New Therapies to Prevent or Cure Auditory Disorders 1st
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Introduction
Hearing disorders affect more than 15% of people worldwide. One out
of three people over 65 years of age has disabling hearing loss, with
80% of young people at significant risk of hearing impairment. The
World Health Organization (WHO) estimates that by 2050, 10% of the
world’s population will have disabling hearing loss. Currently,
sensorineural hearing loss (SNHL) is the most common type of hearing
disorder, accounting for almost 90% of reported hearing loss. SNHL is
characterized by the loss of sensory hair cells in the cochlea and/or
neural damage in the auditory pathway. Since hair cells cannot
regenerate in the human cochlea, SNHL is permanent. Multifactorial
etiologies for SNHL include aging, noisy lifestyles and work
environments, infections, and more than 300 ototoxic drugs on the
market, including the commonly used cancer drug cisplatin. This
volume provides an up-to-date resource on the mechanisms underlying
hearing disorders, including related pathologies such as tinnitus, a
phantom auditory sensation, and hyperacusis, a loudness intolerance
disorder, and provides potential strategies for ameliorating auditory
dysfunction.
The first chapter by Shinichi Someya et al. provides an overview of
the current literature on interventions for age-related hearing loss
(AHL), also known as presbycusis, with a particular emphasis on
calorie restriction (CR), a lifestyle-based intervention. Chapter 1 details
the mechanisms underlying the beneficial effects of CR on auditory
function in laboratory animals and humans. Chapter 2 by Celia Escabi
et al. describes the anatomical, physiological, and perceptual
consequences of noise trauma, as well as emerging treatments to alter
the biological mechanisms, broadly classified as metabolic (oxidative
stress, excitotoxicity, or apoptosis) or mechanical, that normally lead to
injury and death of cells in the organ of Corti, spiral ganglion, and/or
the lateral wall.
Chapter 3 by Chaitanya Mamillapalli et al. outlines the effects of
ototoxic drugs, primarily cisplatin, cyclodextrins, and aminoglycosides,
on the auditory system, and potential strategies to mitigate their impact
on hearing. Chapter 4 by Muhammad Waqas and Renjie Chai details the
most promising therapeutic approaches to regenerate cochlear hair
cells (HCs) and spiral ganglion neurons (SGNs) including gene therapy
and stem cell therapy. Chapter 5 by Bohua Hu and Celia Zhang
describes cochlear inflammatory activities in acute and chronic stress
conditions and suggests that controlling the cochlear immune state
could offer protection against pathogenesis.
In Chap. 6 , Kelly E. Radziwon et al. provide a review on hyperacusis,
including its definition and various manifestations, and describe the
available behavioral procedures used to induce and study hyperacusis
in preclinical animal models. The final chapter (Chap. 7 ) by Amandine
Laboulais et al. introduces two robust measures of hearing loss and
tinnitus in preclinical models involving a new automatic counting
method to quantify hair cell loss and an objective imaging method
developed during a collaborative project between CILcare, KeenEye,
and Charles Coulomb Laboratory. Ultimately, the goal of each chapter is
to provide relevant insight into current models of hearing disorders,
including their underlying mechanisms, which will help pharmaceutical
and biotechnology companies develop therapies to treat and prevent
these hearing impairments.
