Introduction
The sense of hearing is unequalled by our other sensory modalities in terms of its sensitivity, dynamic range, and discrimination of the finest nuances in stimuli. It does serve us well through a part of our lifetime, but beginning in our forties (slightly earlier for men and later for women), our inner ears suffer the influence of aging in a very subtle yet progressive manner. Age-related hearing impairment (ARHI) affects most people aged 65 years and older and represents the predominant neurodegenerative disease of aging. Hippocrates had already noted deafness to be more prevalent among his elderly patients and in The Comedy of Errors, Shakespeare’s elderly merchant, Aegeon, complains of his own “dull deaf ears.” Thus, ARHI or presbycusis is not a disease of modern societies but has been accepted for centuries as one of Lord Byron’s inevitable “woes that wait on age” that it still appears to be.
It was the New York otologist, St. John Roosa, who first drew the attention of his colleagues to hearing loss of the elderly as a medical condition. In 1885 he proposed the name presbycusis that he had coined from the Greek 
, old man, and 
, to hear. Systematic studies of the anatomical pathology began in the late nineteenth century, leading by the 1930s to the realization that the decreased auditory acuity could be attributed to deterioration of the auditory sensory cells and the auditory nerve. These changes frequently affect the perception of the upper frequencies first, resulting in high-frequency hearing loss as a hallmark of presbycusis. However, age-related hearing loss is not a uniform condition, but a multifactorial one combining genetic predispositions with a plethora of lifetime insults to the hearing organ because, in all its versatility and efficacy, our sense of hearing is also uniquely vulnerable to environmental influences. These may include noise, chemicals, and solvents at the workplace, lifestyle (e.g., smoking), and leisure activities (from iPods to rock concerts and target shooting), diseases (e.g., diabetes, respiratory disorders), viral or bacterial infections, and even the adverse effects of the very medications designed to cure the diseases and infections. This spectrum of potential abuse of our auditory organ yields an exceedingly intricate etiology and pathology of hearing loss in the elderly. Age-related pathology of the central auditory system adds to the complexity of the problem. Presbycusis has been defined as “hearing impairment associated with various types of auditory dysfunction, peripheral or central, that accompany aging and that cannot be accounted for by extraordinary ototraumatic, genetic, or pathological conditions” but it is almost impossible in practice to separate the confounding factors from a “true” effect of aging. It has therefore often been debated whether presbycusis indeed exists in populations that are isolated from adverse environmental influences.
Animal models provide hope to resolve some of the basic mechanisms that underlie the deterioration of hearing and point to ways and means to delay or prevent presbycusis. By virtue of the availability of molecular and genetic information and of transgenic and knock-out animals, mice have become one of the preferred model animals although, as we shall point out later, caveats do apply here too. This review will illustrate the features of human presbycusis and draw on animal models to discuss its potential molecular basis.
ARHI is the most frequent sensory impairment in the elderly and the prevalence of the disorder increases with age. In humans, as in most other species, age-related hearing loss begins at the high frequencies and progresses gradually into the lower speech range. Males suffer age-related hearing loss earlier than females, beginning in the late thirties to early forties while women will match the males’ deficits in the later decades of their lives. Approximately 44% of people suffer from a significant hearing loss in their sixties; this number rises to 66% between the ages of 70 and 79 years, and skyrockets to 90% after age 80 years. With an increased life span of the population worldwide, especially in developed countries, the impact of ARHI will continue to increase in the future.
The individual rate of decline in hearing, however, is exceptionally variable and some people may maintain excellent hearing with “golden ears” late into life as a result of genetic traits that have yet to be elucidated. Superimposed on the gender differences, race apparently also plays a role, although whether this role is causative or correlative is unknown. One study of over 2000 elderly Americans aged 73 to 84 years found the incidence of high-frequency hearing loss that met their criteria to be 91.8% in Caucasian American men, 76.1% in African-American men, 74.2% in Caucasian American women, and 59.2% in African-American women. In addition to genetic differences, each group had tendencies toward particular risk factors, suggesting that the incidence of hearing loss across groups is presumably caused by a combination of genetic and risk factor diversity.
