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Aging is the major risk factor for the development of dementia and neurodegenerative disorders, and the aging brain manifests severe deficits in buffering capacity by the proteostasis network. Accordingly, we investigated the significance of the unfolded protein response (UPR), a major signaling pathway that copes with endoplasmic reticulum (ER) stress, to normal mammalian brain aging. Genetic disruption of ER stress sensor IRE1╬▒ accelerated cognitive and motor dysfunction during aging. Exogenous bolstering of the UPR by overexpressing an active form of the transcription factor XBP1 restored synaptic and cognitive function in addition to reducing cell senescence. Remarkably, proteomic profiling of hippocampal tissue indicated that XBP1s expression corrected age-related alterations in synaptic function. Collectively, our data demonstrate that strategies to manipulate the UPR sustain healthy brain aging. ### Competing Interest Statement CH and FCM declare a conflict of interest for a submitted patent application. Inventors: Claudio Hetz, Felipe Cabral. Title: Treatment of aging or age-related disorders using XBP1. Provisional application for patent at USPTO, application number 62800229. Submitted 01/02/2019. Status: patent pending. Disclosure: PS is a Sanofi employee.

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