Long-term NAD+ supplementation prevents the progression of age-related hearing loss in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE213994 | GEO | 2023/09/20
REPOSITORIES: GEO
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Project description:Age-related hearing (ARHL) loss affects a large part of the human population with a major impact on our aging societies. Yet, underlying mechanisms are not understood, and no validated therapy or prevention exists. NADPH oxidases (NOX), are important sources of reactive oxygen species (ROS) in the cochlea and might therefore be involved in the pathogenesis of ARHL. Here we investigate ARHL in a mouse model. Wild type mice showed early loss of hearing and cochlear integrity, while animals deficient in the NOX subunit p22phox remained unaffected up to six months. Genes of the excitatory pathway were down-regulated in p22phox-deficient auditory neurons. Our results demonstrate that NOX activity leads to upregulation of genes of the excitatory pathway, to excitotoxic cochlear damage, and ultimately to ARHL. In the absence of functional NOXs, aging mice conserve hearing and cochlear morphology. Our study offers new insights into pathomechanisms and future therapeutic targets of ARHL.
2020-12-18 | E-MTAB-8668 | biostudies-arrayexpress
Project description:Age-related hearing loss (ARHL) is involved in the hair cell apoptosis, but the underlying mechanism of hair cell apoptosis remains unclear. Here, we explored expression profiles of lncRNAs and mRNAs in an ARHL mouse model by using RNA sequencing and found that the cell apoptosis signaling pathway was activated in the cochlea tissues of old mice compared with those of young mice. We further found that lncRNA Mirg was most correlated with the cell apoptosis signaling pathway by the coexpression analysis. LncRNA Mirg was increased in the cochlea tissues of old mice compared with those of young mice, and its overexpression promoted hair cell apoptosis. H2O2-induced oxidative stress increased hair cell apoptosis by upregulating lncRNA Mirg. Furthermore, the expression of lncRNA Mirg and Foxp1 had the maximal correlation coefficient in the cochlea tissues of old mice, and lncRNA Mirg promoted hair cell apoptosis by increasing Foxp1 expression. In conclusion, we identified that oxidative stress-induced lncRNA Mirg promoted hair cell apoptosis via increasing Foxp1 expression, and these suggest that the lncRNA Mirg/Foxp1 signal may be a potential therapeutic target for ARHL.
2023-06-06 | GSE233798 | GEO
Project description:Age-related hearing loss (ARHL) is a progressive sensorineural hearing loss that occurs as people get older. As many as 35% to 50% of the population aged between 65 and 75 have ARHL. Although age-related changes in the central auditory system can contribute to hearing impairment, degeneration of the mechanosensitive hair cells in the cochlea is the prevalent cause of ARHL. The molecular mechanisms of hair cell aging are largely unknown. To provide a comprehensive dataset of age-related genes and pathways in hair cells, we individually collected inner and outer hair cells, the two types of sensory receptor cells in the cochlea, from 9- and 26-month-old CBA/J mice and performed cell type-specific transcriptomic analysis. Our analysis showed a significant reduction of the expression of genes related to hair cell structure and function such as Tmc1, Kcnq4, Kcnj13, Slc7a14, Slc17a8, Chrna9/Chrna10, and Slc26a5. Our hair cell-specific transcriptome analysis provides a rich resource for mechanistic studies of biological aging of cochlear hair cells.
2022-03-01 | GSE153882 | GEO
Project description:Noise-induced hidden hearing loss (HHL) is a new type of hearing loss that has been identified in recent years and leads to insidious damage to the cochlea, unlike the well-known noise-induced hearing loss (NIHL). However, the cellular and molecular basis for it remains to be elucidated. Here, we established a single-cell transcriptome profile of the C57BL/6J mouse cochlea, in which we describe the transcriptome changes of individual cell types within the cochlea with HHL and NIHL. Mice in the HHL group were exposed to 110 dB of noise for 2 hours, and those in the NIHL group were exposed to 115 dB of noise for 4 hours for 3 days. The cochlea was taken 6 hours after the last noise exposure. The control group was not exposed to noise, with other conditions being the same as those in the noise-exposed group. The results of sequencing at the single-cell level help us gain a deeper understanding of the mechanisms of the development of HHL and NIHL.
