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Long-term treatment with aldosterone slows the progression of age-related hearing loss
... However, these strategies are only at the theoretical level and were conducted in limited studies, some of which were designed based on cross-sectional studies that have found a relation between ARHL and some factors such as nutrition, inflammatory factors, taking some drugs, etc. These strategies include pharmacological interventions such as calcium channel blockers (100)(101)(102), statins (103), cochlear vasodilators (61), adenosine kinase inhibitors (104,105), salicylate (106), rapamycin (107)(108)(109)(110), and some other strategies such as hormone therapy (111)(112)(113)(114)(115), augmented acoustic environment (AAE) (116)(117)(118), modulation of neurotransmitters (e.g., GABA up-regulation) (119), Modulation of Metabotropic Glutamate Receptor 7 (120), electrical stimulation for restoring the endo-cochlear potential (121), long-term exercise therapy (122), enhancing medial olivocochlear feedback (123), and also new methods in amplification such as implant of vibrant sound-bridge (124). Multiple mechanisms have been postulated for each strategy. ...
... As a result, hormone therapy has been suggested as a possible treatment option for ARHL. In agreement with some cross-sectional or cohort studies that showed ARHL is less frequent in those with higher serum aldosterone levels and postmenopausal women who receive hormone replacement therapy, some experimental studies have demonstrated that aldosterone hormone therapy is helpful for cochlear function in aging (111,112). Frisina et al. demonstrated that aldosterone has therapeutic effects on spiral ganglion neurons by increasing their survival, up-regulating mineralocorticoid receptors, and finally, inhibiting apoptosis in the cochlea of mice (111). It has been suggested that it may delay or reverse the metabolic pathogenesis of the stria caused by aging by maintaining the main ion pumps in the cochlear lateral wall cells, including NKCC1 (Na-K-Cl co-transporter 1), which is involved in the homeostatic maintenance of the endo-cochlear potential. ...
... It has been suggested that it may delay or reverse the metabolic pathogenesis of the stria caused by aging by maintaining the main ion pumps in the cochlear lateral wall cells, including NKCC1 (Na-K-Cl co-transporter 1), which is involved in the homeostatic maintenance of the endo-cochlear potential. This is because aldosterone regulates the expression of the sodium (Na+) and potassium (K+) ion transporters NKCC1 and Na-K-ATPase and thereby the level of sodium and Interventions for age-related hearing loss Tavanai et al. potassium (111,112). Researchers evaluated the influence of estradiol and progesterone hormones on middle-aged female CBA/CaJ mice (113). They discovered that animals treated with estradiol had negligible ABR threshold changes in both HRT and recovery period compared with the placebo and all of the other HRT groups. ...
Aging causes progressive degenerative changes in many organs, particularly the auditory system. Several attempts have been conducted to investigate preventive and therapeutic strategy/strategies for age-related auditory dysfunction, such as maintaining a healthy lifestyle through good nutrition, lower anxiety levels, and noise exposure, different pharmacological approaches, gene and cell therapy, and other strategies. However, it is not clear which approach is the best to slow down these dysfunctions because several different underlying mechanistic pathways are associated with presbycusis which eventually leads to different types of this disease. A combination of several methods is probably required, whereas the effectiveness for some people needs to be monitored. The effectiveness of treatments will not be the same for all; therefore, we may need to have a unique and personalized approach to the prevention and treatment of ARHL for each person. In addition, each method needs to specify what type of presbycusis can prevent or treat and provide complete information about the extent, duration of treatment, persistency of treatment, side effects, and whether the approach is for treatment or prevention or even both. This paper reviews the updated literature, which targets current interventions for age-related hearing loss.
... Therefore, to expand the range of treatment options for ARHL, recent studies have been investigating alternative procedures for regaining or preserving hearing sensitivity in the older population. [12][13][14][15] Studies in animal and human models are being performed to identify potential medical treatment to slow the progress and reduce the prevalence of ARHL. ...
... Studies showed that ALD-treated mice had stable ABR thresholds and maintained peak I and IV amplitudes over the time course of treatment. 13 This finding suggested that ALD-treated mice did not show a significant effect of aging because hearing sensitivity remained stable over the course of the treatment. However, the control group showed a significant increase in the ABR threshold (poorer hearing sensitivity) and loss of amplitude robustness over time, which is compatible with poorer neural synchrony due to the aging processes. ...
... However, the control group showed a significant increase in the ABR threshold (poorer hearing sensitivity) and loss of amplitude robustness over time, which is compatible with poorer neural synchrony due to the aging processes. 13 Moreover, ALD implants were provided to aged mice to treat ARHL. 14,30 Hearing sensitivity was evaluated using behavioral and electrophysiological measures. ...
Hearing loss is a common cause of disability in the global population. The prevalence of hearing loss is estimated to dramatically increase in the next decades with an increase in the number of older people. The fact that hearing loss correlates with aging suggests that age-related hearing loss (presbycusis) will be a critical issue and hearing care will be required. Untreated hearing loss has negative effects at multiple levels, such as hearing loss affecting the quality of life of hearing-impaired individuals, deteriorating family relationships, and interfering with economic growth. Unfortunately, treatments for hearing loss are limited to the use of hearing devices. Studies have shown that the number of hearing aid users is approximately 20% of all hearing-impaired individuals. Therefore, having alternative treatments is critical to reduce the number of people with hearing loss and to prevent a dramatic increase in the number of hearing-impaired individuals. In the future, a potential medication may be aldosterone (ALD). Studies have reported positive effects of ALD treatments on hearing loss in aged mice. ALD treatment in aged mice shows an improvement in hearing sensitivity and a healthier cochlear structure. Although higher ALD concentrations are associated with better hearing sensitivity and hearing in noise ability than lower concentrations, there is no clinical trial in ALD treatment in human has been reported.
... Thus, functionally, the MR:GR ratio has been considered crucial for normal adaptation to constantly changing environmental stressors at the organism, tissue, and even cellular level for those cells expressing both receptors (reviewed by [6]). Within the auditory system, stimulated GC signaling in the cochlea activates GR to initiate anti-inflammation programs through NF-κB inhibition [7][8][9], while stimulated MR activity may improve auditory function through stabilization of ionic and water balance [10,11]. Unique combinations of MR and GR expression and intracellular signaling components can produce cell-type-specific responses. ...
... It is possible that MR cKO mice experience an exacerbated decrease in endolymphatic potential (EP) driven by noise, though this possibility was not assessed in these studies. Cochlear MR, especially in the stria vascularis, is implicated in ion homeostasis [11,81,82]. MR expression in supporting cells along the cochlear basilar membrane is likely to be involved in endolymphatic ionic balance where partial loss of MR expression could alter the ionic environment enough to produce the temporary threshold changes observed. ...
... Thus, 9 to as many as 15 days elapsed between the first tamoxifen injections and noise exposure. Custom LabView software (Eaton Peabody Labs, MEEI) was used to generate octave-band noise (8)(9)(10)(11)(12)(13)(14)(15)(16). A maximum of two mice were placed in a wire mesh cage (6 × 6 × 6 in), and up to four cages were placed within a custom-built noise exposure chamber on a rotating platform. ...
Endogenous glucocorticoids (GC) are known to modulate basic elements of cochlear physiology. These include both noise-induced injury and circadian rhythms. While GC signaling in the cochlea can directly influence auditory transduction via actions on hair cells and spiral ganglion neurons, evidence also indicates that GC signaling exerts effects via tissue homeostatic processes that can include effects on cochlear immunomodulation. GCs act at both the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Most cell types in the cochlea express both receptors sensitive to GCs. The GR is associated with acquired sensorineural hearing loss (SNHL) through its effects on both gene expression and immunomodulatory programs. The MR has been associated with age-related hearing loss through dysfunction of ionic homeostatic balance. Cochlear supporting cells maintain local homeostatic requirements, are sensitive to perturbation, and participate in inflammatory signaling. Here, we have used conditional gene manipulation techniques to target Nr3c1 (GR) or Nr3c2 (MR) for tamoxifen-induced gene ablation in Sox9-expressing cochlear supporting cells of adult mice to investigate whether either of the receptors sensitive to GCs plays a role in protecting against (or exacerbating) noise-induced cochlear damage. We have selected mild intensity noise exposure to examine the role of these receptors related to more commonly experienced noise levels. Our results reveal distinct roles of these GC receptors for both basal auditory thresholds prior to noise exposure and during recovery from mild noise exposure. Prior to noise exposure, auditory brainstem responses (ABRs) were measured in mice carrying the floxed allele of interest and the Cre recombinase transgene, but not receiving tamoxifen injections (defined as control (no tamoxifen treatment), versus conditional knockout (cKO) mice, defined as mice having received tamoxifen injections. Results revealed hypersensitive thresholds to mid- to low-frequencies after tamoxifen-induced GR ablation from Sox9-expressing cochlear supporting cells compared to control (no tamoxifen) mice. GR ablation from Sox9-expressing cochlear supporting cells resulted in a permanent threshold shift in mid-basal cochlear frequency regions after mild noise exposure that produced only a temporary threshold shift in both control (no tamoxifen) f/fGR:Sox9iCre+ and heterozygous f/+GR:Sox9iCre+ tamoxifen-treated mice. A similar comparison of basal ABRs measured in control (no tamoxifen) and tamoxifen-treated, floxed MR mice prior to noise exposure indicated no difference in baseline thresholds. After mild noise exposure, MR ablation was initially associated with a complete threshold recovery at 22.6 kHz by 3 days post-noise. Threshold continued to shift to higher sensitivity over time such that by 30 days post-noise exposure the 22.6 kHz ABR threshold was 10 dB more sensitive than baseline. Further, MR ablation produced a temporary reduction in peak 1 neural amplitude one day post-noise. While supporting cell GR ablation trended towards reducing numbers of ribbon synapses, MR ablation reduced ribbon synapse counts but did not exacerbate noise-induced damage including synapse loss at the experimental endpoint. GR ablation from the targeted supporting cells increased the basal resting number of Iba1-positive (innate) immune cells (no noise exposure) and decreased the number of Iba1-positive cells seven days following noise exposure. MR ablation did not alter innate immune cell numbers at seven days post-noise exposure. Taken together, these findings support differential roles of cochlear supporting cell MR and GR expression at basal, resting conditions and especially during recovery from noise exposure.
... NKCC1 is another key channel in the inner ear and it declines with aging. [48,[110][111][112]. Lui and coworkers showed progressive aging declines in NKCC1 protein and gene expressions in C57BL/6J mice [112]. ...
... Lui and coworkers showed progressive aging declines in NKCC1 protein and gene expressions in C57BL/6J mice [112]. Ding and colleagues further confirmed this finding in CBA/CaJ mice, another well-known animal model for carrying out aging auditory studies [111,113]. Diaz et al. [114] generated NKCC1 +/− , α1-Na,K-ATPase +/− , and α2-Na,K-ATPase +/− single-heterozygous mutant mice as well as double-heterozygous mutants NKCC1 +/− α1 +/− and NKCC1 +/− α2 +/− , and performed ABRs and DPOAEs, as well as recording EPs through the insertion of a microelectrode into the SV of scala media. In this study, the three single-heterozygous mutants demonstrated various degrees of ARHL loss, and the double NKCC1 +/− α1 +/− mice exhibited severe ARHL later (51-60 weeks) compared to the single-heterozygous counterparts (31-40 weeks). ...
... Aldosterone is another potential candidate for the prevention/treatment of hearing loss involving inflammatory processes [38,111,113,[204][205][206]. CBA/CaJ mice (15-18 months) that underwent aldosterone treatment for four months displayed stable ABR thresholds, while the control mice showed an increase in their thresholds, characteristic of ARHL, as shown in Figure 5 [111]. ...
The slow accumulation of inflammatory biomarker levels in the body—also known as inflammaging—has been linked to a myriad of age-related diseases. Some of these include neurodegenerative conditions such as Parkinson’s disease, obesity, type II diabetes, cardiovascular disease, and many others. Though a direct correlation has not been established, research connecting age-related hearing loss (ARHL)—the number one communication disorder and one of the most prevalent neurodegenerative diseases of our aged population—and inflammaging has gained interest. Research, thus far, has found that inflammatory markers, such as IL-6 and white blood cells, are associated with ARHL in humans and animals. Moreover, studies investigating ion channels and mitochondrial involvement have shown promising relationships between their functions and inflammaging in the cochlea. In this review, we summarize key findings in inflammaging within the auditory system, the involvement of ion channels and mitochondrial functions, and lastly discuss potential treatment options focusing on controlling inflammation as we age.
... Malfunction of NKCC1 can lead to complications, not least neurodegenerative diseases and attenuation of sensory system acuity like epilepsy, ataxia, hypertension, and hearing loss [46][47][48][49][50][51][52][53][54]. Also, studying interactions between enzyme activation and NKCC1 performance has led to the exploration of therapeutic countermeasures which show promising results. ...
... Mice were divided into four different age groups: 4, 14, 26 and 52 weeks old. There was a steady decline in NKCC1 expression at both protein and gene levels with age; confirmed by immunofluorescence microscopy, Western blotting and quantitative real-time polymerase chain reaction (RT-PCR) techniques, as displayed in Figure 2. Frisina and colleagues reported similar ageing declines in NKCC1 expression for CBA/CaJ mice [47]. The mutation/disruption of NKCC1 led to deafness and structural damage in the inner ear of other mouse models [56,57]. ...
... Given its critical involvement in aging changes in cochlear function, NKCC1 could be a potential therapeutic target for new ARHL treatments. Provocatively, the chronic treatment of aging CBA/CaJ mice with aldosterone, a natural occurring hormone that declines with age in mammals, prevents certain key aspects of ARHL (relative to aging control mice); i.e., aldosterone hormone therapy improved auditory brainstem response thresholds and improved survival of spiral ganglion neurons via inhibition of age-related downregulation of NKCC1 and apoptotic pathways [46][47][48]62]. [55], with permission from the publisher. ...
