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R&D on Ageing: the biomedical viewpoint

ISABEL VARELA-NIETO

Instituto de Investigaciones Biomédicas “Alberto Sols”. CSIC-UAM

TERESA RIVERA

Otorhinolaryngology Department. Hospital Universitario Príncipe de Asturias. University of Alcalá (UAH)

Presbycusis

Presbycusis, or age-related hearing loss, has a significant impact on suffers’ quality of life. Its diagnosis and treatment is a significant public health issue.

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Over the last few decades there has been a significant increase in the prevalence of certain illnesses associated with the increasing average age of the population. Epidemiological studies reveal a notable increase in the size of the population group aged over 60 and it is estimated that HIGHLIGHTSProfiles: Teresa Rivera and Isabel Varela-Nieto
they may account for 40% of the population in the second decade of the 21st century.

Presbycusis, or age-related hearing loss, is the most common cause of hearing impairment, as well as being the most common neurodegenerative disorder. Its incidence is highest among the over-65s, affecting approximate 40% of this population group. Presbycusis has a significant impact on sufferers’ quality of life. Its diagnosis and treatment is therefore a significant public health issue.

A variety of factors contribute to age-related hearing loss, including both genetic and environmental factors (http:// www.nidcd.nih.gov/health/ hearing/presbycusis.asp). The most common form of presbycusis results from changes in the inner ear, but it can also be the result of changes in the middle ear or complex changes along the nerve pathways that lead to the brain. In all species studied, the hearing loss associated with presbycusis generally has a bigger effect on higher pitched sounds. “A variety of factors contribute to age-related hearing loss, including both genetic and environmental factors”Recent histopathological and molecular genetic studies on hypoacusis (hearing impairment) in human beings show animal models to be a useful way of advancing our understanding of presbycusis.

The genetic characteristics of the mouse make it a particularly good model with which to study hearing impairment (http://www. iib.uam.es/servicios/nine/ intro.es.html y http:// hearingimpairment.jax.org/).

Vestibular symptoms are present in almost half of older people, as balance depends on the vestibular, visual and peripheral sensory systems, which generally degenerate at the same time, with the upshot that loss of function in one or more of these systems has repercussions for balance as well as hearing.

Presbycusis has a serious impact on the elderly because it diminishes their ability to communicate and thus their functional independence, therefore limiting their opportunities to participate as active members of society. It is associated with a high economic cost for the patient and the health-care system. The knock-on effects for sufferers of this sensory deficit are changes in perception and personality, particularly in terms of introversion and social isolation.


The ear and how it works
The ear is divided into three parts, the outer ear, middle ear and inner ear. Sound waves reach the outer ear and strike the eardrum or tympanic membrane, causing it to vibrate. On the other side of the eardrum there is a set of tiny bones or ossicles called the malleus, incus and stapes (or hammer, anvil and stirrup). These relay the vibration to the cochlea in the inner ear. The cochlea converts the vibrations produced by the sound wave into electrochemical impulses, which are sent via nerve endings of the cochlear nerve to the brain, thus enabling us to hear (Figure 1).





Types of presbycusis
Presbycusis may be classified according to several subtypes, depending on which structure is damaged (Figure 2). The most common types of presbycusis are sensory (cilia or hair cell loss), neural (spiral ganglion cell loss), metabolic (stria vascularis), and cochlear “Presbycusis has a serious impact on the elderly because it diminishes their ability to communicate and thus their functional independence”conductive (spiral ligament), central, and mixed, in which there is a mixed pattern in which several histopathological changes are combined.

Sensory presbycusis
The histopathological changes taking place are a progressive degeneration of the sense cells of the cochlea, the most severely affected being the outer hair cells (OHC). The earliest change is the loss of stereocilia in the hair cells. It may also affect the pillar cells (IPC, PC, DC, HC and CC), causing the neurosensorial epithelium to be modified so as to present an aspect of undifferentiated epithelium.

Patients with sensory presbycusis typically have a audiometry pattern in which hearing of high frequencies is particularly affected (Figure 3A).

These patients have an audiogram which is very similar to that of noiseinduced hearing impairment. It is possible that sensory presbycusis depends on an interaction between harmful environmental agents and the genes governing cellular protection and regeneration.

