Felipe Cabral‐MirandaGiovanni TamburiniGabriela MartinezArdiles, ÁlvaroÁlvaroArdilesDanilo B MedinasYannis GerakisMei‐Li Diaz HungRené VidalMatias FuentealbaTim MiedemaClaudia Duran‐AniotzJavier DiazCristobal Ibaceta‐GonzalezCarleen M SabusapFrancisca Bermedo‐GarciaPaula MujicaStuart AdamsonKaitlyn VitangcolHernan HuertaXu ZhangTomohiro NakamuraSergio Pablo SardiStuart A LiptonBrian K KennedyJuan Pablo HenriquezJ Cesar CárdenasLars PlatePalacios, AdriánAdriánPalaciosClaudio Hetz2025-12-082025-12-082022-10-3110.15252/embj.20221119522-s2.0-85141150685https://cris-uv-2.scimago.es/handle/123456789/8156WOS:000876359700001Aging 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.enacceso abiertoBiochemistry And Molecular BiologyBiochemistry, Genetics And Molecular BiologyCell BiologyImmunology And MicrobiologyMedicineMolecular BiologyNeurosciencearticle; early access