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

Aging is a major risk factor for 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 associated with synaptic function and pathways linked to neurodegenerative diseases. Similar changes were observed in human brain aging. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.

Automated summary

The unfolded protein response (UPR) plays a crucial role in maintaining healthy brain aging, and genetic disruption of the UPR can accelerate age-related cognitive decline. Overexpression of the UPR transcription factor XBP1 restores synaptic and cognitive function, reduces cell senescence, and reverses proteomic changes associated with aging and neurodegenerative diseases.