Family history plays a role in predisposition to presbycusis. An analysis of hearing thresholds in sibling or parent/child pairs versus spousal pairs (control) in Framingham Heart Study patients found that the inherited genetic effects were significant. The predictive power of family history appeared stronger for females than males and stronger for “metabolic” type rather than sensory type hearing loss (see Schuknecht’s classification of age-related hearing loss in section “Peripheral Pathology of Age-Related Hearing Impairment in Humans”). Overall, the study suggested that about 55% of the variance in age-related hearing loss can be ascribed to genetic factors. This influence is then modulated by external risk factors.
The great variation in the progression and severity of hearing loss has long led to the recognition of ARHI as a complex genetic disorder with environmental risk factors. Major environmental risk factors that may contribute to the manifestations of ARHI, briefly mentioned above, include exposure to excessive noise, ototoxic medications (primarily aminoglycoside antibiotics and anticancer agents of the cisplatin class), and industrial solvents. These environmental factors appear to damage the auditory system by oxidative injury and thus may aggravate the age-related changes in the auditory system. Animal experiments bear out the accelerating influence of these factors, which do not necessarily have to inflict damage by themselves. When mice at 3 months of age received a mild noise exposure causing only temporary threshold shifts, their hearing recovered to normal within 3 days. These mice, however, developed a significantly greater hearing loss with age than control animals.
Age-related hearing loss sets in earlier in males than in females, both in the human population and experimental animals. In the later decades of life, however, these differences diminish, suggesting that differences in hormonal levels between male and female contributes to onset of ARHI. Receptors for steroid hormones are indeed present in the cochlea. In support of a link between ARHI and hormonal levels, fluctuations in hearing thresholds have been observed during the menstrual cycle and estrogen therapy slowed the development of ARHI in postmenopausal women. Furthermore, in patients (and mouse models) with Turner syndrome who do not synthesize estrogen, ARHI sets in early. A correlative study in human saw a protective effect of elevated serum levels of aldosterone on auditory thresholds and an improvement of “hearing-in-noise” in older individuals. Aldosterone receptors in the inner ear influence the ionic homeostasis of inner ear fluids, which is essential for cochlear homeostasis and the transduction of sound.
Both type I and type II diabetes promote hearing loss and cochlear pathology in humans and in animals. Deficits in several aspects of auditory function were significantly more pronounced in a group of people with type II diabetes aged 60 years or older compared with a group of age- and sex-matched controls and excluding those with other significant health problems or a history of hearing problems. Diabetes mellitus and associated deregulated blood glucose levels, in fact, exact a multitude of stresses on a cellular level, which could lead to loss of function in the delicately balanced hearing organ with time and age. Fundamentally, increased blood glucose levels leads to cellular hypoxia and build up of reactive oxygen species and other metabolic by-products, as well as changes in the collagen and microtubule structure of the cells. Also, the effects of diabetes on vasculature are profound, including atherosclerosis and vessel wall dystrophy. In the inner ear, which depends on the stria vascularis to carefully maintain the endocochlear potential, this could result in impaired sensory function and apoptosis.
All conditions that affect the function of blood vessels such as hyperlipidemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, and cardiovascular disease have been implicated in ARHI. Specifically, strial ARHI (see next section) appears to be aggravated because stria vascularis is most vulnerable to any restriction of blood flow. Just as in diabetes, any cardiovascular disease leading to vascular compromise will impair the function of this tissue and, by way of decreased endolymphatic potential, decrease the sensitivity of the cochlear organ to sound.
Poor health habits with regard to exercise, smoking, and diet are also considered risk factors for ARHI based on data of population studies. Since some of these habits influence cardiovascular function and other potential risk factors for ARHI, it remains open how much lifestyle acts directly on the auditory organ or secondary to general health.
Interestingly, adherence to negative stereotypes about the elderly, i.e., the concept in many societies that aging is met with an inevitable decline in function of all faculties, demonstrates as a predicting risk factor for ARHI. External stereotyping (the prevalence of stigmata with aging in the subject’s culture) and negative internal perception (extent of internalization of these stigmata) acted as independent risk factors on hearing loss with age, and had a stronger impact than gender or race. This predicts an observable phenomenon wherein cultures with positive concepts of aging do not expect their elders’ hearing to become enfeebled and, in fact, the incidence of ARHI is then lower. Here again, an influence on the auditory system maybe secondary to the effect of stigmata on general well-being.
