Unfolded protein response IRE1 / XBP1 signaling is required for healthy mammalian brain aging

Article31 October 2022 Source DataTransparent process Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging Felipe Cabral-Miranda Felipe Cabral-Miranda Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil Contribution: Conceptualization, Data curation, Formal analysis, Funding acquisition, ​Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review & editing Search for more papers by this author Giovanni Tamburini Giovanni Tamburini Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Contribution: Data curation, Formal analysis, ​Investigation, Methodology Search for more papers by this author Gabriela Martinez Gabriela Martinez Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Contribution: Formal analysis, Funding acquisition, ​Investigation, Methodology Search for more papers by this author Alvaro O Ardiles Alvaro O Ardiles orcid.org/0000-0001-8295-2133 Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaiso, Valparaiso, Chile Centro de Neurología Traslacional, Escuela de Medicina, Universidad de Valparaíso, Valparaiso, Chile Contribution: Formal analysis, Funding acquisition, Visualization, Methodology Search for more papers by this author Danilo B Medinas Danilo B Medinas orcid.org/0000-0002-1822-1974 Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Contribution: Formal analysis, Funding acquisition, ​Investigation, Methodology Search for more papers by this author Yannis Gerakis Yannis Gerakis Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Mei-Li Diaz Hung Mei-Li Diaz Hung Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Contribution: Formal analysis, Funding acquisition, ​Investigation, Methodology Search for more papers by this author René Vidal René Vidal Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Center for Integrative Biology, Universidad Mayor, Santiago, Chile Contribution: Formal analysis, Methodology Search for more papers by this author Matias Fuentealba Matias Fuentealba Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Tim Miedema Tim Miedema orcid.org/0000-0003-1828-6257 Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Contribution: Formal analysis, ​Investigation Search for more papers by this author Claudia Duran-Aniotz Claudia Duran-Aniotz Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Contribution: Formal analysis, Funding acquisition, ​Investigation, Methodology Search for more papers by this author Javier Diaz Javier Diaz Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Cristobal Ibaceta-Gonzalez Cristobal Ibaceta-Gonzalez Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaiso, Valparaiso, Chile Contribution: Formal analysis, Supervision, Funding acquisition, Methodology Search for more papers by this author Carleen M Sabusap Carleen M Sabusap Departments of Chemistry and Biological Sciences, Vanderbilt University, Nashville, TN, USA Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Francisca Bermedo-Garcia Francisca Bermedo-Garcia Department of Cell Biology, Center for Advanced Microscopy (CMA BioBio), Universidad de Concepción, Concepción, Chile Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Paula Mujica Paula Mujica Centro de Neurología Traslacional, Escuela de Medicina, Universidad de Valparaíso, Valparaiso, Chile Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Stuart Adamson Stuart Adamson orcid.org/0000-0002-1402-8907 Buck Institute for Research on Aging, Novato, CA, USA Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Kaitlyn Vitangcol Kaitlyn Vitangcol Buck Institute for Research on Aging, Novato, CA, USA Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Hernan Huerta Hernan Huerta orcid.org/0000-0002-7392-3311 Center for Integrative Biology, Universidad Mayor, Santiago, Chile Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Xu Zhang Xu Zhang Department of Molecular Medicine and Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA, USA Contribution: Data curation, Formal analysis, ​Investigation, Methodology Search for more papers by this author Tomohiro Nakamura Tomohiro Nakamura Department of Molecular Medicine and Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA, USA Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Sergio Pablo Sardi Sergio Pablo Sardi orcid.org/0000-0001-9805-3677 Rare and Neurological Diseases Therapeutic Area, Sanofi, Framingham, MA, USA Contribution: Funding acquisition, ​Investigation, Methodology Search for more papers by this author Stuart A Lipton Stuart A Lipton orcid.org/0000-0002-3490-1259 Department of Molecular Medicine and Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA, USA Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, USA Contribution: Data curation, Formal analysis, Supervision, Funding acquisition, ​Investigation, Methodology Search for more papers by this author Brian K Kennedy Brian K Kennedy Buck Institute for Research on Aging, Novato, CA, USA Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore; Centre for Healthy Longevity, National University Health System; Departments of Biochemistry and Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore Contribution: Formal analysis, Funding acquisition, ​Investigation, Methodology Search for more papers by this author Juan Pablo Henriquez Juan Pablo Henriquez Department of Cell Biology, Center for Advanced Microscopy (CMA BioBio), Universidad de Concepción, Concepción, Chile Contribution: Formal analysis, Supervision, ​Investigation, Methodology Search for more papers by this author J Cesar Cárdenas J Cesar Cárdenas Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Center for Integrative Biology, Universidad Mayor, Santiago, Chile Buck Institute for Research on Aging, Novato, CA, USA Contribution: Formal analysis, Funding acquisition, ​Investigation, Methodology Search for more papers by this author Lars Plate Lars Plate orcid.org/0000-0003-4363-6116 Departments of Chemistry and