The auditory system is a fascinating sensory organ that overall, converts sound signals to electrical signals of the nervous system. Initially, sound energy is converted to mechanical energy via amplification processes in the middle ear, followed by transduction of mechanical movements of the oval window into electrochemical signals in the cochlear hair cells, and finally, neural signals travel to the central auditory system, via the auditory division of the 8th cranial nerve. The majority of people above 60 years have some form of age-related hearing loss, also known as presbycusis. However, the biological mechanisms of presbycusis are complex and not yet fully delineated. In the present article, we highlight ion channels and transport proteins, which are integral for the proper functioning of the auditory system, facilitating the diffusion of various ions across auditory structures for signal transduction and processing. Like most other physiological systems, hearing abilities decline with age, hence, it is imperative to fully understand inner ear aging changes, so ion channel functions should be further investigated in the aging cochlea. In this review article, we discuss key various ion channels in the auditory system and how their functions change with age. Understanding the roles of ion channels in auditory processing could enhance the development of potential biotherapies for age-related hearing loss.
... Previously we reported that long-term systemic treatment with ALD dramatically improves hearing function and reduces expression of cochlear apoptotic biomarkers in aging mice 39,40 . In the current study we examined the cellular mechanisms that may underlie these biotherapeutic effects of chronic ALD administration. ...
... Overall, NKCC1 plays a key role in various physiological systems including the cochlea, and its age-related declines. Previously, we have shown that long-term systemic treatment with ALD can prevent key aspects of ARHL in aging mice, indicating that ALD could potentially be a therapeutic agent for ARHL clinically 40 . Also, long-term treatment with ALD increased the serum ALD levels in treated animals as compared to control animals, which improved survival of spiral ganglion neurons through upregulation of mineralocorticoid receptors 39 . ...
Na+-K+-2Cl- Cotransporter (NKCC1) is a protein that aids in the active transport of sodium, potassium, and chloride ions across cell membranes. It has been shown that long-term systemic treatment with aldosterone (ALD) can enhance NKCC1 protein expression and activity in the aging cochlea resulting in improved hearing. In the present work, we used a cell line with confirmed NKCC1 expression to demonstrate that in vitro application of ALD increased outward voltage-gated potassium currents significantly, and simultaneously upregulated whole lysate and membrane portion NKCC1 protein expression. These ALD-induced changes were blocked by applying the mineralocorticoid receptor antagonist eplerenone. However, application of the NKCC1 inhibitor bumetanide or the potassium channel antagonist Tetraethyl ammonium had no effect. In addition, NKKC1 mRNA levels remained stable, indicating that ALD modulates NKCC1 protein expression via the activation of mineralocorticoid receptors and post-transcriptional modifications. Further, in vitro electrophysiology experiments, with ALD in the presence of NKCC1, K+ channel and mineralocorticoid receptor inhibitors, revealed interactions between NKCC1 and outward K+ channels, mediated by a mineralocorticoid receptor-ALD complex. These results provide evidence of the therapeutic potential of ALD for the prevention/treatment of inner ear disorders such as age-related hearing loss.
... In humans, those subjects with elevated aldosterone levels have better hearing test in noise. Long-term treatment with aldosterone in middle-aged mice slows the progression of ARHL, through central and peripheral effects, in a group in which this hormone gradually decreases [61]. As counterproductive effects and according to animal models, aldosterone might induce endolymphatic hydrops suppressing the expression of the Af9 gene. ...
... 1.7 μg/day 12 weeks [61] Thyroid hormones 30 hypothyroid patients, with an additional symptom of hearing impairment, treated with levothyroxine. ...
The purpose of this review is to summarize the advances and discoveries in the potential treatment with hormone analogs and some challenges still pending, beyond the classic treatment with corticosteroids. We conduct a review of the functions of hormones on hearing, in human and animal models, the presence of their most relevant receptors, and the desirable and undesirable effects for their therapeutic uses. Different hormones play a regulatory role in the development and maintenance of hearing. Hormone receptors in the ear have been identified over the years, which can be a support to use them as new therapeutic targets Moreover, their mediators, that include cells, neurotrophic factors, or other hormones, could be also useful for treating various hearing impairments The use of synthetic analogs could exert a therapeutic effect on hearing. Hormone therapy, in fact, can contribute positively to the treatment and prevention of various auditory pathologies, through the regeneration or protection. Considering that an optimal result has to be a garantee, it is a must to know their unwanted effects and contraindications. The use of hormones may protect, regenerate, and modulate multiple pathological conditions of the ear, but it would be necessary to standardize drug dosages, find alternative routes, and conduct prospective studies in humans.
... In order to test for co-localization of spiral ganglion neuron rescue with frequency-specific hearing improvements following ALD treatments, the murine cochlear place-frequency map derived by Muller was utilized [34]. Müller and colleagues determined the cochlear location of physiologically characterized auditory nerve fibers along the cochlear partition and then mapped the location with best frequency [34,35]. ...
... In order to test for co-localization of spiral ganglion neuron rescue with frequency-specific hearing improvements following ALD treatments, the murine cochlear place-frequency map derived by Muller was utilized [34]. Müller and colleagues determined the cochlear location of physiologically characterized auditory nerve fibers along the cochlear partition and then mapped the location with best frequency [34,35]. For example, a best frequency of 19.6 kHz was localized to a position 50.2% from the cochlear base, while 40.5 kHz is 18% from the basal end of the cochlea. ...
Age-related hearing loss (ARHL) -presbycusis - is the most prevalent neurodegenerative disease and number one communication disorder of our aged population; and affects hundreds of millions of people worldwide. Its prevalence is close to that of cardiovascular disease and arthritis, and can be a precursor to dementia. The auditory perceptual dysfunction is well understood, but knowledge of the biological bases of ARHL is still somewhat lacking. Surprisingly, there are no FDA-approved drugs for treatment. Based on our previous studies of human subjects, where we discovered relations between serum aldosterone levels and the severity of ARHL, we treated middle age mice with aldosterone, which normally declines with age in all mammals. We found that hearing thresholds and suprathreshold responses significantly improved in the aldosterone-treated mice compared to the non-treatment group. In terms of cellular and molecular mechanisms underlying this therapeutic effect, additional experiments revealed that spiral ganglion cell survival was significantly improved, mineralocorticoid receptors were upregulated via post-translational protein modifications, and age-related intrinsic and extrinsic apoptotic pathways were blocked by the aldosterone therapy. Taken together, these novel findings pave the way for translational drug development towards the first medication to prevent the progression of ARHL.
... In order to test for co-localization of spiral ganglion neuron rescue with frequency-specific hearing improvements following ALD treatments, the murine cochlear place-frequency map derived by Muller was utilized [34]. Müller and colleagues determined the cochlear location of physiologically characterized auditory nerve fibers along the cochlear partition and then mapped the location with best frequency [34,35]. ...
... In order to test for co-localization of spiral ganglion neuron rescue with frequency-specific hearing improvements following ALD treatments, the murine cochlear place-frequency map derived by Muller was utilized [34]. Müller and colleagues determined the cochlear location of physiologically characterized auditory nerve fibers along the cochlear partition and then mapped the location with best frequency [34,35]. For example, a best frequency of 19.6 kHz was localized to a position 50.2% from the cochlear base, while 40.5 kHz is 18% from the basal end of the cochlea. ...
Age-related hearing loss (ARHL) – presbycusis – is the most prevalent neurodegenerative disease and number one communication disorder of our aged population; and affects hundreds of millions of people worldwide. Its prevalence is close to that of cardiovascular disease and arthritis, and can be a precursor to dementia. The auditory perceptual dysfunction is well understood, but knowledge of the biological bases of ARHL is still somewhat lacking. Surprisingly, there are no FDA-approved drugs for treatment. Based on our previous studies of human subjects, where we discovered relations between serum aldosterone levels and the severity of ARHL, we treated middle age mice with aldosterone, which normally declines with age in all mammals. We found that hearing thresholds and suprathreshold responses significantly improved in the aldosterone-treated mice compared to the non-treatment group. In terms of cellular and molecular mechanisms underlying this therapeutic effect, additional experiments revealed that spiral ganglion cell survival was significantly improved, mineralocorticoid receptors were upregulated via post-translational protein modifications, and age-related intrinsic and extrinsic apoptotic pathways were blocked by the aldosterone therapy. Taken together, these novel findings pave the way for translational drug development towards the first medication to prevent the progression of ARHL.
... ARHL is one of the three major chronic medical conditions in the older people, with cardiovascular disease and arthritis being the other two major conditions. 13,14 The mechanisms of ARHL are still poorly understood. 5,7 Prospective studies of ARHL are lacking because the establishment of the patient and control groups is difficult and factors, such as individual immunoinflammatory factors and genetic causes as well as environmental factors, have been suggested to affect ARHL. ...
Objectives: The relationship between age-related diseases and chronic inflammation associated with aging has recently been investigated. This study aimed to investigate how chronic inflammation is associated with age-related hearing loss (ARHL). Methods: Twenty ARHL patients aged ≥65 years were prospectively enrolled from July 1 to 31 December 2015. Audiological tests and serological tests, such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), immunoglobulin G (IgG), interleukin 6 (IL-6), white blood cell (WBC) counts, neutrophil counts, lymphocyte counts, and platelet counts, were performed. The patients were divided into two groups: mild hearing loss group (n = 7) and moderate to profound hearing loss group (n = 13). Results: Immunoinflammatory biomarkers, such as CRP, ESR, and IL-6, and vascular inflammatory biomarkers, such as neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio, were higher in the moderate to profound hearing loss group. IgG, WBC counts, and neutrophil counts were similar in both groups. Conclusion: The present preliminary pilot study demonstrated that high levels of inflammatory biomarkers may be associated with ARHL. The results suggest a possible association between chronic inflammation and ARHL. Further well-designed studies of ARHL, based on a new perspective of chronic inflammation, should be performed.
... Today, drug candidates with potential therapeutic applications for hearing loss include antioxidants, regulators of mitochondrial function, ion channel modulators, hair-cell protectants, and anti-inflammatory drugs (Ji et al., 2021). Other potentially effective drugs that have been experimentally validated are N-acetylcysteine (NAC) (Marie et al., 2018), melatonin (Serra et al., 2020), resveratrol (Xiong et al., 2015), mineralocorticoid aldosterone (ALD) (Campos-Banales et al., 2015;Halonen et al., 2016), teprenone (GGA) (Mikuriya et al., 2008), aspirin (Verschuur et al., 2014), and salicylic acid et al. One example is age-related hearing loss (ARHL); SAMP8 mice models demonstrated notably decreased auditory brainstem response (ABR) thresholds, increased distortion product otoacoustic emission (DPOAE) amplitudes, and memory improvement after the administration of NAC, suggesting that NAC has protective effects on hair cells and neurons of the central nervous system (CNS) . ...
Auditory diseases are disabling public health problems that afflict a significant number of people worldwide, and they remain largely incurable until now. Driven by continuous innovation in the fields of chemistry, physics, and materials science, novel materials that can be applied to hearing diseases are constantly emerging. In contrast to conventional materials, new materials are easily accessible, inexpensive, non-invasive, with better acoustic therapy effects and weaker immune rejection after implantation. When new materials are used to treat auditory diseases, the wound healing, infection prevention, disease recurrence, hair cell regeneration, functional recovery, and other aspects have been significantly improved. Despite these advances, clinical success has been limited, largely due to issues regarding a lack of effectiveness and safety. With ever-developing scientific research, more novel materials will be facilitated into clinical use in the future.
... Previously, consumption of a high-potassium diet was demonstrated to increase the aldosterone level in the body and subsequently leads to the increased expression of Na + /-K + ATPase and NKCC1 in the stria vascularis, suggesting that higher intake of potassium could help in the maintenance of EP in the endolymph and protect against ARHL. [40][41][42][43] Furthermore, a high potassium diet may also protect against HL indirectly via its beneficial effects on hypertension and glycemic control. 36 Current findings also demonstrated that older adults with HL had lower scores in the RAVLT cognitive test. ...
Purpose
This study evaluates the prevalence of and the multidimensional risk factors associated with age-related hearing loss (ARHL) among community-dwelling older adults in Malaysia.
Patients and Methods
A total of 253 participants aged 60 years and above participated in this cross-sectional study. The participants were subjected to pure tone audiometric assessment. The hearing threshold was calculated for the better ear and classified into pure-tone average (PTA) for the octave frequencies from 0.5 to 4 kHz and high-frequency pure-tone average (HFA) for the octave from 2 to 8kHz. Then, the risk factors associated with PTA hearing loss (HL) and HFAHL were identified by using multivariate logistic regression analysis.
Results
The prevalence of ARHL based on PTA and HFA among the community-dwelling older adults was 75.5% and 83.0%, respectively. Following multifactorial adjustments, being older (OR: 1.239; 95% CI: 1.062–1.445), having higher waist circumference (OR: 1.158; 95% CI: 1.015–1.322), lower intake of niacin (OR: 0.909; 95% CI: 0.831–0.988) and potassium (OR: 0.998; 95% CI: 0.996–1.000), and scoring lower in RAVLT T5 (OR: 0.905; 95% CI: 0.838–0.978) were identified as the risk factors of PTAHL. Meanwhile, being older (OR: 1.117; 95% CI: 1.003–1.244), higher intake of carbohydrate (OR: 1.018; 95% CI: 1.006–1.030), lower intake of potassium (OR: 0.998; 95% CI: 0.997–0.999), and lower scores on the RAVLT T5 (OR: 0.922; 95% CI: 0.874–0.973) were associated with increased risk of having HFAHL.
Conclusion
Increasing age, having higher waist circumference, lower intake of niacin and potassium, higher intake of carbohydrates and having lower RAVLT T5 score were associated with increased risk of ARHL. Modifying these risk factors may be beneficial in preventive and management strategies of ARHL among older persons.
