Human Presbycusis Research Articles

Age-Related Hearing Loss Is Dominated by Damage to Inner Ear Sensory Cells, Not the Cellular Battery That Powers Them.

Age-related hearing loss arises from irreversible damage in the inner ear, where sound is transduced into electrical signals. Prior human studies suggested that sensory-cell loss is rarely the cause; correspondingly, animal work has implicated the stria vascularis, the cellular "battery" driving the amplification of sound by hair cell "motors." Here, quantitative microscopic analysis of hair cells, auditory nerve fibers, and strial tissues in 120 human inner ears obtained at autopsy, most of whom had recent audiograms in their medical records, shows that the degree of hearing loss is well predicted from the amount of hair cell loss and that inclusion of strial damage does not improve the prediction. Although many aging ears showed significant strial degeneration throughout the cochlea, our statistical models suggest that, by the time strial tissues are lost, hair cell death is so extensive that the loss of battery is no longer important to pure-tone thresholds and that audiogram slope is not diagnostic for strial degeneration. These data comprise the first quantitative survey of hair cell death in normal-aging human cochleas, and reveal unexpectedly severe hair cell loss in low-frequency cochlear regions, and dramatically greater loss in high-frequency regions than seen in any aging animal model. Comparison of normal-aging ears to an age-matched group with acoustic-overexposure history suggests that a lifetime of acoustic overexposure is to blame.SIGNIFICANCE STATEMENT This report upends dogma about the causes of age-related hearing loss. Our analysis of over 120 autopsy specimens shows that inner-ear sensory cell loss can largely explain the audiometric patterns in aging, with minimal contribution from the stria vascularis, the "battery" that powers the inner ear, previously viewed as the major locus of age-related hearing dysfunction. Predicting inner ear damage from the audiogram is critical, now that clinical trials of therapeutics designed to regrow hair cells are underway. Our data also show that hair cell degeneration in aging humans is dramatically worse than that in aging animals, suggesting that the high-frequency hearing losses that define human presbycusis reflect avoidable contributions of chronic ear abuse to which aging animals are not exposed.

Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway

Mutations in GJB2, the gene that encodes connexin 26 (Cx26), are the most common cause of sensorineural hearing impairment. The truncating variant 35delG, which determines a complete loss of Cx26 protein function, is the prevalent GJB2 mutation in several populations. Here, we generated and analyzed Gjb2+/− mice as a model of heterozygous human carriers of 35delG. Compared to control mice, auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) worsened over time more rapidly in Gjb2+/− mice, indicating they were affected by accelerated age-related hearing loss (ARHL), or presbycusis. We linked causally the auditory phenotype of Gjb2+/− mice to apoptosis and oxidative damage in the cochlear duct, reduced release of glutathione from connexin hemichannels, decreased nutrient delivery to the sensory epithelium via cochlear gap junctions and deregulated expression of genes that are under transcriptional control of the nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal regulator of tolerance to redox stress. Moreover, a statistically significant genome-wide association with two genes (PRKCE and TGFB1) related to the Nrf2 pathway (p-value < 4 × 10−2) was detected in a very large cohort of 4091 individuals, originating from Europe, Caucasus and Central Asia, with hearing phenotype (including 1076 presbycusis patients and 1290 healthy matched controls). We conclude that (i) elements of the Nrf2 pathway are essential for hearing maintenance and (ii) their dysfunction may play an important role in the etiopathogenesis of human presbycusis.

A QTL on Chr 5 modifies hearing loss associated with the fascin-2 variant of DBA/2J mice.

