Enhanced Lipophagy via the Unfolded Protein Response in Neurons Modestly Extends Life in Nematodes
Researchers here show a small effect on life span in nematode worms resulting from an increase in the unfolded protein response in the endoplasmic reticulum in neurons. This is connected with lipophagy, a process that depletes lipids in these cells. In this context, it is worth mentioning that, as a general rule, small effect sizes in nematodes are not interesting from the perspective of producing therapies to extend healthy life for mammals. Short-lived species have life spans that are very plastic in response to environment circumstances and changes in the regulation of cellular housekeeping processes. Longer lived species exhibit far lesser changes in life span under the same circumstances. So a small effect size in nematodes will likely be indistinguishable in humans.
The homeostatic regulation of protein folding (proteostasis), which is monitored in specific subcellular compartments, is an integral player in stress resistance and longevity. The endoplasmic reticulum (ER), in particular, is a central regulator of stress monitoring as it controls nearly a third of the cell's proteins, provides an internal medium for lipid homeostasis and cell signaling, and communicates directly with all other organelles to maintain cellular secretion. Thus, cells have evolved numerous quality control machineries dedicated to protecting the ER both under basal and stressed conditions.
Notably, the ER has evolved three primary branches of its unfolded protein response (UPRER) to maintain proper secretion, protein folding, and lipid homeostasis. While these pathways have been intensively studied for the past two decades, much less is known about the adaptive responses of the ER under long-lived conditions. Work with the nematode C. elegans has shown that its cells become less capable in protein folding and also less able to induce stress responses to proteotoxicity with advanced age. Overexpression of xbp-1, specifically in neurons, extends organismal life span and increases ER stress tolerance in a cell nonautonomous manner. While the precise, small ER stress signal was not identified, small clear vesicles are required for this beneficial effect, which could be host to numerous neurotransmitters.
We hypothesized that induction of the UPRER in neurons, which reverses the age-dependent loss of ER proteostasis, also enacts a marked restructuring of ER morphology, which, in turn, imparts a beneficial metabolic change and promotes longevity. Although whole-organismal metabolic restructuring has been a topic of intense study in the aging field, much less is known about the adaptive responses of organelles in long-lived conditions. Here, we find that neuronal xbp-1 animals have notable ER restructuring and lipid depletion, and that these changes are distinct from chaperone induction. Thus, we argue that the beneficial effects of nonautonomous UPRER are dependent on two independent, yet equally important, arms of UPRER: the protein homeostasis arm, including chaperone induction, and the metabolic arm, which induces ER remodeling and lipophagy.