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BACKGROUND: Presbycusis, also referred to as age-related hearing loss (ARHL), is a condition that results from the cumulative effects of aging on an individual's auditory capabilities. Given the limited understanding of epigenetic mechanisms in ARHL, our research focuses on alterations in chromatin-accessible regions. METHODS: We employed assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) in conjunction with unique identifier (UID) mRNA-seq between young and aging cochleae, and conducted integrated analysis as well as motif/TF-gene prediction. Additionally, the essential role of super-enhancers (SEs) in the development of ARHL was identified by comparative analysis to previous research. Meanwhile, an ARHL mouse model and an aging mimic hair cell (HC) model were established with a comprehensive identification of senescence phenotypes to access the role of SEs in ARHL progression. RESULTS: The control cochlear tissue exhibited greater chromatin accessibility than cochlear tissue affected by ARHL. Furthermore, the levels of histone 3 lysine 27 acetylation were significantly depressed in both aging cochlea and aging mimic HEI-OC1 cells, highlighting the essential role of SEs in the development of ARHL. The potential senescence-associated super-enhancers (SASEs) of ARHL were identified, most of which exhibited decreased chromatin accessibility. The majority of genes related to the SASEs showed obvious decreases in mRNA expression level in aging HCs and was noticeably altered following treatment with JQ1 (a commonly used SE inhibitor). CONCLUSION: The chromatin accessibility in control cochlear tissue was higher than that in cochlear tissue affected by ARHL. Potential SEs involved in ARHL were identified, which might provide a basis for future therapeutics targeting SASEs related to ARHL.
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Envejecimiento , Cromatina , Cóclea , Elementos de Facilitación Genéticos , Presbiacusia , Animales , Ratones , Cóclea/metabolismo , Cóclea/efectos de los fármacos , Cromatina/genética , Cromatina/metabolismo , Envejecimiento/genética , Presbiacusia/genética , Presbiacusia/metabolismo , Elementos de Facilitación Genéticos/genética , Transcriptoma/genética , Modelos Animales de Enfermedad , Epigénesis Genética/genética , Histonas/metabolismo , Histonas/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , MasculinoRESUMEN
Age-related hearing loss is a complex disease caused by a combination of genetic and environmental factors, and a study have conducted animal experiments to explore the association between BCL11B heterozygosity and age-related hearing loss. The present study used established genetic models to examine the association between BCL11B gene polymorphisms and age-related hearing loss. A total of 410 older adults from two communities in Qingdao, China, participated in this study. The case group comprised individuals aged ≥ 60 years with age-related hearing loss, and the control group comprised individuals without age-related hearing loss from the same communities. The groups were matched 1:1 for age and sex. The individual characteristics of the participants were analyzed descriptively using the Mann-Whitney U test and the chi-square test. To explore the association between BCL11B gene polymorphisms and age-related hearing loss, conditional logistic regression was performed to construct genetic models for two single-nucleotide-polymorphisms (SNPs) of BCL11B, and haplotype analysis was conducted to construct their haplotype domains. Two SNP sites of the BCL11B gene, four genetic models of rs1152781 (additive, dominant, recessive, and codominant), and five genetic models of rs1152783 (additive, dominant, recessive, codominant, and over dominant) were significantly associated with age-related hearing loss in the models both unadjusted and adjusted for all covariates (P < 0.05). Additionally, a linkage disequilibrium between rs1152781 and rs1152783 was revealed through haplotype analysis. Our study revealed that BCL11B gene polymorphisms were significantly associated with age-related hearing loss.