2024-06-24 | GSE252285 | GEO
Project description:Age-related hearing loss (AHL) is the progressive loss of auditory function with aging. The DBA/2J (DBA) mice have been used as a model of AHL and undergoes progressive, age-related hearing loss by 12 weeks of age. Here we analyzed cochlear gene expression of 7-week-old and 36-week-old DBA mice using microarrays. Auditory brainstem response (ABR) analysis confrimed that severe age-related hearing loss occured in 36-week-old mice, whereas moderate hearing loss occured in 7-week-old mice. Comprehensive gene expression analysis identified genes correlated with AHL and revealeed that 15 mitochondrial process categories, including â??mitochondrial electron transport chainâ??, â??oxidative phosphorylationâ??, â??respiratory chain complex Iâ??, â??respiratory chain complex IVâ??, and â??respiratory chain complex Vâ??, were statistically associated with AHL-correlated genes in the cochlea of 36-week-old DBA mice, and that 25 genes encoding components of the mitochondrial respiratory chain (respiratory chain complex I, IV, and V) were significantly down-regulated in the cochlea. These observations provide evidence that AHL is associated with down-regulation of genes involved in the mitochondrial respiratory chain in the cochlea of DBA mice, and suggest that mitochondrial respiratory chain dysfunction may be a key feature of AHL in mammalian cochlea. Experiment Overall Design: To determine the effects of age-related hearing loss, each 7-week-old sample (n = 3) was compared to each 36-week-old sample (n = 3), generating a total of nine pairwise comparisons. Using DAVIS and EASE, the identified genes were assign to â??GO: Biological Processâ?? categories of Gene Ontology Consortium. Furthermore, we used EASE to determine the total number of genes that were assigned to each biological process category, and to perform Fisher exact test. Quality control measures were not used. No replicates were done. Dye swap was not used.
2008-06-14 | E-GEOD-6045 | biostudies-arrayexpress
Project description:Presbycusis – age-related hearing loss – is the number one communicative disorder of our aged population. Here we analyzed gene expression for a set of GABA receptors in the cochlea of aging CBA mice using the Affymetrix GeneChip MOE430A. Functional phenotypic hearing measures distortion-product otoacoustic emission (DPOAE) amplitudes (four age groups) were made. The gene expression changes from RMA normalized microarray data (40 replicates) were first subjected to one-way ANOVA, and then linear regression was performed. In addition, the log signal ratio was converted to fold change, and selected gene expression changes were confirmed by relative real-time PCR. Major findings: expression of GABA-A receptor subunit 6was upregulated with age and hearing loss, whereas subunit 1 was repressed. In addition, GABA-A receptor associated protein like-1 and GABA-A receptor associated protein like-2 were strongly downregulated with age and hearing impairment. Lastly, gene expression measures were correlated with pathway/network relationships relevant to the inner ear using Pathway Architect, to identify key pathways consistent with the gene expression changes observed. In the study of expression changes GABA receptors in the in cochlea of young adult and aging presbycusis mice total of forty chips were used. The normal aging mice were in four groups young adults controls with good hearing (8 mice, 8 MOE430A GeneChips), Middle aged group with good hearing ( 17 mice, 17 MOE430A GeneChips), Mild Presbycusis (old) with limited hearing loss (9 mice, 9 MOE430A GeneChips) and Severe Presbycusis (old) (6 mice, 6 MOE430A GeneChips). Each Mice cochlea to each GeneChips, Samples was not pooled. The hearing potential evidence of each mouse is accompanied with each mice DPOAE amplitude.
2013-08-06 | E-GEOD-49543 | biostudies-arrayexpress
Project description:Age-related hearing loss (ARHL) is the most common sensory degenerative disease and can significantly impact the quality of life in elderly people. A previous study using GeneChip miRNA microarray assays showed that the expression of miR-29a changes with age, however, its role in hearing loss is still unclear. In this study, we characterized the cochlear phenotype of miR-29a knockout (miR-29a-/-) mice and found that miR-29a-deficient mice had a rapid progressive elevation of the hearing threshold from 2 to 5 months of age compared with littermate controls as measured by the auditory brainstem response. Stereocilia degeneration, hair cell loss and abnormal stria vascularis were observed in miR-29a-/- mice at 4 months of age. Transcriptome sequencing results showed elevated extracellular matrix (ECM) gene expression in miR-29a-/- mice. Both GO annotation and KEGG pathway enrichment analysis revealed that the key differences were closely related to ECM. Further examination with a transmission electron microscope showed thickening of the basilar membrane in the cochlea of miR-29a-/- mice. Five Col4a genes (Col4a1-a5) and two laminin genes (Lamb2 and Lamc1) were validated as miR-29a direct targets by dual luciferase assays and miR-29a inhibition assays with a miR-29a inhibitor. Consistent with the target gene validation results, the expression of these genes was significantly increased in the cochlea of miR-29a-/- mice, as shown by RT-PCR and Western blot. These findings suggest that miR-29a plays an important role in maintaining cochlear structure and function by regulating the expression of collagen and laminin and that the disturbance of its expression could be a cause of progressive hearing loss.
