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The Complexity of Age-Related Hearing Impairment: Contributing Environmental and Genetic Factors

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Age-related hearing impairment (ARHI) is the most common sensory impairment seen in the elderly. It is a complex disorder, with both environmental as well as genetic factors contributing to the impairment. The involvement of several environmental factors has been partially elucidated. A first step towards the identification of the genetic factors has been made, which will result in the identification of susceptibility genes, and will provide possible targets for the future treatment and/or prevention of ARHI. This paper aims to give a broad overview of the scientific findings related to ARHI, focusing mainly on environmental and genetic data in humans and in animal models. In addition, methods for the identification of contributing genetic factors as well as possible future therapeutic strategies are discussed.
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Review
Audiol Neurotol 2007;12:345–358
DOI: 10.1159/000106478
The Complexity of Age-Related Hearing
Impairment: Contributing Environmental
and Genetic Factors
E. Van Eyken G. Van Camp L. Van Laer
Department of Medical Genetics, University of Antwerp, Antwerp , Belgium
fected with ARHI often experience difficulties adjusting
to their disorder. In fact, hearing loss may have a major
impact on the quality of life and the psychological well-
being of affected persons. Communication difficulties
will lead to poor psychosocial functioning, leading to so-
cial isolation as a consequence. The affected person may
lose his or her independence, and suffer from depression,
anxiety, lethargy, social dissatisfaction and possibly a
cognitive decline, similar to dementia, as a consequence
[Dalton et al., 2003; Gates and Mills, 2005; Heine and
Browning, 2002].
It has become clear that ageing causes histological,
electrophysiological and molecular changes. Deficits in
hair cells, cochlear neurons and the stria vascularis, and
combinations thereof have been described. In its most
typical presentation, ARHI is symmetrical, sensorineu-
ral and more pronounced in the high frequencies. ARHI
has been classified into four types, referred to as
Schuknecht’s topology [Schuknecht and Gacek, 1993],
including sensory ARHI (high-frequency loss; loss of
sensory cells), strial or metabolic ARHI (flat descending
threshold pattern; atrophy of stria vascularis), neural
ARHI (loss of word discrimination; loss of cochlear neu-
rons) and cochlear conductive or mechanical ARHI (un-
known pathology). In reality, many ARHI subjects show
mixtures of these pathologies, which is referred to as
mixed ARHI. When multiple influences interact, their
effects are considered to be additive [Schuknecht and
Gacek, 1993]. Although Schuknechts classification is a
Key Words
Ageing Hearing impairment Presbycusis
Abstract
Age-related hearing impairment (ARHI) is the most common
sensory impairment seen in the elderly. It is a complex disor-
der, with both environmental as well as genetic factors con-
tributing to the impairment. The involvement of several en-
vironmental factors has been partially elucidated. A first
step towards the identification of the genetic factors has
been made, which will result in the identification of suscep-
tibility genes, and will provide possible targets for the future
treatment and/or prevention of ARHI. This paper aims to give
a broad overview of the scientific findings related to ARHI,
focusing mainly on environmental and genetic data in hu-
mans and in animal models. In addition, methods for the
identification of contributing genetic factors as well as pos-
sible future therapeutic strategies are discussed.
Copyright © 2007 S. Karger AG, Basel
Introduction
Age-related hearing impairment (ARHI), also referred
to as presbycusis, is the most common sensory impair-
ment seen in the elderly. The overall population in devel-
oped countries is ageing; therefore, an increasing propor-
tion will develop ARHI in the nearby future. People af-
Received: December 13, 2006
Accepted after revision: May 18, 2007
Published online: July 27, 2007
Neurotolog
y
A udiology
G. Van Camp
Department of Medical Genetics, University of Antwerp, Campus Drie Eiken
Universiteitsplein 1
BE–2610 Wilrijk (Belgium)
Tel. +32 3 820 24 91, Fax +32 3 820 25 66, E-Mail guy.vancamp@ua.ac.be
© 2007 S. Karger AG, Basel
1420–3030/07/0126–0345$23.50/0
Accessible online at:
www.karger.com/aud
Van Eyken/Van Camp/Van Laer
Audiol Neurotol 2007;12:345–358
346
useful guideline, which incorporates testable hypotheses,
refinement of these classifications is occasionally neces-
sary due to the availability of increased knowledge re-
garding genetic defects and environmental conditions
[Ohlemiller, 2004].
To date, several studies to estimate the prevalence of
ARHI have been performed. An overview is given in ta-
ble 1 . In 1999, the World Health Organization estimated
that worldwide 580 million people over the age of 60 suf-
fered from hearing loss. Due to the growing population
of elderly, it is expected that in 2020 this number will have
increased by 75%, meaning that over 1 billion people of
60 years or older will be affected with ARHI (http://www.
who.int/en/).
The prevalence of ARHI grows with increasing age.
Overall, hearing thresholds aggravate on average with
1 dB per year for persons over 60, depending on age, gen-
der and initial thresholds [Lee et al., 2005]. The largest
variation of the hearing loss is found at the high frequen-
cies, and at the older ages ( fig. 1 ) [International Organiza-
Table 1. Prevalence of ARHI
ARHI prevalence References
At the age of 61–70, 37% have a significant HI of at least 25 dB Davis [1989, 1994]
At the age of 71–80, 60% have a significant HI of at least 25 dB
90% of all females with HI are more than 60 years old Davis [1991]
50% of all males with HI are more than 60 years old
Males are more affected than females Cruickshanks et al. [1998b]; Davis [1994];
Helzner et al. [2005]; Pearson et al. [1995]
At the average age of 65, 50% have HI Cruickshanks et al. [1998b, 2003]
65-year-olds account for 37% of all hearing loss Desai et al. [2001]
60% of all 73- to 84-year-olds have HI
High frequencies are mainly affected
Helzner et al. [2005]
HI = Hearing impairment.