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Haplotipos , Polimorfismo de Nucleótido Simple , Proteínas Represoras , Proteínas Supresoras de Tumor , Humanos , Masculino , Femenino , Anciano , China/epidemiología , Estudios de Casos y Controles , Persona de Mediana Edad , Proteínas Represoras/genética , Proteínas Supresoras de Tumor/genética , Pérdida Auditiva/genética , Pérdida Auditiva/epidemiología , Predisposición Genética a la Enfermedad , Anciano de 80 o más Años , Presbiacusia/genética , Presbiacusia/epidemiología , Desequilibrio de LigamientoRESUMEN
PURPOSE: Age-related hearing loss is the most common form of permanent hearing loss that is associated with various health traits, including Alzheimer's disease, cognitive decline, and depression. The present study aims to identify genetic comorbidities of age-related hearing loss. Past genome-wide association studies identified multiple genomic loci involved in common adult-onset health traits. Polygenic risk scores (PRS) could summarize the polygenic inheritance and quantify the genetic susceptibility of complex traits independent of trait expression. The present study conducted a PRS-based association analysis of age-related hearing difficulty in the UK Biobank sample (N = 425,240), followed by a replication analysis using hearing thresholds (HTs) and distortion-product otoacoustic emissions (DPOAEs) in 242 young adults with self-reported normal hearing. We hypothesized that young adults with genetic comorbidities associated with age-related hearing difficulty would exhibit subclinical decline in HTs and DPOAEs in both ears. METHODS: A total of 111,243 participants reported age-related hearing difficulty in the UK Biobank sample (> 40 years). The PRS models were derived from the polygenic risk score catalog to obtain 2627 PRS predictors across the health spectrum. HTs (0.25-16 kHz) and DPOAEs (1-16 kHz, L1/L2 = 65/55 dB SPL, F2/F1 = 1.22) were measured on 242 young adults. Saliva-derived DNA samples were subjected to low-pass whole genome sequencing, followed by genome-wide imputation and PRS calculation. The logistic regression analyses were performed to identify PRS predictors of age-related hearing difficulty in the UK Biobank cohort. The linear mixed model analyses were performed to identify PRS predictors of HTs and DPOAEs. RESULTS: The PRS-based association analysis identified 977 PRS predictors across the health spectrum associated with age-related hearing difficulty. Hearing difficulty and hearing aid use PRS predictors revealed the strongest association with the age-related hearing difficulty phenotype. Youth with a higher genetic predisposition to hearing difficulty revealed a subclinical elevation in HTs and a decline in DPOAEs in both ears. PRS predictors associated with age-related hearing difficulty were enriched for mental health, lifestyle, metabolic, sleep, reproductive, digestive, respiratory, hematopoietic, and immune traits. Fifty PRS predictors belonging to various trait categories were replicated for HTs and DPOAEs in both ears. CONCLUSION: The study identified genetic comorbidities associated with age-related hearing loss across the health spectrum. Youth with a high genetic predisposition to age-related hearing difficulty and other related complex traits could exhibit sub-clinical decline in HTs and DPOAEs decades before clinically meaningful age-related hearing loss is observed. We posit that effective communication of genetic risk, promoting a healthy lifestyle, and reducing exposure to environmental risk factors at younger ages could help prevent or delay the onset of age-related hearing difficulty at older ages.
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Herencia Multifactorial , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Reino Unido/epidemiología , Comorbilidad , Estudio de Asociación del Genoma Completo , Anciano , Predisposición Genética a la Enfermedad , Pérdida Auditiva/genética , Pérdida Auditiva/epidemiología , Presbiacusia/genética , Presbiacusia/epidemiología , Umbral Auditivo , Puntuación de Riesgo GenéticoRESUMEN
The study focuses on the underlying regulatory mechanism of age-related hearing loss (ARHL), which results from autophagy dysregulation mediated by miR-130b-3p targeting PPARγ. We constructed miR-130b-3p knockout (antagomir) and PPARγ over-expression (OE-PPARγ) mice model by injecting mmu-miR-130b-3p antagomir and HBAAV2/Anc80-m-Pparg-T2A-mCHerry into the right ear' round window of each mouse, respectively. In vitro, we introduced oxidative stress within HEI-OC1 cells by H2O2 and exogenously changed the miR-130b-3p and PPARγ levels. MiRNA level was detected by RT-qPCR, proteins by western blotting and immunohistochemistry. Morphology of autophagosomes was observed by electron microscopy. In vivo, the cochlea of aged mice showed higher miR-130b-3p expression and lower PPARγ expression, while exogenous inhibition of miR-130b-3p up-regulated PPARγ expression. Autophagy-related biomarkers expression (ATG5, Beclin-1 and LC3B II/I) decreased in aged mice, which reversely increased after the inhibition of miR-130b-3p. The elevation of PPARγ demonstrated similar effects. Contrarily, exogenous overexpression of miR-130b-3p resulted in the decrease of ATG5, Beclin-1 and LC3B II/I. We created oxidative stress within HEI-OC1 by H2O2, subsequently observed the formation of autophagosomes under electron microscope, so as the elevated cell apoptosis rate and weakened cell viability. MiR-130b-3p/PPARγ contributed to the premature senescence of these H2O2-induced HEI-OC1 cells. MiR-130b-3p regulated HEI-OC1 cell growth by targeting PPARγ, thus leading to ARHL.