Inbred mouse strains serve as important models for human presbycusis or age-related hearing loss. We previously mapped a locus (ahl8) contributing to the progressive hearing loss of DBA/2J (D2) mice and later showed that a missense variant of the Fscn2 gene, unique to the D2 inbred strain, was responsible for the ahl8 effect. Although ahl8 can explain much of the hearing loss difference between C57BL/6J (B6) and D2 strain mice, other loci also contribute. Here, we present results of our linkage analyses to map quantitative trait loci (QTLs) that modify the severity of hearing loss associated with the D2 strain Fscn2 (ahl8) allele. We searched for modifier loci by analyzing 31 BXD recombinant inbred (RI) lines fixed for the predisposing D2-derived Fscn2 (ahl8/ahl8) genotype and found a statistically significant linkage association of threshold means with a QTL on Chr 5, which we designated M5ahl8. The highest association (LOD 4.6) was with markers at the 84-90Mb position of Chr 5, which could explain about 46% of the among-RI strain variation in auditory brainstem response (ABR) threshold means. The semidominant nature of the modifying effect of M5ahl8 on the Fscn2 (ahl8/ahl8) phenotype was demonstrated by analysis of a backcross involving D2 and B6.D2-Chr11D/LusJ strain mice. The Chr 5 map position of M5ahl8 and the D2 origin of its susceptibility allele correspond to Tmc1m4, a previously reported QTL that modifies outer hair cell degeneration in Tmc1 (Bth) mutant mice, suggesting that M5ahl8 and Tmc1m4 may represent the same gene affecting maintenance of stereocilia structure and function during aging.

Cochlear neuropathy in human presbycusis: Confocal analysis of hidden hearing loss in post-mortem tissue

Recent animal work has suggested that cochlear synapses are more vulnerable than hair cells in both noise-induced and age-related hearing loss. This synaptopathy is invisible in conventional histopathological analysis, because cochlear nerve cell bodies in the spiral ganglion survive for years, and synaptic analysis requires special immunostaining or serial-section electron microscopy. Here, we show that the same quadruple-immunostaining protocols that allow synaptic counts, hair cell counts, neuronal counts and differentiation of afferent and efferent fibers in mouse can be applied to human temporal bones, when harvested within 9 h post-mortem and prepared as dissected whole mounts of the sensory epithelium and osseous spiral lamina. Quantitative analysis of five “normal” ears, aged 54–89 yrs, without any history of otologic disease, suggests that cochlear synaptopathy and the degeneration of cochlear nerve peripheral axons, despite a near-normal hair cell population, may be an important component of human presbycusis. Although primary cochlear nerve degeneration is not expected to affect audiometric thresholds, it may be key to problems with hearing in noise that are characteristic of declining hearing abilities in the aging ear.

Genes involved in immunity and apoptosis are associated with human presbycusis based on microarray analysis

Conclusions: Genes involved in immunity and apoptosis were associated with human presbycusis. CCR3 and GILZ played an important role in the pathogenesis of presbycusis, probably through regulating chemokine receptor, T-cell apoptosis, or T-cell activation pathways. Objectives: To identify genes associated with human presbycusis and explore the molecular mechanism of presbycusis. Methods: Hearing function was tested by pure-tone audiometry. Microarray analysis was performed to identify presbycusis-correlated genes by Illumina Human-6 BeadChip using the peripheral blood samples of subjects. To identify biological process categories and pathways associated with presbycusis-correlated genes, bioinformatics analysis was carried out by Gene Ontology Tree Machine (GOTM) and database for annotation, visualization, and integrated discovery (DAVID). Quantitative RT-PCR (qRT-PCR) was used to validate the microarray data. Results: Microarray analysis identified 469 up-regulated genes and 323 down-regulated genes. Both the dominant biological processes by Gene Ontology (GO) analysis and the enriched pathways by Kyoto encyclopedia of genes and genomes (KEGG) and BIOCARTA showed that genes involved in immunity and apoptosis were associated with presbycusis. In addition, CCR3, GILZ, CXCL10, and CX3CR1 genes showed consistent difference between groups for both the gene chip and qRT-PCR data. The differences of CCR3 and GILZ between presbycusis patients and controls were statistically significant (p < 0.05).

Heptanol Application to the Mouse Round Window: A Novel Model for Studying Cochlear Regenerative Potential

Objectives: 1) Introduce a novel model for studying cochlear lateral wall regeneration. 2) Describe implications of this study on research and treatment of human presbycusis. Background: Human presbycusis likely occurs secondary to senile degeneration of the stria vascularis (SV) and spiral ligament fibrocytes (SLFs). SLFs have a limited regenerative capacity. Augmenting this process may play a role in hearing preservation, recovery, or both. Few models currently exist, however, that can selectively and temporarily damage the cochlear lateral wall to study SLF regeneration. Methods: Heptanol, a gap junction uncoupler, was surgically applied to the round window of 25 normal hearing mice, with sacrifice at points 12 hours - 14 days post-treatment. Auditory brainstem response testing, electron microscopy, and immunostaining techniques were used to assess treatment response. Results: Click tone thresholds were significantly elevated (mean +40.5 dB sound pressure level) in all treated mice. Hearing loss plateaued on days 1-7, followed by near complete recovery thereafter. Ultrastructural analysis revealed selective SV injury and SLF apoptosis at the apical, middle, and basal turns. A marked reduction in ion channel immunostaining intensity occurred throughout the lateral wall but resolved by 2 weeks. 3-4 days, SLFs stained positive for EdU, a labeled thymidine analog and marker of cellular proliferation. Conclusions: This is one of the first models described to reliably and selectively induce lateral wall toxicity followed by full hearing recovery and SLF regeneration. Future study of the molecular and genetic expression profiles governing this process will be greatly facilitated by this technique.

