*Corresponding author:Aliocha Nkodila Natuhoyila, Faculty of Public Health, Lomo University of Research, Democratic Republic of Congo
How to cite this article: Sokolo G J, Longo MB, Lepira B F, Mvitu M M, Mambueni T C, et al. Oxidative Stress, Sensorineural Deafness Linked to
Advancing Age - Presbycusis: Systematic Review. Glob J Oto, 2020; 23 (4): 556118 DOI: 10.19080/GJO.2020.23.556118
Background: Oxidative stress in the elderly is a serious problem due to the alteration of the otological system and leads to presbycusis. The aims of this study were to reduce information bias and disseminate the European consensus around oxidative stress in the face of certain controversies around this stress in presbycusis.
Methods: a systematic review using the google scholar, Medline, Home Pubmed, Home PMC and DMS / CDC / ONU / STDA engines, provided scientific and information on oxidative stress, deafness and presbycusis.
Results: This systematic review showed that deafness linked to sound trauma to muscular sound exposure or other loud noises such as gunfire or explosions and to a multifactorial etiology. Aging leads to progressive hearing loss (presbycusis) which is linked to the damage produced by free radicals during oxidative stress.
Conclusion: The complexity of the effects of senescence, senility, genetic factors during fetal life, ecotoxic effects and mutations are involved in presbycusis.
Keywords: Oxidative stress; Advancement in age; Presbycusis; Free radicals
Sensorineural deafness (SNS) linked to advancing age, or presbycusis, is currently the subject of concern of scientific researchers . Indeed, presbycusis is a hearing disorder that develops by a gradual and constant decrease with advancing age or senescence if not natural physiological appearance of the auditory system after the age of 60 years [2-5]. The decrease in average hearing in the very high frequencies from the age of 25 varies according to individuals from 0.5dB per year and accentuated from 65 years, 1dB from 75 years and 2dB from 85 years old . Biological plausibility has also accumulated information relating to oxidative (oxidative) stress in general (1) and oxidative stress in deafness associated with advancing age
better defined as presbycusis in particular [3-8]. Understanding the typical etiology and physiopathological mechanisms allows a holistic approach to oxidative stress in seniors . Thus, the objective of this systematic review was to reduce information bias and disseminate the European consensus around oxidative stress in the face of certain controversies around this stress in presbycusis .
Engines including google scholar, Medline, Home Pubmed, Home PMC and DMS / CDC / ONU / STDA, were used to organize scientific and factual information (evidence = Factorial medicine / Evidence based medicine) around the following
keywords: oxidative stress, deafness and presbycusis [10-12].
The information has been rigorously presented according to the
A. describe the main reactive radicular or non-radicular
a. oxidative stress and mechanisms.
b. etiopathogenic form of deafness.
c. physiopathology of presbycusis in chronobiology /
B. highlight the gene candidate for presbycusis, oxidative
stress and mitochondrial dysfunction:
a. mitochondrial DNA deletion and mutation and
b. animal model of the role of oxidative stress and
mitochondrial dysfunction in presbycusis.
c. preventive approach and action for the late onset of
presbycusis: supplementation / diet and / or calorie restriction.
Presbycusis has been characterized by the following main
a. neurosensory presbycusis in hearing loss involving only
the high frequencies.
b. nervous presbycusis leading to a disturbance of the
thresholds on the acute frequencies and the distinction of
alterations in blood circulation for all frequencies.
c. Mechanical presbycusis disturbs acute frequencies .
Epidemiology of deafness
The World Health Organization (WHO) considers hearing
impairment as concepts of severity-progression: less severe
disabling hearing loss and deafness, a profound progression
from disabling hearing loss [9,14]. Disabling hearing loss forms
deafness according to the advancement of age from childhood
through adulthood to senescence / senility in the world: disabling
hearing loss in children (hearing loss ≥30 dB at tonal audiometry
[9,14,15] with 60% of cases where 34 million among the 466
million people in the world including adults (hearing loss ≥40 dB
in the better ear) in the world [9,15].
The risk factors for deafness vary according to the clinical
forms and the chronobiology at birth have been clearly defined
and updated by Joint Committe or Infant Hearing [16,17]
congenital infections (Rubella, syphilis, CMV, herpes simplex,
toxoplasm), chickenpox zoster, HIV, weight<1000g, premature,
perinatal hypoxia, hyperbilirubinemia, taking ototoxic drugs by
the pregnant mother, bacterial meningitis, the most common
mutation (conferring high risk of congenital deafness and
perinatal deafness) is that of connexin 26, a protein involved in
the ionic exchanges of the organ of corti [18-20].
a) hearing loss related to sound trauma is linked to the
professional use of noisy devices, to muscular sound exposure or
to other loud noises such as gunfire or blasts and to a multifactorial
b) aging leads to progressive hearing loss (presbycusis).