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Autofagia , Modelos Animales de Enfermedad , Ratones Noqueados , MicroARNs , Estrés Oxidativo , PPAR gamma , Presbiacusia , Animales , PPAR gamma/metabolismo , PPAR gamma/genética , MicroARNs/metabolismo , MicroARNs/genética , Ratones , Presbiacusia/genética , Presbiacusia/metabolismo , Presbiacusia/patología , Presbiacusia/fisiopatología , Línea Celular , Envejecimiento/metabolismo , Envejecimiento/patología , Ratones Endogámicos C57BL , Factores de Edad , Transducción de Señal , Audición/genética , Cóclea/metabolismo , Cóclea/patología , Apoptosis , Regulación de la Expresión GénicaRESUMEN
Studies have highlighted oxidative damage in the inner ear as a critical pathological basis for sensorineural hearing loss, especially the presbycusis. Poly(ADP-ribose) polymerase-1 (PARP1) activation responds to oxidative stress-induced DNA damage with pro-repair and pro-death effects resembling two sides of the same coin. PARP1-related cell death, known as parthanatos, whose underlying mechanisms are attractive research hotspots but remain to be clarified. In this study, we observed that aged rats showed stria vascularis degeneration and oxidative damage, and PARP1-dependent cell death was prominent in age-related cochlear disorganization and dysfunction. Based on oxidative stress model of primary cultured stria marginal cells (MCs), we revealed that upregulated PARP1 and PAR (Poly(ADP-ribose)) polymers are responsible for MCs oxidative death with high mitochondrial permeability transition pore (mPTP) opening and mitochondrial membrane potential (MMP) collapse, while inhibition of PARP1 ameliorated the adverse outcomes. Importantly, the PARylation of apoptosis-inducing factor (AIF) is essential for its conformational change and translocation, which subsequently causes DNA break and cell death. Concretely, the interaction of PAR and truncated AIF (tAIF) is the mainstream in the parthanatos pathway. We also found that the effects of AIF cleavage and release were achieved through calpain activity and mPTP opening, both of which could be regulated by PARP1 via mediation of mitochondria Ca2+ concentration. In conclusion, the PAR-Ca2+-tAIF signaling pathway in parthanatos contributes to the oxidative stress damage observed in MCs. Targeting PAR-Ca2+-tAIF might be a potential therapeutic strategy for the early intervention of presbycusis and other oxidative stress-associated sensorineural deafness.
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Factor Inductor de la Apoptosis , Calcio , Estrés Oxidativo , Poli(ADP-Ribosa) Polimerasa-1 , Presbiacusia , Animales , Factor Inductor de la Apoptosis/metabolismo , Factor Inductor de la Apoptosis/genética , Ratas , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/genética , Calcio/metabolismo , Presbiacusia/metabolismo , Presbiacusia/patología , Presbiacusia/genética , Parthanatos/genética , Potencial de la Membrana Mitocondrial , Estría Vascular/metabolismo , Estría Vascular/patología , Apoptosis , Poro de Transición de la Permeabilidad Mitocondrial/metabolismo , Mitocondrias/metabolismo , Mitocondrias/patología , Ratas Sprague-Dawley , Daño del ADN , Envejecimiento/metabolismo , Envejecimiento/patología , Cóclea/metabolismo , Cóclea/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Masculino , Humanos , Células CultivadasRESUMEN
Age-related hearing loss (ARHL), is a pervasive health problem worldwide. ARHL seriously affects the quality of life and reportedly leads to social isolation and dementia in the elderly. ARHL is caused by the degeneration or disorders of cochlear hair cells and auditory neurons. Numerous studies have verified that genetic factors contributed to this impairment, however, the mechanism behind remains unclear. In this study, we analyzed an mRNA expression dataset (GSE49543) from the GEO database. Differentially expressed genes (DEGs) between young control mice and presbycusis mice were analyzed using limma in R and weighted gene co-expression network analysis (WGCNA) methods. Functional enrichment analyses of the DEGs were conducted with the clusterProfiler R package and the results were visualized using ggplot2 R package. The STRING database was used for the construction of the protein-protein interaction (PPI) network of the screened DEGs. Two machine learning algorithms LASSO and SVM-RFE were used to screen the hub genes. We identified 54 DEGs in presbycusis using limma and WGCNA. DEGs were associated with the synaptic vesicle cycle, distal axon, neurotransmitter transmembrane transporter activity in GO analysis, and alcoholic liver disease, pertussis, lysosome pathway according to KEGG analyses. PPI network analysis identified three significant modules. Five hub genes (CLEC4D, MS4A7, CTSS, LAPTM5, ALOX5AP) were screened by LASSO and SVM-RFE. These hub genes were highly expressed in presbycusis mice compared with young control mice. We screened DEGs and identified hub genes involved in ARHL development, which might provide novel clues to understanding the molecular basis of ARHL.