Downregulation of N-methyl-d-aspartate receptor ζ1 subunit (GluN1) gene in inferior colliculus with aging

Presbycusis is the impairment of auditory function associated with aging, which stems from peripheral cochlear lesions and degeneration of the central auditory process. The effect of age-induced peripheral hearing loss on the central auditory process is not fully understood. C57Bl/6 (C57) mice present accelerated peripheral hearing loss, which is well developed by middle-age and mimics the human presbycusis pattern. The aim of this study was to elucidate the molecular effects of peripheral hearing loss in the inferior colliculus (IC) with age between young and middle-aged C57 mice using cDNA microarray. Glutamate receptor ionotropic NMDA ζ1 (GluN1) exhibited the greatest decrease in the middle-aged group as determined using cDNA microarray and by further assessment using real-time PCR (qPCR). Histological assessment with in situ hybridization of GluN1 showed significantly decreased expression in all IC subdivisions of the middle-aged group. GluN1 is a receptor for excitatory neurotransmission, and significant downregulation of this gene may be subsequent to the decline of afferent input from the cochlea in aging C57 mice. Consequently, using the combination of microarray, qPCR, and in situ hybridization, we showed that the decline of GluN1 in the IC of aging animals might have a key role in the pathogenesis of presbycusis.

Oxidative Stress, Inflammation, and Autophagic Stress as the Key Mechanisms of Premature Age-Related Hearing Loss in SAMP8 Mouse Cochlea

In our aging society, age-related hearing loss (ARHL) or presbycusis is increasingly important. Here, we study the mechanism of ARHL using the senescence-accelerated mouse prone 8 (SAMP8) which is a useful model to probe the effects of aging on biological processes. We found that the SAMP8 strain displays premature hearing loss and cochlear degeneration recapitulating the processes observed in human presbycusis (i.e., strial, sensory, and neural degeneration). The molecular mechanisms associated with premature ARHL in SAMP8 mice involve oxidative stress, altered levels of antioxidant enzymes, and decreased activity of Complexes I, II, and IV, which in turn lead to chronic inflammation and triggering of apoptotic cell death pathways. In addition, spiral ganglion neurons (SGNs) also undergo autophagic stress and accumulated lipofuscin. Our results provide evidence that targeting oxidative stress, chronic inflammation, or apoptotic pathways may have therapeutic potential. Modulation of autophagy may be another strategy. The fact that autophagic stress and protein aggregation occurred specifically in SGNs also offers promising perspectives for the prevention of neural presbycusis.

The Fischer 344 rat as a model of presbycusis

Due to the rising number of the aged human population all over the world, presbycusis is a phenomenon that deserves the increasing attention of the medical community as regards to prevention and treatment. This requires finding appropriate animal models for human presbycusis that will be useful in future experiments. Among the available rat strains, the Fischer 344 (F344) strain promises to serve as a model producing prompt and profound presbycusis. Hearing thresholds begin to increase in this strain during the first year of life; toward the end of the second year, the thresholds are very high. The threshold shifts progress independently in both ears. The rapid deterioration of distortion product otoacoustic emissions, with the majority of outer hair cells (OHC) being present and morphologically intact, is apparently produced by the disruption of prestin. The age-related changes within inner ear function are accompanied by deterioration of acoustical signal processing within central auditory system, mainly due to impaired GABA inhibition. The loss of GABA inhibition in old animals is expressed primarily in the inferior colliculus but is also present in the cochlear nuclei and the auditory cortex. Sound-evoked behavioral reactions are also impaired in old F344 rats. Taken together, the described characteristics of the aging F344 rat auditory system supports the idea that this strain may serve as a suitable model for studying the mechanisms of presbycusis, its prevention and treatment.