This presbycusis is the main cause of deafness [21-23].
Origin of presbycusis
Presbycusis is a gradual and insidious hearing loss affecting
both ears symmetrically, particularly at high frequencies, the
effects of which are accentuated in a noisy environment [9,22-27].
Presbycusis affects more than a third of people aged between 60
and 70 in their old age, more than 80% of people over 80 [22-
27]. It causes cognitive, social, and physical disorders. Presbycusis
is an umbrella term for deafness associated with aging [22-27].
The origin of presbycusis is multifactorial, and results from the
physiological aging of the cochlea; In addition, there are additional
effects of extrinsic (exposure to noise, ototoxic drugs) and intrinsic
(systemic diseases and genetic disposition) factors [24,28]. The
etiology of presbycusis is complex, and several factors are involved
. It is the result of an age-related physiological degeneration
of cochlear structures combined with the cumulative effects of
individual environmental, medical, and genetic factors .
Types of presbycusis
Physiologically presbycusis has several types, including the
a) sensory presbycusis with impairment in high frequencies
secondary to the loss of external cells at the base of the cochlea.
b) metabolic or strial presbycusis with plateau deafness
at all frequencies and which is the consequence of degenerative
damage to the vascular structure (atrophy) with alteration of the
c) neural presbycusis, secondary to the loss of spiral
ganglion cells and which partly explains the disorders of verbal
Additive exogenous factors
Regular exposure to sounds over 85dB which increases the
risk of hearing loss [4, 29-31].
a. Ototoxic agents, in particular antibiotics, aminoglycosides
and cisplatin which damage these same cells.
b. Industrial chemical agents (toluene, trichlorethylene)
c. Metabolic disorder and immune diseases by progressive
destruction of vasa nervorum.
Nevertheless, the impact of presbycusis would be attributable
to genetic factors which would be more important for strial
presbycusis (35 to 55%), mitochondrial genes associated with
antioxidant agents protecting against oxidative stress to reduce
the severity of deafness age-related . In addition, there are
other genetic variations in the control of certain enzymes that
can lead to deafness [3,32]. Lin et al have shown that the black
phenotype is better protected against age-related deafness
through protection of the vascular streak by melanin [33-36].
The European cooperation in science and technology (COST)
adopts a multidisciplinary approach around free radicals and
oxidative stress. Free radicals are very reactive molecules which
have one or more unpaired electron (s): OH. Oxygen (O2) is a
biradical that has two unpaired electrons . Free radicals,
highly reactive molecules, produce harmful effects both at the
cellular and extracellular level .
Sources of free radicals
There are several cellular sources of free radicals . These
are endogenous sources:
a. exogenous sources,
b. enzymatic life,
c. non-enzymatic life,
The main sources of free radical formation can be either
endogenous or exogenous; they can be physical, chemical,
and biological in nature. According to enzymes and cofactors:
Xanthine oxidase and hemoglobin in the endoplasmic reticulum,
cytochrome P450 and b5 in the nucleus (DNA) and endoplasmic
Endogenous sources are provided by:
a. mitochondria (Biologies),
b. phagocyte (Biology),
c. Xanthine oxidase,
d. Transition metals,
e. Paroxysms (Biology),
f. Inflammation (Biology) (Figure 1)
Exogenous sources are provided by:
a. the cigarettes,
b. ionizing radicals (physical),
c. various pollution (chemical),
d. UV radiation (physical),
e. chemicals and drugs (chemical),
f. ozone (chemical).
Two production pathways for reactive oxygen species or free
radicals are possible:
A. enzymatic route: activation of enzymes responsible for
the oxidation of O2. These are the following enzymes:
a) NADPH - oxidase or NOX enzymes,
b) Xanthine oxidase (XO),
c) Cytochrome P450 (CytP450),
d) Myelo peroxidase.
B. non-enzymatic route:
a) heavy metals (Iron ++). Reaction of FENTON.