... Another group that explored systemic administration of a drug was out of the University of South Florida. They showed that long-term administration of aldosterone slowed the progression of age-related hearing loss in mice (Halonen et al., 2016). Although aldosterone's benefits to treat presbycusis have only been shown in an animal model, it was previously reported that there is an association between decreased levels of aldosterone and severity of presbycusis in a healthy elderly human population (Tadros et al., 2005). ...
Purpose
More than 460 million people are impacted by disabling hearing loss worldwide. Hearing loss has negative impacts across the life span and varies by individual. Specifically, in children, hearing loss has been shown to affect learning outcomes, behavioral and cognitive growth, and psychosocial development. In adults, hearing loss has been shown to affect quality of life, social isolation, depression, and anxiety. The purpose of this review is to advance the understanding of the latest research in the development of new treatments of hearing loss, including gene therapy, stem cell therapy, and pharmacotherapies. We address the use of animals to model human hearing loss and the importance of animals in previous discoveries and developing new therapies. We highlight the importance of early identification for better speech and developmental outcomes specifically in pediatric individuals. Lastly, we review new possibilities in the prevention of hearing loss and the path to translation into practice.
Conclusions
Research and development of new therapies to treat hearing loss is an ever growing field with many notable successes. However, clinical translation still poses many challenges. Many discoveries related to gene therapy, stem cell therapy, and pharmacotherapy are in the early phases of clinical trials and hold promise. This review empowers audiologists to be aware of these most recent developments and be conscious of the evolving future landscape of treatment and management of hearing loss.
... Walton, Frisina and colleagues performed a prospective animal-model experiment to test the hypothesis that aldosterone supplementation can provide hearing protection with age Halonen et al. 2016 ). This hypothesis builds upon their previous findings that aldosterone (1 mM) increased NKCC1 protein expression in vitro and that this up-regulation of NKCC1 was not dose-dependent (dosing range from 1 nM to 100 mM). ...
Recent advances in audiological research, biomedical and chemical engineering, and hearing sciences suggest that effective biomedical treatments, technological interventions, and acoustic-based therapies will soon bring some exciting opportunities to delay or treat key aspects of age-related hearing loss (ARHL), or presbycusis. In the present chapter, some of the provocative research that is paving the way for these upcoming successful interventions, including the groundwork for a first FDA-approved drug or system to treat acquired hearing loss, including age-related, is presented. Impactful work on drug and medicinal discoveries and developments; localized drug delivery possibilities, including micropumps and hydrogels; and acoustic/technological approaches for effective interventions are highlighted in the present chapter. In the same way that cochlear implant development has been remarkable in the past decades, starting with the initial one-channel cochlear implants developed and tested early on at the House Ear Institute, we will soon experience remarkable breakthroughs for interventions to prevent or treat presbycusis.
... Walton, Frisina and colleagues performed a prospective animal-model experiment to test the hypothesis that aldosterone supplementation can provide hearing protection with age Halonen et al. 2016 ). This hypothesis builds upon their previous findings that aldosterone (1 mM) increased NKCC1 protein expression in vitro and that this up-regulation of NKCC1 was not dose-dependent (dosing range from 1 nM to 100 mM). ...
Provocative research has revealed both positive and negative effects of hormones on hearing as we age; with in some cases, mis-regulation of hormonal levels in instances of medical comorbidities linked to aging, lying at the heart of the problem. Animal model studies have discovered that hormonal fluctuations can sharpen hearing for improved communication and processing of mating calls during reproductive seasons. Sex hormones sometimes have positive effects on auditory processing, as is often the case with estrogen, whereas combinations of estrogen and progesterone, and testosterone, can have negative effects on hearing abilities, particularly in aging subjects. Too much or too little of some hormones can be detrimental, as is the case for aldosterone and thyroid hormones, which generally decline in older individuals. Too little insulin, as in Type 1 diabetics, or poor regulation of insulin, as in Type 2 diabetics, is also harmful to hearing in our aged population. In terms of clinical translational possibilities, hormone therapies can be problematic due to systemic side effects, as has happened for estrogen/progestin combination hormone replacement therapy (HRT) in older women, where the HRT induces a hearing loss. As hormone therapy approaches are further developed, it may be possible to lower needed doses of hormones by combining them with supplements, such as antioxidants. Another option will be to take advantage of emerging technologies for local drug delivery to the inner ear, including biodegradeable, sustained-release hydrogels and micro-pumps which can be implanted in the middle ear near the round window. In closing, exciting research completed to date, summarized in the present report bodes well for emerging biomedical therapies to prevent or treat age-related hearing loss utilizing hormonal strategies.
... Building upon Trune's pioneering work with aldosterone Halonen et al., 2016) demonstrated that application of aldosterone HRT via subcutaneous, time-release pellets for 4 months in aging CBA/CaJ mice could prevent or slow down the progression of key aspect of ARHL. Specifically, the aldosterone -treated aging mice, relative to controls of the same age, showed preservation of hearing: Much improved ABR audiogram sensitivity, higher DPOAE levels and better behavioral measures of auditory pre-pulse inhibition. ...
... Halonen et al. evaluated the effect of long-term systemic aldosterone treatment on ARHI in CBA/CaJ mice [66]. Their results demonstrated upregulation of NKCC1 in the cochlea of mice fed with aldosterone and showed more stable ABR waveforms with aging, indicating that long-term treatment with aldosterone might prevent ARHI. ...
Background:
Age-related hearing impairment (ARHI), the most common sensory deficit in the elderly, is associated with enormous social and public health burdens. Emerging evidence has suggested that obesity and comorbidities might increase the risk of ARHI. However, no reviews have been published that address the role of nutritional interventions for obesity and comorbidities in the prevention of ARHI.
Methods:
A PubMed database search was conducted to identify the relationship between obesity and ARHI. "Obesity", "metabolic syndrome", "adipose-derived hormone", "fatty acid", and "age-related hearing impairment" were included as keywords.
Results:
A total of 89 articles was analyzed with 39 articles of relevance to ARHI. A high-fat diet may induce oxidative stress, mitochondrial damage, and apoptosis in the inner ear. Statins have been shown to delay the progression of ARHI by improving the lipid profile, reducing oxidative stress, and inhibiting endothelial inflammation. Aldosterone could exert protective effects against ARHI by upregulating the Na-K-2Cl co-transporter 1 in the cochlea. Omega-3 polyunsaturated fatty acids could preserve the cochlear microcirculation by reducing dyslipidemia and inhibiting inflammation. Alpha-lipoic acid and lecithin might delay the progression of ARHI by protecting cochlear mitochondrial DNA from damage due to oxidative stress. Tea and ginseng might protect against ARHI through their anti-obesity and anti-diabetic effects.
Conclusions:
Nutritional interventions for obesity and comorbidities, including a low-fat diet, supplementation with statins, aldosterone, omega-3 polyunsaturated fatty acids, alpha-lipoic acids, lecithin, tea, and ginseng, may protect against the development of ARHI.
... Tardos et al. showed that serum aldosterone levels decrease with age in humans and are inversely associated with the severity of presbycusis 26 . In addition, an in vivo study showed that long-term aldosterone treatment increases NKCC1 expression, which prevents the progression of age-related HL 27 . Upregulation of Na + -K + ATPase and NKCC1 through aldosterone would be helpful in maintaining a proper potassium recycle and endocochlear potential, which may be associated with the preventive effects of a high-potassium diet. ...
The aim of this study was to determine and evaluate the association between potassium intake and hearing thresholds in the Korean adult population. Data from the Korean National Health and Nutrition Examination Survey were analyzed. Participants were divided into tertiles on the basis of their potassium intake as follows: low, middle, and high. Pure-tone audiometry was performed using an automated audiometer. We calculated as the average threshold at the low-frequency pure-tone average (0.5 and 1 kHz), mid-frequency pure-tone average (2 and 3 kHz), and high-frequency pure-tone average (4 and 6 kHz). The average hearing threshold (AHT) was calculated as the pure-tone average of the thresholds at 0.5~3 kHz. Hearing loss (HL) was defined as an AHT of >40 dB in the better ear. There were 1975 participants each in the low, middle, and high tertile groups. The four different average hearing thresholds significantly decreased with an increase in the potassium intake tertile. Multivariate analysis revealed that the four different average hearing thresholds were significantly lower in the high tertile group than in the other two groups. In addition, univariate and multivariate linear regression analyses showed that the potassium intake level was inversely associated with each of the four different average hearing thresholds. Analyses of participants matched based on propensity scores and participants not matched based on propensity scores yielded similar results. The results of this study suggest that high potassium intake levels were associated with a lower prevalence of HL and lower hearing thresholds in the Korean adult population.
... **** Wilcoxon test is for the double comparisons in the groups (p < 0.0083 with Bonferonni correction). which may be effective in the progression of presbycusis [14]. In our study, ACTH analogue showed better results at certain frequencies. ...
Objective:
NIHL is a common problem, and steroids are the most effective treatment option. In this study, we aimed to evaluate the protective effects of the synthetic adrenocorticotropic hormone (ACTH) analogues, which induce endogenous steroid secretion, against noise-induced hearing loss (NIHL) and to compare their effectiveness with that of steroid treatment.
Methods:
Twenty-four male Sprague-Dawley albino rats were divided into four subgroups as follows: group 1 (n=6) control, group 2 (n=6) saline, group 3 (n=6) dexamethasone (2mg/kg/day intramuscularly [IM]), group 4 (n=6) ACTH analogue (0,4mg/kg/day IM), respectively. Three groups (groups 2-4) were exposed to white noise (105dB SPL, 12h). All the rats were evaluated for hearing thresholds of 10kHz, 20kHz, and 32kHz via acoustic brainstem responses (ABR) measurement. After the basal threshold measurements, measurements were repeated immediately after the noise and on day 7 and day 21.
Results:
Both steroid and ACTH analogue groups showed significantly better hearing outcomes than the saline group on day 7 (p<0.001) and day 21 (p<0.001) after the noise exposure. No superior treatment effect was demonstrated in either the steroid or ACTH analogue group. None of the related intervention groups reached the basal hearing thresholds.
Conclusion:
Steroids were effective drugs for the treatment of NIHL. ACTH analogues also demonstrated promising therapeutic effects for NIHL. Further studies to establish ACTH analogues as an alternative NIHL treatment option to steroids are needed.
... Age-related hearing loss (ARHL), one of the most prevalent chronic degenerative conditions, is characterized by a decline in auditory function in the elderly (Halonen et al., 2016). The pathology linked to ARHL includes the hair cells loss, stria vascularis atrophy, and spiral ganglion neurons loss. ...
Hearing loss is one of the most frequent health issues in industrialized countries. The pathogenesis and molecular mechanisms of hearing loss are still unclear. Histone deacetylases (HDACs) are emerging as key enzymes in many physiological processes, including chromatin remodeling, regulation of transcription, DNA repair, metabolism, genome stability and protein secretion. Recent studies indicated that HDACs are associated with the development and progression of hearing loss. Dysfunction of HDACs could promote the oxidative stress and aging in the inner ear. In light of considering the current stagnation in the development of therapeutic options, the need for new strategies in the treatment of hearing loss has never been so pressing. In this review, we will summarize the reported literatures for HDACs in hearing loss and discuss how HDAC family members show different performances for the possibility of process of diseases development. The possibility of pharmacological intervention on hearing loss opens a novel path in the treatment of hearing loss.
The adrenal glands are a pair of endocrine organs that produce and secrete mineralocorticoids, glucocorticoids, sex hormones, adrenaline, and noradrenaline. They have a vital role in a range of physiological processes including regulating electrolyte balance, blood pressure and metabolism, immunomodulation, sexual development and the stress response. Adrenal cortex senescence describes the ageing-related decline in the normal functioning of the adrenal cortex, characterised by an alteration in the output of adrenal cortical hormones, in particular reduced secretion of dehydroepiandrosterone (DHEA) and sulfated dehydroepiandrosterone (DHEAS). Such endocrine aberrations may be implicated in adverse clinical outcomes including mood disturbances, impairment in cognitive functioning, metabolic dysfunction and osteopenia. This paper shall address whether adrenal cortex senescence should be recognised as an ageing-related pathology, which has recently been defined as one that develops and/or progresses with increasing chronological age, that is associated with, or contributes to, functional decline, and is evidenced by studies in humans.
Background:
Hearing loss (HL) is a prevalent sensory impairment with a genetic basis. The SLC12A2 gene, encoding NKCC1, is vital for inner ear ion balance. The c.2930-1G > A variant is a novel mutation potentially linked to sensorineural hearing loss.
Objectives:
To investigate the splicing and protein expression effects of the c.2930-1G>A variant in SLC12A2 and its role in hearing loss.
Material and methods:
Minigene assays and plasmid transfection in HEK-293T and Hela cells were used to study splicing. Protein expression and modification were also assessed.
Results:
The c.2930-1G>A variant caused partial exon skipping, altering mRNA splicing in both cell types. This suggests a potential involvement in sensorineural hearing loss. Protein analysis showed the E21del mutation increased expression without altering modification patterns, whereas the 2930_2977del mutation reduced both, possibly impacting stability or modification sites.
Conclusions and significance:
The c.2930-1G>A variant likely contribute to hearing loss by disrupting splicing and protein expression. Currently a Variant of Uncertain Significance (VUS), its pathogenicity is supported by these findings. Further research is needed to confirm its role, emphasizing the need for integrated genetic and clinical data in auditory disorders management.