Richard Salvi
Sylvie Pucheu
Kelly E. Radziwon
Buffalo, NY, USA, CILcare, Advanced Solution for Drug Development
in Hearing Disorder, Montpellier, France, Buffalo, NY, USA
Contents
Lifestyle Intervention to Prevent Age-Related Hearing Loss:
Calorie Restriction
Shinichi Someya, Christina Rothenberger and Mi-Jung Kim
Noise-Induced Hearing Loss and Drug Therapy:Basic and
Translational Science
Celia Escabi, Monica Trevino, Eric Bielefeld and Edward Lobarinas
Review of Ototoxic Drugs and Treatment Strategies for Reducing
Hearing Loss
Chaitanya Mamillapalli, Asmita Dhukhwa, Sandeep Sheth,
Debashree Mukherjea, Leonard P. Rybak and Vickram Ramkumar
Approaches to Regenerate Hair Cell and Spiral Ganglion Neuron in
the Inner Ear
Muhammad Waqas and Renjie Chai
Immune System and Macrophage Activation in the Cochlea:
Implication for Therapeutic Intervention
Bo hua Hu and Celia Zhang
Preclinical Animal Behavioral Models of Hyperacusis and
Loudness Recruitment
Kelly E. Radziwon, Senthilvelan Manohar, Benjamin Auerbach,
Xiaopeng Liu, Guang-Di Chen and Richard Salvi
New Automatic and Robust Measures to Evaluate Hearing Loss and
Tinnitus in Preclinical Models
A. Laboulais, S. Malmströ m, C. Dejean, M. Cardoso, T. Le Meur,
L. Almeida, C. Goze-Bac and S. Pucheu
© Springer Nature Switzerland AG 2020
S. Pucheu et al. (eds.), New Therapies to Prevent or Cure Auditory Disorders
https://doi.org/10.1007/978-3-030-40413-0_1
Lifestyle Intervention to Prevent Age-
Related Hearing Loss: Calorie
Restriction
Shinichi Someya1 , Christina Rothenberger1 and Mi-Jung Kim1
(1) Department of Aging and Geriatric Research, University of Florida,
Gainesville, FL, USA
Shinichi Someya
Email: [email protected]
Keywords Calorie restriction – Oxidative stress – Mitochondrial
dysfunction – Obesity – Aging
Abbreviations
•O2− Superoxide
•OH Hydroxyl radical
ABR Auditory brainstem response
AHL Age-related hearing loss
CAT Catalase
Complex I NADH dehydrogenase
Complex III Ubiquinone–cytochrome c reductase
CR Calorie restriction
GPX1 Glutathione peroxidase 1
GSH Reduced glutathione
GSR Glutathione reductase
GSSG Oxidized glutathione
GSTM1 Glutathione S-transferase mu 1
GSTP1 Glutathione S-transferase pi 1
GSTT1 Glutathione S-transferase theta 1
H2O2 Hydrogen peroxide
IHC Inner hair cells
mtDNA Mitochondrial DNA
NIA National Institute on Aging
NIHL Noise-induced hearing loss
OHC Outer hair cells
PRDX3 Peroxiredoxin 3
ROS Reactive oxygen species
SGN Spiral ganglion neuron
SOD1 Superoxide dismutase 1
SOD2 Superoxide dismutase 2
SV Stria vascularis
TXNRD Thioredoxin reductase
UW University of Wisconsin–Madison
1 Introduction
An accumulating body of evidence indicates that reducing calorie intake
or calorie restriction (CR) extends life span in diverse species and
delays the onset of a variety of age-related diseases, including
hypertension, diabetes, cancer, and cardiovascular disease in laboratory
animals. In humans, CR reduces the incidence of obesity and levels of
cholesterol, blood pressure, oxidative stress, and inflammation, and
increases insulin resistance [1]. In general, CR results in weight loss,
which in turn increases health span of experimental animals [1–3]. The
anti-aging effects of CR require significant reduction of body weight
through reducing food consumption. This idea is supported by the
observation that food shortages during World War I in European
countries were associated with a sharp decrease in coronary heart
disease mortality, which increased again after the war ended [4].
Another study among Spanish nursing home residents undergoing
long-term alternate day feeding regimen also demonstrated decreased
morbidity and mortality [5]. In Japan, inhabitants of Okinawa island,
who ate ~30% fewer calories than the rest of Japanese residents, had
~35% lower rates of cardiovascular disease and cancer mortality than
the average Japanese population and had one of the highest numbers of
centenarians in the world [6]. However, due to Westernization of their
diet and/or excessive calorie intake, the life expectancy at birth for men
in Okinawa is now no higher than the national average in Japan,
reflecting increased mortality due to the increase in heart disease and
cerebrovascular disease [7].
