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Abstract

Presbycusis and presbystasis represent relevant problems of aging, caused by the increase in life expectancy in developed countries. As such, it is advantageous to better understand the physiopathological mechanisms of these age-related inner ear diseases. The hypothesis that presbycusis and presbystasis have a genetic background was proposed some years ago. Several studies (in humans and animals) are available in the literature, and possible genes involved in the physiopathology of both diseases have been identified. The aim of this paper is to present an overview of the information available in the current medical literature on presbycusis and presbystasis.

Keywords

Introduction

The term presbycusis indicates a decrease in hearing ability which arises with age. Typically, it occurs between 55 and 65 years of age, progressively, causing a high-frequency, bilateral, sensorineural hearing loss. The clinical diagnosis of presbycusis is based on the following criteria: (i) the presence of progressive hearing loss; (ii) the deficit is bilateral in nature; and (iii) it starts from high frequencies.

Presbycusis has a major impact on the quality of human life, and is related to a reduction in communication skills. It impacts psycho-social aspects of an individual, inducing progressive isolation, possibly exacerbating anxiety-depressive status and/or accentuating possible cognitive deficits.

The possible genetic description / characterization of presbycusis is of great interest as it could be particularly useful in developing novel therapeutic approaches. Currently, hearing aids represent the only possible therapeutic intervention for patients suffering from different types of presbycusis. Although modern technology has greatly improved hearing aid devices, these can still be inadequate, especially in noisy environments. In addition, many individuals do not accept the use of hearing aids for aesthetic reasons.¹

Presbystasis (presby-vertigo or dizziness) represents a change in the vestibular organ related to age. Vestibular dysfunction can be a specific cause of vertigo in the elderly. However, dizziness can be caused by cardiovascular, neurological or locomotor diseases, by a deterioration in the sensory organs and/or by adverse drug effects. Therefore, the diagnosis of dizziness in older people can be a challenge, as the symptoms are often vague and findings on examination overlap among potential causes; moreover, there is still no convincing diagnostic standard for presbystasis.

The aim of this paper is to present an overview of the information in the current medical literature on the genetic aspect of presbycusis and presbystasis. Such a characterization could help us better understand the physiopathological mechanisms of these age-related inner ear diseases. This could lead to early diagnosis, early intervention or possibly to the development of novel therapeutic approaches. It would be of particular interest to realize a strategy to prevent some of the consequences of these medical conditions, such as the risk for falls in those affected by presbystasis, since falling in the elderly is a significant factor leading to morbidity and mortality.

Methods

The PubMed database was searched up to April 2014 (going back 10 years); full text articles were obtained when the title, abstract or key words suggested that the study may be eligible for this review. The search was carried out independently, and restricted to English language papers. Other papers were also identified from the references in the published literature.

The medical subject headings (MeSH) used included: presbycusis, presbystasis, age-related hearing loss, genetic, animal models.

Epidemiology

Recent estimates indicate that approximately 28 million Americans are currently affected by presbycusis,² and that about 40–60% of adults aged 60 years and more are affected.³ European data show that at least 30% of people over 55 have hearing loss due to aging.^2,3 In particular, according to UK studies, in the group aged 61–70 years, the prevalence of hearing loss (25 dB or more) is about 37%, and this increases to 60% in the group aged 71–80 years.¹ Males demonstrate a higher incidence of presbycusis with a rapid deterioration in hearing threshold (Baltimore Longitudinal Study of Aging).

Considering that the average age of US, EU and Japanese populations is increasing, it is reasonable to assume that the number of people affected by presbycusis is likely to increase.¹ Moreover, it has been reported that about 20–30% of people over the age of 65 experience some kind of dizziness, and that about 40–50% of the very elderly (85+) complain of vertigo.^4,5 In the USA about 7.5 million people annually visit physician offices and hospital outpatient or emergency departments complaining of dizziness or vertigo.^4,5 Women have been described to be more affected than men (M:F=2:1).^4,5

The age-related alteration of inner ear

Cochlea

The multiple functional components of the inner ear (hair cells, spiral ganglion neurons) may be all vulnerable to the effects of aging. In recent years considerable progress has been made especially in documenting the sites of anatomical lesions, as well as the pathophysiological changes that arise in the aging auditory system. Our knowledge of the inner ear aging processes comes mainly from temporal bone histopathological studies (in great part those performed by Schuknecht and colleagues and from additional studies conducted in animal models.^6,7 Currently, six distinct forms of presbycusis, or age-related hearing loss, have been identified, each associated with a pattern of inner ear morphological changes, according to Schuknecht and Gacek:⁶

sensorial = loss of hair cells within the organ of Corti;

neural = loss of neurons within the spiral ganglion and of nerve fibres;

strial = loss of stria vascularis cells;

cochlear transmission = alteration of the physical characteristics of the cochlear duct;

mixed;

indeterminate presbycusis.