Hearing loss represents a multifaceted and pervasive challenge that deeply impacts various aspects of an individual’s life, spanning psychological, emotional, social, and economic realms. Understanding the molecular underpinnings that orchestrate hearing loss remains paramount in the quest for effective therapeutic strategies. This review aims to expound upon the physiological, biochemical, and molecular aspects of hearing loss, with a specific focus on its correlation with diabetes. Within this context, phytochemicals have surfaced as prospective contenders in the pursuit of potential adjuvant therapies. These compounds exhibit noteworthy antioxidant and anti-inflammatory properties, which hold the potential to counteract the detrimental effects induced by oxidative stress and inflammation—prominent contributors to hearing impairment. Furthermore, this review offers an up-to-date exploration of the diverse molecular pathways modulated by these compounds. However, the dynamic landscape of their efficacy warrants recognition as an ongoing investigative topic, inherently contingent upon specific experimental models. Ultimately, to ascertain the genuine potential of phytochemicals as agents in hearing loss treatment, a comprehensive grasp of the molecular mechanisms at play, coupled with rigorous clinical investigations, stands as an imperative quest.
Post-translational modifications (PTMs) affect nearly all systems of the human body due to their role in protein synthesis and functionality. These reversible and irreversible modifications control the structure, localization, activity, and properties of proteins. For this reason, PTMs are essential in regulating cellular processes and maintaining homeostasis. Diseases such as Alzheimer's, cardiovascular disease, diabetes, cancer, and many others have been linked to dysfunctions of PTMs. Recent research has also shown that irregularities in PTMs can be linked to hearing loss, including age-related hearing loss (ARHL) – the number one communication disorder and one of the top neurodegenerative diseases in our aging population. So far, there has been no FDA approved treatment for ARHL; however, translational studies investigating PTMs involvement in ARHL show promising results. In this review, we summarize key findings for PTMs within the auditory system, the involvement of PTMS with aging and ARHL, and lastly discuss potential treatment options focusing on utilizing PTMs as biomarkers and therapeutic pathway components.
The acoustic startle reflex (ASR) amplitude can be enhanced or suppressed by noise-induced hearing loss or age-related hearing loss; however, little is known about how the ASR changes when ototoxic drugs destroy outer hair cells (OHCs) and inner hair cells (IHCs). High doses of 2-hydroxypropyl-beta-cyclodextrin (HPβCD), a cholesterol-lowering drug used to treat Niemann-Pick Type disease type C1, initially destroy OHCs and then the IHCs 6-8 weeks later. Adult rats were treated with doses of HPbCD designed to produce a diversity of hair cell lesions and hearing losses. When HPbCD destroyed OHCs and IHCs in the extreme base of the cochlea and caused minimal high-frequency hearing loss, the ASR amplitudes were enhanced at 4-, 8- and 16 kHz. Enhanced ASR occurred during the first few weeks post-treatment when only OHCs were missing; little change in the ASR occurred 6-8-WK post-treatment. If HPbCD destroyed most OHCs and many IHCs in the basal half of the cochlea, high-frequency thresholds increased ∼50 dB, and ASR amplitudes were reduced ∼50% at 4-, 8- and 16-kHz. The ASR amplitude reduction occurred in the first few weeks post-treatment when the OHCs were degenerating. The ASR was largely abolished when most of the OHCs were missing over the basal two-thirds of the cochlea and a 40-50 dB hearing loss was present at most frequencies. These results indicate that high-doses of HPbCD generally lead to a decline in ASR amplitude as OHCs degenerate; however, ASR amplitudes were enhanced in a few cases when hair cell loss was confined to the extreme base of the cochlea.
Recent evidence suggests that modulation of the large-conductance, calcium activated potassium (BK) channel regulates auditory processing in the brain. Because ion channel expression often changes during aging, this could be a factor in age-related hearing loss. The current study explored how the novel BK channel modulator LS3 shapes central auditory processing in young and old adult mice. In vivo extracellular recordings in the auditory midbrain demonstrated that LS3 differentially modulates neural processing along the tonotopic axis. Though sound-evoked activity was reduced in the mid and ventral tonotopic regions, LS3 enhanced excitatory drive and sound-evoked responses for some neurons in the dorsal, low-frequency region. Behavioral assessment using acoustic reflex medication audiometry indicated improved tone salience following systemic LS3 administration. Moderation of these responses with aging correlated with an age-related decline in BK channel expression. These findings suggest that targeting the BK channel enhances responsivity to tonal sounds, providing the potential to improve hearing acuity and treat hearing loss.
Background
In humans, it is well known that females have better hearing than males. The mechanism of this influence of sex on auditory function in humans is not well understood. Testing the hypothesis of underlying mechanisms often relies on preclinical research, a field in which sex bias still exists unconsciously. Rodents are popular research models in hearing, thus it is crucial to understand the sex differences in these rodent models when studying health and disease in humans.
Objectives
This review aims to summarize the existing sex differences in the auditory functions of rodent species including mouse, rat, Guinea pig, Mongolian gerbil, and chinchilla. In addition, a concise summary of the hearing characteristics and the advantages and the drawbacks of conducting auditory experiments in each rodent species is provided.
Designs
Manuscripts were identified in PubMed and Ovid Medline for the queries “Rodent”, “Sex Characteristics”, and “Hearing or Auditory Function”. Manuscripts were included if they were original research, written in English, and use rodents. The content of each manuscript was screened for the sex of the rodents and the discussion of sex-based results.
Conclusions
The sex differences in auditory function of rodents are prevalent and influenced by multiple factors including physiological mechanisms, sex-based anatomical variations, and stimuli from the external environment. Such differences may play a role in understanding and explaining sex differences in hearing of humans and need to be taken into consideration for developing clinical therapies aim to improve auditory performances.
The conceptual breakthrough that the energy of the Na⁺ gradient generated by the Na⁺/K⁺ ATPase (pump) could be used as the driving force for another membrane transport protein has led to the functional and molecular identification of multiple secondary active transporters. We have organized this chapter to address the expression, function, regulation, and evolutionary importance of the two isoforms of the electroneutral sodium–potassium–chloride cotransporter (NKCC). The combination of basolateral expression of the sodium–potassium pump and NKCC1 in various non-renal epithelial results in salt and water secretion, whereas basolateral expression of the pump with an apical expression of NKCC2 in the thick ascending limb of Henle of the kidney nephron results in salt and water reabsorption. NKCCs are regulated by phosphorylation of specific serine/threonine residues in their cytosolic amino-terminal domains, and the evolutionary conservation of these cotransporters from protists to humans confirms their vital role in cellular and whole-organism physiology.
Rodents live in a wide variety of habitats all over the world. They are known to use vocalizations for communication, requiring good auditory acuity to detect, discriminate, identify, and localize these vocalizations. Most of the work measuring auditory acuity as a function of species, age, and sex has been conducted on laboratory mice and rats. These measurements can be used as baseline functions to determine the effects of hormones on hearing and the auditory system in general. Hormones such as glucocorticoids, mineralocorticoids, estrogen, insulin-like growth factor-1, and thyroid hormone have roles in the development of the auditory system, protection of the aging auditory system, and the restoration of hearing after trauma. More studies are needed to determine whether the findings from laboratory animals translate to wild rodents living in various environments with differing ecological characteristics and evolutionary pressures.
The acoustic startle response (ASR) is an involuntary muscle reflex that occurs in response to a transient loud sound and is a highly-utilized method of assessing hearing status in animal models. Currently, a high level of variability exists in the recording and interpretation of ASRs due to the lack of standardization for collecting and analyzing these measures. An ensembled machine learning model was trained to predict whether an ASR waveform is a startle or non-startle using highly-predictive features extracted from normalized ASR waveforms collected from young adult CBA/CaJ mice. Features were extracted from the normalized waveform as well as the power spectral density estimates and continuous wavelet transforms of the normalized waveform. Machine learning models utilizing methods from different families of algorithms were individually trained and then ensembled together, resulting in an extremely robust model.
•ASR waveforms were normalized using the mean and standard deviation computed before the startle elicitor was presented
•9 machine learning algorithms from 4 different families of algorithms were individually trained using features extracted from the normalized ASR waveforms
•Trained machine learning models were ensembled to produce an extremely robust classifier
Hearing amplification is the mainstay of treatment for presbycusis, but adherence with this therapy remains abysmally low, necessitating the exploration of other treatment modalities. Mineralocorticoids represent one such novel treatment modality. While research on mineralocorticoids to prevent and retard presbycusis in humans shows promise and the potential to radically change the way clinicians approach age-related hearing loss, it remains in its infancy. Future studies that further evaluate the safety and efficacy of mineralocorticoids for presbycusis are still required for this potentially paradigm shifting therapy to gain widespread acceptance.
Hormones such as estrogen, progesterone, and aldosterone all demonstrate vital roles in sustaining auditory function through either the maintenance of cochlear neurons, up/down regulation of critical molecules (i.e., IGF‐1, BDNF, etc.), or generation of the endocochlear potential. With disease and/or age, hormone expression begins to decline drastically, which ultimately affects cochlear structures and the integrity of cochlear cells. The following review explores the latest findings as well as realistic outcomes for hormone therapy treatment in the auditory system. This information could serve as a potential guide for patients considering hormone therapy as a medicinal choice to alleviate the signs of onset of presbycusis—age‐related hearing loss. Additional scientific investigations could also be carried out to further enhance recent findings.
Objective
Hearing impairment (HI) is common in aging adults. Aldosterone, insulin‐like growth factor (IGF1), and brain‐derived neurotrophic factor (BDNF) have been identified as potentially protective of hearing. The present study aims to investigate these relationships.
Methods
The Epidemiology of Hearing Loss Study is a longitudinal population‐based study of aging in Beaver Dam, Wisconsin, that began in 1993. Baseline for the present investigation is the 1998 to 2000 phase. Follow‐up exams occurred approximately every 5 years, with the most recent occurring from 2013 to 2016. Hearing was measured by pure‐tone audiometry. HI was defined as a pure tone average (PTA) > 25 decibels hearing level in either ear. Change in PTA was the difference between follow‐up examinations and baseline. Baseline serum samples were used to measure biomarkers in 2017. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated to assess the effect of biomarker levels in the lowest quintile (Q1) versus the highest (Q5) on incident HI and PTA change.
Results
There were 1,088 participants (69.3% women) at risk of HI included in analyses. The mean baseline age was 63.8 years (standard deviation = 7.0). The 16‐year incidence of HI was 54.9% and was higher in men (61.1%) than women (52.1%). In age‐ and sex‐adjusted models, aldosterone (HR = 1.06, 95% CI = 0.82–1.37), IGF1 (HR = 0.92, 95% CI = 0.71–1.19), and BDNF (HR = 0.86, 95% CI = 0.66–1.12) levels were not associated with risk of HI. PTA change was similarly not affected by biomarker levels.
Conclusion
Aldosterone, IGF1, and BDNF were not associated with decreased risk of age‐related hearing loss in this study.
Level of Evidence
2b. Laryngoscope, 2019
The field of hearing and deafness research is about to enter an era where new cochlear drug delivery methodologies will become more innovative and plentiful. The present report provides a representative review of previous studies where efficacious results have been obtained with animal models, primarily rodents, for protection against acute hearing loss such as acoustic trauma due to noise overexposure, antibiotic use and cancer chemotherapies. These approaches were initiated using systemic injections or oral administrations of otoprotectants. Now, exciting new options for local drug delivery, which opens up the possibilities for utilization of novel otoprotective drugs or compounds that might not be suitable for systemic use, or might interfere with the efficacious actions of chemotherapeutic agents or antibiotics, are being developed. These include interesting use of nanoparticles (with or without magnetic field supplementation), hydrogels, cochlear micropumps, and new transtympanic injectable compounds, sometimes in combination with cochlear implants.
Oxidative stress is considered to be a major contributor to age-related hearing loss (ARHL). Here, we investigated whether pomegranate peel extract (PPE) protected against hearing loss by decreased oxidative stress in the cochlea of D-galactose-induced accelerated aging mice. The aging mice exhibited an increase in hearing threshold shifts and hair cells loss, which were improved in the PPE-treated aging mice. The aging mice also exhibited an increase in 4-HNE, the expression of protein phosphatase 1 nuclear targeting subunit (PNUTS), p53 and caspase-3 and a decrease in protein phosphatase 1 (PP1) and MDM2 in the cochlea. PPE treatment reversed the changes in above mentioned molecules. Our results suggested that PPE can protect against ARHL, the underlying mechanisms may involve in the inhibition of oxidative damage of cochlea, possibly by regulating PNUTS/PP1 pathway. The results from the present study provide a new therapeutic strategy to use PPE for prevention of ARHL.
Conclusions: Af9 protein in cochlea may be closely related to endolymph regulation by aldosterone and thus may be involved in pathogenesis of endolymphatic hydrops (EH).
Objectives: EH is the pathological characteristic of Ménière’s disease (MD). Aldosterone could induce EH, but its relationship with MD is still controversial. The aim of the present study is to investigate the Af9 protein expression in guinea pig cochlea and regulation of Af9 expression and cochlear function by aldosterone. The role of Af9 in pathogenesis of EH is discussed.
Methods: Thirty guinea pigs were randomly divided into two groups. The treatment group was intraperitoneally injected with aldosterone 0.1 mg/kg/d for 5 days, while the control group was done with saline. Hearing and histomorphology of cochlea were examined. In addition, expression of Af9 protein was studied.
Results: The hearing threshold of the treatment group was increased. EH was induced in 73% of guinea pigs in the treatment group, and no EH was found in the control group. Af9 protein was found in spiral limbus, stria vascularis, Reissner’s membrane, organ of Corti and spiral ganglion in both groups. Af9 expression in cochlea decreased significantly at protein level after treatment by aldosterone.