A significant hearing loss of any origin will eventually lead to difficulties in communication and a decreased awareness of the environment. In addition to the social isolation at all ages, subjects with earlyonset presbycusis may suffer economic consequences from difficulties in employment or professional advancement. The question of what constitutes a significant hearing impairment is complex as it involves consideration of both the magnitude of sensitivity loss and the frequencies at which the loss occurs. Although the most convenient assessment criterion for age-related hearing loss is a subjective one—that is, posing the question, “do you have a hearing problem?” or a more elaborate questionnaire like the Hearing Handicap Inventory for the Elderly-Short (HHIE-S)—a more quantitative evaluation can be obtained by an audiogram (see section on “Functional Assessment of Hearing”). While there is not one set paradigm for classification of audiograms into handicapping and nonhandicapping hearing thresholds, the American Medical Association/American Academy of Otolaryngology—Head and Neck Surgery sets the bar at an average threshold shift (hearing loss) of 25 dB or above at frequencies between 500 and 3000 Hz.
What does a loss of 25 dB hearing acuity mean in practical terms? The bel or decibel scale of sound pressure (“intensity”) is logarithmic, such that an increase in 3 bels (30 dB) confers approximately a doubling of the sound intensity (103/10 = 1.995). Therefore, a reduction of sensitivity of 25 dB, as is required for some definitions of occupational hearing impairment, is considerable. In rough terms, a difference of 25 dB in threshold makes normal conversation equivalent to a whisper, and a whisper equivalent to silence (Table 44-1). The crying baby would still be heard—albeit subdued—but the leaves rustling in the forest or the crickets in summer would not be heard.
dB | SOUND |
|---|---|
15 | Pin drop at close range |
15–20 | Rustling leaves, dripping faucet |
35 | Whisper |
50–60 | Normal conversation |
60–70 | Vacuum cleaner |
70–90 | Screaming child |
85 | Safety limit for an 8-h workday |
100 | Safe for 15 min or less |
105–110 | Gas engine mower, chain saw |
110 | Car stereo at maximum volume |
110 | Safe for 1 min 29 s |
115 | Maximum volume from an iPod |
116 | Human body perceives low frequency |
120 | Front row at a rock concert |
120–130 | Jet plane taking off |
127 | High risk of tinnitus |
130–140 | Gun shot from a hunting rifle |
140 | Hearing deficit at exposures <1 s |
ARHI poses a specific problem as the hearing loss mostly sets in at the high frequencies. As a result, many with age-related hearing loss do not recognize their condition for a long time. The frequency spectrum of human hearing, at its best, ranges from about 60 Hz to 16 kHz. A hearing loss at the very high frequencies may not produce any communicative disadvantages since frequencies over 4 kHz contribute little to speech (Table 44-2). Even musical instruments have a limited range in their fundamental frequencies. Since the progression of ARHI is also gradual, the subject maybe unaware of the gradual loss of overtones in speech or instrumental music, which can extend two or three octaves higher than the fundamentals, i.e., to two or three times the frequencies.
SOUND | APPROXIMATE FUNDAMENTAL FREQUENCY RANGE (Hz) |
|---|---|
Guitar | 82–1175 |
Truck engine | 125–250 |
Dog’s bark | 200–300 |
Violin | 196–4400 |
Soprano singer | 200–1400 |
Most spoken consonants | 250–500 |
Middle C of the musical scale | 264 |
Spoken vowels | 500–750 |
Crying baby | 750–1000 |
Consonants: c, p, ch, g, h, sh | 1000–2000 |
Telephone ring | 3000–4000 |
Consonants: f, k, s, t, th | 3000–8000 |
Birds chirping | 4000–8000 |
Although basic hearing needs center on the 1000 to 2000 Hz range, higher frequency losses like those in ARHI cost the ability to discriminate between many words with f, p, k, s, t, th sounds (Table 44-2). For example, to a person with high-frequency hearing loss, “sick” and “thick” maybe difficult to differentiate, and “three socks” may sound like “free fox” unless the listener has developed the ability to read the speakers lips for more information. Such communication errors may seem trivial, but can cause enormous social disability when they happen in work situations or become cumulative.
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