Review

Authors: Michael R Bowl, Sally J Dawson

Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly. This progressive hearing impairment leads to social isolation and is also associated with comorbidities, such as frailty, falls, and late-onset depression. Moreover, there is a growing evidence linking it with cognitive decline and increased risk of dementia. Given the large social and welfare burden that results from ARHL, and because ARHL is potentially a modifiable risk factor for dementia, there is an urgent need for therapeutic interventions to ameliorate age-related auditory decline. However, a prerequisite for design of therapies is knowledge of the underlying molecular mechanisms. Currently, our understanding of ARHL is very limited. Here, we review recent findings from research into ARHL from both human and animal studies and discuss future prospects for advances in our understanding of genetic susceptibility, pathology, and potential therapeutic approaches in ARHL.

Topics: Aged; Animals; Cognitive Dysfunction; Comorbidity; Dementia; Disease Models, Animal; Humans; Mice; Presbycusis; Risk Factors

PubMed: 30291149
DOI: 10.1101/cshperspect.a033217

Review

Authors: Alexander Chern, Justin S Golub

Dementia is a devastating disease and global health challenge that is highly prevalent worldwide. A growing body of research has shown an independent association between age-related hearing loss (ARHL) and dementia, identifying ARHL as a compelling potential target in preventive strategies for dementia. However, a causal linkage between ARHL and dementia needs to be investigated before making definitive clinical guidelines and treatment recommendations regarding ARHL as a modifiable risk factor. In this review, we discuss the association between ARHL and dementia, the importance of addressing this finding, as well as common mechanisms (eg, microvascular disease) and causal mechanisms (eg, depletion of cognitive reserve and social isolation) that may explain the nature of this relationship. Future directions for research are also highlighted, including randomized controlled trials, developing high-resolution microvascular imaging, and further refining audiometric testing.

Topics: Aging; Dementia; Humans; Microvessels; Presbycusis; Prevalence; Risk Factors

PubMed: 31335455
DOI: 10.1097/WAD.0000000000000325

Authors: Guoqiang Sun, Yandong Zheng, Xiaolong Fu...

Progressive functional deterioration in the cochlea is associated with age-related hearing loss (ARHL). However, the cellular and molecular basis underlying cochlear aging remains largely unknown. Here, we established a dynamic single-cell transcriptomic landscape of mouse cochlear aging, in which we characterized aging-associated transcriptomic changes in 27 different cochlear cell types across five different time points. Overall, our analysis pinpoints loss of proteostasis and elevated apoptosis as the hallmark features of cochlear aging, highlights unexpected age-related transcriptional fluctuations in intermediate cells localized in the stria vascularis (SV) and demonstrates that upregulation of endoplasmic reticulum (ER) chaperon protein HSP90AA1 mitigates ER stress-induced damages associated with aging. Our work suggests that targeting unfolded protein response pathways may help alleviate aging-related SV atrophy and hence delay the progression of ARHL.

Topics: Mice; Animals; Transcriptome; Aging; Cochlea; Stria Vascularis; Presbycusis

PubMed: 36933008
DOI: 10.1093/procel/pwac058

Review

Authors: Elizabeth M Keithley

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.

Topics: Aging; Animals; Cochlea; Hair Cells, Auditory; Hearing; Humans; Presbycusis

PubMed: 31066107
DOI: 10.1002/jnr.24439

Review

Authors: Kate Slade, Christopher J Plack, Helen E Nuttall...

Age-related hearing loss (ARHL) is a common problem for older adults, leading to communication difficulties, isolation, and cognitive decline. Recently, hearing loss has been identified as potentially the most modifiable risk factor for dementia. Listening in challenging situations, or when the auditory system is damaged, strains cortical resources, and this may change how the brain responds to cognitively demanding situations more generally. We review the effects of ARHL on brain areas involved in speech perception, from the auditory cortex, through attentional networks, to the motor system. We explore current perspectives on the possible causal relationship between hearing loss, neural reorganisation, and cognitive impairment. Through this synthesis we aim to inspire innovative research and novel interventions for alleviating hearing loss and cognitive decline.

Topics: Aged; Brain; Cognition; Cognitive Dysfunction; Humans; Presbycusis; Speech Perception

PubMed: 32826080
DOI: 10.1016/j.tins.2020.07.005

Review

Authors: Weiming Hu, Junwu Wu, Wenjing Jiang...