Hearing thresholds in elderly humans without a history of noise exposure commonly show a profile of a flat loss at low frequencies coupled with a loss that increases with frequency above approximately 2 kHz. This profile and the relatively robust distortion product otoacoustic emissions that are found in elderly subjects challenge the common belief that age-related hearing loss (presbyacusis) is based primarily on sensory-cell disorders. Here, we examine a model of presbyacusis wherein the endocochlear potential (EP) is reduced by means of furosemide applied chronically to one cochlea of a young gerbil. The model results in an EP that is reduced from 90 to approximately 60 mV, a value often seen in quiet-aged gerbils, with no concomitant loss of hair cells. Resulting measures of cochlear and neural function are quantitatively similar to those seen in aging gerbils and humans, e.g., a flat threshold loss at low frequencies with a high-frequency roll-off of approximately -8.4 dB/octave. The effect of the EP on neural thresholds can be parsimoniously explained by the known gain characteristics of the cochlear amplifier as a function of cochlear location: in the apex, amplification is limited to approximately 20 dB, whereas in the base, the gain can be as high as 60 dB. At high frequencies, amplification is directly proportional to the EP on an approximately 1 dB/mV basis. This model suggests that the primary factor in true age-related hearing loss is an energy-starved cochlear amplifier that results in a specific audiogram profile.
Age-related hearing loss (ARHL) -presbycusis - is the most prevalent neurodegenerative disease and number one communication disorder of our aged population; and affects hundreds of millions of people worldwide. Its prevalence is close to that of cardiovascular disease and arthritis, and can be a precursor to dementia. The auditory perceptual dysfunction is well understood, but knowledge of the biological bases of ARHL is still somewhat lacking. Surprisingly, there are no FDA-approved drugs for treatment. Based on our previous studies of human subjects, where we discovered relations between serum aldosterone levels and the severity of ARHL, we treated middle age mice with aldosterone, which normally declines with age in all mammals. We found that hearing thresholds and suprathreshold responses significantly improved in the aldosterone-treated mice compared to the non-treatment group. In terms of cellular and molecular mechanisms underlying this therapeutic effect, additional experiments revealed that spiral ganglion cell survival was significantly improved, mineralocorticoid receptors were upregulated via post-translational protein modifications, and age-related intrinsic and extrinsic apoptotic pathways were blocked by the aldosterone therapy. Taken together, these novel findings pave the way for translational drug development towards the first medication to prevent the progression of ARHL.
Chronic tinnitus, or "ringing of the ears", affects upwards of 15% of the adult population. Identifying a cost-effective and objective measure of tinnitus is needed due to legal concerns and disability issues, as well as for facilitating the effort to assess neural biomarkers. We developed a modified gap-in-noise (GIN) paradigm to assess tinnitus in mice using the auditory brainstem response (ABR). We then compared the commonly used acoustic startle reflex gap-prepulse inhibition (gap-PPI) and the ABR GIN paradigm in young adult CBA/CaJ mice before and after administrating sodium salicylate (SS), which is known to reliably induce a 16 kHz tinnitus percept in rodents. Post-SS, gap-PPI was significantly reduced at 12 and 16 kHz, consistent with previous studies demonstrating a tinnitus-induced gap-PPI reduction in this frequency range. ABR audiograms indicated thresholds were significantly elevated post-SS, also consistent with previous studies. There was a significant increase in the peak 2 (P2) to peak 1 (P1) and peak 4 (P4) to P1 amplitude ratios in the mid-frequency range, along with decreased latency of P4 at higher intensities. For the ABR GIN, peak amplitudes of the response to the second noise burst were calculated as a percentage of the first noise burst response amplitudes to quantify neural gap processing. A significant decrease in this ratio (i.e. recovery) was seen only at 16 kHz for P1, indicating the presence of tinnitus near this frequency. Thus, this study demonstrates that GIN ABRs can be used as an efficient, non-invasive, and objective method of identifying the approximate pitch and presence of tinnitus in a mouse model. This technique has the potential for application in human subjects and also indicates significant, albeit different, deficits in temporal processing in peripheral and brainstem circuits following drug induced tinnitus.
Sodium/Potassium/Chloride Cotransporter (NKCC1) proteins play important roles in Na+ and K+ concentrations in key physiological systems, including cardiac, vascular, renal, nervous and sensory systems. NKCC1 levels and functionality are altered in certain disease states, and tend to decline with age. A sensitive, effective way of regulating NKCC1 protein expression has significant bio-therapeutic possibilities. The purpose of the present investigation was to determine if the naturally occurring hormone aldosterone (ALD) could regulate NKCC1 protein expression. Application of ALD to a human cell line (HT-29) revealed that ALD can regulate NKCC1 protein expression, quite sensitively and rapidly, independent of mRNA expression changes. Utilization of a specific inhibitor of mineralocorticoid receptors, eplerenone, implicated these receptors as part of the ALD mechanism of action. Further experiments with cycloheximide (protein synthesis inhibitor) and MG132 (proteasome inhibitor) revealed that ALD can upregulate NKCC1 by increasing protein stability, i.e., reducing ubiquitination of NKCC1. Having a procedure for controlling NKCC1 protein expression opens the doors for therapeutic interventions for diseases involving the mis-regulation or depletion of NKCC1 proteins, for example during aging.
Aging listeners experience greater difficulty understanding speech in adverse listening conditions and exhibit degraded temporal resolution, even when audiometric thresholds are normal. When threshold evidence for peripheral involvement is lacking, central and cognitive factors are often cited as underlying performance declines. However, previous work has uncovered widespread loss of cochlear afferent synapses and progressive cochlear nerve degeneration in noise-exposed ears with recovered thresholds and no hair cell loss (Kujawa and Liberman 2009). Here, we characterize age-related cochlear synaptic and neural degeneration in CBA/CaJ mice never exposed to high-level noise. Cochlear hair cell and neuronal function was assessed via distortion product otoacoustic emissions and auditory brainstem responses, respectively. Immunostained cochlear whole mounts and plastic-embedded sections were studied by confocal and conventional light microscopy to quantify hair cells, cochlear neurons, and synaptic structures, i.e., presynaptic ribbons and postsynaptic glutamate receptors. Cochlear synaptic loss progresses from youth (4 weeks) to old age (144 weeks) and is seen throughout the cochlea long before age-related changes in thresholds or hair cell counts. Cochlear nerve loss parallels the synaptic loss, after a delay of several months. Key functional clues to the synaptopathy are available in the neural response; these can be accessed noninvasively, enhancing the possibilities for translation to human clinical characterization.
The authors investigate the impact of hearing loss on quality of life in a large population of older adults.
Data are from the 5-year follow-up Epidemiology of Hearing Loss Study, a population-based longitudinal study of age-related hearing impairment conducted in Beaver Dam, WI. Participants (N = 2,688) were 53-97 years old (mean = 69 years) and 42% were male. Difficulties with communication were assessed by using the Hearing Handicap for the Elderly-Screening version (HHIE-S), with additional questions regarding communication difficulties in specific situations. Health-related quality of life was assessed by using measures of activities of daily living (ADLs), instrumental ADLs (IADLs) and the Short Form 36 Health Survey (SF-36). Hearing loss measured by audiometry was categorized on the basis of the pure-tone average of hearing thresholds at 0.5, 1, 2, and 4 kHz.
Of participants, 28% had a mild hearing loss and 24% had a moderate to severe hearing loss. Severity of hearing loss was significantly associated with having a hearing handicap and with self-reported communication difficulties. Individuals with moderate to severe hearing loss were more likely than individuals without hearing loss to have impaired ADLs and IADLs. Severity of hearing loss was significantly associated with decreased function in both the Mental Component Summary score and the Physical Component Summary score of the SF-36 as well as with six of the eight individual domain scores.
Severity of hearing loss is associated with reduced quality of life in older adults.
To determine the relationship between hearing loss and cognitive function as assessed with a standardized neurocognitive battery. We hypothesized a priori that greater hearing loss is associated with lower cognitive test scores on tests of memory and executive function.
A cross-sectional cohort of 347 participants ≥ 55 years in the Baltimore Longitudinal Study of Aging without mild cognitive impairment or dementia had audiometric and cognitive testing performed in 1990-1994. Hearing loss was defined by an average of hearing thresholds at 0.5, 1, 2, and 4 kHz in the better-hearing ear. Cognitive testing consisted of a standardized neurocognitive battery incorporating tests of mental status, memory, executive function, processing speed, and verbal function. Regression models were used to examine the association between hearing loss and cognition while adjusting for confounders.
Greater hearing loss was significantly associated with lower scores on measures of mental status (Mini-Mental State Exam), memory (Free Recall), and executive function (Stroop Mixed, Trail Making B). These results were robust to analyses accounting for potential confounders, nonlinear effects of age, and exclusion of individuals with severe hearing loss. The reduction in cognitive performance associated with a 25 dB hearing loss was equivalent to the reduction associated with an age difference of 6.8 years.
Hearing loss is independently associated with lower scores on tests of memory and executive function. Further research examining the longitudinal association of hearing loss with cognitive functioning is needed to confirm these cross-sectional findings.
Gerbils aged in quiet show a decline of the endocochlear potential (EP) and elevated auditory nerve compound action potential (CAP) thresholds. However, establishing a direct relationship between an age-related reduction in the EP and changes in the activities of primary auditory neurons is difficult owing to the complexity of age-related histological changes in the cochlea. To address this issue, we developed a young gerbil model of "metabolic" presbyacusis that uses an osmotic pump to deliver furosemide into the round window niche for 7 days, resulting in a chronically reduced EP. In this model, the only major histopathologic changes were restricted to the hook region of the cochlea and consisted of loss of strial intermediate cells and massive edema in the lateral wall. The morphological and physiological evidence suggests that the cochlea can adapt to furosemide application over time. The morphology of spiral ganglion cells and hair cells appeared normal throughout the cochlea. CAP responses and EP values in this model are similar to those of quiet-aged ears. The spontaneous activity of single auditory fibers (n = 188) was assessed in 15 young gerbils treated with furosemide for 7 days. The percentage of recorded low-spontaneous rate (SR) fibers at characteristic frequencies (CFs) > or = 6 kHz was significantly lower in furosemide-treated than in control ears. Recovery function tests of CAP responses after prior stimulation also showed a decline in activity of the low-SR population with CFs > or = 6 kHz in the treated cochleas. A similar loss in the activity of low-SR fiber has been previously shown in quiet-aged gerbils. These results suggest that dysfunction of the cochlear lateral wall and subsequent chronic reduction in the EP can directly affect the activity patterns of primary auditory neurons in a manner similar to that seen in aged gerbils.
Resource accounts of behavioral aging postulate that age-associated impairments within and across intellectual and sensory domains reflect, in part, a common set of senescent alterations in the neurochemistry and neuroanatomy of the aging brain. Hence, these accounts predict sizeable correlations of between-person differences in rates of decline, both within and across intellectual and sensory domains. The authors examined reliability-adjusted variances and covariances in longitudinal change for 8 cognitive measures and for close visual acuity, distant visual acuity, and hearing in 516 participants in the Berlin Aging Study (ages 70 to 103 years at 1st measurement). Up to 6 longitudinal measurements were distributed over up to 13 years. Individual differences in rates of cognitive decline were highly correlated, with a single factor accounting for 60% of the variance in cognitive change. This amount increased to 65% when controlling for age at first measurement, distance to death, and risk of dementia. Contrary to expectations, the correlations between cognitive and sensory declines were only moderate in size, underscoring the need to delineate both domain-general and function-specific mechanisms of behavioral senescence.
The purpose of the present study was to examine, first, whether hearing acuity predicts falls and whether the potential association is explained by postural balance and, second, to examine whether shared genetic or environmental effects underlie these associations.
Hearing was measured using a clinical audiometer as a part of the Finnish Twin Study on Aging in 103 monozygotic and 114 dizygotic female twin pairs aged 63-76 years. Postural balance was indicated as a center of pressure (COP) movement in semi-tandem stance, and participants filled in a fall-calendar daily for an average of 345 days after the baseline.
Mean hearing acuity (better ear hearing threshold level at 0.5-4 kHz) was 21 dB (standard deviation [SD] 12). Means of the COP velocity moment for the best to the poorest hearing quartiles increased linearly from 40.7 mm(2)/s (SD 24.4) to 52.8 mm(2)/s (SD 32.0) (p value for the trend = .003). Altogether 199 participants reported 437 falls. Age-adjusted incidence rate ratios (IRRs) for falls, with the best hearing quartile as a reference, were 1.2 (95% confidence interval [CI] = 0.4-3.8) in the second, 4.1 (95% CI = 1.1-15.6) in the third, and 3.4 (95% CI = 1.0-11.4) in the poorest hearing quartiles. Adjustment for COP velocity moment decreased IRRs markedly. Twin analyses showed that the association between hearing acuity and postural balance was not explained by genetic factors in common for these traits.
People with poor hearing acuity have a higher risk for falls, which is partially explained by their poorer postural control. Auditory information about environment may be important for safe mobility.
Conducted 6 experiments with a total of 69 male Holtzman albino rats. The temporal functions relating inhibition and facilitation of the startle reaction, elicited by an intense auditory stimulus, to momentary and to prolonged acoustic and visual stimuli were studied. The extent of inhibition was positively related to the intensity of the stimulus in both modalities. The extent of facilitation was positively related to the intensity of the visual stimulus but nonmonotonically related to the intensity of the auditory stimulus, a relationship confirmed in a study of the effects of background noise level on startle behavior. Data are correlated with physiological processes which provide similar effects at the electrophysiological level. Some implications drawn for experiments on classical conditioning and habituation are discussed. (46 ref.)
A sensory event that occurs just prior to an intense startle-eliciting stimulus can modify either the latency or the amplitude of the response, depending on the lead time. Systematic analysis of these effects, using different measures across species (including humans), leads to the conclusion that they reflect differential activity within a neural system in which startle is instigated and that one of the inputs to this system is a separate (parallel) inhibitory pathway. Since a sensory event need only be near its absolute threshold to produce a reliable effect, it is also concluded that activity in a neural system in which startle is instigated may always represent one of the earliest steps in an organism's response to events in its sensory environment. It is suggested that analysis of reflex modification provides an avenue for research with intact organisms that can bridge the gap between the isolated preparations studied by the physiologist and the behavioral processes that concern psychologists. (59 ref)
To determine whether functional and psychosocial outcomes associated with hearing impairment are a direct result or stem from
prevalent comorbidity, we analyzed the impact of two levels of reported hearing impairment on health and psychosocial functioning
one year later with adjustments for baseline chronic conditions. Physical functioning, mental health, and social functioning
decreased in a dose-response pattern for those with progressive levels of hearing impairment compared with those reporting
no impairment. Our results demonstrate an independent impact of hearing impairment on functional outcomes, reveal increasing
problems with higher levels of impairment, and support the importance of preventing and treating this highly prevalent condition.
