UPRER promotes lipophagy independent of chaperones to extend life span.

Longevity is dictated by a combination of environmental and genetic factors. One of the key mechanisms to regulate life-span extension is the induction of protein chaperones for protein homeostasis. Ectopic activation of the unfolded protein response of the endoplasmic reticulum (UPRER) specifically in neurons is sufficient to enhance organismal stress resistance and extend life span. Here, we find that this activation not only promotes chaperones but also facilitates ER restructuring and ER function. This restructuring is concomitant with lipid depletion through lipophagy. Activation of lipophagy is distinct from chaperone induction and is required for the life-span extension found in this paradigm. Last, we find that overexpression of the lipophagy component, ehbp-1, is sufficient to deplete lipids, remodel ER, and promote life span. Therefore, UPR induction in neurons triggers two distinct programs in the periphery: the proteostasis arm through protein chaperones and metabolic changes through lipid depletion mediated by EH domain binding protein 1 (EHBP-1).