Fran M Pool, Christina Kiel, Luis Serrano, Philip J Luthert
{"title":"Repository of proposed pathways and protein-protein interaction networks in age-related macular degeneration.","authors":"Fran M Pool, Christina Kiel, Luis Serrano, Philip J Luthert","doi":"10.1038/s41514-019-0039-5","DOIUrl":"https://doi.org/10.1038/s41514-019-0039-5","url":null,"abstract":"<p><p>Age-related macular degeneration (AMD) is one of the commonest causes of sight loss in the elderly population and to date there is no intervention that slows or prevents early AMD disease progressing to blinding neovascularization or geographic atrophy. AMD is a complex disease and factors proposed to contribute to the development and progression of disease include aging, genetics, epigenetics, oxidative stress, pro-inflammatory state, and life-style factors such as smoking, alcohol, and high fat diet. Here, we generate a knowledge repository of pathways and protein-protein interaction (PPI) networks likely to be implicated in AMD pathogenesis, such as complement activation, lipid trafficking and metabolism, vitamin A cycle, oxidative stress, proteostasis, bioenergetics, autophagy/mitophagy, extracellular matrix (ECM) turnover, and choroidal vascular dropout. Two disctinct clusters ermerged from the networks for parainflamation and ECM homeostasis, which may represent two different disease modules underlying AMD pathology. Our analyses also suggest that the disease manifests primarily in RPE/choroid and less in neural retina. The use of standardized syntax when generating maps of these biological processes (SBGN standard) and networks (PSI standard) enables visualization of complex information in graphical programs such as CellDesigner and Cytoscape and enhances reusability and extension of data. The ability to focus onto subnetworks, multiple visualizations and simulation options will enable the AMD research community to computationally model subnetworks or to test experimentally new hypotheses arising from connectivities in the AMD pathway map.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"6 ","pages":"2"},"PeriodicalIF":5.0,"publicationDate":"2020-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-019-0039-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37539750","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}
Mustafa N Okur, Beatrice Mao, Risako Kimura, Scott Haraczy, Tracy Fitzgerald, Kamren Edwards-Hollingsworth, Jane Tian, Wasif Osmani, Deborah L Croteau, Matthew W Kelley, Vilhelm A Bohr
{"title":"Short-term NAD<sup>+</sup> supplementation prevents hearing loss in mouse models of Cockayne syndrome.","authors":"Mustafa N Okur, Beatrice Mao, Risako Kimura, Scott Haraczy, Tracy Fitzgerald, Kamren Edwards-Hollingsworth, Jane Tian, Wasif Osmani, Deborah L Croteau, Matthew W Kelley, Vilhelm A Bohr","doi":"10.1038/s41514-019-0040-z","DOIUrl":"10.1038/s41514-019-0040-z","url":null,"abstract":"<p><p>Age-related hearing loss (ARHL) is one of the most common disorders affecting elderly individuals. There is an urgent need for effective preventive measures for ARHL because none are currently available. Cockayne syndrome (CS) is a premature aging disease that presents with progressive hearing loss at a young age, but is otherwise similar to ARHL. There are two human genetic complementation groups of CS, A and B. While the clinical phenotypes in patients are similar, the proteins have very diverse functions, and insight into their convergence is of great interest. Here, we use mouse models for CS (<i>CSA</i> <sup>-<i>/-</i></sup> and <i>CSB</i> <sup><i>m/m</i></sup> ) that recapitulate the hearing loss in human CS patients. We previously showed that NAD<sup>+</sup>, a key metabolite with various essential functions, is reduced in CS and associated with multiple CS phenotypes. In this study, we report that NAD<sup>+</sup> levels are reduced in the cochlea of <i>CSB</i> <sup><i>m/m</i></sup> mice and that short-term treatment (10 days) with the NAD<sup>+</sup> precursor nicotinamide riboside (NR), prevents hearing loss, restores outer hair cell loss, and improves cochlear health in <i>CSB</i> <sup><i>m/m</i></sup> mice. Similar, but more modest effects were observed in <i>CSA</i> <sup>-<i>/-</i></sup> mice. Remarkably, we observed a reduction in synaptic ribbon counts in the presynaptic zones of inner hair cells in both <i>CSA</i> <sup><i>-/-</i></sup> and <i>CSB</i> <sup><i>m/m</i></sup> mice, pointing to a converging mechanism for cochlear defects in CS. Ribbon synapses facilitate rapid and sustained synaptic transmission over long periods of time. Ribeye, a core protein of synaptic ribbons, possesses an NAD(H) binding pocket which regulates its activity. Intriguingly, NAD<sup>+</sup> supplementation rescues reduced synaptic ribbon formation in both <i>CSA</i> <sup><i>-/-</i></sup> and <i>CSB</i> <sup><i>m/m</i></sup> mutant cochleae. These findings provide valuable insight into the mechanism of CS- and ARHL-associated hearing loss, and suggest a possible intervention.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"6 ","pages":"1"},"PeriodicalIF":5.0,"publicationDate":"2020-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37539749","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}
Trevor R. Nash, Eileen S. Chow, Alexander D. Law, Samuel D. Fu, E. Fuszara, A. Bilska, P. Bebas, D. Kretzschmar, J. Giebultowicz