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Perfilación de la Expresión Génica , Presbiacusia , ARN Mensajero , Animales , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratones , Perfilación de la Expresión Génica/métodos , Presbiacusia/genética , Presbiacusia/metabolismo , Presbiacusia/patología , Redes Reguladoras de Genes , Mapas de Interacción de Proteínas/genética , Transcriptoma/genética , Envejecimiento/genética , Bases de Datos Genéticas , Biología Computacional/métodosRESUMEN
Hair cells in the cochlear sensory epithelia serve as mechanosensory receptors, converting sound into neuronal signals. The basal sensory epithelia are responsible for transducing high-frequency sounds, while the apex handles low-frequency sounds. Age-related hearing loss predominantly affects hearing at high frequencies and is indicative of damage to the basal sensory epithelia. However, the precise mechanism underlying this site-selective injury remains unclear. In this study, we employed a microscale proteomics approach to examine and compare protein expression in different regions of the cochlear sensory epithelia (upper half and lower half) in 1.5-month-old (normal hearing) and 6-month-old (severe high-frequency hearing loss without hair cell loss) C57BL/6J mice. A total of 2,386 proteins were detected, and no significant differences in protein expression were detected in the upper half of the cochlear sensory epithelia between the two age groups. The expression of 20 proteins in the lower half of the cochlear sensory epithelia significantly differed between the two age groups (e.g., MATN1, MATN4, and AQP1). Moreover, there were 311 and 226 differentially expressed proteins between the upper and lower halves of the cochlear sensory epithelia in 1.5-month-old and 6-month-old mice, respectively. The expression levels of selected proteins were validated by Western blotting. These findings suggest that the spatial differences in protein expression within the cochlear sensory epithelia may play a role in determining the susceptibility of cells at different sites of the cochlea to age-related damage.
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Cóclea , Ratones Endogámicos C57BL , Presbiacusia , Proteómica , Animales , Cóclea/metabolismo , Cóclea/patología , Presbiacusia/metabolismo , Presbiacusia/patología , Presbiacusia/fisiopatología , Presbiacusia/genética , Factores de Edad , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patología , Envejecimiento/metabolismo , Envejecimiento/patología , Modelos Animales de Enfermedad , Audición , Epitelio/metabolismo , Masculino , RatonesRESUMEN
BACKGROUND: Previous studies have shown that lifestyle/environmental factors could accelerate the development of age-related hearing loss (ARHL). However, there has not yet been a study investigating the joint association among genetics, lifestyle/environmental factors, and adherence to healthy lifestyle for risk of ARHL. We aimed to assess the association between ARHL genetic variants, lifestyle/environmental factors, and adherence to healthy lifestyle as pertains to risk of ARHL. METHODS: This case-control study included 376,464 European individuals aged 40 to 69 years, enrolled between 2006 and 2010 in the UK Biobank (UKBB). As a replication set, we also included a total of 26,523 individuals considered of European ancestry and 9834 individuals considered of African-American ancestry through the Penn Medicine Biobank (PMBB). The polygenic risk score (PRS) for ARHL was derived from a sensorineural hearing loss genome-wide association study from the FinnGen Consortium and categorized as low, intermediate, high, and very high. We selected lifestyle/environmental factors that have been previously studied in association with hearing loss. A composite healthy lifestyle score was determined using seven selected lifestyle behaviors and one environmental factor. RESULTS: Of the 376,464 participants, 87,066 (23.1%) cases belonged to the ARHL group, and 289,398 (76.9%) individuals comprised the control group in the UKBB. A very high PRS for ARHL had a 49% higher risk of ARHL than those with low PRS (adjusted OR, 1.49; 95% CI, 1.36-1.62; P < .001), which was replicated in the PMBB cohort. A very poor lifestyle was also associated with risk of ARHL (adjusted OR, 3.03; 95% CI, 2.75-3.35; P < .001). These risk factors showed joint effects with the risk of ARHL. Conversely, adherence to healthy lifestyle in relation to hearing mostly attenuated the risk of ARHL even in individuals with very high PRS (adjusted OR, 0.21; 95% CI, 0.09-0.52; P < .001). CONCLUSIONS: Our findings of this study demonstrated a significant joint association between genetic and lifestyle factors regarding ARHL. In addition, our analysis suggested that lifestyle adherence in individuals with high genetic risk could reduce the risk of ARHL.