At the level of endogenous sources: According to enzymes and
cofactors, xanthine oxidase and hemoglobin in the endoplasmic
reticulum, cytochrome P450 and b5 in the DNA nucleus and
endoplasmic reticulum. Oxygen brerst / NASPH oxidase,
Myeloperoxidase at the level of lysosomes, the respiratory chain
at the level of mitochondria, Oxidases, Flavoproteins at the level of
peroxisomes. Lipo-oxygen and peroxidase in lipid membranes and
lipid peroxidation and transition metals (iron) in mitochondria
[41-43]. The information has been presented rigorously according
to the following sections: Free radicals relate to very reactive
molecules which present one or more unpaired electrons, on the
other hand the reactive species (RE) can be radicular or not, they
are highly reactive molecules. , corresponding respectively to O,
N and Cl.
Primary reactive oxygen species (ROS):
a. Free radicals (ion): Superoxide ion (O2-), Radial hydroxyl
(OH−), Nitric oxide (NO−) and Hypochlorite (OCl−)
b. Molecules: Peroxide (H2O2)
Secondary or organic reactive oxygen species: lipids,
carbohydrates, proteins or nucleic acids and peroxide radical
(ROO−) (Table 1)
Role of free radicals
The attack or oxidation of the constituents of our body due
to an excess of particularly harmful molecules called free radicals
which come from the inspired oxygen. Thus lipids, proteins,
sugars, and DNA are denatured by the oxidation of cells; this is
a form of cell aggression. In addition, these various attacks on
cells are one of the causes of cellular aging in humans. Due to
their unstable or oxidative nature, active oxygen species (EOR)
interact with a whole series of biological substances existing
in the environment. The cellular damage produced by EOA is
applied to the DNA level of protein and lipid mutations. We
observe mutations in DNA, proteins and lipids or observe protein
inactivation, lipid peroxidation in polyunsaturated fatty acids of
the cell membrane or lipoproteins . The very delicate balance
between the production of energy and that of the highly oxidizing
molecules generated by the mitochondria  ensures the normal
functioning of the cell despite the formation of EOA .
Physio pathological mechanisms of oxidative stress
Under physiological conditions, there is a balance that is
established between the pro-oxidant and antioxidant system
not harmful to the cellular components (lupid, carbohydrate,
proteins and DNA). Under pathological conditions, an imbalance
of the balance is created in favor of the pro-oxidant system. Hence
oxidative stress. Which leads to cellular toxicity.
Thus, oxidative stress can be defined as an attack or oxidation
of the constituents of the body due to an excess of particularly
harmful molecules called free radicals which come from the
oxygen in the air that we breathe to live. This oxygen denatures
proteins, fats, carbohydrates and even DNA, and thereby cell
membranes and cells. Cells and their finest constituents “Rust”
much like a piece of metal left in the open. This cellular aggression
or oxidation of cells is one of the essential causes of cellular aging.
Oxidation of cells remains a major cause of aging in our cells.
Due to their unstable or oxidizing nature, active oxygen species
will interact with a whole series of biological substances present
in the environment where they are produced . There are 3
physiopathological mechanisms of oxidative stress:
a) Overproduction of free radicals exceeding the
b) Normal production of free radicals and decreased
capacity of the antioxidant system
c) A combination or association of two previous
mechanisms. (cos of HIV / AIDS infections).
Biological consequences of oxidative stress
These consequences are at the cellular level as well as the
organs and systems.
At the cellular level
At this stage, we observe an oxidation of the essential
components of the cells leading to mitochondrial lesions, an
energy deficit stupefying to cell death.
At the level of organs or systems
Mono-organic or multi-organic dysfunction is observed with
structural damage (cells and tissues) leading to overcoming
defense, adaptation, and repair mechanisms. Hence the
dysfunction of organs and systems. The cell continues to evolve,
thanks to the very delicate balance between the production of
energy and that of the highly oxidizing molecules generated by the
mitochondria . This balance is ensured by several antioxidant
defense systems that regulate the production of EOA . These
means of protection consist of enzymes.
Cellular protection against free radicals
This cellular protection corresponds to the catabolism or
neutralization of reactive oxygen species or free radicals .
There are primary and organic antioxidants grouped into 2
types, 2 types of antioxidants: enzymatic antioxidants and nonenzymatic
antioxidants. Regarding enzymatic antioxidants we
A. superoxide dismutase (SOD),
B. catalase (CAT)
On the other hand, non-enzymatic antioxidants come from the
oxygenated blood, i.e. in the diet including vitamin C, vitamin C,
β carotene, micronutrients (Se, Zn, Cu, Mn / antioxidant enzyme
cofactors). Others come from endogenous sources including
glutathione, albumin, uric acid, bilirubin and sometimes from
plant sources including flavonoids, polyphenols.