Neural presbycusis
In neural presbycusis there is atrophy of the spiral ganglion (SG) and nerve fibres of the osseous spiral lamina which occurs primarily in the basal turn of the cochlea. The audiogram (Figure 3B) shows a gradual loss of hearing with a slightly greater loss at higher frequencies, although speech audiometry (Figure 3C) is the acid test, as what affects sufferers most is the loss of speech discrimination. This loss affects their quality of life, as it reduces their ability to enjoy a group conversation in a noisy location, for example, which can contribute to their social isolation.



The cochlea is divided into three scalas, the scala media (SM), the scala vestibuli (SV) and the scala tympani (ST), separated by Reissner’s membrane (RM) and the basilar membrane (BM). The scala media contains the Organ of Corti, the sensory organ of hearing. This contains the sensory cells, which are divided into the outer hair cells (OHC) and inner hair cells (IHC) and the pillar cells (IPC, PC, DC, HC, CC). The tectorial membrane (TM) is responsible for mechanically opening the ion channels when the sound vibration moves the tufts of cilia of the sensorial cells. Ion exchange takes place via a system of narrow connections and channels that connect the cells of the Organ of Corti with the spiral ligament and the cells of the vascular stria (BsC, IC, MC). The nerve impulse is relayed to the brain via the spiral ganglion (SG).


Metabolic or strial presbycusis
This form of hearing impairment may begin in the third decade of life and progresses slowly and gradually. The dysfunction caused by the degeneration of the vascular stria is believed to be the underlying cause of metabolic presbycusis. The presence of strial atrophy in ageing has been described in animal models, accompanied by alterations in ion homeostasis and a reduction in the vascularisation of the stria, which precedes changes in the hearing thresholds and may be correlated with a reduction in endocochlear potential.

The audiometric pattern typical of patients with serial presbycusis is a flat audiograma (Figure 3D), with all frequencies affected similarly, including the lower frequencies, unlike the types of presbycusis described above. The impact on speech audiometry is limited.

Strial presbycusis has a hereditary component, and is more frequent in women. It presents in association with cardiovascular disease, and in animal models, with insulin resistance.

Cochlear conductive presbycusis
This type of presbycusis has not been correlated with clear anatomical changes, but it is postulated that there is a stiffening of the basilar membrane (MB) and changes in the spiral ligament (SL), in particular a loss of type IV fibrocytes adjacent to the basilar membrane. Audiograms of patients with this type of presbycusis present bilateral neurosensorial hypoacusis with greater hearing loss at higher frequencies (Figure 3E).

Central presbycusis
Given the complexity of the neural connections through which the auditory stimulus is transmitted to the cerebral cortex, it is logical to assume that any lesions in these pathways will affect hearing. Central or neural presbycusis is defined as a central dysfunction in which the intelligibility of speech is particularly affected. Primary neural lesions of the auditory pathway are infrequent and little studied. In general, it is assumed that central degenerative lesions are secondary and the result of the loss of sense cells in the cochlea.

The interpretation of this fact is that there is a reduction in the inhibitory influence of the media olivocochlear efferent with ageing. The activation of this pathway may help protect the cochlea against noise, with the result that degeneration of the medial olivocochlear bundle reduces the individuals’ ability to protect themselves from the damage noise can do and thus makes them more susceptible to it.



Graph A.- Tonal audiometry of sensory presbycusis showing how all frequencies are affected, but particularly higher frequencies.
Graph B.- Audiometry of neural presbycusis showing how the higher frequencies are affected.
Graph C.Speech audiometry of the same case as shown in Graph B in which the marked impact on intelligibility can be observed (normal hearing in black, reaching 100% word discrimination, presbycusis in blue, with a maximum intelligibility of 70%). The disproportionate effect on intelligibility can be seen.
Graph D.- Tonal audiometry of metabolic or strial presbycusis with all frequencies affected, particularly higher frequencies.
Graph E.- Tonal audiometry of cochlear conductive presbycusis, showing alteration of the perception of higher frequencies.



Ethiopathogenesis
The ethiopathogenesis of presbycusis lies in the interaction of the genome and the environment, and is influenced by genetic factors, age-related cellular mechanisms, the environment and associated illnesses.

A genetic predisposition to premature presbycusis exists, but despite the research done, the genetic factors are poorly identified. Work in this field is progressing by studying animal models. There is evidence pointing to age-related cellular mechanisms, “A genetic predisposition to premature presbycusis exists, but despite the research done, the genetic factors are poorly identified”such as the precursor cells of the spiral ligament and vascular stria losing the ability to divide, the death of the sense cells and auditory neurons, which are not replaced in adult mammals, and cell stress and oxidation mechanism associated with ageing.