Presbycusis (age-related hearing loss) is the most universal sensory degenerative disease in elderly people caused by the degeneration of cochlear cells. Non-coding microRNAs (miRNAs) play a fundamental role in gene regulation in almost every multicellular organism, and control the aging processes. It has been identified that various miRNAs are up- or down-regulated during mammalian aging processes in tissue-specific manners. Most miRNAs bind to specific sites on their target messenger-RNAs (mRNAs) and decrease their expression. Germline mutation may lead to dysregulation of potential miRNAs expression, causing progressive hair cell degeneration and age-related hearing loss. Therapeutic innovations could emerge from a better understanding of diverse function of miRNAs in presbycusis. This review summarizes the relationship between miRNAs and presbycusis, and presents novel miRNAs-targeted strategies against presbycusis.

PubMed: 29392088
DOI: 10.14336/AD.2017.0119

Meta-Analysis

Authors: David G Loughrey, Michelle E Kelly, George A Kelley...

IMPORTANCE

Epidemiologic research on the possible link between age-related hearing loss (ARHL) and cognitive decline and dementia has produced inconsistent results. Clarifying this association is of interest because ARHL may be a risk factor for outcomes of clinical dementia.

OBJECTIVES

To examine and estimate the association between ARHL and cognitive function, cognitive impairment, and dementia through a systematic review and meta-analysis.

DATA SOURCES AND STUDY SELECTION

A search of PubMed, the Cochrane Library, EMBASE, and SCOPUS from inception to April 15, 2016, with cross-referencing of retrieved studies and personal files for potentially eligible studies was performed. Keywords included hearing, cognition, dementia, and Alzheimer disease. Cohort and cross-sectional studies published in peer-reviewed literature and using objective outcome measures were included. Case-control studies were excluded.

DATA EXTRACTION AND SYNTHESIS

One reviewer extracted and another verified data. Both reviewers independently assessed study quality. Estimates were pooled using random-effects meta-analysis. Subgroup and meta-regression analyses of study-level characteristics were performed.

MAIN OUTCOMES AND MEASURES

Hearing loss measured by pure-tone audiometry only and objective assessment measures of cognitive function, cognitive impairment, and dementia. Cognitive function outcomes were converted to correlation coefficients (r value); cognitive impairment and dementia outcomes, to odds ratios (ORs).

RESULTS

Forty studies from 12 countries met our inclusion criteria. Of these, 36 unique studies with an estimated 20 264 unique participants were included in the meta-analyses. Based on the pooled maximally adjusted effect sizes using random-effects models, a small but significant association was found for ARHL within all domains of cognitive function. Among cross-sectional studies, a significant association was found for cognitive impairment (OR, 2.00; 95% CI, 1.39-2.89) and dementia (OR, 2.42; 95% CI, 1.24-4.72). Among prospective cohort studies, a significant association was found for cognitive impairment (OR, 1.22; 95% CI, 1.09-1.36) and dementia (OR, 1.28; 95% CI, 1.02-1.59) but not for Alzheimer disease (OR, 1.69; 95% CI, 0.72-4.00). In further analyses, study, demographic, audiometric, and analyses factors were associated with cognitive function. Vascular dysfunction and impaired verbal communication may contribute to the association between hearing loss and cognitive decline.

CONCLUSIONS AND RELEVANCE

Age-related hearing loss is a possible biomarker and modifiable risk factor for cognitive decline, cognitive impairment, and dementia. Additional research and randomized clinical trials are warranted to examine implications of treatment for cognition and to explore possible causal mechanisms underlying this relationship.

Topics: Age Factors; Audiometry, Pure-Tone; Cognition; Cognitive Dysfunction; Dementia; Humans; Presbycusis; Risk Factors

PubMed: 29222544
DOI: 10.1001/jamaoto.2017.2513

Review

Authors: Yasue Uchida, Saiko Sugiura, Yukiko Nishita...

The amount of attention to age-related hearing loss (ARHL) has been growing, not only from the perspective of being one of the most common health conditions affecting older adults, but also from the perspective of its relation to cognition. Results from a number of epidemiological and laboratory studies have demonstrated a significant link between ARHL and cognitive decline. The Lancet International Commission on Dementia, Prevention, Intervention, and Care has estimated that mid-life hearing loss, if eliminated, might decrease the risk of dementia by nine percent, since hearing loss is a modifiable age-associated condition linked to dementia. Despite numerous research efforts, elucidation of the underlying causal relationships between auditory and cognitive decline has not yet reached a consensus. In this review article, we focused on the hypotheses of etiological mechanisms between ARHL and cognitive decline: (1) cognitive load hypothesis; (2) common cause hypothesis; (3) cascade hypothesis; and (4) overdiagnosis or harbinger hypothesis. Factual evidence obtained in previous studies was assessed to understand the link between ARHL and cognitive decline or dementia. Additionally, an overview of the conceivable effects of hearing intervention, e.g., hearing aids and cochlear implants, on cognition were presented, and the role of hearing aid use was considered for the relevant hypotheses. We should continue to strive for social enlightenment towards the importance of 'hearing well', and cultivate a necessity for hearing screening among patients at risk of cognitive decline.