90
Hearing threshold (dB HL)
125
80
70
60
50
40
30
20
10
0
+
20
30
40
50
60
70
80
+
250 500 1000 2000 4000 8000
Frequency (Hz)
+
+
+
+
+
+
90
Hearing threshold (dB HL)
125
80
70
60
50
40
30
20
10
0
+
20
30
40
50
60
70
80
+
250 500 1000 2000 4000 8000
Frequency (Hz)
+
+
+
+
+
+
ab
Fig. 1. ARHI according to the ISO 7029 standard for males ( a ) and for females ( b ). The x-axis displays the fre-
quencies (Hz) and the y-axis displays the hearing thresholds (dB HL). Each particular graph is representative
of the median of the hearing thresholds at a given frequency for a particular age (ranging from 20 to 80 years
old with an increment of 10 years).
Complexity of Age-Related Hearing
Impairment
Audiol Neurotol 2007;12:345–358
347
tion of Standardization, 2000]. In general, males are more
severely affected than females. The median hearing
threshold shifts relatively compared to a group of persons
aged 18 years (= the audiometric zero) have been de-
scribed in the International Standard ISO 7029 [Interna-
tional Organization of Standardization, 2000]. In addi-
tion, ISO 7029 gives the expected statistical distribution
above and below the mean values for a group of normal-
hearing subjects within the age range of 1870 years at
each audiometric frequency ranging between 125 to 8000
Hz. As such, ISO 7029 is a very useful resource for the
evaluation of audiograms in function of age and sex, if
the screening method employed for the populations that
were used to compile this standard is taken into ac-
count.
Hearing aids are the only therapeutic treatment avail-
able for ARHI at the moment, and are only helpful for a
restricted group of affected people. They are capable of
amplifying sounds, but speech recognition gain is often
experienced as poor, particularly in noisy environments.
Hearing aids are not used by all who would benefit from
them. This is partly due to social attitudes that under-
value hearing, the cost, and the fact that many people re-
fuse to use a hearing aid due to social stigmatization
[Gates and Mills 2005]. Therefore, the development of
new therapeutic strategies is necessary.
With this review, we will mainly focus on ARHI as a
complex disease influenced by genetic as well as environ-
mental factors. We will also briefly describe some ARHI
mouse models and therapeutic possibilities.
ARHI Is a Complex Genetic Disorder
Even though every individual shows a steady decline
in hearing ability with ageing, there is a large variation in
age of onset, severity of hearing loss and progression of
disease, which results in a wide spectrum of pure-tone
threshold patterns and word discrimination scores. ARHI
has always been considered to be an incurable and an un-
preventable disorder, thought to be part of the natural
process of ageing. Nowadays, ARHI is recognized as a
complex disorder, with both environmental and genetic
factors contributing to the etiology of the disease. This
also means that it is not an inevitable disorder. Instead,
ARHI should be considered as any other complex disease
with a possible treatable and/or preventable nature. Sci-
entific research should aim at the elucidation of the con-
tributing factors. Many studies on environmental risk
factors have been performed, which is in contrast with
the limited number of studies that have attempted to
identify genetic susceptibility factors contributing to the
disease.
The heritability of a disease expresses the relative im-
portance of the genetic component of a disease. It is de-
fined as the proportion of the phenotypic variance attrib-
uted to the effect of genes. Karlsson et al. [1997] per-
formed a twin study that estimated heritability values for
ARHI. They studied 250 monozygotic and 307 dizygotic
twins (aged between 36 and 80), using a questionnaire
and audiometric data. The heritability for the age group
above 64 was 0.47, indicating that about half of the popu-
lation variance for this age category is due to genetic fac-
tors, while the other half is due to environmental factors.
Another study compared audiometric data from geneti-
cally related subjects with those from genetically unre-
lated subjects. This study also revealed a familial aggrega-
tion for ARHI and resulted in heritability estimates be-
tween 0.35 and 0.55, depending on the frequencies that
were analyzed [Gates et al., 1999]. Finally, a Danish twin
study tested the heritability of self-reported hearing loss
in mono- and dizygotic twins of 75 and older. In the lat-
ter study, a heritability of 40% was estimated [Chris-
tensen et al., 2001].
It is not known how many environmental and genetic
factors contribute to the etiology of the disease, how they
interact with each other and what their individual contri-
bution is. The next section will aim to give an overview
of the environmental and genetic factors that are known
today, and the approaches that are used to identify ge-
netic factors.
Environmental and Medical Factors
Environmental Factors
Extensive research has been carried out so far to elu-
cidate the contribution of several environmental risk fac-
tors to ARHI, such as noise exposure, medical conditions,
exposure to chemicals, ototoxic medication, hormones,
alcohol and tobacco intake ( table 2 ).