2023-04-11 | GSE228284 | GEO
Project description:Age-related hearing loss (AHL) is the progressive loss of auditory function with aging. The DBA/2J (DBA) mice have been used as a model of AHL and undergoes progressive, age-related hearing loss by 12 weeks of age. Here we analyzed cochlear gene expression of 7-week-old and 36-week-old DBA mice using microarrays. Auditory brainstem response (ABR) analysis confrimed that severe age-related hearing loss occured in 36-week-old mice, whereas moderate hearing loss occured in 7-week-old mice. Comprehensive gene expression analysis identified genes correlated with AHL and revealeed that 15 mitochondrial process categories, including “mitochondrial electron transport chain”, “oxidative phosphorylation”, “respiratory chain complex I”, “respiratory chain complex IV”, and “respiratory chain complex V”, were statistically associated with AHL-correlated genes in the cochlea of 36-week-old DBA mice, and that 25 genes encoding components of the mitochondrial respiratory chain (respiratory chain complex I, IV, and V) were significantly down-regulated in the cochlea. These observations provide evidence that AHL is associated with down-regulation of genes involved in the mitochondrial respiratory chain in the cochlea of DBA mice, and suggest that mitochondrial respiratory chain dysfunction may be a key feature of AHL in mammalian cochlea. Keywords: Disease state analysis, Time course analysis
2007-10-16 | GSE6045 | GEO
Project description:Alzheimer's disease (AD) is the most common type of dementia and is characterized by cognitive and behavioral impairment that significantly interferes with social functioning. Over the last decade, there has been an increased interest in whether sensory deficiency may be associated with the development of AD. Notably, the relationship between hearing impairment and AD is of great relevance, but still poorly understood. In this study, we found an early-onset hearing loss in 3xTgAD and 3xTgAD/Polβ+/− mouse models. The hearing assessment was measured by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) recordings. Herein, we report that both 3xTgAD and 3xTgAD/Polβ+/− mice showed increased ABR thresholds between at 16 and 32 kHz at 4 weeks of age, much earlier than any AD behavioral changes. The ABR thresholds were significantly higher in 3xTgAD/Polβ+/− mice than in 3xTgAD mice at 16 kHz, and DPOAE signals were also reduced, indicating that DNA damage may affect hearing impairment in AD. Poly ADP-ribosylation levels and protein expression of DNA damage markers increased significantly and NAD+ levels were reduced in the cochlea of 3xTgAD and 3xTgAD/Polβ+/− mice. Remarkably, we observed the downregulation of phosphoglycerate mutase 2 (PGAM2) in cochlea and a decrease in the number of synaptic ribbons in the presynaptic zones of inner hair cells in 3xTgAD/Polβ+/− mice. We also find that the activity of sirtuin 3 (SIRT3) is downregulated in cochlea, indicative of impaired mitochondrial function. Taken together, hearing impairment may be a potential early marker of AD. In addition, these findings provide new insights into the mechanism of the relationship between hearing dysfunction and AD and suggest that DNA damage in the cochlea can contributes to the development of early hearing loss of AD. The hearing assessment was measured by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) at 4 weeks of age, thereafter whole cochlea and auditory cortex tissue were collected from each mouse (WT, Polβ+/−, 3xTgAD, and 3xTgAD/Polβ+/−) and subjected to total RNA isolation to understand what metabolism-related gene expression changes in cochlea and auditory cortex.
2024-03-27 | GSE232205 | GEO
Project description:Age-related hearing loss (ARHL) is a prevalent disease that affects millions of people worldwide. BCL-2 gene plays a tremendous role in cellular senescence, and it was confirmed that the BCL-2 family is closely associated with neurological disorders and ARHL. In addition to modulating apoptosis and oxidative stress, as well as other effects, this study we report here that BCL-2 plays a crucial position in regulating phospholipid and lipid metabolism in the developing cochlear tissues of rats and a sensory epithelial cell line(OC1), including the cholesterol synthesis pathway that is differentially expressed by genes such as LSS,NSDHL, and CYP51, which further demonstrates the mechanism of the action of BCL-2 in hair cells. In conclusion our data provide a new molecular framework for the regulatory mechanism of BCL-2 down-regulation in senescent cells. These findings provide valuable insights into the molecular mechanisms of ARHL and may set the stage for new therapeutic approaches for this prevalent age-related disease.
2023-09-12 | GSE242359 | GEO