NPJ Aging and Mechanisms of Disease最新文献

{"title":"Organotypic human skin culture models constructed with senescent fibroblasts show hallmarks of skin aging.","authors":"Regina Weinmüllner,&nbsp;Barbara Zbiral,&nbsp;Adnan Becirovic,&nbsp;Elena Maria Stelzer,&nbsp;Fabian Nagelreiter,&nbsp;Markus Schosserer,&nbsp;Ingo Lämmermann,&nbsp;Lisa Liendl,&nbsp;Magdalena Lang,&nbsp;Lucia Terlecki-Zaniewicz,&nbsp;Orestis Andriotis,&nbsp;Michael Mildner,&nbsp;Bahar Golabi,&nbsp;Petra Waidhofer-Söllner,&nbsp;Karl Schedle,&nbsp;Gerhard Emsenhuber,&nbsp;Philipp J Thurner,&nbsp;Erwin Tschachler,&nbsp;Florian Gruber,&nbsp;Johannes Grillari","doi":"10.1038/s41514-020-0042-x","DOIUrl":"https://doi.org/10.1038/s41514-020-0042-x","url":null,"abstract":"<p><p>Skin aging is driven by intrinsic and extrinsic factors impacting on skin functionality with progressive age. One factor of this multifaceted process is cellular senescence, as it has recently been identified to contribute to a declining tissue functionality in old age. In the skin, senescent cells have been found to markedly accumulate with age, and thus might impact directly on skin characteristics. Especially the switch from young, extracellular matrix-building fibroblasts to a senescence-associated secretory phenotype (SASP) could alter the microenvironment in the skin drastically and therefore promote skin aging. In order to study the influence of senescence in human skin, 3D organotypic cultures are a well-suited model system. However, only few \"aged\" skin- equivalent (SE) models are available, requiring complex and long-term experimental setups. Here, we adapted a previously published full-thickness SE model by seeding increasing ratios of stress-induced premature senescent versus normal fibroblasts into the collagen matrix, terming these SE \"senoskin\". Immunohistochemistry stainings revealed a shift in the balance between proliferation (Ki67) and differentiation (Keratin 10 and Filaggrin) of keratinocytes within our senoskin equivalents, as well as partial impairment of skin barrier function and changed surface properties. Monitoring of cytokine levels of known SASP factors confirmedly showed an upregulation in 2D cultures of senescent cells and at the time of seeding into the skin equivalent. Surprisingly, we find a blunted response of cytokines in the senoskin equivalent over time during 3D differentiation.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"6 ","pages":"4"},"PeriodicalIF":5.0,"publicationDate":"2020-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-020-0042-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37757506","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":"CMV-independent increase in CD27-CD28+ CD8+ EMRA T cells is inversely related to mortality in octogenarians.","authors":"Carmen Martin-Ruiz, Jedrzej Hoffmann, Evgeniya Shmeleva, Thomas von Zglinicki, Gavin Richardson, Lilia Draganova, Rachael Redgrave, Joanna Collerton, Helen Arthur, Bernard Keavney, Ioakim Spyridopoulos","doi":"10.1038/s41514-019-0041-y","DOIUrl":"10.1038/s41514-019-0041-y","url":null,"abstract":"<p><p>Cytomegalovirus (CMV) seropositivity in adults has been linked to increased cardiovascular disease burden. Phenotypically, CMV infection leads to an inflated CD8 T-lymphocyte compartment. We employed a 8-colour flow cytometric protocol to analyse circulating T cells in 597 octogenarians from the same birth cohort together with NT-proBNP measurements and followed all participants over 7 years. We found that, independent of CMV serostatus, a high number of CD27-CD28+ CD8 EMRA T-lymphocytes (TEMRA) protected from all-cause death after adjusting for known risk factors, such as heart failure, frailty or cancer (Hazard ratio 0.66 for highest vs lowest tertile; confidence interval 0.51-0.86). In addition, CD27-CD28+ CD8 EMRA T-lymphocytes protected from both, non-cardiovascular (hazard ratio 0.59) and cardiovascular death (hazard ratio 0.65). In aged mice treated with the senolytic navitoclax, in which we have previously shown a rejuvenated cardiac phenotype, CD8 effector memory cells are decreased, further indicating that alterations in T cell subpopulations are associated with cardiovascular ageing. Future studies are required to show whether targeting immunosenescence will lead to enhanced life- or healthspan.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"6 ","pages":"3"},"PeriodicalIF":5.0,"publicationDate":"2020-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-019-0041-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37588675","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":"Repository of proposed pathways and protein-protein interaction networks in age-related macular degeneration.","authors":"Fran M Pool,&nbsp;Christina Kiel,&nbsp;Luis Serrano,&nbsp;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}

{"title":"Short-term NAD⁺ 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> ^-<i>/-</i> and <i>CSB</i> ^<i>m/m</i> ) that recapitulate the hearing loss in human CS patients. We previously showed that NAD⁺, a key metabolite with various essential functions, is reduced in CS and associated with multiple CS phenotypes. In this study, we report that NAD⁺ levels are reduced in the cochlea of <i>CSB</i> ^<i>m/m</i> mice and that short-term treatment (10 days) with the NAD⁺ precursor nicotinamide riboside (NR), prevents hearing loss, restores outer hair cell loss, and improves cochlear health in <i>CSB</i> ^<i>m/m</i> mice. Similar, but more modest effects were observed in <i>CSA</i> ^-<i>/-</i> mice. Remarkably, we observed a reduction in synaptic ribbon counts in the presynaptic zones of inner hair cells in both <i>CSA</i> ^<i>-/-</i> and <i>CSB</i> ^<i>m/m</i> 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⁺ supplementation rescues reduced synaptic ribbon formation in both <i>CSA</i> ^<i>-/-</i> and <i>CSB</i> ^<i>m/m</i> 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}

{"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}

{"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}

{"title":"Tissue-specific alteration of gene expression and function by RU486 and the GeneSwitch system.","authors":"Maricela Robles-Murguia,&nbsp;Liam C Hunt,&nbsp;David Finkelstein,&nbsp;Yiping Fan,&nbsp;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,&nbsp;Yoshimasa Saito,&nbsp;Kazuki Nogami,&nbsp;Yohei Kajiyama,&nbsp;Yukana Suzuki,&nbsp;Yasuhiro Kawase,&nbsp;Toshiaki Nakaoka,&nbsp;Toshihide Muramatsu,&nbsp;Masaki Kimura,&nbsp;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,&nbsp;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}

{"title":"Occupational-like organophosphate exposure disrupts microglia and accelerates deficits in a rat model of Alzheimer's disease.","authors":"Jaymie R Voorhees,&nbsp;Matthew T Remy,&nbsp;Claire M Erickson,&nbsp;Laura M Dutca,&nbsp;Daniel J Brat,&nbsp;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}