Nonetheless, it is likely that more than one type of the models described by Schuknecht can occur at the same time in the inner ear with age, and that even ‘pure’ forms of presbycusis (i.e. only sensorial or only strial) are difficult to distinguish. The audiological profile of presbycusis therefore results from an array of co-existing inner ear pathological changes.

Vestibule

Temporal bone studies have shown a decreased number of otoconia in the macula utriculi and sacculi in elderly individuals. Otoconial degeneration and loss seems to increase in severity with increasing age.⁸ Also, the number of type I and type II vestibular hair cells, within the maculae and cristae ampullaris, in humans, decreases after 70 years of age.⁸

Central auditory pathways

Presbycusis is often associated with reduced verbal discrimination ability. This feature could indicate not just the inner ear (organ of Corti, vestibule and the spiral ganglia), but also a central auditory pathway involvement.¹ According to experimental data from psychoacoustic evaluations using complex verbal stimuli,¹ elderly subjects with an intact auditory periphery show a progressive deterioration of the discriminative capabilities in terms of the duration, the localization of the sound-source and its temporal perception. Therefore in the elderly, a verbal temporal distortion of perception (i.e. time-compression, reverberation etc.) can occur frequently in everyday listening conditions. The age-related changes observed at the central nervous system level, particularly in the temporal binaural processing areas, manifest with a reduction of the number and volume of neurons, alterations of the synaptic connections and interneuronal neurochemical changes.¹ These aging complications have been examined in previous studies aiming to identify those at risk for neuronal loss in the temporal processing areas.¹

Genetics of presbycusis

The hypothesis that presbycusis has a genetic background has been considered for a number of years, even in the absence of specific findings.¹ A number of studies have shown that high-frequency hearing loss can also occur in early age (<45 years) and in the absence of environmental risk factors:³ these observations could provide initial evidence of a genetic background of presbycusis.

According to a Swedish study on 250 identical twins and 307 dizygotic twins, aged between 36 and 80 years, high-frequency hearing loss can be caused by the concomitant presence of genetic and environmental factors.⁹ Data from the Framingham study¹ show that some families present a higher incidence of presbycusis ranging from 25% to 55%, and according to a Danish study the inheritance of presbycusis is estimated to be 40%.¹⁰ It has recently been estimated that 35–55% of cases of inner ear aging have a genetic background.¹¹

Data on humans (identification of presbycusis genes in humans)

Genome-wide association studies, linkage studies (both based on the analysis of genetic polymorphism) and histopathological and genetic examinations of human temporal bones could all represent useful tools to identify the genes possibly involved in human presbycusis. Consequently, it may be possible to classify potential candidate genes related to auditory aging, according to the methodology employed.

Genome-wide association studies

Genome-wide association studies compare the presence of ‘candidate’ genes in defined groups of individuals. The selection of candidate genes is based on physiological and functional data. Only few association studies for presbycusis have been published to date. Van Laer et al. investigated the possible involvement of the gene DFNA5 in the Framingham study population.¹ DFNA5 was selected as a candidate gene because mutations in this gene produce a hearing loss that phenotypically is very similar to presbycusis (bilateral high-frequency sensorineural loss). However, no significant connection has been identified.¹² Another study, evaluating a candidate gene linked to the synthesis of glutathione antioxidant enzymes (such as GSTM1, GSTT1, GSTP1), has been also published, but also in this case there was no evidence of any significant relationship to presbycusis.¹

