NPJ Aging and Mechanisms of Disease最新文献

{"title":"The killifish visual system as an in vivo model to study brain aging and rejuvenation.","authors":"Sophie Vanhunsel,&nbsp;Steven Bergmans,&nbsp;An Beckers,&nbsp;Isabelle Etienne,&nbsp;Jolien Van Houcke,&nbsp;Eve Seuntjens,&nbsp;Lut Arckens,&nbsp;Lies De Groef,&nbsp;Lieve Moons","doi":"10.1038/s41514-021-00077-4","DOIUrl":"10.1038/s41514-021-00077-4","url":null,"abstract":"<p><p>Worldwide, people are getting older, and this prolonged lifespan unfortunately also results in an increased prevalence of age-related neurodegenerative diseases, contributing to a diminished life quality of elderly. Age-associated neuropathies typically include diseases leading to dementia (Alzheimer's and Parkinson's disease), as well as eye diseases such as glaucoma and age-related macular degeneration. Despite many research attempts aiming to unravel aging processes and their involvement in neurodegeneration and functional decline, achieving healthy brain aging remains a challenge. The African turquoise killifish (Nothobranchius furzeri) is the shortest-lived reported vertebrate that can be bred in captivity and displays many of the aging hallmarks that have been described for human aging, which makes it a very promising biogerontology model. As vision decline is an important hallmark of aging as well as a manifestation of many neurodegenerative diseases, we performed a comprehensive characterization of this fish's aging visual system. Our work reveals several aging hallmarks in the killifish retina and brain that eventually result in a diminished visual performance. Moreover, we found evidence for the occurrence of neurodegenerative events in the old killifish retina. Altogether, we introduce the visual system of the fast-aging killifish as a valuable model to understand the cellular and molecular mechanisms underlying aging in the vertebrate central nervous system. These findings put forward the killifish for target validation as well as drug discovery for rejuvenating or neuroprotective therapies ensuring healthy aging.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"7 1","pages":"22"},"PeriodicalIF":5.0,"publicationDate":"2021-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-021-00077-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10646619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Klotho inhibits neuronal senescence in human brain organoids.","authors":"Mohammed R Shaker,&nbsp;Julio Aguado,&nbsp;Harman Kaur Chaggar,&nbsp;Ernst J Wolvetang","doi":"10.1038/s41514-021-00070-x","DOIUrl":"https://doi.org/10.1038/s41514-021-00070-x","url":null,"abstract":"<p><p>Aging is a major risk factor for many neurodegenerative diseases. Klotho (KL) is a glycosylated transmembrane protein that is expressed in the choroid plexus and neurons of the brain. KL exerts potent anti-aging effects on multiple cell types in the body but its role in human brain cells remains largely unclear. Here we show that human cortical neurons, derived from human pluripotent stem cells in 2D cultures or in cortical organoids, develop the typical hallmarks of senescent cells when maintained in vitro for prolonged periods of time, and that moderate upregulation or repression of endogenous KL expression in cortical organoids inhibits and accelerates senescence, respectively. We further demonstrate that KL expression alters the expression of senescence-associated genes including, extracellular matrix genes, and proteoglycans, and can act in a paracrine fashion to inhibit neuronal senescence. In summary, our results establish an important role for KL in the regulation of human neuronal senescence and offer new mechanistic insight into its role in human brain aging.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"7 1","pages":"18"},"PeriodicalIF":5.0,"publicationDate":"2021-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10634824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two separate, large cohorts reveal potential modifiers of age-associated variation in visual reaction time performance.","authors":"J S Talboom,&nbsp;M D De Both,&nbsp;M A Naymik,&nbsp;A M Schmidt,&nbsp;C R Lewis,&nbsp;W M Jepsen,&nbsp;A K Håberg,&nbsp;T Rundek,&nbsp;B E Levin,&nbsp;S Hoscheidt,&nbsp;Y Bolla,&nbsp;R D Brinton,&nbsp;N J Schork,&nbsp;M Hay,&nbsp;C A Barnes,&nbsp;E Glisky,&nbsp;L Ryan,&nbsp;M J Huentelman","doi":"10.1038/s41514-021-00067-6","DOIUrl":"https://doi.org/10.1038/s41514-021-00067-6","url":null,"abstract":"<p><p>To identify potential factors influencing age-related cognitive decline and disease, we created MindCrowd. MindCrowd is a cross-sectional web-based assessment of simple visual (sv) reaction time (RT) and paired-associate learning (PAL). svRT and PAL results were combined with 22 survey questions. Analysis of svRT revealed education and stroke as potential modifiers of changes in processing speed and memory from younger to older ages (n_total = 75,666, n_women = 47,700, n_men = 27,966; ages 18-85 years