N o i s e E x p o s u r e
The most extensively studied environmental factor is
noise exposure, which is responsible for both mechanical
and metabolic damage to the cochlea [Flock et al., 1999;
Mulroy et al., 1998; Pujol and Puel, 1999; Yamasoba et al.,
1998]. A daily exposure to noise of 85 dB or higher ele-
vates the risk of noise-induced hearing loss, leading to a
primary loss of outer hair cells followed by inner hair cell
Van Eyken/Van Camp/Van Laer
Audiol Neurotol 2007;12:345–358
348
degenerations [Emmerich et al., 2000]. The contribution
of noise exposure to the development of ARHI has ini-
tially been suggested by two studies performed in isolated
African tribes living in relatively noise-free environ-
ments. ARHI appeared to be absent in those tribes [Jarvis
and Van Heerden, 1967; Rosen et al., 1962]. This notion
is not uncontroversial, since subsequent studies have
shown that ARHI may be present in these cultures, al-
beit to a lesser extent [Driscoll and Royster, 1984]. In per-
sons subjected to lifelong noise exposure, the audiologi-
cal and histological differences between noise-induced
hearing loss and ARHI are difficult to distinguish [Cor-
so, 1992; Li, 1992]. Gates et al. [2000] suggested that noise
exposure reduces the effect of ageing at the exposed fre-
quencies, but that it accelerates the effect of ageing on
hearing thresholds in adjacent frequencies. Indeed, it has
been noted that the rate of ARHI in noise-damaged ears
differs from the rate in nonexposed ears [Gates et al.,
2000]. It is, therefore, thought that a predisposition for
ARHI might be expressed at an earlier age due to noise
exposure [Erway et al., 1996]. Kujawa and Liberman
[2006] detected an increased vulnerability to ageing in
inner ears of mice that were exposed to noise at a young-
er age. In addition, BALB/C and C57Bl/6J mouse models,
Table 2. Environmental factors
Environmental
factor
Comments on risk factor References
Noise Leisure noise causes ARHI Clark [1991]; Lutman and Spencer [1990]
Gunfire noise causes ARHI
Noise exposure increases vulnerability to ARHI Gates et al. [2000]; Kujawa and Liberman [2006]
Chemical
exposure
Toluene, trichloroethylene, styrene,
xylene cause ARHI
Johnson and Nylen [1995]; Fuente and McPherson [2006];
Fuente et al. [2006]; Morata et al. [2002]
Causes ARHI in combination with noise
exposure
Rybak [1992]; Chang et al. [2006]; Fuente and McPherson [2006];
Fuente et al. [2006]; Sliwinska-Kowalska et al. [2004]
Tobacco Tobacco use: increased risk Mellstrom et al. [1982]; Rosenhall et al. [1993];
Helzner et al. [2005]; Cruickshanks et al. [1998a];
Itoh et al. [2001]; Nomura et al. [2005]
Tobacco use: no effect Brant et al. [1996]; Gates et al. [1993]; Fuortes et al. [1995]
Alcohol Alcohol abuse: increased risk Rosenhall et al. [1993]; Helzner et al. [2005]
Alcohol abuse: no effect Brant et al. [1996]; Itoh et al. [2001]
Ototoxic
medication
Aminoglycosides, cisplatin, salicylate, and
loop diuretics cause ARHI
Stypulkowski [1990]; Aran et al. [1992]; Boettcher et al. [1992];
Mills et al. [1999]; Chen et al. [2006]; Lee et al. [1998];
Rybak et al. [2007]; Selimoglu [2007]
Medical Renal failure Antonelli et al. [1990]
conditions Diabetes Kurien et al. [1989]; Frisina et al. [2006]
Cardiovascular disease Kurien et al. [1989]; Gates et al. [1993]; Brant et al. [1996];
Picciotti et al. [2004]; Torre et al. [2005]
High bone mineral density: protective effect Clark et al. [1995]; Helzner et al. [2005]
Head trauma causes ARHI Danielidis et al. [2007]; Feldmann [1987]; Fitzgerald [1996];
Rosenhall et al. [1993]
Immune function impairment is a risk factor Iwai et al. [2003]; Iwai et al. [2001]; Iwai et al. [1999]
Diet Nutritional intake Houston et al. [1999]
Caloric restriction: protective effect Seidman [2000]
Caloric restriction: no effect Willot et al. [1995]; Torre et al. [2004]
Antioxidant intake: protective effect Le and Keithley [2007]
Hormonal
factors
Estrogen and aldosterone have a protective effect;
progestin causes ARHI
Guimaraes et al. [2004, 2006]; Hultcrantz et al. [2006];
Tadros et al. [2005]
Socioeconomic
status
Lower social class, no higher education is a risk
factor for ARHI
Sixt and Rosenhall [1997]; Poortinga [2007]
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Audiol Neurotol 2007;12:345–358
349
which show pronounced age-related hearing loss, are also
more vulnerable to noise compared to CBA mice strains.
Hence, genes associated with ARHI might contribute to
the vulnerability to noise insults [Ohlemiller et al., 2000],
whereas noise and age might have an additive or an inter-
active effect on hearing [Corso, 1992].
Exposure to Chemicals
Exposure to industrial chemicals such as toluene, tri-
chloroethylene, styrene and xylene is considered a caus-
ative environmental factor for ARHI [Johnson and Ny-
len, 1995]. In addition, exposure to these chemicals often
displays a nonlinear effect in combination with noise ex-
posure ( table 2 ) [Chang et al., 2006; Fuente and McPher-
son, 2006; Morata et al., 2002; Rybak, 1992; Sliwinska-
Kowalska et al., 2004]. Therefore, the odds ratio to de-
velop hearing loss not only increases with age [Morata et
al., 2002; Sliwinska-Kowalska et al., 2004] but also with a
lifetime exposure to solvents [Sliwinska-Kowalska et al.,
2004].
Sliwinska-Kowalska et al. [2004] detected increased
odds ratios for hearing loss in noise- and solvent-coex-
posed workers, exposed to a mixture of organic solvents,
mainly existing of xylene isomers. Morata et al. [2002]
described a higher prevalence of high-frequency hearing
loss in workers exposed to styrene and noise and workers
exposed to styrene alone, compared to noise-exposed and
nonexposed workers. Styrene-exposed groups showed
poorer hearing thresholds, even at small doses [Morata et
al., 2002]. When compared to noise alone, elevated hear-
ing thresholds were detected for workers exposed to tolu-
ene and noise [Chang et al., 2006]. Mainly the speech
frequencies were affected, although the poorest hearing
thresholds were measured at 6 kHz [Chang et al., 2006].
Similarly to styrene exposure [Morata et al., 2002], the
hearing loss due to small doses of toluene was only slight-
ly lower than that of highly exposed workers, indicating
that even at low doses chemical solvents might damage
the inner ear [Chang et al., 2006].
Smoking and Alcohol (Ab)Use
Smoking habits and alcohol (ab)use may also have an
effect on the development of ARHI, although the study
results are controversial ( table 2 ). Cigarette smoking may
increase the need for oxygen. As such, it may reduce the
oxygen supply to the inner ear due to the presence of car-
bon monoxide. Cigarette smoke may also lead to a hyper-
coagulable state and coronary vasoconstriction, while the
nicotine may induce hemodynamic effects [Ludvig et al.,
2005]. Due to the reduced oxygen supply in the inner ear,
the hypoxia may cause cochlear damage as well as an in-
creased number of mitochondrial mutations, resulting in
hearing loss.