Auditory filter shapes of CBA/CaJ mice: Behavioral assessments

Auditory filter shape and frequency tuning may be derived by measuring changes in pure tone thresholds as a function of the bandwidth of notched-noise maskers. When these psychophysical methods were applied to CBA/CaJ mice, the resulting filter shapes were well fit by roex(p,r) functions originally developed for human subjects. The equivalent rectangular bandwidths (ERBs) of the filter shapes ranged from 16 to 19% of test frequencies between 8 to 16 kHz. These ERBs correspond well to the performance of humans at high frequencies and the limited number of mammalian species that have been characterized with notched-noise procedures. Frequency tuning was maintained throughout most of the adult lifespan and then showed a selective high-frequency loss at ages beyond 2 years. These results suggest that auditory filtering effects in adult CBA/CaJ mice are similar to normal processes in other mammalian species and provide an excellent model of human presbycusis when they begin to degrade in aging individuals.

Age-related hearing loss and the ahl locus in mice

C57BL/6 (B6) mice experience hearing loss and cochlear degeneration beginning about mid-life, whereas CAST/Ei (CAST) mice retain normal hearing until old age. A locus contributing to the hearing loss of B6 mice, named age-related hearing loss ( ahl), was mapped to Chromosome 10. A homozygous, congenic strain of mice (B6.CAST-+ ahl ), generated by crossing B6 ( ahl / ahl ) and CAST (+ ahl /+ ahl ) mice has the same genomic material as the B6 mice except in the region of the ahl locus, which is derived from CAST. In this study, we have determined the extent of the CAST-derived region of Chromosome 10 in the congenic strain and have examined mice of all three strains for hearing loss and cochlear morphology between 9 and 25 months of age. Results for B6 mice were similar to those described previously. CAST mice showed no detectable hearing loss even at 24 months of age; however, they had a small amount of ganglion cell degeneration. B6.CAST-+ ahl mice were protected from early onset hearing loss and basal turn degeneration, but older animals did show some hearing loss and ganglion cell degeneration. We conclude that loci in addition to ahl contribute to the differences in hearing loss between B6 and CAST mice. These results illustrate the complex inheritance of age-related hearing loss in mice and may have implications for the study of human presbycusis.

, a Second Locus Affecting Age-Related Hearing Loss in Mice

Inbred mouse strains with age-related hearing loss (AHL) provide valuable models for studying the genetic basis of human presbycusis. Here we report the genetic mapping of a second AHL locus in mice (designated Ahl2) that is a major contributor to the 8- to 10-month difference in hearing loss onset times between NOD/LtJ and C57BL/6J mice. A whole-genome linkage scan of 110 progeny from a (C57BL/6J×NOD/LtJ)×NOD/LtJ backcross revealed statistically significant associations of ABR thresholds with markers on chromosome 5, with a peak lod score of 5.5 for D5Mit309. At 6 months of age, backcross progeny that inherited two copies of the recessive NOD/LtJ-derived allele at this locus (genotype ahl2/ahl2) exhibited ABR thresholds that were on average 26 decibels above those of heterozygous mice. Analysis of a (CAST/Ei×NOD/LtJ)×NOD/LtJ backcross, which segregates strain-specific alleles at both Ahl2 and the Ahl locus on chromosome 10, showed that the hearing loss attributable to Ahl2 is dependent on a predisposing Ahl genotype. The statistically significant effect of Ahl2 observed in crosses with NOD/LtJ was not seen in crosses involving three other strains with early onset AHL: A/J, BUB/BnJ, and SKH2/J.

