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      Pathology and mechanisms of cochlear aging

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          Abstract

          Presbycusis, or age‐related hearing loss (ARHL), occurs in most mammals with variations in the age of onset, rate of decline, and magnitude of degeneration in the central nervous system and inner ear. The affected cochlear structures include the stria vascularis and its vasculature, spiral ligament, sensory hair cells and auditory neurons. Dysfunction of the stria vascularis results in a reduced endocochlear potential. Without this potential, the cochlear amplification provided by the electro‐motility of the outer hair cells is insufficient, and a high‐frequency hearing‐loss results. Degeneration of the sensory cells, especially the outer hair cells also leads to hearing loss due to lack of amplification. Neuronal degeneration, another hallmark of ARHL, most likely underlies difficulties with speech discrimination, especially in noisy environments. Noise exposure is a major cause of ARHL. It is well‐known to cause sensory cell degeneration, especially the outer hair cells at the high frequency end of the cochlea. Even loud, but not uncomfortable, sound levels can lead to synaptopathy and ultimately neuronal degeneration. Even in the absence of a noisy environment, aged cells degenerate. This pathology most likely results from damage to mitochondria and contributes to degenerative changes in the stria vascularis, hair cells, and neurons. The genetic underpinnings of ARHL are still unknown and most likely involve various combinations of genes. At present, the only effective strategy for reducing ARHL is prevention of noise exposure. If future strategies can improve mitochondrial activity and reduce oxidative damage in old age, these should also bring relief.

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          The role of mitochondria in aging.

          Over the last decade, accumulating evidence has suggested a causative link between mitochondrial dysfunction and major phenotypes associated with aging. Somatic mitochondrial DNA (mtDNA) mutations and respiratory chain dysfunction accompany normal aging, but the first direct experimental evidence that increased mtDNA mutation levels contribute to progeroid phenotypes came from the mtDNA mutator mouse. Recent evidence suggests that increases in aging-associated mtDNA mutations are not caused by damage accumulation, but rather are due to clonal expansion of mtDNA replication errors that occur during development. Here we discuss the caveats of the traditional mitochondrial free radical theory of aging and highlight other possible mechanisms, including insulin/IGF-1 signaling (IIS) and the target of rapamycin pathways, that underlie the central role of mitochondria in the aging process.
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            Tinnitus with a normal audiogram: physiological evidence for hidden hearing loss and computational model.

            Ever since Pliny the Elder coined the term tinnitus, the perception of sound in the absence of an external sound source has remained enigmatic. Traditional theories assume that tinnitus is triggered by cochlear damage, but many tinnitus patients present with a normal audiogram, i.e., with no direct signs of cochlear damage. Here, we report that in human subjects with tinnitus and a normal audiogram, auditory brainstem responses show a significantly reduced amplitude of the wave I potential (generated by primary auditory nerve fibers) but normal amplitudes of the more centrally generated wave V. This provides direct physiological evidence of "hidden hearing loss" that manifests as reduced neural output from the cochlea, and consequent renormalization of neuronal response magnitude within the brainstem. Employing an established computational model, we demonstrate how tinnitus could arise from a homeostatic response of neurons in the central auditory system to reduced auditory nerve input in the absence of elevated hearing thresholds.
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              Age-related cochlear synaptopathy: an early-onset contributor to auditory functional decline.

              Aging listeners experience greater difficulty understanding speech in adverse listening conditions and exhibit degraded temporal resolution, even when audiometric thresholds are normal. When threshold evidence for peripheral involvement is lacking, central and cognitive factors are often cited as underlying performance declines. However, previous work has uncovered widespread loss of cochlear afferent synapses and progressive cochlear nerve degeneration in noise-exposed ears with recovered thresholds and no hair cell loss (Kujawa and Liberman 2009). Here, we characterize age-related cochlear synaptic and neural degeneration in CBA/CaJ mice never exposed to high-level noise. Cochlear hair cell and neuronal function was assessed via distortion product otoacoustic emissions and auditory brainstem responses, respectively. Immunostained cochlear whole mounts and plastic-embedded sections were studied by confocal and conventional light microscopy to quantify hair cells, cochlear neurons, and synaptic structures, i.e., presynaptic ribbons and postsynaptic glutamate receptors. Cochlear synaptic loss progresses from youth (4 weeks) to old age (144 weeks) and is seen throughout the cochlea long before age-related changes in thresholds or hair cell counts. Cochlear nerve loss parallels the synaptic loss, after a delay of several months. Key functional clues to the synaptopathy are available in the neural response; these can be accessed noninvasively, enhancing the possibilities for translation to human clinical characterization.
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                Author and article information

                Contributors
                ekeithley@ucsd.edu
                Journal
                J Neurosci Res
                J. Neurosci. Res
                10.1002/(ISSN)1097-4547
                JNR
                Journal of Neuroscience Research
                John Wiley and Sons Inc. (Hoboken )
                0360-4012
                1097-4547
                07 May 2019
                September 2020
                : 98
                : 9 , Age‐related hearing loss ( doiID: 10.1002/jnr.v98.9 )
                : 1674-1684
                Affiliations
                [ 1 ] Division of Otolaryngology ‐ Head and Neck Surgery University of California San Diego California
                Author notes
                [*] [* ] Correspondence

                Elizabeth M. Keithley, Division of Otolaryngology ‐ Head and Neck Surgery, UCSD 0666, 9500 Gilman Dr., La Jolla, San Diego, CA 92093‐0666.

                Email: ekeithley@ 123456ucsd.edu

                Author information
                https://orcid.org/0000-0001-7710-5052
                Article
                JNR24439
                10.1002/jnr.24439
                7496655
                31066107
                814a0f61-5540-47ec-bf07-f3a4abe3c96c
                © 2019 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 28 January 2019
                : 22 March 2019
                : 23 April 2019
                Page count
                Figures: 2, Tables: 0, Pages: 11, Words: 30682
                Categories
                Minireview
                Minireviews
                Custom metadata
                2.0
                September 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.0 mode:remove_FC converted:11.09.2020

                Neurosciences
                acoustic trauma,cochlear amplifier,cochlear hair cells,spiral ganglion,stria vascularis

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