Linkage studies

In linkage studies, large groups of individuals suffering from the same condition are identified in order to determine the modified chromosomal regions. In the study by Zhu et al., some families with bilateral high-frequencies sensorineural hearing loss were selected and those phenotypes have been linked to a mutation on chromosome 17 (17q25.3).² The cochlear-expressed gene is transmitted as an autosomal dominant trait. Destefano et al., using a similar methodology, correlated the presence of some specific mutations on chromosome 11p (11q13.5) with the presence of presbycusis.¹³ Presbycusis-type audiograms have also been found in members of a Dutch family. An autosomal dominantly inherited sensorineural hearing loss was genetically assessed and a mutation of the MYO6 gene was found (myosin VI might be involved in anchoring the apical hair cell membrane to the cuticular plate within the organ of Corti).¹⁴ Other reported identified genes involved in human presbycusis type hearing loss include GRM7, GRHL2 and KCNQ4.^15-17

Histopathological and genetic examinations

Histopathological and genetic examinations of human temporal bones of deceased presbyacusic patients¹⁸ represent another possible source of information, and mutations of the mitochondrial gene coding for cytochrome oxidase and the presence of a 4977 bp deletion in mitochondrial DNA has been detected using this approach.¹⁸

Interestingly, according to other authors,¹¹ potential candidate genes related to auditory aging may also be found in genes related to inner ear structures and/or inner ear cells, and in genes related to inner ear oxidative stress.

Genes related to inner ear structures and/or inner ear cells

The genes that have been identified belong to different gene families: (i) the family of transcription factors (i.e. transcription factor grainy head-like 2 (GRHL2), involved in neural receptors of the inner ear); (ii) the family of cytoskeleton components (i.e. cadherin 23 and Myosin VIIA, both involved in the stereocilia function of hair cells); (iii) the family of ion channels (i.e. the KCNQ4 gene encoding the voltage-gated K+ channel; (iv) the family of transporters (i.e. SLC26A4 encoding an anion transmembrane transporter, pendrin); (v) the family of extracellular matrix molecules (i.e. connexins); (vi) the family of genes associated to stria vascularis disorders.^11,19

Genes related to inner ear oxidative stress and mitochondria

Two main types of anti-oxidant enzymes are involved in cochlea senescence: glutathione enzymes, such as glutathione S-transferase, glutathione peroxidase and glutathione reductase, and enzymes that reduce superoxide anion and hydrogen peroxide, such as catalase and superoxide dismutase. Loss of function in glutathione and superoxide dismutase genes can cause presbycusis-like deafness.¹¹

The mechanisms involved in the age-related central auditory impairment remain unclear. However, some studies have proposed that mitochondrial DNA deletions accumulated with age in the auditory system could be involved in the pathogenesis of central presbycusis. In particular a cytochrome c oxidase deficiency has been claimed to be a causal factor in the mitochondrial function decline of age-related deterioration in the auditory cortex.^20,21 However, this field still has to be adequately investigated.

Animal models

Presently, at least 10 loci and one mitochondrial mutant have been determined as relevant to presbycusis in a mouse ‘inbred’ model. Every type of cochlear presbycusis mentioned above in the ‘age-related alteration of inner ear’ has its respective animal models, with the characterized histological changes caused by mutant alleles, leading to many studies. So, for example, according to Erway et al., there is evidence of a recessive gene located on chromosome 10 and named AHL (Age Hearing Loss); this gene has been associated with early degeneration of the Corti organ, stria vascularis and spiral ganglion neurons.²² A second locus AHL2 has been identified on mouse chromosome 5 and a third AHL3 on chromosome 17.^23,24

Particularly interesting are the studies in ‘SAM’ mice (Senescence Accelerated Mouse).²⁵ Histological analysis has shown that the age-related loss of outer and inner hair cells is greater at the cochlear apex and base. In particular, the degeneration of inner hair cells, attributable to aging, is estimated to be about 10% of the total hair cells number, while that of the spiral ganglion neurons can involve 25–60% of the total. Another significant finding is the capillary atrophy within the stria vascularis, as these changes may produce biochemical modification of the inner ear endolymph environment, and this can directly affect the hair cells’ metabolism.²⁵

Other mouse strains have been studied. In particular, C57BL/6J and CBA/J mice showed that changes in miRNA expression (miRNAs are a class of RNA also involved in the regulation of cellular senescence and aging) are involved in age-related degeneration of the organ of Corti.²⁶

In the CD1 mouse model, some molecules (BCL-2 family molecules), encoded by mitochondrial DNA and involved in anti-oxidant defence, have been identified to be involved in cochlear apoptosis and development of presbycusis.²⁷