A study performed by Itoh et al. [2001] found an as-
sociation between drinking habits and hearing loss. Light,
occasional drinkers appear to be protected against hear-
ing loss, while heavy drinkers had an increased risk for
developing ARHI. A similar association was also found
for cardiovascular diseases (CVDs) and drinking habits,
with a general health advantage for light drinkers and an
increased risk for heavy drinkers [Wannamethee and
Shaper, 1998].
O t o t o x i c M e d i c a t i o n
Ototoxic medication frequently results in hearing loss
in older subjects. This is probably due to an elevated uti-
lization of medication and an altered renal and liver func-
tion in the elderly, with higher medication blood levels as
a consequence. Examples of frequently used ototoxic
medication are aminoglycoside antibiotics, chemothera-
peutics like cisplatin, which cause nonreversible hearing
loss [Aran et al., 1992; Boettcher et al., 1992], and salicy-
late and loop diuretics, which cause reversible hearing
loss [Aran et al., 1992; Boettcher et al., 1992; Stypulkows-
ki, 1990]. Possibly, the ototoxic effect of aminoglycosides
and chemotherapeutics is induced by the formation of
free radicals which could subsequently cause permanent
damage to sensory cells and neurons [Chen et al., 2007;
Rybak et al., 2007; Selimoglu, 2007]. This has been sug-
gested because an antioxidant treatment preserves hear-
ing in gentamicin-treated [Schacht, 1998], cisplatin-treat-
ed [Rybak et al., 2007] and aminoglycoside-treated sub-
jects [Chen et al., 2007; Selimoglu, 2007]. Although the
ototoxic effect of salicylate has been well documented,
long-term administration of small doses of the drug may
improve hearing [Huang et al., 2005]. The mechanisms
behind this phenomenon are still unclear. It may be that
long-term salicylate administration enhances cochlear
mechanisms due to prestin upregulation or to an in-
creased affinity of prestin for anionic ions which in turn
may increase the motility of the hair cells. Alternatively,
this could result from an increase in stereocilia transduc-
tion or in an altered cyclooxygenase activity [Huang et
al., 2005]. In addition, salicylate as an antioxidant has a
protective effect on aminoglycoside-induced hearing loss
[Chen et al., 2007]. Some studies have demonstrated a
gender-specific effect of certain drugs on the hearing lev-
els in aged subjects [Lee et al., 1998; Mills et al., 1999],
with females being more sensitive to treatment with cer-
tain drugs than males. Although the authors did not pro-
Van Eyken/Van Camp/Van Laer
Audiol Neurotol 2007;12:345–358
350
vide a good explanation for the differences between males
and females, most probably factors like noise history or
hormonal influences may be responsible. Because 80% of
the males reported a history of noise exposure (females
only 20%) [Mills et al., 1999], this may lead to damage to
the male inner ear, which in turn may reduce the effect of
the drug.
Medical Factors
Diabetes
Mitochondrial DNA mutations leading to a combina-
tion of late-onset diabetes and sensorineural hearing loss
have been described [Janssen et al., 1999; Kurien et al.,
1989]. Kakarlapudi et al. [2003] also noted that sensori-
neural hearing loss was more common in diabetic pa-
tients than in their age-matched controls. Moreover,
young diabetic subjects (up to 60 years) have significant-
ly more high-frequency hearing loss than healthy age-
matched controls, but the difference in hearing loss be-
tween the two groups diminishes from 60 years of age
onwards [Vaughan et al., 2006]. In addition, diabetes has
been associated with ARHI [Kurien et al., 1989]. Presum-
ably, diabetes acts synergistically with the processes in-
volved in the development of ARHI [Kakarlapudi et al.,
2003]. In a study investigating hearing loss in aged type
II diabetics and age-matched controls, a significant dif-
ference between both study groups in inner ear and cen-
tral hearing loss was found. Interestingly, in this study
the lower frequencies tended to be more affected than the
high frequencies [Frisina et al., 2006], while diabetes as-
sociated with hearing loss, as well as ARHI, is usually
thought to lead to progressive high-frequency losses.
Cardiovascular Disease
Due to the high prevalence of cardiovascular disease
(CVD) in ageing subjects, many studies have looked for a
possible association between CVD and ARHI. In the
Framingham cohort, for example, an association between
low-frequency hearing loss and cardiovascular events
was observed [Gates et al., 1993]. In addition, high-den-
sity lipoprotein levels were correlated with hearing
thresholds, especially in women [Gates et al., 1993; Lee et
al., 1998]. Torre et al. [2005] detected a gender-specific
association between CVD and hearing loss in the elderly
as well; women with a self-reported history of myocar-
dial infarction were twice as likely to develop ARHI as
women without a history of myocardial infarction. This
was not observed in men. Again, these differences be-
tween genders may be due to hormonal differences. Hy-
pertension and systolic blood pressure have also been
shown to be associated with ARHI [Brant et al., 1996].
Finally, the effect of CVD on ARHI was confirmed in
mouse studies [Picciotti et al., 2004]. A possible explana-
tion for the relationship between CVD and ARHI can be
sought in the occurrence of hypoxia during CDV events.
Hypoxia of the cochlea may cause a reduction of mito-
chondrial oxidative phosphorylation, cochlear damage,
and an accumulation of mitochondrial mutations, with a
decreased function of the acoustic neural system and
hearing loss as a consequence [Dai et al., 2004].
