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

EMBO J. 2022 Nov 17;41(22):e111952. doi: 10.15252/embj.2022111952. Epub 2022 Oct 31.


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.

Keywords: ER stress; UPR; XBP1s; aging brain; proteostasis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging* / genetics
  • Animals
  • Brain* / metabolism
  • Endoplasmic Reticulum Stress / genetics
  • Mice
  • Protein Serine-Threonine Kinases* / genetics
  • Proteomics
  • Signal Transduction / physiology
  • Unfolded Protein Response*
  • X-Box Binding Protein 1* / genetics
  • X-Box Binding Protein 1* / metabolism


  • Protein Serine-Threonine Kinases
  • X-Box Binding Protein 1
  • Ern2 protein, mouse
  • Xbp1 protein, mouse