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Estudio de Asociación del Genoma Completo , Presbiacusia , Humanos , Estudios de Casos y Controles , Factores de Riesgo , Presbiacusia/genética , Estilo de Vida Saludable , Predisposición Genética a la EnfermedadRESUMEN
OBJECTIVE: Age-related hearing loss (ARHL), also known as presbycusis, is a debilitating sensory impairment that affects the elderly population. There is currently no ideal treatment for ARHL. Long-term caffeine intake was reported to have anti-aging effects in many diseases. This study is to identify whether caffeine could ameliorate ARHL in mice and analyze its mechanism. METHODS: Caffeine was administered in drinking water to C57BL/6J mice from the age of 3 months to 12 months. The body weight, food intake and water intake of the mice were monitored during the experiment. The metabolic indicators of serum were detected by ELISA. The function of the hearing system was evaluated by ABR and hematoxylin and eosin staining of the cochlea. Genes' expression were detected by Q-PCR, immunofluorescencee and Western blot. RESULTS: The results showed that the ARHL mice exhibited impaired hearing and cochlear tissue compared with the young mice. However, the caffeine-treated ARHL mice showed improved hearing and cochlear tissue morphology. The expression of inflammation-related genes, such as TLR4, Myd88, NF-κB, and IL-1ß, was significantly increased in the cochleae of ARHL mice compared with young mice but was down-regulated in the caffeine-treated cochleae. CONCLUSIONS: Inflammation is involved in ARHL of mice, and long-term caffeine supplementation could ameliorate ARHL through the down-regulation of the TLR4/NF-κB inflammation pathway. Our findings provide a new idea for preventing ARHL and suggest new drug targets for ARHL treatment.
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Presbiacusia , Anciano , Humanos , Animales , Ratones , Lactante , Presbiacusia/tratamiento farmacológico , Presbiacusia/genética , Cafeína/farmacología , Cafeína/uso terapéutico , FN-kappa B , Receptor Toll-Like 4 , Ratones Endogámicos C57BL , Inflamación/tratamiento farmacológicoRESUMEN
Age-related hearing loss (ARHL), also known as presbycusis, is the number one communication disorder for aging adults. Connexin proteins are essential for intercellular communication throughout the human body, including the cochlea. Mutations in connexin genes have been linked to human syndromic and nonsyndromic deafness; thus, we hypothesize that changes in connexin gene and protein expression with age are involved in the etiology of ARHL. Here, connexin gene and protein expression changes for CBA/CaJ mice at different ages were examined, and correlations were analyzed between the changes in expression levels and functional hearing measures, such as ABRs and DPOAEs. Moreover, we investigated potential treatment options for ARHL. Results showed significant downregulation of Cx30 and Cx43 gene expression and significant correlations between the degree of hearing loss and the changes in gene expression for both genes. Moreover, dose-dependent treatments utilizing cochlear cell lines showed that aldosterone hormone therapy significantly increased Cx expression. In vivo mouse treatments with aldosterone also showed protective effects on connexin expression in aging mice. Based on these functionally relevant findings, next steps can include more investigations of the mechanisms related to connexin family gap junction protein expression changes during ARHL; and expand knowledge of clinically-relevant treatment options by knowing what specific members of the Cx family and related inter-cellular proteins should be targeted therapeutically.
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Conexina 30 , Conexina 43 , Presbiacusia , Animales , Ratones , Aldosterona , Cóclea/fisiología , Conexina 30/metabolismo , Conexinas/genética , Conexinas/metabolismo , Uniones Comunicantes/metabolismo , Ratones Endogámicos CBA , Presbiacusia/genética , Presbiacusia/metabolismo , Conexina 43/genética , Conexina 43/metabolismoRESUMEN
Age-related hearing loss (ARHL) is a major health concern among the elderly population. It is hoped that increasing our understanding of its underlying pathophysiological processes will lead to the development of novel therapies. Recent genome-wide association studies (GWASs) discovered a few dozen genetic variants in association with elevated risk for ARHL. Integrated analysis of GWAS results and transcriptomics data is a powerful approach for elucidating specific cell types that are involved in disease pathogenesis. Intriguingly, recent studies that applied such bioinformatics approaches to ARHL resulted in disagreeing findings as for the key cell types that are most strongly linked to the genetic pathogenesis of ARHL. These conflicting studies pointed either to cochlear sensory epithelial or to stria vascularis cells as the cell types most prominently involved in the genetic basis of ARHL. Seeking to resolve this discrepancy, we integrated the analysis of four ARHL GWAS datasets with four independent inner-ear single-cell RNA-sequencing datasets. Our analysis clearly points to the cochlear sensory epithelial cells as the key cells for the genetic predisposition to ARHL. We also explain the limitation of the bioinformatics analysis performed by previous studies that led to missing the enrichment for ARHL GWAS signal in sensory epithelial cells. Collectively, we show that cochlear epithelial cells, not stria vascularis cells, are the main inner-ear cells related to the genetic pathogenesis of ARHL.