Ahl2, a Second Locus Affecting Age-Related Hearing Loss in Mice

Inbred mouse strains with age-related hearing loss (AHL) provide valuable models for studying the genetic basis of human presbycusis. Here we report the genetic mapping of a second AHL locus in mice (designated Ahl2) that is a major contributor to the 8- to 10-month difference in hearing loss onset times between NOD/LtJ and C57BL/6J mice. A whole-genome linkage scan of 110 progeny from a (C57BL/6J×NOD/LtJ)×NOD/LtJ backcross revealed statistically significant associations of ABR thresholds with markers on chromosome 5, with a peak lod score of 5.5 for D5Mit309. At 6 months of age, backcross progeny that inherited two copies of the recessive NOD/LtJ-derived allele at this locus (genotype ahl2/ ahl2) exhibited ABR thresholds that were on average 26 decibels above those of heterozygous mice. Analysis of a (CAST/Ei×NOD/LtJ)×NOD/LtJ backcross, which segregates strain-specific alleles at both Ahl2 and the Ahl locus on chromosome 10, showed that the hearing loss attributable to Ahl2 is dependent on a predisposing Ahl genotype. The statistically significant effect of Ahl2 observed in crosses with NOD/LtJ was not seen in crosses involving three other strains with early onset AHL: A/J, BUB/BnJ, and SKH2/J.

A Major Gene Affecting Age-Related Hearing Loss Is Common to at Least Ten Inbred Strains of Mice

Inbred strains of mice offer promising models for understanding the genetic basis of human presbycusis or age-related hearing loss (AHL). We previously mapped a major gene affecting AHL in C57BL/6J mice. Here, we show that the same Chromosome 10 gene (Ahl) is a major contributor to AHL in nine other inbred mouse strains—129P1/ReJ, A/J, BALB/cByJ, BUB/BnJ, C57BR/cdJ, DBA/2J, NOD/LtJ, SKH2/J, and STOCK760. F1 hybrids between each of these inbred strains and the normal-hearing inbred strain CAST/Ei retain good hearing, indicating that inheritance of AHL is recessive. To follow segregation of hearing loss, F1 hybrids were backcrossed to the parental strains with AHL. Auditory-evoked brain-stem response thresholds were used to assess hearing in more than 1500 N2 mice and analyzed as quantitative traits for linkage associations with Chromosome 10 markers. Highly significant linkage was found in all nine strain backcrosses, with the highest probability (LOD > 70) near the marker D10Mit112. This map position for Ahl is near the waltzer mutation (v) and the modifier of deaf waddler locus (mdfw), suggesting the possibility of allelism. Results from an intercross of C57BL/6J and NOD/LtJ mice indicate that the 6- to 10-month difference in AHL onset between these two strains is not due to allelic heterogeneity of the Ahl gene.

Age-Related Changes In Acetylcholinesterase Activity In The Efferent System Of The Cochlea Of C57bl/6 Mice

C57BL/6 mice, along with other mouse genotypes, have served as models of human presbycusis. C57BL/6 mice suffer from progressively severe hearing impairments, attributable primarily to losses of both hair cells (sensory receptors) and spiral ganglion cells (afferent neurons). Their age-related hair cell degeneration in the cochlea begins in the basal turn and progresses to the apex.Auditory nerves also undergo age-related changes. The mammalian cochlear nerve is mixed, being composed largely of afferent (sensory) fibers and a small population of efferent fibers. Because efferent nerves are primarily cholinergic, we used acetylcholinesterase (AChE) as a marker enzyme for determining both age-related changes in AChE activity of the efferent fibers and also for tracing degenerative patterns in efferent pathways within the organ of Corti.Twelve C57BL/6 mice of the following ages were used: four young (23 days), four middle-aged (13 months), and four old (22.5 months) mice.

Acid Phosphatase Activity in Spiral Ganglion Neurons of C57BL/6 Mice

C57BL/6 mice, along with several other mouse genotypes, have served as models for human presbycusis (age-related hearing losses). C57BL/6 mice and their genetic substrain C57/M6 show progressively severe hearing losses, starting as early as 30 days postnatally. The hearing losses result from sweeping degeneration of sensory (hair) cells and neurons that begins in the basal end of the cochlea and advances apically. Although the underlying mechanisms orchestrating sensory and neural degeneration are not known, it is possible to correlate degenerative events with the cytoplasmic levels and distribution patterns of a marker molecule, such as acid phosphatase (AP). AP, a representative lysosomal enzyme, plays a role in both normal cellular metabolism and degenerative changes (trauma and senescence). AP activity is visualized histochemically at the light and electron microscopic levels by the presence of dense deposits within lysosomes.

Age-related changes in the cochlea and cochlear nuclei of dogs.