Objectives:This study examines the association of hearing impairment and chronic diseases (diabetes mellitus, lung disease, cardiac disease, stroke, cancer, peripheral artery disease, osteoarthritis, rheumatoid arthritis) with psychosocial status (depression, self-efficacy, mastery, loneliness, social network size) in older persons. Methods:The sample consists of 3,107 persons (55 to 85 years) participating in the Longitudinal Aging Study Amsterdam. MANOVA, adjusted for covariates, was used to test the effect of hearing impairment on the combined outcomes. The association of hearing impairment and chronic diseases with psychosocial status was studied using multivariate regression analyses. Results:Hearing impaired elderly report significantly more depressive symptoms, lower self-efficacy and mastery, more feelings of loneliness, and a smaller social network than normally hearing peers. Whereas chronic diseases show significant associations with some outcomes, hearing impairment is significantly associated with all psychosocial variables. Discussion:The findings emphasize the negative effect of hearing impairment on quality of life.
Hearing thresholds in elderly humans without a history of noise exposure commonly show a profile of a flat loss at low frequencies coupled with a loss that increases with frequency above approximately 2 kHz. This profile and the relatively robust distortion product otoacoustic emissions that are found in elderly subjects challenge the common belief that age-related hearing loss (presbyacusis) is based primarily on sensory-cell disorders. Here, we examine a model of presbyacusis wherein the endocochlear potential (EP) is reduced by means of furosemide applied chronically to one cochlea of a young gerbil. The model results in an EP that is reduced from 90 to approximately 60 mV, a value often seen in quiet-aged gerbils, with no concomitant loss of hair cells. Resulting measures of cochlear and neural function are quantitatively similar to those seen in aging gerbils and humans, e.g., a flat threshold loss at low frequencies with a high-frequency roll-off of approximately -8.4 dB/octave. The effect of the EP on neural thresholds can be parsimoniously explained by the known gain characteristics of the cochlear amplifier as a function of cochlear location: in the apex, amplification is limited to approximately 20 dB, whereas in the base, the gain can be as high as 60 dB. At high frequencies, amplification is directly proportional to the EP on an approximately 1 dB/mV basis. This model suggests that the primary factor in true age-related hearing loss is an energy-starved cochlear amplifier that results in a specific audiogram profile.
Although the phosphorylation-dependent activation of the Na-K-Cl cotransporter (NKCC1) has been previously well documented, the identity of the kinase(s) responsible for this regulation has proven elusive. Recently, Piechotta et al. (Piechotta, K., Lu, J., and Delpire, E. (2002) J. Biol. Chem. 277, 50812-50819) reported the binding of PASK (also referred as SPAK (STE20/SPS1-related proline-alanine-rich kinase)) and OSR1 (oxidative stress response kinase) to cation-chloride cotransporters KCC3, NKCC1, and NKCC2. In this report, we show that overexpression of a kinase inactive, dominant negative (DN) PASK mutant drastically reduces both shark (60 +/- 5%) and human (80 +/- 3%) NKCC1 activation. Overexpression of wild type PASK causes a small (sNKCC1 22 +/- 8% p < 0.05, hNKCC1 12 +/- 3% p < 0.01) but significant increase in shark and human cotransporter activity in HEK cells. Importantly, DNPASK also inhibits the phosphorylation of two threonines, contained in the previously described N-terminal regulatory domain. We additionally show the near complete restoration of NKCC1 activity in the presence of the protein phosphatase type 1 inhibitor calyculin A, demonstrating that DNPASK inhibition results from an alteration in kinase/phosphatase dynamics rather than from a decrease in functional cotransporter expression. Coimmunoprecipitation assays confirm PASK binding to NKCC1 in transfected HEK cells and further suggest that this binding is not a regulated event; neither PASK nor NKCC1 activity affects the association. In cells preloaded with 32Pi, the phosphorylation of PASK, but not DNPASK, coincides with that of NKCC1 and increases 5.5 +/- 0.36-fold in low [Cl]e. These data conclusively link PASK with the phosphorylation and activation of NKCC1.
Primary aldosteronism causes severe hypertension in humans (Conn's syndrome) with cardiac hypertrophy, characterized by a fibrosis more severe than the one observed in patients with essential hypertension. This suggests that aldosterone by itself may have specific and direct effects on cardiac remodeling through the activation of the cardiac mineralocorticoid receptor. Experimental evidence obtained in studying uninephrectomized rats treated with aldosterone or deoxycorticosterone (DOC) together with salt loading has led to similar conclusions. To examine the direct consequences of chronically elevated aldosterone levels on cardiac pathophysiology, we analyzed a mouse model (alpha-epithelial Na channel -/-Tg) that is normotensive under normal-salt diet but exhibits chronic hyperaldosteronism. Sixteen-month-old transgenic rescue mice that were kept under a regular salt diet that contains a small amount of sodium (0.3% Na(+)) displayed a compensated PHA-1 phenotype with normal body weight, normal kidney index, normal blood pressure, but 6.3-fold elevated plasma aldosterone levels compared with the age-matched control group. Peripheral resistance of distal colon to aldosterone was shown by a significant decrease of the amiloride-sensitive rectal potential difference, and its diurnal cyclicity was blunted. Despite chronically high plasma aldosterone levels, these animals do not show any evidence of cardiac hypertrophy, remodeling, or fibrosis, using collagen staining and anti-alpha-skeletal and alpha-smooth actin immunochemical labeling of heart sections. Cardiac fibrosis as seen in DOC- or aldosterone/salt-treated animal models is therefore likely to be due to the synergistic effect of salt, aldosterone, and other confounding factors rather than to the elevated circulating aldosterone levels alone.
Potassium channels have been identified as targets for a large number of therapeutic indications. The ability to use a high-throughput functional assay for the detection and characterization of small-molecule modulators of potassium channels is very desirable. However, present techniques capable of screening very large chemical libraries are limited in terms of data quality, temporal resolution, ease of use, and requirements for specialized instrumentation. To address these issues, the authors have developed a fluorescence-based thallium flux assay. This assay is capable of detecting modulators of both voltage and ligand-gated potassium channels expressed in mammalian cells. The thallium flux assay can use instruments standard to most high-throughput screening laboratories, and using such equipment has been successfully employed to screen large chemical libraries consisting of hundreds of thousands of compounds.
Female hormone influences on auditory system aging are not completely understood. Because of widespread clinical use of hormone replacement therapy (HRT), it is critical to understand HRT effects on sensory systems. The present study retrospectively analyzed and compared hearing abilities among 124 postmenopausal women taking HRT, treated with estrogen and progestin (E+P; n = 32), estrogen alone (E; n = 30), and a third [non-hormone replacement therapy (NHRT; n = 62)] control group. Subjects were 60–86 years old and were matched for age and health status. All had relatively healthy medical histories and no significant noise exposure, middle-ear problems, or major surgeries. Hearing tests included pure-tone audiometry, tympanometry, distortion-product otoacoustic emissions (DPOAEs), transient otoacoustic emissions, and the hearing-in-noise test (HINT). The HINT tests for speech perception in background noise, the major complaint of hearing-impaired persons. Pure-tone thresholds in both ears were elevated (poorer) for the E+P relative to the E and control groups. For DPOAEs, the E+P group presented with lower (worse) levels than the E and control groups, with significant differences for both ears. For the HINT results, the E+P group had poorer speech perception than the E and control groups across all background noise speaker locations and in quiet. These findings suggest that the presence of P as a component of HRT results in poorer hearing abilities in aged women taking HRT, affecting both the peripheral (ear) and central (brain) auditory systems, and it interferes with the perception of speech in background noise.
• estrogen
• hearing loss
• hormone replacement therapy
• presbycusis
• progesterone
Studies in rat aorta have shown that the Na-K-2Cl cotransporter NKCC1 is activated by vasoconstrictors and inhibited by nitrovasodilators, contributes to smooth muscle tone in vitro, and is upregulated in hypertension. To determine the role of NKCC1 in systemic vascular resistance and hypertension, blood pressure was measured in rats before and after inhibition of NKCC1 with bumetanide. Intravenous infusion of bumetanide sufficient to yield a free plasma concentration above the IC(50) for NKCC1 produced an immediate drop in blood pressure of 5.2% (P < 0.001). The reduction was not prevented when the renal arteries were clamped, indicating that it was not due to a renal effect of bumetanide. Bumetanide did not alter blood pressure in NKCC1-null mice, demonstrating that it was acting specifically through NKCC1. In third-order mesenteric arteries, bumetanide-inhibitable efflux of (86)Rb was acutely stimulated 133% by phenylephrine, and bumetanide reduced the contractile response to phenylephrine, indicating that NKCC1 influences tone in resistance vessels. The hypotensive effect of bumetanide was proportionately greater in rats made hypertensive by a 7-day infusion of norepinephrine (12.7%, P < 0.001 vs. normotensive rats) but much less so when hypertension was produced by a fixed aortic coarctation (8.0%), again consistent with an effect of bumetanide on resistance vessels rather than other determinants of blood pressure. We conclude that NKCC1 influences blood pressure through effects on smooth muscle tone in resistance vessels and that this effect is augmented in hypertension.
The medial olivocochlear efferent (MOC) system enhances signals in noise and helps mediate auditory attention. Contralateral suppression (CS) of distortion product otoacoustic emissions (DPOAEs) has revealed age-related MOC declines. Here, differences in CS as a function of contralateral noise intensity (43-67 dB sound pressure level) were measured; 2f1-f2 DPOAE grams were recorded for young adult CBA and C57 mice. In CBAs, CS was a monotonic function of contralateral noise level. The C57s showed normal hearing, measured with DPOAE amplitudes and auditory brainstem response thresholds, but showed little CS, suggesting a loss of efferent dynamics preceding any deficiencies of the afferent auditory system.
Age-related hearing impairment (ARHI) is the most common sensory impairment seen in the elderly. It is a complex disorder, with both environmental as well as genetic factors contributing to the impairment. The involvement of several environmental factors has been partially elucidated. A first step towards the identification of the genetic factors has been made, which will result in the identification of susceptibility genes, and will provide possible targets for the future treatment and/or prevention of ARHI. This paper aims to give a broad overview of the scientific findings related to ARHI, focusing mainly on environmental and genetic data in humans and in animal models. In addition, methods for the identification of contributing genetic factors as well as possible future therapeutic strategies are discussed.
In physiological doses, mineralocorticoids (MC) normalize the high salt intake developed after adrenalectomy. We have studied whether this effect of MC is accompanied by changes in the mRNA of neuronal α3 and β1 subunits of the (Na,K)-ATPase because this enzyme could by a mediator of MC action in target cells. We employed [35S]oligonucleotide probes for the mentioned subunits hybridized to brain sections from adrenalectomized rats and adrenalectomized rats receiving aldosterone (ALDO) during 4 days. Using t-test statistics to measure differences in mean levels of grain density, and the Kolmogorov–Smirnov non-parametric test applied to frequency histograms, we showed that ALDO increased the α3 subunit mRNA in the septum medialis, preoptic area medialis, caudate-putamen, periventricular gray substance, amygdala lateralis, hippocampal subfields CA1 to CA4 and the gyrus dentatus. Significant increases for the β1 subunit mRNA were found in periventricular gray substance, the CA1–CA4 hippocampal subfields and gyrus dentatus. Therefore, the salt-suppression effect of MC was accompanied by coordinate increases in (Na,K)-ATPase α3 and β1 subunit mRNA in the hippocampus, gyrus dentatus and periventricular gray substance, whereas in other regions the stimulatory effect was exclusive of the α3 subunit mRNA only. The results suggest that the enzyme could be a target of ALDO action not only in areas related to salt appetite control (amygdala, preoptic area) but also in brain regions subserving other functions of the MC.
Na+,K+-ATPase has been implicated in the maintenance of high [K+], low [Na+] in endolymph of the inner ear, ionic properties condered to support transduction by the receptor cells6. In exocrine ion-transporting epithelia, Na+,K+-ATPase activity is modulated by aldosterone mineralocorticoid hormone31. In the present study, the effect of alteratio of serum aldosterone levels on Na+, K+-ATPase in ion-transporting regions of the mammalian inner ear was investigated. A high Na+/low K+ diet offered ad libitum for 5 days was utilized to significantly decrease serum aldosterone in male Hartley guinea pigs compared to controls. An injection of aldosterone (10 μg/100 g b.wt.) 21 h prior to sacrifice resulted in significant elevation of serum aldosterone over that obtained with the high Na+/low K+ diet. Binding of [3H]ouabain, a specific inhibitor of Na+,K+-ATPase, was significantly elevated in microdissected lateral wall of the basal turn of the cochlea and in the ampulla of the semicircular canal, for aldosterone-injected vs. vehicle-injected animals. Serum [Na+] and [Cl−] were elevated in animals on the high Na+/low K+ diet and unaltered by administration of exogenous aldosterone. The enhancement of ouabain binding in inner ear tissues observed in aldosterone-injected animals, therefore, did not appear to reflect an alteration of serum electrolytes per se. The results of these experiments are consistent with the hypothesis that aldosterone increases the number of Na+,K+-ATPase sites in ion-transporting epithelia of the mammalian cochlea and semicircular canal.
