatures of Primary Neural Degeneration OPEN
Auditory neuropathy is a significant and understudied cause of human hearing loss, diagnosed in patients who demonstrate abnormal function of the cochlear nerve despite typical function of sensory cells. Because the human inner ear cannot be visualized during life, histopathological analysis of autopsy specimens is critical to understanding the cellular mechanisms underlying this pathology. Here we present statistical models of severe primary neuronal degeneration and its relationship to pure tone audiometric thresholds and word recognition scores in comparison to age-matched control patients, spanning every decade of life. Analysis of 30 ears from 23 patients shows that severe neuronal loss correlates with elevated audiometric thresholds and poor word recognition. For each ten percent increase in total neuronal loss, average thresholds across patients at each audiometric test frequency increase by 6.0 dB hearing level (HL). As neuronal loss increases, threshold elevation proceeds more rapidly in low audiometric test frequencies than in high frequencies. Pure tone average closely agrees with word recognition scores in the case of severe neural pathology. Histopathologic study of the human inner ear continues to emphasize the need for non-or minimally invasive clinical tools capable of establishing cellular-level diagnoses. In individuals with normal hearing, bipolar neurons in the cochlear branch of the eighth cranial nerve project to sensory hair cells in the organ of Corti, relaying precisely timed signals from the spiral-shaped cochlea up the ascending auditory pathway to the brainstem. Damage to the auditory nerve (AN), via demyelination or loss of synapses, axons, or neuronal cell bodies in the spiral ganglion, can result in imprecise temporal coding and a disruption in firing synchrony, yielding a faulty representation of the input signal 1, 2. In 1996, Arnold Starr and colleagues coined the term " auditory neuropathy " as a means of classifying patients who demonstrated aberrant responses to assessments of AN function despite normal responses to assessments of sensory cell function 3. In Starr's patients, (1) the auditory brainstem response (ABR), an electrophysiological measurement consisting of several peaks, the first of which reflects the summed activity of the AN, was absent or severely distorted; (2) auditory brainstem reflexes, such as the stapedius muscle reflex, were absent; and (3) speech intelligibility scores were disproportionately poorer than expected based on audiometric threshold measurements , though (4) typical measures of outer hair cell (OHC) function, such as otoacoustic emissions and coch-lear microphonic potentials, remained within normal limits 3. These criteria remain the diagnostic hallmarks of auditory neuropathy, though further evaluation via electrocochleography and advanced tests of neural function can refine a diagnosis 4. Recent studies suggest that auditory neuropathy is a more prevalent form of hearing loss than initially assumed. Among preterm infants, 1 in every 423 graduates of the newborn intensive care unit meets Starr's criteria for auditory neuropathy 5 , and among healthy infants, routine screening identifies AN dysfunction in 1 in every 7000 2. This phenotype has been documented to accompany an array of medical conditions, ranging from developmental dystrophies and genetic mutations 1, 6 to acquired neuropathies, such as those induced by neo-plasm, infection, exposure to noise or drugs, or the deleterious effects of age 4, 7, 8 .
Cellular correlates of age-related endocochlear potential reduction in a mouse model
Hearing Research, 2006
Age-related degeneration of cochlear stria vascularis and resulting reduction in the endocochlear potential (EP) are the hallmark features of strial presbycusis, one of the major forms of presbycusis, or age-related hearing loss (ARHL) (Schuknecht, H.F., 1964. Further observations on the pathology of presbycusis. Archives of Otolaryngology 80, 369-382; Schuknecht, H.F., 1993. Pathology of the Ear. Lea and Febiger, Philadelphia; Schuknecht, H.F., Gacek, M.R., 1993. Cochlear pathology in presbycusis. Annals of Otology, Rhinology and Laryngology 102, 1-16). It is unclear whether there are multiple forms of strial ARHL having different sequences of degenerative events and different risk factors. Human temporal bone studies suggest that the initial pathology usually affects strial marginal cells, then spreads to other strial cell types. While inheritance studies support a moderate genetic influence, no contributing genes have been identified. Establishment of mouse models of strial ARHL may promote the identification of underlying genes and gene/environment interactions. We have found that BALB/cJ mice show significant EP reduction by 19 months of age. The reduction only occurs in a subset of animals. To identify key anatomical correlates of the EP reduction, we compared several cochlear lateral wall metrics in BALBs with those in C57BL/6J (B6) mice, which show little EP reduction for ages up to 26 months. Among the measures obtained, marginal cell density and spiral ligament thickness were the best predictors of both the EP decline in BALBs, and EP stability in B6. Our results indicate that the sequence of strial degeneration in BALBs is like that suggested for humans. Additional strain comparisons we have performed suggest that genes governing strial melanin production do not play a role.
Annals of the New York Academy of Sciences, 2009
Loss of sensory function in the aged has serious consequences for economic productivity, quality of life, and healthcare costs in the billions each year. Understanding the neural and molecular bases will pave the way for biomedical interventions to prevent, slow, or reverse these conditions. This chapter summarizes new information regarding age changes in the auditory system involving both the ear (peripheral) and brain (central). A goal is to provide findings that have implications for understanding some common biological underpinnings that affect sensory systems, providing a basis for eventual interventions to improve overall sensory functioning, including the chemical senses.
Experimental Gerontology, 2007
Pathologies of senescence, in particular those of neurosensory organs represent an important health problem. The improvement of the life expectation entails the fast increase of the frequency of the age-related hearing loss (ARHL) in the population. There are numerous factors that contribute to this process, which include altered vascular characteristics, hypoxia/ischemia, genetic mutations and production of reactive oxygen species. We were interested in understanding the mechanisms involved in the cochlear degeneration in a mouse model of ARHL, the cd/1 mice. Since in human, hypoxia/ischemia is an important pathogenetic factor for inner ear disease, the regulation of HIF-1 activity in the cochlea, the presence of radical oxygen species in the cochlea and its subsequent disturbances of cellular signaling cascades were investigated. In this study, we explored auditory function of cd/1 mice at the age of 4, 12 and 24 weeks and correlated it with the presence of oxidative damage in the cochlea, and cochlear HIF-1 responsive target genes regulation, involved in pathways promoting inflammation such as tumor necrosis factor (TNF-a), or cell death with the p53 protein, Bax protein and surviving factors with insulin-like growth factor-1 (IGF-1).