Topics: Aged; Causality; Cochlear Implantation; Cochlear Implants; Cognitive Dysfunction; Hearing Aids; Humans; Presbycusis

PubMed: 30177417
DOI: 10.1016/j.anl.2018.08.010

Review

Authors: Bret R Rutherford, Katharine Brewster, Justin S Golub...

Recent research has linked age-related hearing loss to impaired performance across cognitive domains and increased risk for dementia diagnosis. The data linking hearing impairment to incident late-life depression are more mixed but suggest that diminished hearing does increase risk for depression. Behavioral mechanisms may explain these associations, such as the withdrawal of older adults from situations in which they may have difficulty hearing and communicating, which may contribute to the development of social isolation, loneliness, and consequent cognitive decline and depression. At a neural level, chronic hearing loss leads to reduced activation in central auditory pathways, resulting in compensatory increased activation in the cognitive control network, dysfunctional auditory-limbic connectivity, and deafferentation-induced atrophy in frontal brain regions. These pathologic changes decrease cognitive performance and increase depression risk by reducing cognitive reserve, increasing executive dysfunction, and disrupting normative emotion reactivity and regulation. Based on the available data and informed by this model, evidence-based suggestions are proposed for clinicians treating older adults, and a research agenda is advanced to facilitate the development of rationally designed and age-appropriate psychiatric treatments for older adults with age-related hearing loss. First and foremost, treating hearing loss should be investigated as a means of improving cognitive and depressive outcomes in well-designed studies incorporating comprehensive psychiatric assessments, randomization, objective documentation of compliance, and analyses of treatment mediators that will facilitate further therapeutic development. Multimodal neuroimaging studies integrating audiometric, neuropsychological, and clinical assessments also are needed to further evaluate the model proposed. [AJP at 175: Remembering Our Past As We Envision Our Future April 1995: Effect of Hearing Enhancement on Medical Status Ratings Twenty-one elderly psychiatric patients had lower levels of psychopathology when assessed while wearing hearing aids. (Am J Psychiatry 1995; 152:629-631 )].

Topics: Aged; Aged, 80 and over; Aging; Cognitive Dysfunction; Depression; Humans; Presbycusis

PubMed: 29202654
DOI: 10.1176/appi.ajp.2017.17040423

Authors: Zu-Hong He, Ming Li, Qiao-Jun Fang...

Presbycusis is the cumulative effect of aging on hearing. Recent studies have shown that common mitochondrial gene deletions are closely related to deafness caused by degenerative changes in the auditory system, and some of these nuclear factors are proposed to participate in the regulation of mitochondrial function. However, the detailed mechanisms involved in age-related degeneration of the auditory systems have not yet been fully elucidated. In this study, we found that FOXG1 plays an important role in the auditory degeneration process through regulation of macroautophagy/autophagy. Inhibition of FOXG1 decreased the autophagy activity and led to the accumulation of reactive oxygen species and subsequent apoptosis of cochlear hair cells. Recent clinical studies have found that aspirin plays important roles in the prevention and treatment of various diseases by regulating autophagy and mitochondria function. In this study, we found that aspirin increased the expression of FOXG1, which further activated autophagy and reduced the production of reactive oxygen species and inhibited apoptosis, and thus promoted the survival of mimetic aging HCs and HC-like OC-1 cells. This study demonstrates the regulatory function of the FOXG1 transcription factor through the autophagy pathway during hair cell degeneration in presbycusis, and it provides a new molecular approach for the treatment of age-related hearing loss.: AHL: age-related hearing loss; baf: bafilomycin A1; CD: common deletion; D-gal: D-galactose; GO: glucose oxidase; HC: hair cells; mtDNA: mitochondrial DNA; RAP: rapamycin; ROS: reactive oxygen species; TMRE: tetramethylrhodamine, ethyl ester.

Topics: Aging; Apoptosis; Autophagy; Cell Survival; Forkhead Transcription Factors; Hair Cells, Auditory; Humans; Nerve Tissue Proteins; Presbycusis

PubMed: 34006186
DOI: 10.1080/15548627.2021.1916194