The Kv1.1 potassium channel subunit, encoded by the Kcna1 gene, is heavily expressed in the auditory brainstem and is thought to have a critical role in producing the high temporal precision of action potentials characteristic of the auditory system. Our intent was to determine whether temporal acuity was reduced in Kcna1 null-mutant (-/-) mice, compared to wild-type (+/+) and heterozygotic mice (+/-), as measured by the encoding of gaps in the inferior colliculus by near-field auditory evoked potentials (NFAEP) or behavioral gap detection (BGD) using a prepulse inhibition paradigm. NFAEPs were collected at 40, 60 and 80 dB SPL with gap durations from 0.5 to 64 ms. BGD data were collected using silent gaps in 70 dB noise from 1 to 15 ms in duration. There were no systematic effects of Kcna1 genotype on NFAEP recovery functions, NFAEP latencies, or the time constant for BGD, but there was a small reduction in asymptotic prepulse inhibition for the longest gap stimuli in -/- mice. Gap thresholds were approximately 1-2 ms across genotypes, stimulus conditions, and paradigms. These data suggest that the neural pathways encoding behaviorally relevant, rapid auditory temporal fluctuations are not limited by the absence of Kv1.1 expression.
Age-related changes in functional activity of the glomerular zone were studied in the adrenal cortex of Wistar rats. It was shown that secretion of the basic mineralocorticoid hormone aldosterone was decreased with age. The glomerular zone of old rats showed the reduced sensitivity to the stimulant action of corticotropin, marked by the pronounced reaction to less doses of the hormone administered. At the same time the reactivity and the range of shifts in the course of ACTH dosage build-up decrease with aging.
We measured urinary and plasma aldosterone in normal subjects, aged 20 to 59 years, during a period of unrestricted sodium intake and after sodium depletion, using furosemide or a 20 meq sodium diet. Before and after sodium depletion, the mean and the upper limit of the range of urinary aldosterone excretion were considerably lower in subjects over 50 years compared with subjects under 30 years. Aging had no effect on plasma aldosterone concentration when the subjects were on an unrestricted sodium diet and blood was sampled while they were recumbent. In contrast, when the subjects were upright, both before and after sodium depletion, the mean and the upper limit of the range of plasma aldosterone concentration were lower in the subjects over 50 years compared with those under 30 years. The metabolic clearance of aldosterone was the same in the younger and the older subjects. Of eight patients over 40 years of age with aldosterone-producing adenoma, four had normal aldosterone excretion rates when the normal range was not age adjusted, but with age adjustment, all of the patients had clearly elevated excretion rates. Similarly, six of seven patients over 40 years of age had normal upright plasma aldosterone concentrations if the normal range of plasma aldosterone concentration was not age adjusted. We conclude that aldosterone secretion declines with advancing age. The effect of age on aldosterone secretion is an important consideration when evaluating older hypertensive patients for primary aldosteronism.
The acoustic startle reflex in the rat is inhibited if a relatively weak stimulus precedes the startle-eliciting tone burst. This research explored the effect of brief silent periods (gaps) in white noise on the startle reflex, in order to describe the limits of temporal resolution in the auditory system of the rat. Brief silent periods did depress reflex behavior, and two responsible processes were identified. One was most evident at a 190-msec lead time between gap and startle tone. It yielded a linear decrement in reflex expression over a dynamic range of 0-7 msec, and an estimate for the threshold of temporal acuity of 3.5 msec. The second was evident primarily at a 40-msec interstimulus interval and had a linear effect over a dynamic range of at least 40 msec. Very brief gaps had a greater inhibitory effect at the 190-msec interval between gap and startle stimulus; prolonged gaps had their greater effect at the 40-msec interval. The first process was identified as reflex inhibition, which is sensitive to the sensory properties of the lead stimulus. The second process was identified as sensory adaptation, produced by noise exposure but unmasked by silence.
The presence of aldosterone (Type 1) binding sites in the mammalian inner ear has been previously suggested by an increase in inner ear Na, K-ATPase ouabain binding sites in response to the administration of aldosterone in vivo (Pitovski et al., 1993). Type I binding sites have now been identified and characterized in the lateral wall of the basal turn of the cochlea and in the ampullae of the semicircular canals of the guinea pig. In the presence of RU 28362, which blocks low-affinity binding of the labeled hormone to Type II sites, [3H]-aldosterone binds to a single class of high-affinity (Type I) sites with Kd values of 34.7 nM in lateral wall of the basal turn of the cochlea and 31.3 nM in the ampullae of the semicircular canals. Bmax is 17.1 fmol/mg dry tissue for the cochlear sample and 17.4 fmol/mg dry tissue for the ampullae, comparable to reported values in renal tissue (17-31 fmol/mg protein). Thus, the results of receptor-binding experimental protocols with [3H]-aldosterone clearly suggest that these inner ear tissues are a target site of mineralocorticoid action.
Age-related changes in the renin-aldosterone system in normal humans are well documented. The most pronounced changes are observed at the extremes of life: plasma renin activity and plasma aldosterone levels are highest in the newborn, and lowest in the elderly population. There is a close temporal and directional relationship between the age-related decrease in plasma renin activity and the age-related decrease in plasma aldosterone. The renin-aldosterone system is also influenced by sex and race.
The activation of the renin-aldosterone system in newborns and infants probably represents an important physiological mechanism designed to maintain positive sodium balance. The decreases in plasma renin activity and plasma aldosterone levels observed in elderly persons are usually only modest, and are not associated with clinical alterations in fluid or electrolyte metabolism. The superimposition of a disease process, or the injudicious prescription of a drug, inhibiting renin release or angiotensin II production, could theoretically facilitate sodium wasting in newborns or infants, or precipitate hyporeninaemic hypoaldosteronism in older adults.
The primary clinical importance of age-related changes in the renin-aldosterone system relates to its impact on the proper classification of an individual’s renin-aldosterone profile when attempting to diagnose a clinical condition (e.g. low, normal or high renin hypertension). This is particularly true for newborns, infants and children to age 4, and for adults entering the sixth decade of life.
Age-related changes in plasma adrenocorticotropic hormone (ACTH), corticosterone, and aldosterone responses to exogenous corticotropin-releasing hormone (CRH) were studied concomitantly in both old and adult Long-Evans female rats. All animals were pretreated with dexamethasone and pentobarbital anesthetized. An acute intravenous injection of 1 micrograms rat CRH/100 g body weight markedly increased the plasma concentrations of ACTH, corticosterone, and aldosterone--with similar temporal kinetics in the two groups of rats. However, the incremental CRH responses were significantly lower in old (approximately -70, -45-60, and -30-50%, respectively, for ACTH, corticosterone, and aldosterone) as compared with adult rats. Together with our recent findings, the present results suggest that the previously reported reduced secretion of corticosteroids in aged rats is due to both an impaired steroidogenetic capacity of adrenocortical cells to respond to ACTH and to a decreased ability of corticotropes to produce ACTH in response to CRH.
Because hearing is accomplished by the brain (with neural input from the cochlea), presbyacusis can be ultimately accounted for by changes in brain activity that accompany aging. The anatomic and physiologic changes that accompany aging are of two basic types: the central effects of biological aging (CEBA) and the central effects of peripheral pathology (CEPP). Research using inbred mice and other animal models has provided insights into both CEPP and CEBA, and some implications of this research are reviewed, including the following. Age-related cochlear pathology results in changes in how frequency is "mapped" in the central auditory system (CAS), especially at higher anatomic levels, and this has potentially negative consequences for hearing. Aging and/or age-related hearing loss may impair neural inhibition in the CAS. CEPP may result in abnormalities in neural responses involved in binaural hearing and cause exaggerated "masking" of neural responses by noise. The extent of age-related anatomic change (CEBA and CEPP) varies among CAS subdivisions and accelerates during the terminal phase of life. Genes have been found to influence the time course and severity of presbyacusis as well as the role dietary restriction plays in ameliorating age-related hearing loss in mice.
This study is part of ongoing efforts to characterize and determine the neural bases of presbycusis. These efforts utilize humans and animals in sets of overlapping hypotheses and experiments. Here, 50 young adult and elderly subjects, with normal audiometric thresholds or high-frequency hearing loss, were presented three types of linguistic materials at suprathreshold levels to determine speech recognition performance in noise. The study sought to determine how peripheral and central auditory system dysfunctions might be implicated in the speech recognition problems of elderly humans. There were four main findings. (1) Peripheral auditory nervous system pathologies, manifested as reduced sensitivity for speech-frequency pure tones and speech materials, contribute to elevated speech reception thresholds in quiet, and to reduced speech recognition in noise. (2) Good cognitive ability was demonstrated in the old subjects who took advantage of supportive context as well or better than young subjects, strongly indicating that the cortical portions of the speech/language nervous system did not account for the speech understanding dysfunctions of the old subjects. (3) When audibility and cognitive functioning were not affected, the demonstrated speech-recognition in-noise dysfunction remained in old subjects. This implicates auditory brainstem or auditory cortex temporal-resolution dysfunctions in accounting for the observed differences in speech processing. (4) Performance differences between young and elderly subjects with elevated thresholds illustrate the effects of age plus hearing loss and thereby implicate both peripheral and central dysfunctions in presbycusics. This is because the differences in performance between young and elderly subjects with normal peripheral sensitivity identified a central auditory dysfunction.
Temporal acuity for brief gaps in noise was studied in mice of different ages (1-36 months) from strains with differing susceptibility to age-related hearing loss, using reflex modification audiometry. Prepulse inhibition of the acoustic startle reflex (ASR) increased with gap depth (GD: 10-40 dB in 70 dB SPL noise) and lead time (LT: 1-15 ms). The increase in inhibition with LT followed an exponential function in which the two parameters, asymptotic inhibition (AINH) and the time constant (tau), were both affected by GD. AINH rapidly declined from 1 to 6 and then to 18 months of age in C57BL/6J mice with progressively severe hearing loss, but first increased with maturation and then gradually declined beyond 6-12 months of age in CBA/CaJ and CBA x C57BL Fl-hybrid mice, which show no apparent change in sensory function at these ages. In contrast, tau was unaffected by hearing loss or by age, this suggesting that age-related changes in this form of temporal acuity occur because of a reduction in the efficiency with which gaps are centrally processed, not from any reduced ability to follow their rapid shift in noise level.
The effects of exposure to an augmented acoustic environment (AAE) on auditory function were evaluated in mouse strains that exhibit high-frequency hearing loss beginning during young adulthood (the C57BL/6J strain [C57]) or around the time of weaning/ adolescence (the DBA/2J strain [DBA]). Beginning at age 25 days, mice were exposed 12 h every night to a 70 dB SPL broad-band noise AAE. The AAE was maintained until age 14 months in C57 mice and 9 months in DBA mice. Control mice were age-matched and maintained under normal vivarium acoustic conditions. The auditory brainstem response (ABR), acoustic startle response amplitude, and prepulse inhibition (PPI) were used to assess the auditory system. Exposure to the AAE resulted in improved auditory performance in both strains (better PPI, lower ABR thresholds, bigger startle amplitudes).
Clinical reports have revealed impaired sodium and water balance in elderly persons. The present studies were designed to investigate the effects and involved mechanisms of aging on aldosterone secretion in zona glomerulosa (ZG) cells of young and old ovariectomized (Ovx) rats.
Young (3 months) and old (24 months) female rats were Ovx for 4 days before decapitation. ZG cells of young and old rats were incubated with angiotensin II (Ang II), tetrandrine, nifedipine, adrenocorticotropic hormone (ACTH), forskolin, 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP), and precursors at 37 degrees C for 30 minutes. Aldosterone concentrations in plasma and cell media as well as 3':5'-cAMP production in ZG cells were determined by radioimmunoassay. The effects of aging on the activity of aldosterone synthase and the expression of cytochrome P450 side-chain cleavage enzyme (P450scc) in ZG cells were determined by thin-layer chromatography and Western blot analysis, respectively.
Old rats had a lower plasma aldosterone level and a reduced basal aldosterone release from ZG cells than those in young rats. The conversions of steroidogenic precursors to aldosterone and the activity of aldosterone synthase as well as the expression of P450scc in ZG cells were lower in the old group than in the young group. Ang II-, ACTH-, forskolin- or 8-Br-cAMP-stimulated aldosterone secretion was attenuated in the old group as compared with the young group. Nifedipine decreased aldosterone secretion in the young group but not in the old group. The basal and forskolin-stimulated cAMP accumulations were lower in the old than in the young group.
These results suggest that the age-related decline in aldosterone secretion is in part a consequence of the reduced activities of biosynthetic enzymes, adenylyl cyclase and L-type calcium channels, as well as the expression of P450scc protein in ZG cells.
Although the glucocorticoid prednisone is the standard therapy for autoimmune sensorineural hearing loss, what this hormone does in the ear to restore hearing is not known. MRL/MpJ-Fas(lPr) autoimmune mice consistently have shown only stria vascularis disease, implying that abnormal ion balances in the endolymph underlie cochlear dysfunction. Previously we have shown that hearing loss in these mice is reversed with prednisolone treatment. This, coupled with the complete lack of cochlear inflammation, suggests that the restoration of hearing with prednisolone is due to its sodium transport function and not to its anti-inflammatory or immune suppression effects. Therefore the hypothesis of this study was that the mineralocorticoid aldosterone, which only increases sodium transport, would be as effective as prednisolone in reversing autoimmune hearing loss.
MRL/MpJ-Fas(lPr) autoimmune mice were treated with either prednisolone or aldosterone to compare steroid effects on auditory brainstem response (ABR) thresholds and stria morphology.
After baseline ABR audiometry, autoimmune mice were given prednisolone (5 mg/kg per day), aldosterone (15 microg/kg per day), or water in their drinking bottles. After 2 months of treatment the ABR thresholds were remeasured, and ears collected for histological examination.
The untreated controls showed continued elevation of ABR thresholds and edematous stria. However, thresholds in most steroid mice were improved or unchanged and their stria morphology improved, particularly with aldosterone treatment.
Restoration of hearing with steroid treatment is due to increased sodium transport to re-establish cochlear ionic balances. Aldosterone therapy may offer advantages over prednisone for long-term management of not only autoimmune hearing loss, but also other forms of nonimmune-related deafness for which steroids are currently prescribed.