Dietary weight loss can also impact physical function by improving
muscle quality and reducing intramuscular adipose tissue [8, 9].
Consistent with these reports, age-related hearing loss (AHL), a
common feature of aging, is also associated with decreased physical
function among older adults [10, 11], while long-term exercise reduces
body weight and slows the progression of AHL in mice [12]. Increasing
evidence indicates that CR has beneficial effects on hearing in
laboratory animals. This chapter reviews the current literature on
interventions for AHL, particularly focusing on a lifestyle-based
intervention, CR, and what has been learned about the mechanisms
underlying the beneficial effects of CR on auditory function in
laboratory animals and humans.
2 Effects of Age on Auditory Function
Hearing gradually declines with age in laboratory animals and humans
[13]. Hearing loss is the third most prevalent chronic health condition
affecting older adults and AHL, also known as presbycusis, is the most
common form of hearing impairment [13–15]. WHO estimates that
one-third of persons over 65 years are affected by disabling hearing
loss [16]. Worldwide, approximately 466 million people suffer from
hearing impairment and this number is expected to rise to 630 million
by 2030 and over 900 million in 2050 [16]. Approximately, 30 million
or 13% of Americans 12 years and older have bilateral hearing loss in
2001–2008, and this number rises to 48 million when individuals with
unilateral hearing loss are included [17]. Because the prevalence of
AHL is expected to rise dramatically as the world’s population ages,
AHL will become a major social and health care problem for which
there are no established cures or treatments.
AHL is characterized by poor speech understanding particularly in
noise, impaired temporal resolution, and central auditory processing
deficits [13–15]. AHL is also associated with dementia [18]. Despite its
name, AHL is likely a multifactorial condition resulting from the
interaction of numerous causes including aging, exposure to noise and
ototoxic chemicals, genetics, epigenetic variables, comorbidities, and
lifestyle [13]. The major sites of age-related cochlear pathology include
inner hair cells (IHC), outer hair cells (OHC), spiral ganglion neurons
(SGN), stria vascularis (SV), and synaptic loss [13, 14, 19]. The IHC are
the sensory receptors that relay their electrical response to the central
auditory system through the SGN [20]. Postmitotic hair cells and SGN
are particularly susceptible to injury from a combination of noise
exposure, ototoxic chemicals, and oxidative damage [13, 14]. The blood
vessels coursing through the cochlea are essential for transporting
oxygen and nutrients such as glucose into the cochlea [13]. Thus, age-
related degeneration of the hair cells, SGN, and cochlear vasculature
will disrupt auditory function and lead to permanent hearing
impairment. Schuknecht [21] identified four major categories of
presbycusis, namely (1) sensory (hair cell loss), (2) neural (SGN loss),
(3) strial (SV degeneration), and (4) cochlear conductive based on
correlations between cochlear pathology and the audiogram. Numerous
studies indicate that age-related degeneration of the stria vascularis is
one of the most prominent features of AHL in animals and humans [14,
22]. Indeed, AHL is often associated with significant loss of strial
capillaries in the lateral wall of the gerbil cochlea [23], suggesting that
an age-related decline in blood flow, oxygen, and nutrient transport to
the cochlea plays a key role in the development of AHL.
3 Effects of Calorie Restriction on Aging
An accumulating body of evidence indicates that reducing calorie
intake, i.e., CR, is the only intervention that can slow the rate of aging in
diverse species. Indeed, CR extends the life span of rodents, nonhuman
primates, birds, protozoans, water fleas, spiders, and guppies [1, 3]. CR
also delays the onset of a variety of age-related diseases, including
hypertension, diabetes, cancer, cardiovascular disease, Parkinson’s
disease, Alzheimer’s disease, cataracts, and AHL in rodents [1–3, 24]. In
rhesus monkeys, CR results in signs of improved health, including
reduced incidence of obesity, diabetes, and tumors [25, 26]. In humans,
CR reduces the incidence of obesity, levels of cholesterol, blood
pressure, oxidative stress, and inflammation, and increases insulin
resistance [1]. At the molecular level, CR results in a reduction in the
levels of oxidative protein damage in the brain, heart, and liver of aged
mice [27].