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Presbiacusia , Estría Vascular , Anciano , Humanos , Estría Vascular/patología , Estudio de Asociación del Genoma Completo , Cóclea/patología , Presbiacusia/genética , Presbiacusia/patología , Epitelio/patologíaRESUMEN
As one of the most common otologic diseases in the elderly, age-related hearing loss (ARHL) usually characterized by hearing loss and cognitive disorders, which have a significant impact on the elderly's physical and mental health and quality of life. However, as a typical disease of aging, it is unclear why aging causes widespread hearing impairment in the elderly. As molecular biological experiments have been conducted for research recently, ARHL is gradually established at various levels with the application and development of integrated multi-omics analysis in the studies of ARHL. Here, the recent progress in the application of multi-omics analysis in the molecular mechanisms of ARHL development and therapeutic regimens, including the combined analysis of different omics, such as transcriptome, proteome, and metabolome, to screen for risk sites, risk genes, and differences in lipid metabolism, etc., is outlined and the integrated histological data further promote the profound understanding of the disease process as well as physiological mechanisms of ARHL. The advantages and disadvantages of multi-omics analysis in disease research are also discussed and the authors speculate on the future prospects and applications of this part-to-whole approach, which may provide more comprehensive guidance for ARHL and aging disease prevention and treatment.
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Disfunción Cognitiva , Presbiacusia , Humanos , Anciano , Calidad de Vida , Multiómica , Presbiacusia/genética , Presbiacusia/terapia , Envejecimiento/genética , Envejecimiento/patología , Disfunción Cognitiva/complicacionesRESUMEN
KCNMA1 encodes the K+ potassium channel α-subunit that plays a significant role in the auditory system. Our previous studies indicated that KCNMA1 is associated with age-related hearing loss(AHL). However, the detailed mechanism of KCNMA1 involvement in auditory age-related degradation has not been fully clarified. Therefore, we explored the expression of KCNMA1 in the peripheral auditory of 2-month-old and 12-month-old mice by Western blotting and immunofluorescence. The results of animal experiments showed that KCNMA1 expression was decreased in 12-month-old mice compared with 2-month-old mice, whereas the ferroptosis level was increased. To verify the role of KCNMA1 in AHL, we downregulated KCNMA1 in HEI-OC1 cells by transfecting shRNA. After downregulation, the ferroptosis level was increased and the aging process was accelerated. Furthermore, the aging process was affected by the expression of ferroptosis. In conclusion, these results revealed that KCNMA1 is associated with the aging process in auditory hair cells by regulating ferroptosis, which deepens our understanding of age-related hearing loss.
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Ferroptosis , Presbiacusia , Animales , Ratones , Regulación hacia Abajo , Ferroptosis/genética , Células Ciliadas Auditivas/metabolismo , Presbiacusia/genéticaRESUMEN
Age-related hearing loss (ARHL) is a prevalent concern in the elderly population. Recent genome-wide and phenome-wide association studies (GWASs and PheWASs) have delved into the identification of causative variants and the understanding of pleiotropy, highlighting the polygenic intricacies of this complex condition. While recent large-scale GWASs have pinpointed significant SNPs and risk variants associated with ARHL, the detailed mechanisms, encompassing both genetic and epigenetic modifications, remain to be fully elucidated. This review presents the latest advances in association studies, integrating findings from both human studies and model organisms. By juxtaposing historical perspectives with contemporary genomics, we aim to catalyze innovative research and foster the development of novel therapeutic strategies for ARHL.
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Presbiacusia , Humanos , Anciano , Presbiacusia/genética , Presbiacusia/epidemiología , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Age-related hearing loss (ARHL) or presbycusis is the phenomenon of hearing loss due to the aging of auditory organs with age. It seriously affects the cognitive function and quality of life of the elderly. This study is based on comprehensive bioinformatic and machine learning methods to identify the critical genes of ARHL and explore its therapy targets and pathological mechanisms. The ARHL and normal samples were from GSE49543 datasets of the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was applied to obtain significant modules. The Limma R-package was used to identify differentially expressed genes (DEGs). The 15 common genes of the practical module and DEGs were screened. Functional enrichment analysis suggested that these genes were mainly associated with inflammation, immune response, and infection. Cytoscape software created the protein-protein interaction (PPI) layouts and cytoHubba, support vector machine-recursive feature elimination (SVM-RFE), and random forests (RF) algorithms screened hub genes. After validating the hub gene expressions in GSE6045 and GSE154833 datasets, Clec4n, Mpeg1, and Fcgr3 are highly expressed in ARHL and have higher diagnostic efficacy for ARHL, so they were identified as hub genes. In conclusion, Clec4n, Mpeg1, and Fcgr3 play essential roles in developing ARHL, and they might become vital targets in ARHL diagnosis and anti-inflammatory therapy.
