Selective activation of IRE-1 safeguards restoration of translation and organismal rejuvenation from adult reproductive diapause

Abstract In C. elegans , prolonged food deprivation during early larval development results in aging-like phenotypes that can be fully reversed upon refeeding, but it remains unknown whether and how this ability persists into later life stages. Here we subjected C. elegans of the last larval stage to starvation, driving them into adult reproductive diapause (ARD). During starvation, ARD worms exhibited a wide spectrum of aging-like phenotypes, including transcriptomic reprogramming accompanying cellular and functional declines. These phenotypes are largely restored within one day of refeeding, suggesting a rejuvenation effect. Time-series transcriptomics, proteomics, and follow-up analyses of the refeeding/rejuvenation process uncovered an intricate coordination between: (1) activation of the IRE-1 branch of UPR ER (unfolded protein response of endoplasmic reticulum) to induce chaperone expression; (2) quiescence of the PEK-1 branch of UPR ER to avoid translation suppression; (3) up-regulation of the translation machinery to boost protein synthesis. IRE-1, together with its downstream effector, XBP-1, play an essential role in boosting protein synthesis, which is required for complete rejuvenation from the ARD state. These findings indicate that coordination between a high protein synthesis activity and a high protein folding capacity is key to refeeding-associated rejuvenation. Highlights Refeeding rapidly reverses aging-like phenotypes in adult reproductive diapause Refeeding selectively activates the IRE-1 branch of UPR ER Refeeding restores protein synthesis in an IRE-1 dependent manner Rejuvenation requires enhanced translation activity and protein folding capacity