old, mean (M)_Age = 46.54, standard deviation (SD)_Age = 18.40). To complement this work, we evaluated complex visual recognition reaction time (cvrRT) in the UK Biobank (n_total = 158,249 n_women = 89,333 n_men = 68,916; ages 40-70 years old, M_Age = 55.81, SD_Age = 7.72). Similarities between the UK Biobank and MindCrowd were assessed using a subset of MindCrowd (UKBb MindCrowd) selected to mirror the UK Biobank demographics (n_total = 39,795, n_women = 29,640, n_men = 10,155; ages 40-70 years old, M_Age = 56.59, SD_Age = 8.16). An identical linear model (LM) was used to assess both cohorts. Analyses revealed similarities between MindCrowd and the UK Biobank across most results. Divergent findings from the UK Biobank included (1) a first-degree family history of Alzheimer's disease (FHAD) was associated with longer cvrRT. (2) Men with the least education were associated with longer cvrRTs comparable to women across all educational attainment levels. Divergent findings from UKBb MindCrowd included more education being associated with shorter svRTs and a history of smoking with longer svRTs from younger to older ages.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"7 1","pages":"14"},"PeriodicalIF":5.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-021-00067-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10610266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling transcriptomic age using knowledge-primed artificial neural networks.","authors":"Nicholas Holzscheck, Cassandra Falckenhayn, Jörn Söhle, Boris Kristof, Ralf Siegner, André Werner, Janka Schössow, Clemens Jürgens, Henry Völzke, Horst Wenck, Marc Winnefeld, Elke Grönniger, Lars Kaderali","doi":"10.1038/s41514-021-00068-5","DOIUrl":"10.1038/s41514-021-00068-5","url":null,"abstract":"<p><p>The development of 'age clocks', machine learning models predicting age from biological data, has been a major milestone in the search for reliable markers of biological age and has since become an invaluable tool in aging research. However, beyond their unquestionable utility, current clocks offer little insight into the molecular biological processes driving aging, and their inner workings often remain non-transparent. Here we propose a new type of age clock, one that couples predictivity with interpretability of the underlying biology, achieved through the incorporation of prior knowledge into the model design. The clock, an artificial neural network constructed according to well-described biological pathways, allows the prediction of age from gene expression data of skin tissue with high accuracy, while at the same time capturing and revealing aging states of the pathways driving the prediction. The model recapitulates known associations of aging gene knockdowns in simulation experiments and demonstrates its utility in deciphering the main pathways by which accelerated aging conditions such as Hutchinson-Gilford progeria syndrome, as well as pro-longevity interventions like caloric restriction, exert their effects.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"7 1","pages":"15"},"PeriodicalIF":5.4,"publicationDate":"2021-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10610243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abnormal brain cholesterol homeostasis in Alzheimer's disease-a targeted metabolomic and transcriptomic study.","authors":"Vijay R Varma,&nbsp;H Büşra Lüleci,&nbsp;Anup M Oommen,&nbsp;Sudhir Varma,&nbsp;Chad T Blackshear,&nbsp;Michael E Griswold,&nbsp;Yang An,&nbsp;Jackson A Roberts,&nbsp;Richard O'Brien,&nbsp;Olga Pletnikova,&nbsp;Juan C Troncoso,&nbsp;David A Bennett,&nbsp;Tunahan Çakır,&nbsp;Cristina Legido-Quigley,&nbsp;Madhav Thambisetty","doi":"10.1038/s41514-021-00064-9","DOIUrl":"https://doi.org/10.1038/s41514-021-00064-9","url":null,"abstract":"<p><p>The role of brain cholesterol metabolism in Alzheimer's disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson's disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"7 1","pages":"11"},"PeriodicalIF":5.0,"publicationDate":"2021-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-021-00064-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10642762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FKBP52 overexpression accelerates hippocampal-dependent memory impairments in a tau transgenic mouse model.","authors":"Marangelie Criado-Marrero,&nbsp;Niat T Gebru,&nbsp;Lauren A Gould,&nbsp;Danielle M Blazier,&nbsp;Yamile Vidal-Aguiar,&nbsp;Taylor M Smith,&nbsp;Salma S Abdelmaboud,&nbsp;Lindsey B Shelton,&nbsp;Xinming Wang,&nbsp;Jan Dahrendorff,&nbsp;David Beaulieu-Abdelahad,&nbsp;Chad A Dickey,&nbsp;Laura J Blair","doi":"10.1038/s41514-021-00062-x","DOIUrl":"https://doi.org/10.1038/s41514-021-00062-x","url":null,"abstract":"<p><p>Abnormal accumulation of hyperphosphorylated tau induces pathogenesis in neurodegenerative diseases, like Alzheimer's disease. Molecular chaperones with peptidyl-prolyl cis/trans isomerase (PPIase) activity are known to regulate these