Insulin-like growth factor (IGF-I) plays a central role in ageing over the whole evolutionary range and is fundamental for hearing in humans and mice (http://www.ncbi.nlm. nih.gov/omim/608747). Its study is revealing the keys to understanding the molecular basis of otic development and the factors influencing auditory ageing. For instance, IGF-I modulates the expression of cell cycle regulation factors such as FoxM1 and p27kip, and differentiation of stem cells such as MEF2. IGF-I deficiency causes cell alterations in the vascular stria and loss of auditory neurons through apoptosis.

In terms of environmental factors, those which can have a negative impact on the progression of presbycusis include noise exposure, which can cause mechanical, metabolic damage or vascular changes. Presbycusis has also been described in association with other diseases, but it is not clear whether it is influenced by them or if they occur in parallel, as a result of shared underlying cellular and molecular alterations. Illnesses with a potential impact include cardiovascular disease, diabetes mellitus, other metabolic causes such as hyper-lipoproteinemia, obesity, vitamin deficiency, etc. Additionally, it has been described in association with cognitive deficit, particularly in the case of Alzheimer’s disease, and with immune and auto-immune dysfunction.


Treatment, prevention and Outlook
Therapeutic measures addressing presbycusis are targeted on improving sufferers’ communication capacity. This can be done by amplifying the sound they hear using hearing aids and addressing certain environmental factors. Progress in the development of electronic devices, based on an understanding of the anatomy and physiology of hearing, has made a significant contribution to alleviating hearing loss.

Presbycusis is in some cases inevitable, but we can influence its course to minimise or slow the rate of deterioration by avoiding noise exposure. Cardiovascular diseases and their risk factors, such as diabetes mellitus, can also affect hearing. Staying in good health and taking exercise can reduce future hearing impairment. The current lines of research and development of new therapeutic “Cardiovascular diseases and their risk factors, such as diabetes mellitus, can also affect hearing”approaches include designing small molecules that interfere with apoptosis (programmed cell death) or the generation of free radicals; gene therapy aimed at endowing supporting cells with the ability to turn themselves into hair nerve cells; and cell therapies aimed at replacing damaged or missing neurons and sense cells. These are therapies which require the support and parallel development of medical imaging, minimally invasive microsurgery techniques and the design of biocompatible nanomaterials allowing localised access and treatment of the cochlea. Finally, basic research, human genetics, and the use of animal models are essential to exploring new avenues for the future treatment and prevention of presbycusis.

Profiles: Teresa Rivera and Isabel Varela-Nieto

Teresa Rivera
Began as a Specialist in Otorhinolaryngology at the Puerta de Hierro University Hospital in 1987, becoming a Doctor of Medicine and Surgery at the Madrid Autonomous University a 1992 and has held numerous positions with roles in health care delivery and teaching. She is currently head of the Otorhinolaryngology Department at the Príncipe de Asturias University Hospital in Alcalá de Henares and Associate professor of Health Science at the University of Alcalá. She is also chair of the research committee of the Sociedad Española de Otorrinolaringología, and has published numerous articles in books and scientific journals.

Isabel Varela-Nieto
Has a PhD in Chemical Sciences (UCM, Madrid 1985), and was an EMBO postdoctoral fellow at the Universities of Glasgow and Leuven and a Visiting Scientist at the Universities of Uppsala and San Diego. A member of CSIC since 1992, and CSIC Research Professor since 2005, she is Principal investigator of the Hearing Neurobiology Group and scientific manager of the Hearing Evaluation service, a member of CIBER on rare diseases and is on the Scientific Advisory Committee of Fundación Retina España. She is also the elected scientific secretary of SEBBM and the Spanish representative on the Core group del European Medical Research Councils (ESF), and a winner of the Boehringer Mannheim prize.

Comments

Page 1
select * from comentarios where txtTabla='articulos' and numId='17' and cmsEstado='1' order by fehFecha desc limit 0,5
3.
JOSÉ ANTONIO ÁLVAREZ DÍEZ
Soy un Perito Médico y me enfrento normalmente a casos como éste, el de la presbiacusia. El artículo me ha encantado por su claridad, sobre todo para los profanos (en este caso jueces) a los que se lo tengo que aclarar. Muchas gracias.
2.
Lucía.
Buenísimo, lo mejor que he encontrado en la web sobre presbiacusia. Me ha ayudado sobremanera en mi proyecto de fin de estudios. Gracias y enhorabuena.
1.
Patience O. Fada
This is exactly what am lookin 4. Thanks.

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Published in No. 02


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