The Role Of The Unfolded Protein Response In Determining Lifespan

Activation of cellular stress responses can extend longevity in model organisms. One of these stress responses, the endoplasmic reticulum unfolded protein response (UPR), can increase lifespan when activated specifically within the nervous system of C. elegans, through an inter-tissue signaling pathway that communicates UPR activation between neurons and other tissues of the organism. In order to determine whether UPR activation can improve cellular protein folding conditions, either cell-autonomously or cell non-autonomously, we have combined tissue-specific UPR activation with tissue-specific expression of disease-associated misfolded proteins. Our findings suggest that activation of the UPR can reduce the toxicity of misfolded proteins, with differing effects depending upon the type and subcellular localization of the proteotoxic species. In addition, we have examined the metabolic changes that occur downstream of inter-tissue UPR signaling, and, surprisingly, have identified changes in lipid metabolism that may underlie some of the effects of cell non-autonomous UPR activation on both proteostasis and lifespan. These results indicate that UPR signaling affects longevity through changes in metabolism and proteostasis, and suggest that this pathway may represent a promising therapeutic