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Genetics of presbycusis and presbystasis

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0010.1177/0394632015570819International Journal of Immunopathology and PharmacologyCiorba et al.
research-article2015

Article
International Journal of

Genetics of presbycusis and presbystasis Immunopathology and Pharmacology

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DOI: 10.1177/0394632015570819
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A Ciorba1, S Hatzopoulos1, C Bianchini1, C Aimoni1, H
Skarzynski2,3 and PH Skarzynski2,4

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
age-related hearing loss, animal models, genetic, presbycusis, presbystasis

Date received: 4 September 2014; accepted: 4 November 2014

Introduction
The term presbycusis indicates a decrease in hear-
ing ability which arises with age. Typically, it
occurs between 55 and 65 years of age, progres-
sively, causing a high-frequency, bilateral, sensori-
neural 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 com-
munication 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 / characteriza-
tion 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) repre-
sents 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 diag-
nosis of dizziness in older people can be a challenge,
as the symptoms are often vague and findings on
examination overlap among potential causes; more-
over, there is still no convincing diagnostic standard
for presbystasis.
1ENT and Audiology Department University of Ferrara, Italy
2Instituteof Physiology and Pathology of Hearing, Warsaw, Poland
3World Hearing Center, Warsaw, Poland
4Department of Heart Failure and Cardiac Rehabilitation, Medical
University of Warsaw
Corresponding author:
Andrea Ciorba, MD PhD, ENT & Audiology Department, University
Hospital of Ferrara, Via Aldo Moro 8, 44124 (Cona) Ferrara, Italy.
Email: andrea.ciorba@unife.it
2 International Journal of Immunopathology and Pharmacology
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 presbysta-
sis. 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 pos-
sibly to the development of novel therapeutic
approaches. It would be of particular interest to
realize a strategy to prevent some of the conse-
quences 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 sug-
gested 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 pub-
lished 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 pres-
bycusis,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 preva-
lence 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 models6,7.
Currently, six distinct forms of presbycusis, or age-
related hearing loss, have been identified, each asso-
ciated 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 audiologi-
cal 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 utri-
culi 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
Ciorba et al.
Central auditory pathways. Presbycusis is often asso-
ciated 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 psychoacous-
tic evaluations using complex verbal stimuli,1
elderly subjects with an intact auditory periphery
show a progressive deterioration of the discrimina-
tive capabilities in terms of the duration, the locali-
zation of the sound-source and its temporal
perception. Therefore in the elderly, a verbal tempo-
ral 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, par-
ticularly 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 previ-
ous studies aiming to identify those at risk for neu-
ronal loss in the temporal processing areas.1
Genetics of presbycusis
The hypothesis that presbycusis has a genetic back-
ground 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 inherit-
ance 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)
3
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 clas-
sify potential candidate genes related to auditory
aging, according to the methodology employed.
Genome-wide association studies. Genome-wide
association studies compare the presence of ‘can-
didate’ genes in defined groups of individuals.
The selection of candidate genes is based on
physiological and functional data. Only few asso-
ciation studies for presbycusis have been pub-
lished 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 phenotypi-
cally 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 mem-
bers of a Dutch family. An autosomal dominantly
inherited sensorineural hearing loss was geneti-
cally 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 pres-
bycusis type hearing loss include GRM7, GRHL2
and KCNQ4.15-17
4 International Journal of Immunopathology and Pharmacology
Histopathological and genetic examinations. Histo-
pathological 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 poten-
tial 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 transcrip-
tion factors (i.e. transcription factor grainy head-
like 2 (GRHL2), involved in neural receptors of the
inner ear); (ii) the family of cytoskeleton compo-
nents (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 mito-
chondria. Two main types of anti-oxidant enzymes
are involved in cochlea senescence: glutathione
enzymes, such as glutathione S-transferase, glu-
tathione peroxidase and glutathione reductase, and
enzymes that reduce superoxide anion and hydro-
gen peroxide, such as catalase and superoxide dis-
mutase. Loss of function in glutathione and
superoxide dismutase genes can cause presbycu-
sis-like deafness.11
The mechanisms involved in the age-related
central auditory impairment remain unclear.
However, some studies have proposed that mito-
chondrial DNA deletions accumulated with age in
the auditory system could be involved in the patho-
genesis 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 ade-
quately investigated.
Animal models
Presently, at least 10 loci and one mitochondrial
mutant have been determined as relevant to pres-
bycusis 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 degenera-
tion of inner hair cells, attributable to aging, is esti-
mated 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 modifica-
tion of the inner ear endolymph environment, and
this can directly affect the hair cells’ metabolism.25
Other mouse strains have been studied. In par-
ticular, 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 mitochon-
drial 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 dis-
orders affecting both the peripheral and central ves-
tibular 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
Ciorba et al.
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 sub-
jects 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 condi-
tions of reduced vestibular function that can mani-
fest 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 chromo-
some 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 ver-
tigo, fluctuating hearing loss and tinnitus.
Ménière’s disease has a variable clinical course
and presentation modalities. The causes underly-
ing Ménière’s disease remain unknown, but famil-
ial association has recently been reported in two
large independent cohorts in Spain38 and Finland.39
Most of these families showed an autosomal
5
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 capa-
bility 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 dis-
eases, particularly with regard to the genetic muta-
tions related to each disorder. Unfortunately the
available data so far are still inadequate, particu-
larly 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/ther-
apy to inner ear problems. Recently it was sug-
gested 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
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.
[AQ: 1]
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