Bone Mineral Density
It has been suggested that a reduced bone mineral den-
sity (BMD) contributes to ARHI, although this remains
controversial. In males, an inverse relation between BMD
and hearing loss was found, but this relation was not ob-
served in females [Helzner et al., 2005]. Nevertheless, in
a study performed on a population of rural women, an
association between ARHI and reduced BMD was de-
tected in females as well [Clark et al., 1995]. Although no
significant association could be found between estrogen
supplement intake in the past and current hearing loss,
hormonal changes may be the cause of the reduced BMD
and ARHI in these woman [Clark et al., 1995]. None of
the women were current users of estrogen supplements,
and beneficial effects of estrogen on bone density is only
seen among current users [Sowers et al., 1993]. Finally, a
third study could not detect a relation between hearing
ability and BMD [Purchase-Helzner et al., 2004]. The in-
consistencies between these various studies may be caused
by the investigation of BMD derived from bones that were
different from the cochlear bones. Femoral neck bone
contains a higher percentage of cancellous bone similar
to the temporal bone, while the radius and the hip bone
are less similar.
H e a d T r a u m a
Head trauma has been shown to have an effect on
hearing loss [Rosenhall et al., 1993]. This may be due to
the disruption of the membranous portion of the cochlea,
to alterations in the microcirculation of the cochlea, or to
hemorrhage into the fluids of the inner ear [Fitzgerald,
1996]. The hair cell damage due to head trauma is most
pronounced at 4–8 kHz and mimics the damage caused
by acoustic trauma. Generally, the hearing loss occurs
immediately and recovers gradually over a 6-month pe-
riod after the injury [Fitzgerald, 1996]. In a rabbit model
for closed head injury, increased otoacoustic emission la-
tencies were observed, which would indicate that cochle-
ar damage had occurred [Danielidis et al., 2007]. After
Complexity of Age-Related Hearing
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Audiol Neurotol 2007;12:345–358
351
histopathological examination of the temporal lobe and
brainstem of these rabbits, multiple hemorrhagic and ne-
crotic areas were found [Danielidis et al., 2007], indicat-
ing that both peripheral and central damage occurs after
head injury.
I m m u n e S y s t e m
Dysfunction of the immune system possibly contrib-
utes to the development of ARHI. This was shown in a
study using SAMP1 mice, a model for accelerated senes-
cence, which suffer from hearing impairment and a de-
creased immune function. In a first study, the transplan-
tation of bone marrow of BALB/c mice into SAMP1 mice
prevented the development of immunological dysfunc-
tion and hearing loss, indicating that some types of ac-
celerated ARHI are not caused by effects in the cochlea,
but are due to hematopoietic stem cell defects and failing
immunocompetent cells derived from these stem cells
[Iwai et al., 2001]. The authors could rule out an autoim-
mune mechanism as causative factor. They suggested that
pathogen-induced infections led to an impaired immune
function, followed by a decline in various functions, in-
cluding hearing [Iwai et al., 2003].
D i e t
It has been suggested that a poor nutritional status has
an effect on ARHI [Houston et al., 1999]. Caloric restric-
tion studies in animal models have had contradictory re-
sults to date. Caloric restriction in mice does not seem to
have an effect on hearing [Willott et al., 1995], while the
hearing ability of rats on a caloric-restricted diet was pre-
served [Seidman, 2000]. In agreement with the findings
of Willott et al. [1995], no significant effects of caloric re-
striction could be detected in rhesus monkeys [Torre et
al., 2004]. However, a study by Sweet et al. [1988] sug-
gested that the age of onset of caloric restriction may be
a determining factor for the preservation of the hearing
abilities at an older age. Restriction until midlife had no
protective effect on ARHI, while whole-life and after-
midlife restriction did have an effect on ARHI. This fact
could provide an explanation for the controversial results
amongst the different studies to date.
H o r m o n e s
Hormonal effects may also contribute to hearing loss.
Gender differences observed in ARHI may be due to the
difference in estrogen levels between males and females.
In menopausal women, estrogen therapy may slow down
the development of ARHI [Hederstierna et al., 2007;
Hultcrantz et al., 2006]. Animal models support these
findings, as mice lacking estrogen receptor showed
progressive hearing loss [Hultcrantz et al., 2006]. High
levels of aldosterone within the normal clinical range
may have a protective effect on ARHI [Tadros et al.,
2005]. Progestin, on the other hand, may have a negative
effect on the hearing abilities in aged women receiving
hormone replacement therapy, and might affect both the
peripheral as well as the central auditory systems [Gui-
maraes et al., 2006].
Socioeconomic Status
A persons socioeconomic status has been correlated
with ARHI. Lower social class and a low level of educa-
tion were correlated with hearing impairment. One pos-
sible explanation could be the exposure to occupational
noise. Nevertheless, the effect of the socioeconomic sta-
tus remains after correcting for occupational noise.
Hence, higher social class and higher education may be
related to life experiences that help preserve hearing abil-
ities, while noise exposure cannot be regarded as the only
causative factor for ARHI in lower social classes [Sixt and
Rosenhall, 1997]. Other possible risk factors may be re-
lated to lifestyle factors like smoking and heavy drinking,
which are more prevalent in lower socioeconomic classes
[Poortinga, 2007]. As mentioned previously, both smok-
ing and heavy drinking may have a negative effect on
hearing.
Genetic Factors
Little is known about the genes involved in ARHI, es-
pecially in humans. The perception of sound requires
complex molecular pathways and age-related changes in
any component of these pathways may contribute to hear-
ing loss. Therefore, it is expected that many genes will
participate in the etiology of ARHI. However, until re-
cently, little research effort has been put into the identifi-
cation of ARHI susceptibility genes.