Biological Sciences, Vanderbilt University, Nashville, TN, USA Contribution: Formal analysis, Supervision, Funding acquisition, ​Investigation, Methodology Search for more papers by this author Adrian G Palacios Adrian G Palacios orcid.org/0000-0003-1532-7527 Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaiso, Valparaiso, Chile Contribution: Data curation, Formal analysis, Supervision, Funding acquisition, ​Investigation Search for more papers by this author Claudio Hetz Corresponding Author Claudio Hetz [email protected] [email protected] orcid.org/0000-0003-1120-7966 Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Buck Institute for Research on Aging, Novato, CA, USA Contribution: Conceptualization, Resources, Supervision, Funding acquisition, ​Investigation, Writing - original draft, Project administration, Writing - review & editing Search for more papers by this author Felipe Cabral-Miranda Felipe Cabral-Miranda Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil Contribution: Conceptualization, Data curation, Formal analysis, Funding acquisition, ​Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review & editing Search for more papers by this author Giovanni Tamburini Giovanni Tamburini Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Contribution: Data curation, Formal analysis, ​Investigation, Methodology Search for more papers by this author Gabriela Martinez Gabriela Martinez Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Contribution: Formal analysis, Funding acquisition, ​Investigation, Methodology Search for more papers by this author Alvaro O Ardiles Alvaro O Ardiles orcid.org/0000-0001-8295-2133 Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaiso, Valparaiso, Chile Centro de Neurología Traslacional, Escuela de Medicina, Universidad de Valparaíso, Valparaiso, Chile Contribution: Formal analysis, Funding acquisition, Visualization, Methodology Search for more papers by this author Danilo B Medinas Danilo B Medinas orcid.org/0000-0002-1822-1974 Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Contribution: Formal analysis, Funding acquisition, ​Investigation, Methodology Search for more papers by this author Yannis Gerakis Yannis Gerakis Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Mei-Li Diaz Hung Mei-Li Diaz Hung Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Contribution: Formal analysis, Funding acquisition, ​Investigation, Methodology Search for more papers by this author René Vidal René Vidal Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Center for Integrative Biology, Universidad Mayor, Santiago, Chile Contribution: Formal analysis, Methodology Search for more papers by this author Matias Fuentealba Matias Fuentealba Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Tim Miedema Tim Miedema orcid.org/0000-0003-1828-6257 Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Contribution: Formal analysis, ​Investigation Search for more papers by this author Claudia Duran-Aniotz Claudia Duran-Aniotz Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Contribution: Formal analysis, Funding acquisition, ​Investigation, Methodology Search for more papers by this author Javier Diaz Javier Diaz Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Cristobal Ibaceta-Gonzalez Cristobal Ibaceta-Gonzalez Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaiso, Valparaiso, Chile Contribution: Formal analysis, Supervision, Funding acquisition, Methodology Search for more papers by this author Carleen M Sabusap Carleen M Sabusap Departments of Chemistry and Biological Sciences, Vanderbilt University, Nashville, TN, USA Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Francisca Bermedo-Garcia Francisca Bermedo-Garcia Department of Cell Biology, Center for Advanced Microscopy (CMA BioBio), Universidad de Concepción, Concepción, Chile Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Paula Mujica Paula Mujica Centro de Neurología Traslacional, Escuela de Medicina, Universidad de Valparaíso, Valparaiso, Chile Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Stuart Adamson Stuart Adamson orcid.org/0000-0002-1402-8907 Buck Institute for Research on Aging, Novato, CA, USA Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Kaitlyn Vitangcol Kaitlyn Vitangcol Buck Institute for Research on Aging, Novato, CA, USA Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Hernan Huerta Hernan Huerta orcid.org/0000-0002-7392-3311 Center for Integrative Biology, Universidad Mayor, Santiago, Chile Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Xu Zhang Xu Zhang Department of Molecular Medicine and Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA, USA Contribution: Data curation, Formal analysis, ​Investigation, Methodology Search for more papers by this author Tomohiro Nakamura Tomohiro Nakamura Department of Molecular Medicine and Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA, USA Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Sergio Pablo Sardi Sergio Pablo Sardi orcid.org/0000-0001-9805-3677 Rare and Neurological Diseases Therapeutic Area, Sanofi, Framingham, MA, USA Contribution: Funding acquisition, ​Investigation, Methodology Search for more papers by this author Stuart A Lipton Stuart A Lipton orcid.org/0000-0002-3490-1259 Department of Molecular Medicine and Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA, USA Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, USA Contribution: Data curation, Formal analysis, Supervision, Funding acquisition, ​Investigation, Methodology Search for more papers by this author Brian K Kennedy Brian K Kennedy Buck Institute for Research on Aging, Novato, CA, USA Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore; Centre for Healthy Longevity, National University Health System; Departments of Biochemistry and Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore Contribution: Formal analysis, Funding acquisition, ​Investigation, Methodology Search for more papers by