Four glial cells regulate ER stress resistance and longevity via neuropeptide signaling

The ability for the nervous system to sense cellular stress and coordinate protein homeostasis is essential for cellular viability and organismal health. Unfortunately, stress responses which mitigate disturbances in proteostasis, such as the unfolded protein response of the endoplasmic reticulum (UPRER), become defunct with age. We find that expression of the constitutively active UPRER transcription factor, xbp-1s, in a subset of astrocyte-like glia extends lifespan in C. elegans. Glial xbp-1s initiates a robust cell non-autonomous activation of the UPRER in distal cells and renders animals more resistant to age-dependent protein aggregation and chronic ER stress. Perturbing glia is sufficient to block this cell non-autonomous activation of the UPRER and reverses ER stress resistance and longevity. Lastly, mutants deficient in neuropeptide processing and secretion suppress glial cell non-autonomous induction of the UPRER and lifespan extension. These data identify astrocyte-like glial cells as central and before unknown, regulators of organismal ER stress resistance and longevity.