{"title":"Daily blue-light exposure shortens lifespan and causes brain neurodegeneration in Drosophila","authors":"Trevor R. Nash, Eileen S. Chow, Alexander D. Law, Samuel D. Fu, E. Fuszara, A. Bilska, P. Bebas, D. Kretzschmar, J. Giebultowicz","doi":"10.1038/s41514-019-0038-6","DOIUrl":"https://doi.org/10.1038/s41514-019-0038-6","url":null,"abstract":"","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2019-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-019-0038-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49090221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
T. Tezil, Manish Chamoli, Che-Ping Ng, Roman P. Simon, Victoria J. Butler, M. Jung, J. Andersen, A. Kao, E. Verdin
{"title":"Lifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy","authors":"T. Tezil, Manish Chamoli, Che-Ping Ng, Roman P. Simon, Victoria J. Butler, M. Jung, J. Andersen, A. Kao, E. Verdin","doi":"10.1038/s41514-019-0037-7","DOIUrl":"https://doi.org/10.1038/s41514-019-0037-7","url":null,"abstract":"","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"5 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2019-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-019-0037-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46721784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maricela Robles-Murguia, Liam C Hunt, David Finkelstein, Yiping Fan, Fabio Demontis
{"title":"Tissue-specific alteration of gene expression and function by RU486 and the GeneSwitch system.","authors":"Maricela Robles-Murguia, Liam C Hunt, David Finkelstein, Yiping Fan, Fabio Demontis","doi":"10.1038/s41514-019-0036-8","DOIUrl":"https://doi.org/10.1038/s41514-019-0036-8","url":null,"abstract":"<p><p>The GeneSwitch (GS) is a modified Gal4/UAS system, whereby transgene expression is induced in <i>Drosophila</i> by adding the drug RU486 to food. The GS system is routinely used in <i>Drosophila</i> aging and behavioral studies to avoid confounding effects related to genetic background mutations. Here, we report transcriptional and functional defects that are induced by RU486 in a stock- and tissue-dependent manner, such as defects in flight and mitochondrial gene expression. In addition to including proper controls, our findings suggest that context-specific side effects induced by RU486 should be considered in the experimental design and when interpreting the observed phenotypes.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"5 ","pages":"6"},"PeriodicalIF":5.0,"publicationDate":"2019-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-019-0036-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37270829","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":"Erratum: Publisher Correction: Epigenetic silencing of <i>Lgr5</i> induces senescence of intestinal epithelial organoids during the process of aging.","authors":"Ryoei Uchida, Yoshimasa Saito, Kazuki Nogami, Yohei Kajiyama, Yukana Suzuki, Yasuhiro Kawase, Toshiaki Nakaoka, Toshihide Muramatsu, Masaki Kimura, Hidetsugu Saito","doi":"10.1038/s41514-019-0035-9","DOIUrl":"https://doi.org/10.1038/s41514-019-0035-9","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1038/s41514-018-0031-5.].</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"5 ","pages":"5"},"PeriodicalIF":5.0,"publicationDate":"2019-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-019-0035-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37041539","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":"Caveolin-1 as a pathophysiological factor and target in psoriasis.","authors":"Ilja L Kruglikov, Philipp E Scherer","doi":"10.1038/s41514-019-0034-x","DOIUrl":"https://doi.org/10.1038/s41514-019-0034-x","url":null,"abstract":"<p><p>Low expression of caveolin-1 (Cav-1) is typical in psoriatic lesions and overexpression of Cav-1 leads to a reduction of inflammation and suppression of epidermal hyperproliferation, thus ameliorating these two well-known hallmarks of psoriasis. At the same time, the interfacial layers of the white adipose tissue (WAT) adjacent to psoriatic lesions demonstrate much higher stiffness, which also points to a modification of Cav-1 expression in this tissue. These processes are connected with each other and regulated via exosomal exchange. Here we discuss the role of Cav-1 expression in inflammatory and hyperproliferative processes and analyze the ways to provide spatially different modulation of Cav-1 expression in the skin and WAT. Such modulation can be induced by different pharmacological and physical factors. These include application of mechanical stress and supra-physiological temperatures. Cav-1 should therefore be considered as an important target in treatment of psoriasis.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"5 ","pages":"4"},"PeriodicalIF":5.0,"publicationDate":"2019-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-019-0034-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36936091","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}
Jaymie R Voorhees, Matthew T Remy, Claire M Erickson, Laura M Dutca, Daniel J Brat, Andrew A Pieper