Maximum life span is thought to be increased by reducing the rate
of aging, while the average life span is primarily influenced by
improving environmental conditions [1–3]. Consistent with this idea,
the average life span of humans has dramatically increased as a result
of improved diet and environmental health conditions, whereas the
maximum life span has remained largely unchanged. Herein, we review
the current literature on the beneficial effects of CR on AHL in
laboratory animals and humans.
3.1 Types of Calorie Restriction Regimens
Two different dietary feeding regimens of CR have been widely used
because of their feasibility and ability to reliably slow aging in
laboratory animals [28]. In an “every day feeding” regimen, animals
receive food daily, but are limited to a specified amount which is usually
30–50% less than the ad libitum consumption by the control group. In
an “every other day feeding” or “intermittent fasting” regimen, animals
are deprived of food for a full day, every other day, and are fed ad
libitum on the intervening days. In animal CR studies, the species are
generally housed individually since it allows for the food intake of each
animal to be controlled with great accuracy [29].
3.2 Effects of Calorie Restriction on Hearing Loss in
Laboratory Animals
Increasing evidence indicates that CR has beneficial effects on auditory
function in laboratory rodents. The C57BL/6 (B6) mouse strain has
been used extensively to study aging and this murine species responds
to CR with a robust extension of life span [2, 30]. B6 mice also display
the classic pattern of AHL, which includes severe to profound loss of
hearing beginning at the high frequencies and loss of high-frequency,
basal turn cochlear hair cells by 10–12 months of age [31, 32]. To
investigate the effects of CR on AHL in B6 mice, Someya et al. [24]
restricted the calorie intake of male B6 mice to 75% of that given to
control mice starting at 2 months of age using an every other day
feeding regime. Both control and CR mice were fed diets only on
Mondays, Wednesdays, and Fridays. CR mice received 63 kcal/week of
the diet, while control mice received 84 kcal/week of the diet. The
control mice were not fed ad libitum daily to avoid large individual
variations among the caloric intake of the control group and obesity.
These animals were housed individually until they reached 12 months
of age or for a 13-month period. Auditory brainstem response (ABR)
testing was used to assess hearing sensitivity in these animals. Middle-
age control diet mice displayed profound hearing loss at 4, 8, and
16 kHz, whereas the thresholds of age-matched CR mice were
significantly lower than those age-matched controls. However, the
thresholds of CR and controls were not significantly different from one
another at 4 months of age at all the frequencies measured. These
results indicate that CR can slow the onset of AHL that would otherwise
occur in male B6 mice by 15 months of age. CR mice weighed 25% less
than the controls and displayed only minor cochlear degeneration
compared to age-matched control diet mice. Willott et al. [33] also
investigated the effects of CR on AHL in B6 mice. Male B6 mice were
calorie restricted to 70% of the control intake. Animals were housed
four per cage for a 22-month period from 1 month of age until
23 months of age and fed the CR or control measured amount of food
daily. Total amounts of all diet components except starch and corn oil
were the same. ABR testing was used to monitor hearing sensitivity and
the progression of AHL. Consistent with the report by Someya and
coworkers [24], CR significantly reduced SGN loss compared to
controls. However, no ABR thresholds were measureable at 4, 8, 16, 24,
and 32 kHz in both the control and CR mice at 23 months of age,
indicating that all the mice displayed complete to nearly complete
hearing loss. This may be due to the fact that the time at which hearing
was measured in these B6 (23 months of age) was too late for CR to be
beneficial since the B6 strains develop severe to complete hearing loss
by 10–12 months of age [31, 32]. Summaries of studies demonstrating
beneficial effects of CR on AHL in laboratory animals are given in Table
1.