Mouse Models
Due to the significant similarities of the auditory sys-
tem between mice and humans, mice are very useful as a
model for human hearing loss [Ohlemiller, 2006]. In fact,
the first ARHI genes have been identified in mice, and
some of the causative genes that are being discovered in
mice may be homologous to human AR HI genes. By mea-
suring auditory brainstem responses in 80 inbred mouse
strains, it was demonstrated that many strains develop
age-related hearing loss, resembling human ARHI [Grat-
Van Eyken/Van Camp/Van Laer
Audiol Neurotol 2007;12:345–358
352
ton and Vazquez, 2003]. For example, the CBA/Ca,
C57BL/6J and 129S6/SvEv inbred mouse strains display
age-related hearing loss similar to humans. These mice
show a progressive primary decline in the high frequen-
cies followed by increasing hearing thresholds of the low
frequencies [Li and Borg, 1991; Ohlemiller and Gagnon,
2004]. BALB/c mice also show a progressive high-fre-
quency hearing loss, but with a more rapid decline in
hearing loss than seen in the C57BL/6J mouse strain
[Willott et al., 1998]. Moreover, the gender differences
found for human ARHI were also observed in mouse
models [Guimaraes et al., 2004; Henry, 2004]. The differ-
ent mouse models known for age-related hearing loss
have recently been reviewed by Ohlemiller [2006].
To study the genetics of age-related hearing loss in
mice, Erway et al. [1993] used different inbred and F1 hy-
brid strains. Their results support a genetic model for re-
cessive alleles at three different loci which contribute to
the development of age-related hearing loss in mice. They
demonstrated that CBA/H-T6J mice possessed none of
the recessive alleles, that DBA/2J mice were homozygous
for all three loci and that C57BL/6J, BALB/cByJ and WB/
ReJ strains were homozygous for one of the three loci re-
sponsible for age-related hearing loss [Erway et al.,
1993].
S u b s e q u e n t l y , Ahl1 (age-related hearing loss 1 gene)
was mapped to chromosome 10 in C57BL/6J mice. A mu-
tation in Ahl1 causes elevated hearing thresholds in mid-
dle-aged and old mice at high frequencies [Johnson et al.,
1997]. Although this mutation causes accelerated hearing
loss in mice, it is currently not known whether this is re-
sponsible for human ARHI as well. Later, it was demon-
strated that the Ahl1 gene contributes to age-related hear-
ing loss in 9 other inbred mouse strains in a recessive way
(129P1/ReJ, BALB/cByJ, A/J, BUB/BnJ, C57BR/cdJ, DBA/
2J, NOD/LtJ, SKH2/J and STOCK760) [Johnson et al.,
2000], and that it was allelic to the modifier of deaf wad-
dler gene [Zheng and Johnson, 2001]. Cadherin 23 was
found to be t he responsible gene at the Ahl1 locus [Noben-
Trauth et al., 2003]. The B6.CAST-+
ahl
mouse was engi-
neered to be genetically identical to the C57BL/6 mouse
except for the Ahl1 allele that originated from the CAST/
Ei mouse, which has no hearing loss. B6.CAST-+
ahl
mice
are protected from early-onset hearing loss, but older an-
imals develop hearing loss, indicating that other loci be-
sides Ahl1 contribute to the differences in hearing loss
observed between C57BL/6 and CAST/Ei mice.
Up- and downregulation of genes have also been im-
plicated in ARHI. For instance, Bao et al. [2005] could
demonstrate that downregulation of
2
nicotinic acetyl-
choline receptors contributes to age-related hearing loss
in C57BL/6J mice, while upregulation of the serotonin 2B
receptor was detected in the auditory system in aged
CBA/CaJ mice with hearing loss [Tadros et al., 2007a].
Also, glutamate-related genes, such as pyrroline-5-car-
boxylate synthetase and high-affinity glutamate receptor
(Slc1a3) are down- and upregulated in the ageing audi-
tory midbrain, respectively [Tadros et al., 2007b]. This
illustrates the complexity of age-related hearing loss in
mice, and suggests that it may be very complex in human
ARHI as well [Keithley et al., 2004].
In 2002, Johnson and Zheng [2002] detected a second
locus for age-related hearing loss in mice. Ahl2 was lo-
cated to chromosome 5, and was restricted to the NOD
mouse strain and NOD-related strains. Recently, a third
locus, Ahl3, was located to chromosome 17 [Nemoto et
al., 2004] using a C57BL/6J ! MSM backcross, and fine-
mapped to a 14-Mb region [Morita et al., 2007]. In addi-
tion to the limited number of inbred mouse strains that
present with age-related hearing loss, 17 ENU-induced
mouse models have been identified showing high-fre-
quency hearing loss. These might be good ARHI models
that could shed light on the underlying mechanisms lead-
ing to ARHI [Kermany et al., 2006].
How to Analyze Genetic Factors Involved in Human
ARHI
There are two major approaches to identify suscepti-
bility genes for complex disorders like ARHI. The first
possible study design consists of a linkage study. This is
always a family-based approach in which the cosegrega-
tion of the disease and an allele of a genetic marker at a
certain locus are investigated. The second possible strat-
egy to study complex diseases is an association study,
which studies the co-occurrence of a disease and an allele
of a genetic marker. Association studies can be performed
in unrelated as well as in family-based samples, but the
majority of studies uses unrelated samples in a case-con-
trol study design.
Both strategies analyze genetic markers. These are
variants within the genome that can be analyzed in the
laboratory. Frequently used genetic markers include mi-
crosatellite markers and single nucleotide polymor-
phisms (SNPs). SNPs are the most frequent genetic vari-
ants within the human genome, occurring on average ev-
ery 300 bp. Many frequently occurring SNPs have been
identified to date, and all are enlisted in a database (http://
www.ncbi.nlm.nih.gov/). These SNPs and other com-
mon variants are thought to be responsible for much of
the variation seen amongst individuals. Moreover, some
Complexity of Age-Related Hearing
Impairment
Audiol Neurotol 2007;12:345–358
353
of them are considered to be causative for complex disor-
ders. This is referred to as thecommon variant, common
disease hypothesis.
During the past 10–15 years, linkage genome scans
have been widely used for localization of genes involved
in monogenic diseases on the basis of families segregat-
ing the disease. Such a scan consists of an analysis of a
limited set of microsatellite markers (300–500) or more
recently, of a limited number of SNPs (2000–10000). For
association studies, SNPs have always been the preferred
type of polymorphism, but many more markers need to
be analyzed to cover the whole genome compared to link-
age studies. Until very recently, association studies were
limited to the analysis of candidate genes. Nowadays
however, genome-wide scans for association are feasible.
