Translational Regulation of Non-autonomous Mitochondrial Stress Response Promotes Longevity.

Reduced mRNA translation delays aging， but the underlying mechanisms remain underexplored. Mutations in both DAF-2 (IGF-1 receptor) and RSKS-1 (ribosomal S6 kinase/S6K) cause synergistic lifespan extension in C.?elegans. To understand the roles of translational regulation in this process， we performed polysomal profiling and identified translationally regulated ribosomal and cytochrome c (CYC-2.1) genes as key mediators of longevity. cyc-2.1 knockdown significantly extends lifespan by activating the intestinal mitochondrial unfolded protein response (UPR)， mitochondrial fission， and AMP-activated kinase (AMPK). The germline serves as the key tissue for cyc-2.1 to regulate lifespan， and germline-specific cyc-2.1 knockdown non-autonomously activates intestinal UPR and AMPK. Furthermore， the RNA-binding protein GLD-1-mediated translational repression of cyc-2.1 in the germline is important for the non-autonomous activation of UPR and synergistic longevity of the daf-2 rsks-1 mutant. Altogether， these results illustrate a translationally regulated non-autonomous mitochondrial stress response mechanism in the modulation of lifespan by insulin-like signaling and S6K.