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Sordera , Presbiacusia , Anciano , Humanos , Presbiacusia/diagnóstico , Presbiacusia/genética , Presbiacusia/terapia , Calidad de Vida , Envejecimiento/genética , BiomarcadoresRESUMEN
Age-related hearing loss (ARHL), also known as presbycusis, is one of the most common neurodegenerative disorders in elderly individuals and has a prevalence of approximately 70-80% among individuals aged 65 and older. As ARHL is an intricate and multifactorial disease, the exact pathogenesis of ARHL is not fully understood. There is evidence that transcriptional dysregulation mediated by epigenetic modifications is widespread in ARHL. However, the potential role of N6-methyladenosine (m6A) modification, as a crucial component of epigenetics, in ARHL progression remains unclear. In this study, we confirmed that the downregulation of m6A modification in cochlear tissues is related to ARHL and found that the expression of the m6A methylation regulators Wilms tumour suppressor-1-associated protein (WTAP), methyltransferase-like 3 (METTL3), ALKB homologous protein 5 (ALKBH5) and fat mass and obesity-associated protein (FTO) is decreased significantly at the mRNA and protein levels in ARHL mice. Then, we used methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and RNA sequencing (RNA-Seq) to identify the differentially m6A-methylated genes in the cochlear tissues of ARHL mice. A total of 3438 genes with differential m6A methylation were identified, of which 1332 genes were m6A-hypermethylated and 2106 genes were m6A-hypomethylated in the ARHL group compared to the control group according to MeRIP-seq. Further joint analysis of RNA-Seq and MeRIP-Seq data showed that 262 genes had significant differences in both mRNA expression and m6A methylation. GO and KEGG analyses indicated that 262 unique genes were enriched mainly in the PI3K-AKT signalling pathway. In conclusion, the results of this study reveal differential m6A methylation patterns in the cochlear tissues of ARHL mice, providing a theoretical basis for further study of the pathogenesis of ARHL and potential therapeutic strategies.
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Fosfatidilinositol 3-Quinasas , Presbiacusia , Humanos , Anciano , Animales , Ratones , Presbiacusia/genética , Transcriptoma/genética , Perfilación de la Expresión Génica , ARN Mensajero/genética , Metiltransferasas/genética , Dioxigenasa FTO Dependiente de Alfa-CetoglutaratoRESUMEN
The GJB2 gene, encoding Connexin26 (Cx26), is one of the most common causes of inherited deafness. Clinically, mutations in GJB2 cause congenital deafness or late-onset progressive hearing loss. Recently, it has been reported that Cx26 haploid deficiency accelerates the development of age-related hearing loss (ARHL). However, the roles of cochlear Cx26 in the hearing function of aged animals remain unclear. In this study, we revealed that the Cx26 expression was significantly reduced in the cochleae of aged mice, and further explored the underlying molecular mechanism for Cx26 degradation. Immunofluorescence co-localization results showed that Cx26 was internalized and degraded by lysosomes, which might be one of the important ways for Cx26 degradation in the cochlea of aged mice. Currently, whether the degradation of Cx26 in the cochlea leads directly to ARHL, as well as the mechanism of Cx26 degradation-related hearing loss are still unclear. To address these questions, we generated mice with Cx26 knockout in the adult cochlea as a model for the natural degradation of Cx26. Auditory brainstem response (ABR) results showed that Cx26 knockout mice exhibited high-frequency hearing loss, which gradually progressed over time. Pathological examination also revealed the degeneration of hair cells and spiral ganglions, which is similar to the phenotype of ARHL. In summary, our findings suggest that degradation of Cx26 in the cochlea accelerates the occurrence of ARHL, which may be a novel mechanism of ARHL.