This is due to improved technology, and more specifi-
cally to the development of microarrays enabling the
analysis of up to 500000 SNPs on a single array. Because
of rapidly evolving methodologies for SNP genotyping
and statistical analysis, coupled to a reduction in cost per
genotype, nowadays SNPs increasingly become the first-
choice genetic marker for linkage as well as association
studies. In October 2002, the HapMap project was start-
ed (http://www.hapmap.org), which intended to map hu-
man variation taking into account linkage disequilibri-
um between neighboring SNPs. Several studies have
demonstrated that the HapMap data are also useful for
other closely related populations [Montpetit et al., 2006;
Willer et al., 2006]. As such, the HapMap database has
become a useful tool for effective SNP selection.
For linkage analysis of complex diseases, usually non-
parametric analysis methods are preferred. This means
that no assumptions about the mode of inheritance, the
disease frequency or other parameters are being made. A
large collection of families is a prerequisite for linkage
studies. A problem that presents itself when using linkage
approaches to study late-onset disorders like ARHI is the
collection of families, because parents are often deceased.
Therefore, very few linkage studies have been performed
for ARHI to date. Within the Framingham cohort, audio-
metric data were collected from parents during a first
phase (1973–1975) and from their children in a second
phase (1995–1999). Analysis of these data resulted in
linkage for ARHI at six different loci on 4 chromosomes
[DeStefano et al., 2003]. In a second genome-wide linkage
analysis for ARHI, a seventh locus was identified which
coincided with the DFNA18 locus [Garringer et al., 2006].
Genome-wide scans for complex diseases require replica-
tion in independent sample sets. Because so far only two
genome-wide scans have been performed for ARHI, there
is still a lot of work to be done before the genetic basis of
ARHI will be clarified.
Association studies for ARHI can be performed in two
ways. ARHI can either be described as a dichotomous
trait, where a SNP allele, which confers susceptibility to
a disease, is expected to occur more in affected individu-
als (cases) compared to the unaffected group (controls).
A disadvantage of treating ARHI as a dichotomous trait
(affected/unaffected) is the loss of statistical power, as
generally information is lost when a quantitative trait
such as ARHI is dichotomized [Page and Amos, 1999].
Fransen et al. [2004] proposed the calculation of a Z-
score to enable treatment of ARHI as a quantitative trait.
This Z-score is an age- and gender-independent value,
based upon the ISO 7029 standard [Fransen et al., 2004].
Using this approach, random samples genotyped for a
particular SNP in a candidate gene can be grouped ac-
cording to their genotype and subsequently statistically
analyzed using ANOVA-based methods.
Although genome-wide association studies are feasi-
ble, they are still very expensive. Up to now only associa-
tion studies on functional candidate genes have been
published. These candidate genes are selected based on
biological and physiological information and the bio-
chemical pathways in which they are acting. Genes caus-
ing monogenic forms of a disease are obvious candidate
susceptibility genes for the complex forms of the disease
[Tabor et al., 2002].
Previous association studies performed for ARHI have
investigated such candidate genes. For example, Van Laer
et al. [2002] analyzed DFNA5, a gene causing autosomal
dominant hearing loss, but no association could be de-
tected. Ates et al. [2005] performed a case-control study
to test the hypothesis that glutathione-related antioxi-
dant enz yme levels were associated wit h t he risk of AR HI,
but they could not detect an association. An association
study analyzing N-acetyltransferase 2 (NAT2), a carcino-
gen-metabolizing enzyme, as a candidate gene for ARHI
resulted in a significant association for the NAT2 * 6A
polymorphism and ARHI [Unal et al., 2005]. In addition,
association with ARHI was found for different SNPs
within a 13-kb region in the middle of KCNQ4, a gene for
autosomal dominant hearing loss, in two independent
sample sets [Van Eyken et al., 2006].
Do Mitochondrial Mutations and Reactive Oxygen
Species Contribute to ARHI?
Mitochondrial mutations cause diseases typically seen
in the elderly [Wallace, 1997]. Different mouse models for
ageing in general have indicated that the accumulation of
Van Eyken/Van Camp/Van Laer
Audiol Neurotol 2007;12:345–358
354
mitochondrial DNA mutations might contribute to ARHI
[Kujoth et al., 2005; Trifunovic et al., 2004; Zhang et al.,
2002]. Indeed, in patients with ARHI, a highly significant
increase in mitochondrial mutations in auditory tissue
has been demonstrated [Fischel-Ghodsian et al., 1997].
The acquired mitochondrial mutation that occurs most
frequently in humans is the mitochondrial deletion
mtDNA
4977
, which deletes 4977 bp between two 13-bp re-
peats starting at nucleotides 8470 and 13447. Analyses of
human temporal bones indicated that mtDNA
4977
, the so-
called ‘common’ deletion, occurred frequently in ARHI
patients [Bai et al., 1997; Dai, 2004], while it was almost
absent in age-matched control patients without a history
of ARHI [Seidman et a l., 1996]. Similar analyses were con-
ducted in rats, where a 4834-bp deletion was associated
with ARHI and ageing in general [Seidman et al., 1997].
Cells that accumulate large numbers of mitochondrial
mutations become bioenergetically deficient [Seidman et
al., 2002a], with cell loss as a consequence. This is main-
ly a problem in postmitotic tissue, like the inner ear,
where no regeneration of cells is possible, resulting in a
permanent loss of sensory cells. Mitochondrial metabo-
lites, which upregulate mitochondrial function and im-
prove energy-producing capabilities within the cell, have
been shown to delay the progression of cellular losses and
ARHI [Seidman et al., 2000].
Reactive oxygen species (ROS), like the superoxide an-
ion, hydroxyl and peroxyl, are produced both in healthy
and diseased state and are controlled by antioxidant de-
fense mechanisms. Although these repair mechanisms
exist, an imbalance between production and removal of
ROS can occur, with oxidative stress as a consequence
[Evans and Halliwell, 1999]. While investigating oxida-
tive stress in the cochlea of ageing CBA/J mice, Jiang et
al. [2006] detected different ROS and time-specific oxida-
tive changes in the different tissues of the ageing cochlea.
