ReviewCurrent concepts in age-related hearing loss: Epidemiology and mechanistic pathways
Highlights
► We did comprehensive review of human and animal studies of age-related hearing loss. ► Epidemiologic studies indicated four categories of risk factors. ► Genetic investigation identified several associating genes. ► Animal studies supported the role of oxidative stress and mitochondrial dysfunction. ► We proposed conceptual model of the development of AHL.
Introduction
Age-related hearing loss (AHL), or presbycusis, is a complex degenerative disease and is one of the most prevalent chronic conditions of the aged, affecting tens of millions of people worldwide. AHL is a multifactorial condition, representing the end stage sequela of multiple intrinsic (e.g. genetic predisposition) and extrinsic (e.g. noise exposure) factors acting on the inner ear over a lifetime that cumulatively lead to impairments in cochlear transduction of acoustic signals (Ohlemiller, 2009; Schuknecht, 1955).
Potential sites of pathology include the inner and outer hair cells, the stria vascularis, and afferent spiral ganglion neurons (Schuknecht et al., 1993). The stria vascularis and hair cells are particularly susceptible to injury. The stria vascularis is highly metabolically active and depends on an elaborate cellular machinery to maintain the steady-state endocochlear resting potential. Consequently, injury from multiple different pathways (e.g. age-related cell losses within the stria, oxidative stress from noise exposure, genetic polymorphisms leading to inefficient oxidative pathways or dysfunctional supporting cells, or microvascular disease in the strial vessels) could all affect strial function (Ohlemiller, 2009). The resulting loss of the endocochlear potential would impair the function of the cochlear amplifier and lead to an increase in hearing thresholds (Schmiedt et al., 2002; Schuknecht et al., 1974).
A similar multimodal pathway of injury and dysfunction is also observed in the cochlear hair cells and cochlear nerve. Post-mitotic hair cells are susceptible to accumulated injury over time from a combination of poor cellular repair mechanisms associated with aging, direct mechanical or mitochondrial oxidative injury from noise, and toxicity from aminoglycosides or other ototoxic medications (Liu et al., 2007; Ohlemiller, 2004; Pickles, 2008). Neuronal degeneration of spiral ganglion afferents can also be triggered by cumulative exposures to loud noise leading to glutamate excitotoxicity and loss of the afferent dendrites (Kujawa et al., 2006). Interestingly, such a mechanism of injury may allow for relative preservation of pure tone threshold sensitivity but disproportionate effects on speech perception in noise and speech understanding given the complexity of speech sounds and the need for precise temporal and frequency coding by the spiral ganglion afferents.
The complexity of factors (aging, genetic, epigenetic, environmental, health co-morbidity) and importantly the interaction of the different mechanistic pathways that can cause AHL have greatly complicate our interpretation of basic and clinical research into AHL (Van et al., 2007) and have led to some latent cynicism about the precise value of key factors contributing to AHL (Ohlemiller, 2009). In particular, the same functional consequences of increased hearing thresholds and poor frequency resolution generally occur regardless of etiology of AHL or the cochlear mechanistic pathway (Pickles, 2008). Consequently, for elderly with AHL, the main issue is often the inability to understand words rather than the inability to hear, leading to the refrains of “I can hear you but I can't understand you” or perhaps more commonly, “My hearing is fine. You're just mumbling”. Most importantly, AHL gradually impairs an individual's ability to understand the meaning of everyday language (e.g. “I'll see you Sunday” versus “I’ll see you someday”), in which fine auditory cues encoding semantic meaning are critical for understanding communicative meaning.
In this review, we have chosen to focus on recent works that have improved our understanding of the cellular and molecular mechanisms that could cause age-related degeneration of the cochlea. Particularly, we have emphasized the role of oxidative stress and mitochondrial dysfunction due to accumulation of mitochondrial DNA (mtDNA) mutations/deletions in the development of AHL.
Section snippets
Prevalence of ARHL
Estimating hearing loss prevalence and identifying epidemiologic risk factors can be ascertained from large cohorts where audiometric testing was performed. A sampling of such studies include Beaver Dam (Cruickshanks et al., 2003), Framingham (Gates et al., 1990), Blue Mountains (Gopinath et al., 2009), Baltimore Longitudinal Study of Aging (BLSA) (Brant et al., 1990), and National Health and Nutrition Examination Survey (NHANES) (Agrawal et al., 2008). Reports of hearing loss prevalence across
General pathological and physiological findings
As discussed earlier, AHL is generally classified into three major types based on the relationship between cochlear pathology and hearing levels: sensory (loss of sensory hair cells), neuronal (loss of spiral ganglion neurons), and metabolic (strial atrophy) hearing loss (Schuknecht, 1955). Age-related stria atrophy or degeneration is one of the common features of AHL in both animals and humans (Gates and Mills, 2005; Ohlemiller, 2009; Fetoni et al., 2011). Aged gerbils display loss of stria
Putative mechanisms of AHL
As discussed above by reviewing recent human and animal studies, it is now well established that oxidative stress and mtDNA mutations/deletions play a crucial role in the development of AHL. Substantial evidence has accumulated from animal studies that cumulative effect of oxidative stress could induce damage to macromolecules such as mtDNA in the cochlea and that the resulting accumulation of mtDNA mutations/deletions and decline of mitochondrial function over time progressively induce
Disclosures
Dr. Lin has served as a consultant to Pfizer, Autifony, and Cochlear Corp. Dr. Lin is on the scientific advisory board of Autifony.
Acknowledgements
This work was supported by grants from 1) The University of Tokyo, Global Center of Education and Research for Chemical Biology of the Diseases, 2) Ministry of Education, Culture, Sports, Science & Technology, and 3) Ministry of Health, Labour and Welfare in Japan to T.Y., NIH/NIDCD 1R03DC011840-01, American Federation for Aging Research to S.S, NIH K23DC011279, Triological Society/American College of Surgeons Clinician Scientist Award, and Eleanor Schwartz Charitable Foundation to F.R.L.
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