Abstract
SummaryThe unfolded protein response of the endoplasmic reticulum (UPRER) is a crucial mediator of secretory pathway homeostasis. Expression of the spliced and active form of the UPRER transcription factor XBP-1, XBP-1s, in the nervous system triggers activation of the UPRER in the intestine of Caenorhabditis elegans (C. elegans) through release of a secreted signal, leading to increased longevity. We find that expression of XBP-1s in the neurons or intestine of the worm strikingly improves proteostasis in multiple tissues, through increased clearance of toxic proteins. To identify the mechanisms behind this enhanced proteostasis, we conducted intestine-specific RNA-seq analysis to identify genes upregulated in the intestine when XBP-1s is expressed in neurons. This revealed that neuronal XBP-1s increases the expression of genes involved in lysosome function. Lysosomes in the intestine of animals expressing neuronal XBP-1s are more acidic, and lysosomal protease activity is higher. Moreover, intestinal lysosome function is necessary for enhanced lifespan and proteostasis. These findings suggest that activation of the UPRER in the intestine through neuronal signaling can increase the activity of lysosomes, leading to extended longevity and improved proteostasis across tissues.
Highlights
Aging is a process that occurs in a coordinated fashion throughout the body, leading to a susceptibility to deterioration and disease across tissues
To investigate the mechanisms by which XBP-1s might extend longevity, we started by asking whether its expression could improve proteostasis, either cell-autonomously or cell non-autonomously
To determine whether xbp-1s affects phenotypes associated with proteotoxicity, pan-neuronal expression of Ab1–42, with a signal peptide directing it to the secretory pathway [13], was combined with tissue-specific expression of xbp-1s in neuronal, intestinal, and body wall muscle cells, and the function of neurons measured by chemotaxis—movement of worms toward an attractive volatile odorant
Summary
Aging is a process that occurs in a coordinated fashion throughout the body, leading to a susceptibility to deterioration and disease across tissues. In C. elegans, mutations in genes that affect nervous system function can significantly increase longevity [1] This effect is observed in other species—in Drosophila melanogaster, sensory perception of food can alter lifespan in a similar way to consumption of that food, while, in mice, loss of the neuronal pain receptor TRPV1 creates animals that live substantially longer, with improved metabolic profiles [2, 3]. The ability of neurons to modulate aging is a conserved phenomenon It is not clear whether these neuronal signals converge upon the same core mechanisms in distal tissues. Understanding these mechanisms could allow them to be engaged directly in order to improve aging phenotypes and increase cellular health
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