Actions of free oxygen radicals may cause genetic and cel-
lular alterations preceding cell dysfunction with senes-
cence as a consequence [Seidman et al., 2002a]. As such,
ROS have been implicated in ARHI by several lines of
evidence. For example, in 24-month-old Fisher rats, the
glutathione level is reduced by 86% in the auditory nerve
[Lautermann et al., 1997]. As glutathione is a scavenger
for ROS, this may increase the concentration of free rad-
icals in the inner ear. In addition, Unal et al. [2005] de-
tected an association for N-acetyltransferase and ARHI
in humans. N-acetyltransferases are known to contribute
to the detoxification process of exogenic compounds and
the protection against ROS by N-acetylation or O-acety-
lation of the toxic compounds.
The superoxide anion is the most common ROS. It
causes auditory sensory cell damage, eventually resulting
in apoptosis of auditory neurons and hair cells [Huang et
al., 2000]. Superoxide dismutases (SODs) form the first
line of defense against cochlear damage caused by super-
oxide anion [Coling et al., 2003]. Under normal circum-
stances, copper/zinc superoxide dismutase (SOD1) is
highly expressed within the cochlea. SOD1 deficiency in
mice induces cochlear hair cell degeneration and loss of
spiral ganglion cells and nerve fibers, with ARHI as a
consequence [McFadden et al., 1999a, b, 2001]. Lecithin,
a polyunsaturated phosphatidylcholine responsible for
SOD activation, has a protective effect and preserves the
hearing abilities in ageing subjects [Seidman et al.,
2002b].
T h e r a p i e s
The only intervention currently available for subjects
with ARHI is a hearing aid. Although hearing aids can
improve the hearing ability of affected individuals, they
are only suitable for a limited number of people. This is
mainly due to the limited efficacy in improving speech
understanding, especially in noisy environments. Future
therapies for ARHI might rely on basic rather than on
symptomatic approaches. This requires a better under-
standing of the molecular and cellular processes taking
place in the inner ear, which will demand further re-
search efforts.
One of the possible future strategies is gene therapy.
Recently, a very promising gene therapeutic experiment
has been conducted, which raises hopes for the future. By
the introduction of Math1, a gene that is important in
hair cell development in the cochlea, regrowth of hair
cells has been obtained. Most interestingly, the recovery
of hearing abilities could be demonstrated in mice [Izu-
mikawa et al., 2005].
Many different administration routes for gene therapy
have been suggested, such as infusion with osmotic mini-
pumps, direct microinjection into the cochlea and appli-
cation of a vector-transgene complex-soaked Gelfoam
directly onto the round window [Lalwani et al., 2002].
Similar approaches can also be used to administer phar-
macological substances into the inner ear [Wang et al.,
2002], such as antioxidants [Lefebvre et al., 2002] and
growth factors [Bowers et al., 2002; Lefebvre et al., 2002;
Malgrange et al., 2002].
Due to the identification of ARHI susceptibility genes
new leads for pharmacological intervention may be dis-
Complexity of Age-Related Hearing
Impairment
Audiol Neurotol 2007;12:345–358
355
covered. To administer pharmacological substances, two
strategies can be used: systemic administration, and local
therapy. Systemic therapy requires high doses of the drug,
which might lead to toxic high concentrations, while due
to the isolated localization of the cochlea, high drug con-
centrations can be obtained within the inner ear by means
of local therapy. However, a disadvantage of local therapy
is the fact that it is invasive and potentially harmful for the
cochlea. In the future, this may be circumvented by new
and safer administration routes such as described above.
Another treatment strategy under development is the
implantation of stem cells. Ito et al. [2001] demonstrated
that neural stem cells survive when grafted into newborn
rat cochleae. These neural stem cells adopted the mor-
phologies and positions of hair cells and were well adapt-
ed to the environment of the cochlea [Ito et al., 2001]. Also,
stem cells and embryonic neurons transplanted in the in-
ner ear have been shown to survive, migrate, differentiate
and extend neurotic projections in the auditory system of
adult mammals [Hu and Ulfendahl, 2006]. Rivolta et al.
[2006] succeeded in the generation of inner ear progenitor
cells from murine embryonic cells, which were subse-
quently differentiated into hair cells and potentially also
into other inner ear cell types. Out of all these efforts, a
new treatment for ARHI may arise in the future.
C o n c l u s i o n
Despite the growing interest in ARHI as a complex
disease, currently little is known about the genetic factors
contributing to the disease. Up to now, the emphasis has
been on the investigation of the contribution of environ-
mental factors. Although there is still some controversy
about some of these, the results obtained for environmen-
tal factors start to contribute to the formulation of pre-
vention strategies for ARHI.
The first steps to elucidate the genetic factors involved
in ARHI have also been made. Genome-wide linkage
studies have resulted in seven candidate susceptibility
regions for ARHI [DeStefano et al., 2003; Garringer et
al., 2006]. Association studies have revealed the first two
genes involved in ARHI [Unal et al., 2005; Van Eyken et
al., 2006]. The newly found genetic interest in ARHI will
result in the identification of several susceptibility genes
in the coming years. This will surely have an impact on
our molecular genetic knowledge of the disease, and
will, hopefully, in the long term lead to the development
of new treatments. As the overall population is still age-
ing, and as hearing loss is the most common sensory
impairment affecting the elderly, these new therapies
will surely contribute to a better quality of life and im-
proved economic productivity for an increasing number
of people.
Acknowledgements
E.V.E. holds a predoctoral research position with the Instituut
voor aanmoediging van Innovatie voor Wetenschap en Technolo-
gie van Vlaanderen (IWT-Vlaanderen). This work is supported by
grants from the FWO-Vlaanderen (to G.V.C.) and from the Uni-
versity of Antwerp (to G.V.C).
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