Glial regulation of longevity through a transcellular unfolded protein response

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Cells are repeatedly exposed to various stressors that disrupt protein homeostasis (such as infection, excess nutrients, heat, genetic mutations), resulting in protein misfolding and aggregation. To maintain protein homeostasis (proteostasis), cells have evolved compartment specific stress responses such as the Unfolded Protein Response of the endoplasmic reticulum (UPRER). In times of ER stress when the load of misfolded or unfolded proteins overwhelms the ER, the UPRER is initiated to restore proteostasis. Unfortunately, the ability to mount an effective UPRER is impaired with age, which likely contributes to the accumulation of misfolded proteins - a central molecular hallmark of aging and many degenerative diseases. Our laboratory discovered that ectopic expression of the UPRER transcription factor xbp-1s in neurons is sufficient to prevent age-onset loss of UPRER throughout the organism. Surprisingly, neuronal expression of xbp-1s leads to cell non-autonomous activation of the UPRER in distal, intestinal cells and extends lifespan in C. elegans. Initially this phenomenon was ascribed only to neurons, however recent data from our lab suggests glial cells are more potent cell non-autonomous regulators of ER stress resistance and longevity. Animals lacking a subtype of glial cell are more susceptible to chronic ER stress. Conversely, expressing xbp-1s in glia results in robust ER stress resistance and lifespan extension in a mechanism that is distinct from that initiated by neuronal xbp-1s. Therefore, we hypothesize that glial cells play a central role in coordinating organismal ER stress resistance and longevity. In this proposal, we outline our strategy to pinpoint the origin and identity of the glial cell non-autonomous signal (Aim 1) and to uncover the mechanism by which the signal is perceived in distal tissues (Aim 2). Our approach utilizes techniques which combine the traditional advantages of using C. elegans as a model system (genetic tractability, transparency, short lifespan), with advanced technologies (large particle flow cytometry and tissue-specific ribosomal profiling) to study cell non-autonomous signaling between tissues in the context of aging. Data generated through this proposal will implicate glia as cell non-autonomous regulators of aging and open new avenues for metabolic and neurodegenerative disease therapeutics.