Recently this laboratory showed aldosterone, a mineralocorticoid that only enhances sodium transport, was as effective as the glucocorticoid prednisolone in restoring cochlear function in autoimmune mice. To further test this relationship between sodium transport and autoimmune hearing loss, dosage comparisons were made of prednisolone and aldosterone control of the auditory dysfunction in autoimmune MRL/MpJ-Fas(lpr) mice. Mice were tested at 2 months of age to establish baseline auditory brainstem response (ABR) thresholds, hematocrit, serum immune complexes, and anti-nuclear antibodies. Mice were then given different doses of prednisolone or aldosterone in their drinking water for 2 months. After the treatment period, most untreated water controls showed elevation of ABR thresholds due to the ongoing autoimmune disease. However, the steroid groups had significantly more mice with improved or unchanged thresholds. Both steroids improved stria vascularis morphology, although aldosterone appeared to be more effective. The immune suppressive prednisolone caused a dose-related improvement in levels of serum immune complexes and hematocrit, hallmarks of systemic autoimmune disease. Aldosterone, which has no immune suppressive function, did not alter systemic disease. The comparable efficacy of prednisolone and aldosterone in restoring auditory function suggests steroid reversal of autoimmune hearing loss in mice is due to increasing stria vascularis sodium transport and not suppression of systemic autoimmune reactions.
Traditionally the auditory system was considered a hard-wired sensory system; this view has been challenged in recent years in light of the plasticity of other sensory systems, particularly the visual and somatosensory systems. Practical experience in clinical audiology together with the use of prosthetic devices, such as cochlear implants, contributed significantly to the present view on the plasticity of the central auditory system, which was originally based on data obtained in animal experiments. The loss of auditory receptors, the hair cells, results in profound changes in the structure and function of the central auditory system, typically demonstrated by a reorganization of the projection maps in the auditory cortex. These plastic changes occur not only as a consequence of mechanical lesions of the cochlea or biochemical lesions of the hair cells by ototoxic drugs, but also as a consequence of the loss of hair cells in connection with aging or noise exposure. In light of the aging world population and the increasing amount of noise in the modern world, understanding the plasticity of the central auditory system has its practical consequences and urgency. In most of these situations, a common denominator of central plastic changes is a deterioration of inhibition in the subcortical auditory nuclei and the auditory cortex. In addition to the processes that are elicited by decreased or lost receptor function, the function of nerve cells in the adult central auditory system may dynamically change in the process of learning. A better understanding of the plastic changes in the central auditory system after sensory deafferentation, sensory stimulation, and learning may contribute significantly to improvement in the rehabilitation of damaged or lost auditory function and consequently to improved speech processing and production.
At the start of the last century in the United Kingdom, only 24% of the 587,830 deaths registered were of individuals over 65, but by the end of the century these figures had changed markedly. Of the 558,052 deaths in 1997, 84% were in the population over 65. This "right shift" in the survival curve is projected to continue. The UK Government Actuary's Department forecast that by 2020, 11.75 million people (19% of the population) will be over 65 rising to 15.1 million people (25% of the population) by 2040. Older members of society show infections of the urinary tract, respiratory tract, skin, soft tissue or intra-abdominal region, infectious endocarditis, bacterial meningitis, tuberculosis, and herpes zoster, at a higher incidence than among younger adults. Moreover, mortality rates for these diseases are often 2-3 times higher among elderly patients than younger individuals with the same disease. The higher morbidity and mortality from these infections, plus the increased prevalence of specific cancers and certain autoimmune diseases point to an immune system deteriorating with age. At the core of the immune system are the T cells and this review analyses possible causes for the changes in T cell function that may account for the deterioration of the immune system. Any intervention to reverse the decline in the immune system must have a rational basis built on a hypothesis-driven inquiry, and one such intervention process is presented here.
Aldosterone hormone is a mineralocorticoid secreted by adrenal gland cortex and controls serum sodium (Na(+)) and potassium (K(+)) levels. Aldosterone has a stimulatory effect on expression of sodium-potassium ATPase (Na, K-ATPase) and sodium-potassium-chloride cotransporter (NKCC) in cell membranes. In the present investigation, the relation between serum aldosterone levels and age-related hearing loss (presbycusis) and the correlation between these levels versus the degree of presbycusis in humans were examined. Serum aldosterone concentrations were compared between normal hearing and presbycusic groups. Pure-tone audiometry, transient evoked otoacoustic emissions (TEOAE), hearing in noise test (HINT) and gap detection were tested for each subject and compared to the serum aldosterone levels. A highly significant difference between groups in serum aldosterone concentrations was found (p = 0.0003, t = 3.95, df = 45). Highly significant correlations between pure-tone thresholds in both right and left ears, and HINT scores versus serum aldosterone levels were also discovered. On the contrary, no significant correlations were seen in the case of TEOAEs and gap detection. We conclude that aldosterone hormone may have a protective effect on hearing in old age. This effect is more peripheral than central, appearing to affect inner hair cells more than outer hair cells.
NKCC1 null mice are hypotensive, in part, from the absence of NKCC1-mediated vasoconstriction. Whether these mice have renal defects in NaCl and water handling which contribute to the hypotension is unexplored. Therefore, we asked 1) whether NKCC1 (-/-) mice have a defect in the regulation of NaCl and water balance, which might contribute to the observed hypotension and 2) whether the hypotension observed in these mice is accompanied by endocrine abnormalities and/or downregulation of renal Na+ transporter expression. Thus we performed balance studies, semiquantitative immunoblotting, and immunohistochemistry of kidney tissue from NKCC1 (+/+) and NKCC1 (-/-) mice which consumed either a high (2.8% NaCl)- or a low-NaCl (0.01% NaCl) diet for 7 days. Blood pressure was lower in NKCC1 (-/-) than NKCC1 (+/+) mice following either high or low dietary NaCl intake. Relative to wild-type mice, NKCC1 null mice had a lower plasma ANP concentration, a higher plasma renin and a higher serum K+ concentration with inappropriately low urinary K+ excretion, although serum aldosterone was either the same or only slightly increased in the mutant mice. Expression of NHE3, the alpha-subunit of the Na-K-ATPase, NCC, and NKCC2 were higher in NKCC1 null than in wild-type mice, although differences were generally greater during NaCl restriction. NKCC1 null mice had a reduced capacity to excrete free water than wild-type mice, which resulted in hypochloremia following the NaCl-deficient diet. Hypochloremia did not occur from increased aquaporin-1 (AQP1) or 2 protein expression or from redistribution of AQP2 to the apical regions of principal cells. Instead, NKCC1 null mice had a blunted increase in urinary osmolality following vasopressin administration, which should increase free water excretion and attenuate the hypochloremia. In conclusion, aldosterone release is inappropriately low in NKCC1 null mice. Moreover, the action of aldosterone and vasopressin is altered within kidneys of NKCC1 null mice, which likely contributes to their hypotension. Increased Na+ transporter expression, increased plasma renin, and reduced plasma ANP, as observed in NKCC1 null mice, should increase vascular volume and blood pressure, thus minimizing hypotension.
The standard treatment for many hearing disorders is glucocorticoid therapy, although the cochlear mechanisms involved in steroid-responsive hearing loss are poorly understood. Cochlear dysfunction in autoimmune mice has recently been shown to be controlled with the mineralocorticoid aldosterone as effectively as with the glucocorticoid prednisolone. Because aldosterone regulates sodium, potassium, and other electrolyte homeostasis, this implied the restoration of hearing with the mineralocorticoid was due to its impact on cochlear ion transport, particularly in the stria vascularis. This also suggested glucocorticoids may be controlling hearing recovery in part through their binding to the mineralocorticoid receptor in addition to their glucocorticoid receptor-mediated anti-inflammatory and immunosuppressive functions. Therefore, the aim of the present study was to better delineate the role of the mineralocorticoid receptor in steroid control of hearing in the autoimmune mouse. Spironolactone, a mineralocorticoid receptor antagonist, was administered to MRL/MpJ-Fas(lpr) autoimmune mice in combination with either aldosterone or prednisolone to compare their hearing and systemic disease with mice that received either steroid alone. ABR thresholds showed either aldosterone or prednisolone alone preserved hearing in the mice, but spironolactone prevented both steroids from maintaining normal cochlear function. This suggested both steroids are preserving hearing through the mineralocorticoid receptor within the ear to regulate endolymph homeostasis. The spironolactone treatment did not block normal glucocorticoid receptor-mediated immune-suppression functions because mice receiving prednisolone, either with or without spironolactone, maintained normal body weights, hematocrits, and serum immune complexes. Thus, reducing systemic autoimmune disease was not sufficient to control hearing if mineralocorticoid receptor-mediated functions were blocked. It was concluded the inner ear mineralocorticoid receptor is a significant target of glucocorticoids and a factor that should be considered in therapeutic treatments for steroid-responsive hearing loss.
Maintenance of a stable cell volume and intracellular pH is critical for normal cell function. Arguably, two of the most important ion transporters involved in these processes are the Na+/H+ exchanger isoform 1 (NHE1) and Na+ -K+ -2Cl- cotransporter isoform 1 (NKCC1). Both NHE1 and NKCC1 are stimulated by cell shrinkage and by numerous other stimuli, including a wide range of hormones and growth factors, and for NHE1, intracellular acidification. Both transporters can be important regulators of cell volume, yet their activity also, directly or indirectly, affects the intracellular concentrations of Na+, Ca2+, Cl-, K+, and H+. Conversely, when either transporter responds to a stimulus other than cell shrinkage and when the driving force is directed to promote Na+ entry, one consequence may be cell swelling. Thus stimulation of NHE1 and/or NKCC1 by a deviation from homeostasis of a given parameter may regulate that parameter at the expense of compromising others, a coupling that may contribute to irreversible cell damage in a number of pathophysiological conditions. This review addresses the roles of NHE1 and NKCC1 in the cellular responses to physiological and pathophysiological stress. The aim is to provide a comprehensive overview of the mechanisms and consequences of stress-induced stimulation of these transporters with focus on the heart, brain, and blood. The physiological stressors reviewed are metabolic/exercise stress, osmotic stress, and mechanical stress, conditions in which NHE1 and NKCC1 play important physiological roles. With respect to pathophysiology, the focus is on ischemia and severe hypoxia where the roles of NHE1 and NKCC1 have been widely studied yet remain controversial and incompletely elucidated.
The C57BL/6J mouse has been a useful model of presbycusis, as it displays an accelerated age-related peripheral hearing loss. The medial olivocochlear efferent feedback (MOC) system plays a role in suppressing cochlear outer hair cell (OHC) responses, particularly for background noise. Neurons of the MOC system are located in the superior olivary complex, particularly in the dorsomedial periolivary nucleus (DMPO) and in the ventral nucleus of the trapezoid body (VNTB). We previously discovered that the function of the MOC system declines with age prior to OHC degeneration, as measured by contralateral suppression (CS) of distortion product otoacoustic emissions (DPOAEs) in humans and CBA mice. The present study aimed to determine the time course of age changes in MOC function in C57s. DPOAE amplitudes and CS of DPOAEs were collected for C57s from 6 to 40 weeks of age. MOC responses were observed at 6 weeks but were gone at middle (15-30 kHz) and high (30-45 kHz) frequencies by 8 weeks. Quantitative stereological analyses of Nissl sections revealed smaller neurons in the DMPO and VNTB of young adult C57s compared with CBAs. These findings suggest that reduced neuron size may underlie part of the noteworthy rapid decline of the C57 efferent system. In conclusion, the C57 mouse has MOC function at 6 weeks, but it declines quickly, preceding the progression of peripheral age-related sensitivity deficits and hearing loss in this mouse strain.
Aldosterone Increases the Protein Expression of Na-K-Cl Cotransporter (NKCC1) via an Ubiquitination Mechanism. Program No. 367
- B Ding
- R D Frisina
- X Zhu
- D R Frisina
- J P Walton
Ding, B., Frisina, R.D., Zhu, X., Frisina, D.R., Walton, J.P., 2012. Aldosterone Increases
the Protein Expression of Na-K-Cl Cotransporter (NKCC1) via an Ubiquitination
Mechanism. Program No. 367.10. 2012 Neuroscience Meeting Planner. Society
for Neuroscience, New Orleans, LA (Online).
Hormonal modulation of a key sodium-potassium co-transporter (NKCC1) that maintains the endocochlear potential through the SGK1-Nedd4e2 pathway. Aging & speech communication
- B Ding
- R D Frisina
- X Zhu
- J P Walton
Ding, B., Frisina, R.D., Zhu, X., Walton, J.P., 2013a. Hormonal modulation of a key
sodium-potassium co-transporter (NKCC1) that maintains the endocochlear
potential through the SGK1-Nedd4e2 pathway. Aging & speech communication. In: 5th International & Interdisciplinary Research Conference Abstract.
Age related Naþ/Kþ-ATPase isoform gene and protein expression changes in the cochlear stria vascularis
- B Ding
- X Zhu
- R D Frisina
- J P Walton
Ding, B., Zhu, X., Frisina, R.D., Walton, J.P., 2013b. Age related Naþ/Kþ-ATPase isoform gene and protein expression changes in the cochlear stria vascularis.
Assoc. Res. Otolaryngol. Abs 304.
Aging and the Auditory System: Anatomy, Physiology, and Psychophysics
- J F Willott
Willott, J.F., 1991. Aging and the Auditory System: Anatomy, Physiology, and Psychophysics. Singular, San Diego, CA.
Age-associated changes of Na, K-ATPase subunit isoform distribution and expression in the CBA/CaJ mouse cochlea
- X Zhu
- B Ding
- J P Walton
- R D Frisina
Zhu, X., Ding, B., Walton, J.P., Frisina, R.D., 2013. Age-associated changes of Na, K-ATPase subunit isoform distribution and expression in the CBA/CaJ mouse cochlea. Assoc. Res. Otolaryngol. Abs. 628.