To study the underlying morphological changes of presbycusis, cochlea and cochlear nuclei from twenty three dogs, ranging in age from 3 days to 17 years, were examined histologically. Dogs used in this study were house dogs kept in an environment similar to that of humans. Four types of histological changes reported in human presbycusis, that is, loss of spiral ganglion cells, atrophy of the organ of Corti, atrophy of the stria vascularis, and thickening of the basilar membrane were observed in dogs. The changes were prominent at the base of the cochlea. Less intense changes were also observed in the apex of the cochlea. The degree of these changes appeared to progress as a function of age. All four types of changes with varied intensity were found in all dogs over 12 years old. In addition to the changes in the cochlea, cochlear nuclei changes including nerve cell loss, astrogliosis and ubiquitin deposition were found in dogs over 10 years old. Hearing dysfunction was accompanied by the morphological changes, though the degree of the hearing dysfunction did not always parallel to that of morphological changes. The morphological changes seen in the cochlea and cochlear nuclei of dogs were qualitatively and quantitatively similar to those reported in aged humans, indicating that otopathologic changes in the inner ear may be due to aging plus exposure to certain environmental ototoxic factors.

Age-related decline of auditory function in the chinchilla (Chinchilla laniger)

The aim of this study was to examine the functional consequences of aging in the chinchilla, a rodent with a relatively long life span and a range of hearing similar to that of humans. Subjects were 21 chinchillas aged 10–15 years, and 23 young controls. Thresholds were determined from auditory evoked potentials (EVPs), and outer hair cell (OHC) functioning was assessed by measuring 2f1−f2 distortion product otoacoustic emissions (DPOAEs). Six cochleas from 11–12-year-old animals were examined for hair cell loss and gross strial pathology. The results show that the chinchilla exhibits a small but significant decline of auditory sensitivity and OHC functioning between 3 and 15 years of age, with high-frequency losses exceeding and growing more rapidly than low-frequency losses. Compared to rodents with shorter life spans, the chinchilla has a rate of loss that is more similar to that of humans, which could make it a valuable model for understanding the etiology of human presbycusis.

Sensorineural hearing loss alters recovery from short-term adaptation in the C57BL/6 mouse

Several strains of laboratory mouse ( Mus musculus) have a pattern of hearing loss which resembles that found in humans. The C57BL/6 strain of mouse has a genetic defect that results in degeneration of the organ of Corti, originating in the basal, high-frequency region and then proceeding apically over time. The end result is a severe-to-profound sensorineural hearing loss (SNHL) by 14 months of age. In contrast, auditory function of the CBA strain remains normal through its early life span then slowly declines later in life, much like that typified by human presbycusis. The purpose of the present study was to compare ABR (peak 5) forward masking recovery functions in young, normal-hearing CBA and C57BL/6 mice to hearing-impaired C57BL/6 mice. ABR audiograms were obtained prior to collecting the tone-on-tone forward masking data. Masking was defined as a 50% reduction in the P5 component of the ABR, elicited and masked by 12 kHz tone bursts, using masker/probe time delays from 0 to 100 ms. Time constants were computed from an exponential model fit to the recovery functions (masker level vs. time delay). In hearing-impaired animals there was a significant increase in recovery from short-term adaptation as measured by the time constants, as well as a significant latency shift in the P5 component. The effects of SNHL on the recovery of the P5 component from short-term adaptation was comparable to that reported behaviorally for human hearing-impaired listeners and physiologically from the inferior colliculus (IC) of chinchillas suffering permanent threshold shifts.

Age-related Loss of Auditory Sensitivity in Two Mouse Genotypes

Frequency-specific auditory brainstem responses (ABR) (frequency range 2-31.5 kHz) were used to describe age-dependent alterations in frequency sensitivity in CBA/ca (to 30 months) and C57BL/6J (to 16 months) mouse genotypes. The two strains displayed an age-related loss similar to that of humans, with a primary decline in high-frequency sensitivity. CBA mice showed a slow, yet gradual decrease in sensitivity to high- followed by low-frequency until 18 months of age and a rapid deterioration at all frequencies thereafter. C57 mice demonstrated precocious aging in auditory sensitivity in an unsteady rather than gradual manner. By testing the same individuals on repeated occasions it was shown that, for C57 mice, the degenerative process was more precipitous with three phases, and that the individual variability was larger than that of CBA mice. It is suggested that the two mouse genotypes can be used to express the different aspects of human presbycusis in individual variability and modes of gradual or staggered progression.