Table 1 Studies demonstrating beneficial effects of CR on hearing in laboratory animals
Species Sex CR method Beneficial effects (age at test) Reference
(strain)
Mouse
C57BL/6 Male Every other Lower ABR thresholds (15 months old) [24]
day
25% CR
CBA/J NA Every other Lower ABR thresholds (27 months old) [34]
day
AU/Ss NA Every other Lower ABR thresholds (18 months old) [35]
day
Rat
Fischer 344 NA Every day Lower ABR thresholds (24–25 months [36]
old)
30% CR
Sprague– Female Every day Reduced degeneration of SV (30 months [37]
Dawley old)
30% CR
Monkey
Rhesus monkey Male Every day Larger ABR wave amplitudes (11–23 [38]
years old)
Female 30% CR
The CBA/J (CBA) mouse strain is long-lived (mean life
span = 679 days) [39], has normal hearing until later in life, and
displays AHL by 18–20 months of age [32, 34]. Sweet and coworkers
[34] investigated the effects of CR on CBA mice. CR animals were fed
standard lab chow ad libitum every other day (on Mondays,
Wednesdays, and Fridays), while control mice were fed ad libitum daily
from 2 until 10 months of age or for an 8-month period (early-onset
CR) or from 10 until 27 months of age for a 17-month period (middle
age-onset CR). All mice were housed with one to three per cage and
ABR testing was used to assess hearing sensitivity. Both control and CR
mice from the early-onset CR study displayed similar ABR threshold
elevations at 4, 8, 16, 32, and 64 kHz at 10 months of age. However, in
the middle-age-onset CR study, the mean ABR thresholds from CR mice
were significantly lower than those of control mice at 8, 16, and 32 kHz
at 27 months of age (Table 1), indicating that middle-age onset CR can
delay the onset of AHL in CBA mice.
The AU/Ss (AU) mouse strain has normal hearing in early life, but
develops gradual hearing loss in the second half of its life. The AKR
strain is a short-lived mouse strain (mean life span = 323 days) [39]
and develops early onset of hearing loss by 1–2 months of age [35].
Henry [35] investigated the effects of CR on AHL in AU and AKR mice.
CR animals were fed standard lab chow ad libitum every other day on
Mondays, Wednesdays, and Fridays, while control mice were fed ad
libitum daily from 1 until 18 months of age for a 17-month period. All
mice were housed one to three per cage and ABR testing was used to
monitor the progression of AHL. At 18 months of age, the mean ABR
thresholds of CR mice at 2, 4, 8, 32, and 64 kHz were significantly lower
than those of controls, indicating that CR delayed the onset of AHL in
AU mice (Table 1). CR mice also weighed 14% less than controls. In the
CR study of AKR mice, CR animals were fed standard lab chow ad
libitum every other day on Mondays, Wednesdays, and Fridays, while
control mice were fed ad libitum daily from 2 until 4 months of age for a
2-month period. At 4 months of age, both control and CR mice
displayed large threshold elevations at 2, 4, 32, and 64 kHz, and there
were no differences in hearing threshold between control and CR
animals at all the frequencies measured. This may be due to the fact
that the onset of AHL in this strain occurs at a very young age (1–
2 months of age), which may be too early for CR to be beneficial.
The Fischer 344 rat strain is long-lived with a median life span of
28–31 months [40] and develops age-related loss of hair cells and SGN
cells and hearing loss by 18–20 months of age that begins in the high
frequencies [41, 42]. In a study of CR in male Fischer 344 rats, animals
were calorie restricted to 70% of the control intake from 2 months of
age until 24–25 months of age [36]. Rats were housed individually. CR
rats were fed 11.2 g of a standard rodent diet daily, while control rats
were fed ad libitum. The Fischer 344 strain of rats displayed severe
hearing loss by 20 months of age [36]. At 24–25 months of age, both
control and CR rats displayed large ABR threshold elevations at 3, 6, 9,
12, and 18 kHz, but the mean ABR thresholds of CR rats were
significantly lower than those of controls at all the frequencies
measured. Old CR animals also had significantly less hair cell loss
compared to age-matched controls suggesting that CR delays the onset
of AHL in Fischer 344 rats by suppressing hair cell degeneration (Table
1).