{"title":"Occupational-like organophosphate exposure disrupts microglia and accelerates deficits in a rat model of Alzheimer's disease.","authors":"Jaymie R Voorhees, Matthew T Remy, Claire M Erickson, Laura M Dutca, Daniel J Brat, Andrew A Pieper","doi":"10.1038/s41514-018-0033-3","DOIUrl":"https://doi.org/10.1038/s41514-018-0033-3","url":null,"abstract":"<p><p>Occupational exposure to organophosphate pesticides, such as chlorpyrifos (CPF), increases the risk of Alzheimer's disease (AD), though the mechanism is unclear. To investigate this, we subjected 4-month-old male and female wild-type (WT) and TgF344-AD rats, a transgenic AD model, to an occupational CPF exposure paradigm that recapitulates biomarkers and behavioral impairments experienced by agricultural workers. Subsequent cognition and neuropathology were analyzed over the next 20 months. CPF exposure caused chronic microglial dysregulation and accelerated neurodegeneration in both males and females. The effect on neurodegeneration was more severe in males, and was also associated with accelerated cognitive impairment. Females did not exhibit accelerated cognitive impairment after CPF exposure, and amyloid deposition and tauopathy were unchanged in both males and females. Microglial dysregulation may mediate the increased risk of AD associated with occupational organophosphate exposure, and future therapies to preserve or restore normal microglia might help prevent AD in genetically vulnerable individuals exposed to CPF or other disease-accelerating environmental agents.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"5 ","pages":"3"},"PeriodicalIF":5.0,"publicationDate":"2019-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-018-0033-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36912992","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}
Sergei Vatolin, Tomas Radivoyevitch, Jaroslaw P Maciejewski
{"title":"New drugs for pharmacological extension of replicative life span in normal and progeroid cells.","authors":"Sergei Vatolin, Tomas Radivoyevitch, Jaroslaw P Maciejewski","doi":"10.1038/s41514-018-0032-4","DOIUrl":"https://doi.org/10.1038/s41514-018-0032-4","url":null,"abstract":"<p><p>A high-throughput anti-aging drug screen was developed that simultaneously measures senescence-associated β-galactosidase activity and proliferation. Applied to replicatively pre-aged fibroblasts, this screen yielded violuric acid (VA) and 1-naphthoquinone-2-monoxime (N2N1) as its top two hits. These lead compounds extended the replicative life spans of normal and progeroid human cells in a dose-dependent manner and also extended the chronological life spans of mice and C. elegans. They are further shown here to function as redox catalysts in oxidations of NAD(P)H. They thus slow age-related declines in NAD(P)<sup>+</sup>/NAD(P)H ratios. VA participates in non-enzymatic electron transfers from NAD(P)H to oxidized glutathione or peroxides. N2N1 transfers electrons from NAD(P)H to cytochrome c or CoQ<sub>10</sub> via NAD(P)H dehydrogenase (quinone) 1 (NQO1). Our results indicate that pharmacologic manipulation of NQO1 activity via redox catalysts may reveal mechanisms of senescence and aging.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"5 ","pages":"2"},"PeriodicalIF":5.0,"publicationDate":"2019-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-018-0032-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36891308","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":"Epigenetic silencing of <i>Lgr5</i> induces senescence of intestinal epithelial organoids during the process of aging.","authors":"Ryoei Uchida, Yoshimasa Saito, Kazuki Nogami, Yohei Kajiyama, Yukana Suzuki, Yasuhiro Kawase, Toshiaki Nakaoka, Toshihide Muramatsu, Masaki Kimura, Hidetsugu Saito","doi":"10.1038/s41514-018-0031-5","DOIUrl":"https://doi.org/10.1038/s41514-018-0031-5","url":null,"abstract":"<p><p>To understand the molecular features underlying stem cell aging, we established intestinal epithelial organoids derived from both young and aged mice and investigated alterations in their senescence and epigenetic status. Senescence-related changes including accumulation of senescence-associated β-galactosidase and up-regulation of <i>Cdkn1a</i> (<i>p21)</i> by DNA demethylation were observed in intestinal epithelial organoids derived from aged mice. We also demonstrated that the important stem cell marker <i>Lgr5</i> was epigenetically silenced by trimethylation of histone H3 lysine 27, inducing suppression of Wnt signaling and a decrease of cell proliferation in organoids from aged mice. We further treated intestinal epithelial organoids from aged mice with nicotinamide mononucleotide (NMN), a key NAD<sup>+</sup> intermediate. As a result, the organoids showed a higher NAD<sup>+</sup> level, increased cell proliferative ability, activation of <i>Lgr5</i> and suppression of senescence-associated genes, indicating that treatment with NMN could ameliorate senescence-related changes in intestinal epithelia. These findings suggest that organoids derived from aged animals could be a powerful research tool for investigating the molecular mechanisms underlying stem cell aging and for development of some form of anti-aging intervention, thus contributing to prolongation of healthy life expectancy.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"5 ","pages":"1"},"PeriodicalIF":5.0,"publicationDate":"2018-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-018-0031-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36813363","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}