processes. Previously, in vitro studies have shown that the 52 kDa FK506-binding protein (FKBP52) interacts with tau inducing its oligomerization and fibril formation to promote toxicity. Thus, we hypothesized that increased expression of FKBP52 in the brains of tau transgenic mice would alter tau phosphorylation and neurofibrillary tangle formation ultimately leading to memory impairments. To test this, tau transgenic (rTg4510) and wild-type mice received bilateral hippocampal injections of virus overexpressing FKBP52 or GFP control. We examined hippocampal-dependent memory, synaptic plasticity, tau phosphorylation status, and neuronal health. This work revealed that rTg4510 mice overexpressing FKBP52 had impaired spatial learning, accompanied by long-term potentiation deficits and hippocampal neuronal loss, which was associated with a modest increase in total caspase 12. Together with previous studies, our findings suggest that FKBP52 may sensitize neurons to tau-mediated dysfunction via activation of a caspase-dependent pathway, contributing to memory and learning impairments.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"7 1","pages":"9"},"PeriodicalIF":5.0,"publicationDate":"2021-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-021-00062-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9198059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The GSK3β-β-catenin-TCF1 pathway improves naive T cell activation in old adults by upregulating miR-181a.","authors":"Zhongde Ye,&nbsp;Timothy M Gould,&nbsp;Huimin Zhang,&nbsp;Jun Jin,&nbsp;Cornelia M Weyand,&nbsp;Jörg J Goronzy","doi":"10.1038/s41514-021-00056-9","DOIUrl":"https://doi.org/10.1038/s41514-021-00056-9","url":null,"abstract":"<p><p>MicroRNAs play an important role in the regulation of T cell development, activation, and differentiation. One of the most abundant microRNAs in lymphocytes is miR-181a, which controls T cell receptor (TCR) activation thresholds in thymic selection as well as in peripheral T cell responses. We previously found that miR-181a levels decline in T cells in the elderly. In this study, we identified TCF1 as a transcriptional regulator of pri-miR-181a. A decline in TCF1 levels in old individuals accounted for the reduced miR-181a expression impairing TCR signaling. Inhibition of GSK3ß restored expression of miR-181a by inducing TCF1 in T cells from old adults. GSK3ß inhibition enhanced TCR signaling to increase downstream expression of activation markers and production of IL-2. The effect involved the upregulation of miR-181a and the inhibition of DUSP6 expression. Thus, inhibition of GSK3ß can restore responses of old T cells by inducing miR-181a expression through TCF1.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":" ","pages":"4"},"PeriodicalIF":5.0,"publicationDate":"2021-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-021-00056-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25346830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of dementia with immunoglobulin G N-glycans in a Chinese Han Population.","authors":"Xiaoyu Zhang,&nbsp;Hui Yuan,&nbsp;Jihui Lyu,&nbsp;Xiaoni Meng,&nbsp;Qiuyue Tian,&nbsp;Yuejin Li,&nbsp;Jie Zhang,&nbsp;Xizhu Xu,&nbsp;Jing Su,&nbsp;Haifeng Hou,&nbsp;Dong Li,&nbsp;Baoliang Sun,&nbsp;Wei Wang,&nbsp;Youxin Wang","doi":"10.1038/s41514-021-00055-w","DOIUrl":"https://doi.org/10.1038/s41514-021-00055-w","url":null,"abstract":"<p><p>Immunoglobulin G (IgG) functionality can drastically change from anti- to proinflammatory by alterations in the IgG N-glycan patterns. Our previous studies have demonstrated that IgG N-glycans associated with the risk factors of dementia, such as aging, dyslipidemia, type 2 diabetes mellitus, hypertension, and ischemic stroke. Therefore, the aim is to investigate whether the effects of IgG N-glycan profiles on dementia exists in a Chinese Han population. A case-control study, including 81 patients with dementia, 81 age- and gender-matched controls with normal cognitive functioning (NC) and 108 non-matched controls with mild cognitive impairment (MCI) was performed. Plasma IgG N-glycans were separated by ultra-performance liquid chromatography. Fourteen glycan peaks reflecting decreased of sialylation and core fucosylation, and increased bisecting N-acetylglucosamine (GlcNAc) N-glycan structures were of statistically significant differences between dementia and NC groups after controlling for confounders (p < 0.05; q < 0.05). Similarly, the differences for these 14 initial glycans were statistically significant between AD and NC groups after adjusting for the effects of confounders (p < 0.05; q < 0.05). The area under the receiver operating curve (AUC) value of the model consisting of GP8, GP9, and GP14 was determined to distinguish dementia from NC group as 0.876 [95% confidence interval (CI): 0.815-0.923] and distinguish AD from NC group as 0.887 (95% CI: 0.819-0.936). Patients with dementia were of an elevated proinflammatory activity via the significant changes of IgG glycome. Therefore, IgG N-glycans might contribute to be potential novel biomarkers for the neurodegenerative process risk assessment of dementia.