The Sprague–Dawley rat strain also exhibits a loss of hair cells and
spiral ganglion neurons that increases with age [43, 44] and severe age-
related hearing loss by 18–20 months of age [45]. In female Sprague–
Dawley rats, animals were calorie restricted to 70% of the control
intake from 2 months of age until 30 months of age. Rats were group-
housed three or four per cage and control rats were fed ad libitum [37].
In the CR groups, 73% of the CR rats displayed only modest
degeneration of the SV, while age-matched control diet rats showed a
marked thinning, cellular degeneration, and loss of cell processes in the
SV (Table 1). The extent of loss of sensory hair cells was similar in both
CR and control diet groups, while neither group showed a significant
reduction in the number of SGN across their adult life span. These
results indicate that CR delayed age-related degeneration of SV in
Sprague–Dawley rats rather than delaying the degeneration of hair cells
or SGN.
Rhesus monkeys are long-lived nonhuman primates with a
maximum life span of 40 years [46] and display decreased auditory
function by 25–31 years of age [46, 47]. Currently, there are two studies
ongoing at the University of Wisconsin–Madison (UW) and the National
Institute on Aging (NIA) designed to investigate the effects CR on life
span and health span in rhesus monkeys [25, 26]. In the UW study, CR
was maintained at 30% less than the calories consumed by the ad
libitum group for a period of 3–9 years [25]. The animals were housed
individually to minimize aggressive encounters and to control food
access. All animals were daily fed pelleted, semi-purified diets, which
contained 15% lactalbumin, 10% corn oil, and 65% carbohydrate in the
form of sucrose and corn starch. At the time of the auditory tests, the
ages of the monkeys were 11–23 years. ABR testing was used to
monitor the progression of AHL [38]. The authors found that: (1) wave I
amplitudes were larger for females and for younger monkeys than male
monkeys, (2) amplitudes decreased in aging males, (3) wave IV
amplitudes were larger for females than males, (4) wave IV amplitudes
for CR females were larger than for female controls, whereas the
amplitudes from control and CR males were not different, and (5) the
mean ABR threshold (click stimuli) of CR male monkeys was lower than
that of control males, but the difference was not statistically significant
(Table 1). In general, these results were in agreement with the previous
reports that women of virtually all ages demonstrate lower hearing
thresholds, shorter auditory brainstem response (ABR) latencies, and
larger ABR amplitudes than men [17, 48–54]. Together, these results
indicate that CR delayed age-related decline in some components of
auditory function in aged monkeys. In the NIA study, CR was
maintained at 30% less than the calories consumed by the control
group [55]. Dietary feeding and housing regimens were similar to those
of the UW study. ABR testing was used to monitor the progression of
AHL. In contrast to the UW study, no significant effects of CR were
found on any ABR parameters examined. At the time of the hearing
tests, the age range of the control diet monkeys was 13–32 years, while
that of the CR monkeys was 13–36 years. Therefore, the lack of effect of
CR may be due to the fact that some of the monkeys were still relatively
young at the time of the tests and had not reached the age (~25 years)
at which AHL begins to be clearly evident with hearing tests where CR
is most likely to have an effect on auditory function.
4 Mechanisms Underlying the Beneficial
Effects of CR on AHL
It is well documented that CR delays the development of a variety of
age-related diseases and extends life span in a variety of species [1–3].
Despite numerous reports, the question still remains whether CR slows
aging and other disease in long-living humans. This is primarily
because the maximum life span of humans is 122+ years and it is
impractical as well as unethical to conduct randomized, diet-controlled,
long-term survival studies in humans. Similarly, the beneficial effects of
CR against human AHL have not been tested. Nonetheless, increasing
evidence from animal research suggests that CR likely has beneficial
effects on human auditory function. Herein, we discuss the potential
mechanisms underlying the beneficial effects of CR on the auditory
system in mammals.