this author Juan Pablo Henriquez Juan Pablo Henriquez Department of Cell Biology, Center for Advanced Microscopy (CMA BioBio), Universidad de Concepción, Concepción, Chile Contribution: Formal analysis, Supervision, ​Investigation, Methodology Search for more papers by this author J Cesar Cárdenas J Cesar Cárdenas Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Center for Integrative Biology, Universidad Mayor, Santiago, Chile Buck Institute for Research on Aging, Novato, CA, USA Contribution: Formal analysis, Funding acquisition, ​Investigation, Methodology Search for more papers by this author Lars Plate Lars Plate orcid.org/0000-0003-4363-6116 Departments of Chemistry and Biological Sciences, Vanderbilt University, Nashville, TN, USA Contribution: Formal analysis, Supervision, Funding acquisition, ​Investigation, Methodology Search for more papers by this author Adrian G Palacios Adrian G Palacios orcid.org/0000-0003-1532-7527 Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaiso, Valparaiso, Chile Contribution: Data curation, Formal analysis, Supervision, Funding acquisition, ​Investigation Search for more papers by this author Claudio Hetz Corresponding Author Claudio Hetz [email protected] [email protected] orcid.org/0000-0003-1120-7966 Center for Geroscience, Brain Health and Metabolism, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Buck Institute for Research on Aging, Novato, CA, USA Contribution: Conceptualization, Resources, Supervision, Funding acquisition, ​Investigation, Writing - original draft, Project administration, Writing - review & editing Search for more papers by this author Author Information Felipe Cabral-Miranda1,2,3,4, Giovanni Tamburini1,2,3, Gabriela Martinez1,2,3, Alvaro O Ardiles5,6, Danilo B Medinas1,2,3, Yannis Gerakis1,2,3, Mei-Li Diaz Hung1,2,3, René Vidal1,2,7, Matias Fuentealba1,2,3, Tim Miedema1,2,3, Claudia Duran-Aniotz1,2,3, Javier Diaz1,2,3, Cristobal Ibaceta-Gonzalez5, Carleen M Sabusap8, Francisca Bermedo-Garcia9, Paula Mujica6, Stuart Adamson10, Kaitlyn Vitangcol10, Hernan Huerta7, Xu Zhang11, Tomohiro Nakamura11, Sergio Pablo Sardi12, Stuart A Lipton11,13, Brian K Kennedy10,14, Juan Pablo Henriquez9, J Cesar Cárdenas1,7,10, Lars Plate8, Adrian G Palacios5 and Claudio Hetz *,*,1,2,3,10 1Center for Geroscience, Brain Health and Metabolism, Santiago, Chile 2Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile 3Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile 4Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil 5Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaiso, Valparaiso, Chile 6Centro de Neurología Traslacional, Escuela de Medicina, Universidad de Valparaíso, Valparaiso, Chile 7Center for Integrative Biology, Universidad Mayor, Santiago, Chile 8Departments of Chemistry and Biological Sciences, Vanderbilt University, Nashville, TN, USA 9Department of Cell Biology, Center for Advanced Microscopy (CMA BioBio), Universidad de Concepción, Concepción, Chile 10Buck Institute for Research on Aging, Novato, CA, USA 11Department of Molecular Medicine and Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA, USA 12Rare and Neurological Diseases Therapeutic Area, Sanofi, Framingham, MA, USA 13Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, USA 14Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore; Centre for Healthy Longevity, National University Health System; Departments of Biochemistry and Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore *Corresponding author. Tel: +56229786506; E-mail: [email protected] or [email protected] The EMBO Journal (2022)41:e111952https://doi.org/10.15252/embj.2022111952 Full textView the full text of the articlePDFDownload PDF of article text and main figures.PDF PLUSDownload PDF of article text, main figures, expanded view figures and appendix. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Aging is a major risk factor to develop neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age-related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors involved in synaptic function and pathways linked to neurodegenerative diseases. The genes modified by XBP1 in the aged hippocampus where also altered. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging. Synopsis The UPR pathway sustains brain function, delaying the natural appearance of age-associated phenotypes in mammals. IRE1/XBP1 signaling improves neuronal physiology, possibly by regulation of synaptic protein expression. Impairment of UPR signaling begins by middle age in the mouse brain. Ablation of IRE1 expression in the brain accelerates and exacerbates age-associated cognitive decline. Overexpression of XBP1s, the active form of XBP1, in the brain improves age-associated phenotypes in mice. XBP1s gene delivery to aged mice can revert brain dysfunction at the morphological, electrophysiological, molecular, and behavioral level. Proteomic profiling of aged animals overexpressing XBP1s highlights the modification of pathways related to synapse physiology and neurodegeneration. Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 41,Issue 22,17 November 2022This cover highlights the article Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging by Felipe Cabral-Miranda, Claudio Hetz and colleagues. Studies in invertebrate models suggest that the buffering activity of the proteostasis network at the ER level declines with age. The ER stress sensor IRE1 restores proteostasis by activating the transcription factor XBP1s, a central regulator of the unfolded protein response (UPR). Increasing XBP1s levels in brain cells prevented brain function decline during aging in mice at the behavioral, electrophysiological and molecular level. Conversely, switching off the UPR accelerates brain aging and the accumulation of senescent cells. (Cover concept by the authors. Scientific illustration by Felipe Serrano, www.illustrative-science.com) Volume 41Issue 2217 November 2022In this issue RelatedDetailsLoading ...