A secondary defense system composed of proteolytic
enzymes aims to prevent the accumulation in the cell of oxidized
proteins, lipids, and DNA and to degrade their toxic fragments.
This constitutes the means of protection against EOA (Figure 2)
[24,46,47]. The notion of regulation and not of total inhibition is
important because the advent of molecular biology and genomics
has made it possible to show that EOA, like antioxidants, have
a key role in the regulation of apoptosis (programmed suicide
of cells progressing to a cancerous state), in the expression of
certain transcription factors or as modulators of the expression
of structural genes, including antioxidant enzymes [24,46,47].
In the body, but under the action of environmental elements,
several biochemical mechanisms can be activated (Table 1) 
by producing excessively EOA which will therefore very quickly
overwhelm all our antioxidant defenses (Table 2).
There is therefore the appearance of oxidative stress which
is defined as a profound imbalance in the balance between prooxidants
(EAO) and antioxidants in favor of the former, which
leads to cell damage which is often irreversible (Figure 3) .
Oxidative stress is involved in the development of more than
200 pathologies (cardiovascular diseases, degenerations and
inflammatories, cancer, diabetes, AIDS) [24,48,49]. This oxidative
stress is a state of imbalance between the production of reactive
species and the body’s defenses . A state of oxidative stress
exists when at least one of the following three conditions is
present (Figure 1) [24,40]:
a) the excess of reactive species of O2, N2 or cl2,
b) insufficient defenses (endogenous, exogenous),
c) insufficient repair mechanisms.
Oxidative stress and sensorineural deafness related to
Age-related sensorineural deafness considered to be
presbycusis remains a phenomenon in which oxidative stress is
involved. An expert group has carried out several works in the
redox regulation of neurological and psychiatric diseases with
particular emphasis on two relatively unexplored areas: the inner
ear and schizophrenia. Of all the NOX isoforms, NOX3 is the most
elusive, least studied, and even less well understood, primarily
due to its restricted topological expression in the inner ear. One
of the laboratories involved in this COST action shed light on the
function of NOX3 in the regulation of balance and hearing function
by developing sophisticated mouse models that lend themselves
to investigation of this problem. The situation of hearing loss, of
genetic origin or acquired after environmental exposure to noise
or aging, has recently been given an important place in Redox
Indeed, a very compelling report has described that pejvakin,
a protein linked to peroxisomal function and proliferation, is the
basis of a form of hereditary sensorineural deafness and that its
absence or dysfunction induced by oxidative stress makes inner
ear extremely vulnerable to noise, damage . NOX3 is expressed
in the cochlea even though mice lacking it do not have an apparent
phenotype related to hearing loss. The peroxisoma generation
of ROS is related to the NOX3 function is an issue that remains
to be investigated. Thus, much evidence has been established
on the role of oxidative stress in neurodegenerative diseases
. In addition, the role played by oxidative stress in metabolic
syndrome and in type 2 diabetes mellitus . The levels of O2
• - and • NO including their interaction significantly determine the
alteration of physiological signaling by ROS / RNS is implicated
in the etiopathology of diabetes . The O2 • - / • NO ratio is
regulated and affects the synthesis and degradation of insulin. In
addition, oxidative stress contributes to the loss of pancreatic β
cells, which impairs insulin secretion  (Figure 4).
This section covers a wide range of disorders on the topic of
redox signaling and nitroxidative stress as a common modulator
of disturbances related to tumor cell migration, fibrogenesis,
hearing loss, neuropsychiatric disorders, metabolic syndrome. ,
drug metabolism, renal hemodynamics and pulmonary hypoxia.
In the slide, the participation of the relevant enzymatic pathways
(NOX, SOD, ALDH-2) is indicated. BMI: body mass index. The
other abbreviations are defined in the text. Therefore, therapeutic
strategies to prevent β cell dysfunction require better knowledge
of how to protect them against the direct or indirect effects of free
radicals and lipid peroxidation.
Insulin sensitivity and metabolic homeostasis depend on the
ability of adipose tissue to absorb and use excess glucose and
fatty acids. This buffering capacity depends on the physiological
levels of • NO, the function of which can be impaired by excessive
O2 formation . It should be noted that redox signaling and
oxidative stress can contribute to the remodeling of adipose
tissue. The COST action has also addressed the toxicity and
tolerance issues arising from the clinical use of organic nitrites.