4.1 Oxidative Stress
It is well documented that CR reduces oxidative damage to DNA,
proteins, and lipids [13–15, 56, 57] caused by reactive oxygen species
(ROS) [2, 56, 58]. Mitochondria are a major source of ROS and ROS are
known to damage key cellular components, including nuclear DNA,
mitochondrial DNA (mtDNA), membranes, enzymes, and proteins [56].
Such damage accumulates with age, causes cell death, and eventually
leads to tissue dysfunction. The majority of intracellular ROS are
continuously generated as a by-product of mitochondrial respiratory
metabolism during the generation of ATP [56, 58]. These ROS include
superoxide (•O2−) and the hydroxyl radical (•OH), which are extremely
reactive, and hydrogen peroxide (H2O2) that is freely diffusible and
relatively long-lived [59, 60]. The production of superoxide as a by-
product of mitochondrial respiration metabolism is thought to occur at
two mitochondrial electron transport chain sites: Complex I (NADH
dehydrogenase) and Complex III (ubiquinone–cytochrome c reductase).
But under normal metabolic conditions, Complex III is thought to be the
main site of ROS production (Fig. 1).
Fig. 1 The production of superoxide as a by-product of mitochondrial respiration metabolism.
The production of superoxide as a by-product of mitochondrial respiration metabolism is thought
to occur at two mitochondrial electron transport chain sites: Complex I (NADH dehydrogenase)
and Complex III (ubiquinone–cytochrome c reductase). But under normal metabolic conditions,
Complex III is thought to be the main site of ROS production
An elaborate defense system has evolved to reduce the damaging
effects of ROS. This system includes the antioxidant enzymes such as
superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase
(GPX), glutathione reductase (GSR), peroxiredoxin (PRDX), and
thioredoxin reductase (TXNRD) [59, 60]. In mitochondria, SOD2
converts superoxide into hydrogen peroxide, which in turn is
decomposed to water by GPX1 or PRDX3, thereby protecting key cell
components such as nuclear DNA, mtDNA, proteins, and lipids from
ROS-induced damage (Fig. 2). A variety of small-molecule antioxidants
also scavenge ROS. These include glutathione, thioredoxin, carotenoids,
ascorbate, and flavonoids [59–61]. Evidence indicates that the
mitochondrial antioxidant defense systems do not keep pace with the
age-related increase in ROS production, and that during aging, the
balance between the antioxidant defenses and ROS production shifts
progressively toward a more pro-oxidant state [62]. Thus, the balance
between ROS production and antioxidant defenses may determine the
degree of ROS-induced oxidative damage.
Fig. 2 Mitochondrial antioxidant defense system. In mitochondria, SOD2 converts superoxide into
hydrogen peroxide, which in turn is decomposed to water by GPX1 or PRDX3, thereby protecting
key cell components such as nuclear DNA, mtDNA, proteins, and lipids from ROS-induced damage
Increased production of ROS is thought to play a role in driving the
aging process and the development of age-related disease [2, 56, 58].
This idea is supported by the fact that overexpressing the
mitochondrial antioxidant gene Sod2 [63] or the mitochondrial iron
regulator protein frataxin [64] significantly increases longevity in
Drosophila. Similarly, overexpressing a mitochondrially targeted
catalase gene (CAT) results in reduced age-related pathology and a
moderate increase in life span in mice [65]. ROS are thought to play a
major role in AHL [13, 66–68]. Several studies have shown that ROS are
generated in cochleae exposed to high-intensity noise [69]. Age-related
cochlear hair cell loss is enhanced in mice lacking the antioxidant
enzyme Sod1 [70], while mice lacking the antioxidant enzymes Gpx1
[71] or Sod1 [72] show enhanced susceptibility to noise-induced
hearing loss. Moreover, oxidative protein damage increases with age in
the cochleae of CBA/J mice [73]. Overexpression of mitochondrially
targeted CAT also results in decreased loss of outer hair cells and inner
hair cells in the cochlea and lower ABR thresholds compared to age-
matched wild-type mice [74]. In agreement with the ABR results,
cochlear oxidative DNA damage increased during aging, while oxidative