Genetics of presbystasis

Vestibular aging is a very poorly researched field. Moreover, since patients with imbalance or vertigo can present a heterogeneous group of complex disorders affecting both the peripheral and central vestibular system, they also represent a diagnostic challenge for clinicians. In fact, visual, hearing and vestibular functions physiologically deteriorate with age; moreover, elderly people can also present deficits in these sensory systems, and this fact could further impair (i) the compensatory information on body position and (ii) their personal confidence in maintaining a balanced position.^28,29 This can have an impact on walking abilities (in up to 15% of subjects over age 60), and can therefore significantly increase the risk of falling.³⁰

The genetic basis of presbystasis is largely unknown, as studies in this field are inadequate to date. Nonetheless, a very few age-related conditions of reduced vestibular function that can manifest in the elderly have been genetically characterized recently, and are reported below.^8,31-33

Data on humans

Familial episodic ataxia

Familial episodic ataxias are monogenic recurrent vertigo syndromes. These are mainly autosomal dominant disorders of early onset characterized by recurrent attacks of incoordination, dysarthria and truncal ataxia. However, episodic ataxia type 4 and 5 have been described to involve adults aged >50 years.^8,31-33 Episodic ataxia 4 locus has not yet been identified, while episodic ataxia 5 has been linked to mutations in the calcium channel b4 subunit CACNB4, on chromosome 2q22-23.^8,31-33

Vestibular migraine

Vestibular migraine, a common cause of spontaneous recurrent vertigo, consists of recurrent episodes of vestibular symptoms with current or previous history of migraine. Familial occurrence of vestibular migraine has been reported to occur in adults, with genetic heterogeneity and a suspected autosomal dominant feature. Genome-wide analyses have revealed linkage to chromosome 5q35, 11q and 22q12.^8,31-36

Bilateral vestibular hypofunction

Bilateral vestibular hypofunction without hearing loss, also referred to as bilateral vestibulopathy, has been described in adult members of families without migraine and has been linked to chromosome 6q.^8,31-37

Ménière’s disease

Familial Ménière’s disease is a complex disease characterized by episodic vertigo, fluctuating hearing loss and tinnitus. Ménière’s disease has a variable clinical course and presentation modalities. The causes underlying Ménière’s disease remain unknown, but familial association has recently been reported in two large independent cohorts in Spain³⁸ and Finland.³⁹ Most of these families showed an autosomal dominant mode of inheritance; however, recessive or mitochondrial transmission is also observed, therefore suggesting genetic heterogeneity.^8,31-33

Animal/experimental data

Animal studies available in this field are also scant. However, structural and functional investigations of the labyrinth have shown that the otoconial layer and other macular structures are modified during aging. In aged mice a significant decrease in the number of the globular substances (precursor of otoconia) was found in comparison with young mice. These findings may indicate a reduced capability of otoconia production in the aged vestibular organ;⁸ however, there are no reports of a genetic substrate for presbystasis in animal models.

Future perspectives

The study of the genetic features of presbycusis and presbystasis could help us to better understand the physiopathological mechanisms of these diseases, particularly with regard to the genetic mutations related to each disorder. Unfortunately the available data so far are still inadequate, particularly for presbystasis.

Although still in its infancy, this approach in the future could (i) help us to identify those subjects /families more at risk of developing some kind of inner ear disease, and (ii) could therefore offer tools to prevent/delay the manifestation/onset of some phenotypes and (iii) offer a genomic approach/therapy to inner ear problems. Recently it was suggested that novel approaches such as inner-ear regeneration therapy or stem cell therapy could be deployed in the elderly, to restore auditory function, replacing apoptotic neurons.⁴⁰

Footnotes

Declaration of conflict interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Genetics of presbycusis and presbystasis

Abstract

Keywords

Introduction

Methods

Epidemiology

The age-related alteration of inner ear

Cochlea

Vestibule

Central auditory pathways

Genetics of presbycusis

Data on humans (identification of presbycusis genes in humans)

Genome-wide association studies

Linkage studies

Histopathological and genetic examinations

Genes related to inner ear structures and/or inner ear cells

Genes related to inner ear oxidative stress and mitochondria

Animal models

Genetics of presbystasis

Data on humans

Familial episodic ataxia

Vestibular migraine

Bilateral vestibular hypofunction

Ménière’s disease

Animal/experimental data

Future perspectives

Footnotes

Declaration of conflict interests

Funding

References