Asunto(s)
Conexina 26 , Sordera , Presbiacusia , Animales , Ratones , Cóclea/metabolismo , Conexinas/genética , Conexinas/metabolismo , Sordera/congénito , Sordera/genética , Sordera/patología , Ratones Noqueados , Presbiacusia/genética , Presbiacusia/metabolismo , Conexina 26/metabolismoRESUMEN
This study aimed to dig new molecular mechanisms and medications for age-related hearing loss (ARHL or presbycusis) by extracting common results of publicly available datasets. Based on five datasets (GSE153882, GSE121856, GSE98070, GSE45026, and GSE98071) in studies of cochlear hair cells, we explored the interrelationships among presbycusis-related genes, including gene interactions, enrichment analysis, miRNA-mRNA matching pairs, and potential new drugs. Together, there were 25 common increased mRNAs. A total of 183 drugs can simultaneously target 11 of these mRNAs. In the interaction network, hub genes included: Cbln1, Prl, Mpp6 and Gh. Meanwhile, there were 74 common decreased mRNAs. The hub genes include Cdkn1a, Egr1, and Ctgf. After de-duplication, the 25 common increased mRNAs had 946 matched miRNAs, with 34 decreased ones; and the 74 decreased mRNAs had 1164 matched miRNAs, with 26 increased ones. Between the inhibitors of increased mRNAs and enhancers of decreased mRNAs, there were 26 common drugs. Besides, we discovered six key genes that may play a crucial role in the onset of presbycusis. In conclusion, by jointly analyzing multiple datasets, we found 25 common increased mRNAs (e.g., Cbln1, Prl, Mpp6 and Gh) and 74 common decreased mRNAs (Cdkn1a, Egr1, and Ctgf), as well as 34 potential therapeutic miRNAs and 26 pathogenic miRNAs, and three candidate drugs (calcitriol, diclofenac, and diethylstilbestrol). They may provide new targets and strategies for mechanistic and therapeutic studies in ARHL.
Asunto(s)
MicroARNs , Presbiacusia , Animales , Ratones , Presbiacusia/genética , Perfilación de la Expresión Génica , Células Ciliadas Auditivas , Calcitriol , Factor de Crecimiento del Tejido Conjuntivo , MicroARNs/genética , ARN Mensajero/genéticaRESUMEN
BACKGROUND: We previously showed that aging accelerates after 3 months of exposure to hypoxia and environmental change but not genetic modifications. Here, we aimed to simply induce early-onset age-related hearing loss within a short period based on our previous method. METHODS: We randomly divided 16 C57BL/6 mice into four groups that were maintained under conditions of normoxia and hypoxia with or without injected D-galactose for 2 months. Deteriorated hearing, the expression of age-related factors, and oxidative stress responses were detected using the click and tone burst auditory brainstem response test, reverse transcription-polymerase chain reaction, and by measuring superoxide dismutase (SOD). RESULTS: The group maintained under hypoxia combined with D-galactose lost hearing particularly at 24 Hz and 32 Hz at 6 weeks compared with the other groups. Aging-related factors were also significantly decreased in the hypoxia and D-galactose groups. However, SOD levels did not significantly differ among the groups. CONCLUSION: Age-related hearing loss is an environmental disorder induced by chronic oxidative stress associated with genetic backgrounds. Our findings suggested that D-galactose and hypoxia can induce the phenotypes of age-related hearing loss and aging-associated molecules in a murine model within a short time with environmental stimulation alone.
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Galactosa , Presbiacusia , Ratones , Animales , Galactosa/efectos adversos , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Presbiacusia/inducido químicamente , Presbiacusia/genética , Presbiacusia/metabolismo , Superóxido Dismutasa , HipoxiaRESUMEN
The c-Jun N-terminal kinase (JNK) pathway is a vital component of the mitogen-activated protein kinase cascade, which regulates cell death and survival. The present study aimed to explore the Spatio-temporal changes in all JNK isoforms in the cochleae of C57/BL6J mice with age-related hearing loss. Changes in the three isoforms of JNKs in the cochleae of an animal model with presbycusis and the senescent HEI-OC1 cell line were tested by immunohistochemistry staining and western blotting. Our results demonstrated that all three JNK isoforms are distributed in the cochleae, and the expression patterns of JNK1, JNK2, and JNK3 differed in hair cells, spiral ganglion neurons, and stria vascularis, with great significance in the cochleae of adult C57BL/6J mice. The levels of JNK1, JNK2, and JNK3 showed various spatio-temporal changes in the aging mice. In a senescent hair cell model, changes in JNK1, JNK2, and JNK3 expression levels were similar to those observed in the cochleae. Our study is the first to show that JNK3 is highly expressed in the hair cells of C57BL/6J mice and further increases in conjunction with age-related hearing loss, suggesting that it may play a more critical role than previously believed in hair cell loss and spiral ganglion degeneration.