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":" ","pages":"3"},"PeriodicalIF":5.0,"publicationDate":"2021-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-021-00055-w","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25334799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential transcript usage unravels gene expression alterations in Alzheimer's disease human brains.","authors":"Diego Marques-Coelho,&nbsp;Lukas da Cruz Carvalho Iohan,&nbsp;Ana Raquel Melo de Farias,&nbsp;Amandine Flaig,&nbsp;Jean-Charles Lambert,&nbsp;Marcos Romualdo Costa","doi":"10.1038/s41514-020-00052-5","DOIUrl":"https://doi.org/10.1038/s41514-020-00052-5","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the leading cause of dementia in aging individuals. Yet, the pathophysiological processes involved in AD onset and progression are still poorly understood. Among numerous strategies, a comprehensive overview of gene expression alterations in the diseased brain could contribute for a better understanding of the AD pathology. In this work, we probed the differential expression of genes in different brain regions of healthy and AD adult subjects using data from three large transcriptomic studies: Mayo Clinic, Mount Sinai Brain Bank (MSBB), and ROSMAP. Using a combination of differential expression of gene and isoform switch analyses, we provide a detailed landscape of gene expression alterations in the temporal and frontal lobes, harboring brain areas affected at early and late stages of the AD pathology, respectively. Next, we took advantage of an indirect approach to assign the complex gene expression changes revealed in bulk RNAseq to individual cell types/subtypes of the adult brain. This strategy allowed us to identify previously overlooked gene expression changes in the brain of AD patients. Among these alterations, we show isoform switches in the AD causal gene amyloid-beta precursor protein (APP) and the risk gene bridging integrator 1 (BIN1), which could have important functional consequences in neuronal cells. Altogether, our work proposes a novel integrative strategy to analyze RNAseq data in AD and other neurodegenerative diseases based on both gene/transcript expression and regional/cell-type specificities.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"7 1","pages":"2"},"PeriodicalIF":5.0,"publicationDate":"2021-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-020-00052-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10293875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of the NRF2 pathway in Keap1-knockdown mice attenuates progression of age-related hearing loss.","authors":"Tetsuya Oishi,&nbsp;Daisuke Matsumaru,&nbsp;Nao Ota,&nbsp;Hiroshi Kitamura,&nbsp;Tianxiang Zhang,&nbsp;Yohei Honkura,&nbsp;Yukio Katori,&nbsp;Hozumi Motohashi","doi":"10.1038/s41514-020-00053-4","DOIUrl":"https://doi.org/10.1038/s41514-020-00053-4","url":null,"abstract":"<p><p>Age-related hearing loss (AHL) is a progressive sensorineural hearing loss in elderly people. Although no prevention or treatments have been established for AHL, recent studies have demonstrated that oxidative stress is closely related to pathogenesis of AHL, suggesting that suppression of oxidative stress leads to inhibition of AHL progression. NRF2 is a master transcription factor that regulates various antioxidant proteins and cytoprotection factors. To examine whether NRF2 pathway activation prevents AHL, we used Keap1-knockdown (Keap1^FA/FA) mice, in which KEAP1, a negative regulator of NRF2, is decreased, resulting in the elevation of NRF2 activity. We compared 12-month-old Keap1^FA/FA mice with age-matched wild-type (WT) mice in the same breeding colony. In the Keap1^FA/FA mice, the expression levels of multiple NRF2 target genes were verified to be significantly higher than the expression levels of these genes in the WT mice. Histological analysis showed that cochlear degeneration at the apical and middle turns was ameliorated in the Keap1^FA/FA mice. Auditory brainstem response (ABR) thresholds in the Keap1^FA/FA mice were significantly lower than those in the WT mice, in particular at low-mid frequencies. Immunohistochemical detection of oxidative stress markers suggested that oxidative stress accumulation was attenuated in the Keap1^FA/FA cochlea. Thus, we concluded that NRF2 pathway activation protects the cochlea from oxidative damage during aging, in particular at the apical and middle turns. KEAP1-inhibiting drugs and phytochemicals are expected to be effective in the prevention of AHL.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"6 1","pages":"14"},"PeriodicalIF":5.0,"publicationDate":"2020-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-020-00053-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38710140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}