Recently, insight has been gained on the molecular mechanisms
linked to the side effects of nitroglycerin and other nitrates in
mitochondrial dysfunction and disruption of redox homeostasis.
Disturbed vascular redox balance underlies the pathophysiology
of important disease conditions in other organs such as the
lungs and kidneys. In the lungs, chronic hypoxic pulmonary
hypertension causes vasoconstriction and vascular remodeling,
two phenomena that perpetuate the vicious cycle. In the kidney,
animal studies using superoxide dismutase (SOD) mimetics
indicate an important role of redox dysfunction in the increased
vascular resistance associated with chronic kidney disease and
open the possibility of therapeutic intervention.
Recent research has demonstrated the major role of ROS in
hearing impairment, including overexposure to noise, ototoxic
drugs (eg cisplatin) and age-related hearing loss . Although
the sources of ROS are complex and partially understood as at
the level of mitochondria. Activation of NOX enzymes, especially
NOX3, plays a key role in hearing loss. An elevated level and specific
expression in the inner ear identify NOX3 as a prime drug target
for combating hearing loss . NOX3 is a multi-subunit NADPH
oxidase, functionally and structurally closely related to NOX1
and NOX2. NOX3 is active as a multiprotein complex comprising
membrane bound NOX3 and p22phox and cytosolic subunits
NOXO1 and NOXA1. NOX3 is crucial for the formation of otoconia,
small crystals of protein carbonate involved in equilibrium .
The experiment carried out in mice carrying a loss-of-function
mutation in the NOX3- complex including the common NOX1 to
NOX4 subunit p22phox, or the cytosolic NOXO1- subunit have a
vestibular phenotype similar to mutant NOX3 mice (called tilted
head mouse). In addition, the role of NOXA1 is still poorly defined,
especially in vitro. On the other hand, the physiological relevance
of the expression of NOX3 in the cochlea remains uncertain
because no auditory phenotype has been described for the loss
of NOX3 in mutant animals. The role of NOX3 in cisplatin-induced
hearing loss is in fact the best documented. In vitro the potential
role of NOX3 has been demonstrated in cochlear damage on
NADPH oxidase activity . And therefore, an increase in the
level of NOX3 mRNA has been described in the cochlea of rats
treated with cisplatin, while siRNAs against NOX3 could prevent
hearing loss by cisplatin .
Currently, NOX3 is a major source of ROS in the cochlea.
However, the role of NOX3 may not be limited to ototoxicity induced
by cisplatin. Likewise, oxidative stress is also a major element in
other hearing pathologies such as presbycusis, Meniere’s disease
or noise-induced hearing loss. The role of NOX3 in hearing loss
based on the loss of functional mutant mice will be shown to be
experimental in the field. Three mouse models of hearing loss
have been successfully developed in one of the laboratories of
this COST- action namely overexposure to noise, cisplatin and agerelated
hearing loss models and an investigation of the role of NOX3
is currently ongoing through NOX3 and p22phox mutant mice. It
is therefore difficult to predict whether classical pharmacological
approaches, i.e., small molecule NOX3 inhibitors, therapies based
on molecular biology, i.e. siRNA-mediated knock-down will be the
ultimate tools for targeted NOX3 therapies, specific approaches
allowing the inhibition of pathological NOX3 activity.
Information relating to the role of NOX3 in the pathologies of the inner ear demonstrated over the last decades, associating
ENT specialists, professionals (speech therapists), physiologists
and practicing physicians to understand overexposure to noise,
the effects of ototoxic drugs well demonstrated in the genesis of
age-related hearing loss . Indeed, NOX3 will become a drug
target of choice to fight deafness .
This review article highlighted the complexity of the effects
of senescence, senility, genetic factors during fetal life, ecotoxic
effects and mutations involved in presbycusis. Further studies
are needed to develop prevention programs and drug molecules
to delay the pejorative effects of oxidative stress associated with
Klinger Vagner Teixeira da Costa, Kelly Cristina Lira de Andrade, Maria Eduarda di Cavalcanti, Ana Claudia FigueiredoFrizzo, Aline TenórioLinsCarnaúba, et al. (2018) Hearing Loss at High Frequencies and Oxidative Stress: A New Paradigm for Different Etiologies, An Excursus into Hearing Loss, Stavros Hatzopoulos and Andrea Ciorba, IntechOpen.