Translational Regulation of Non-autonomous Mitochondrial Stress Response Promotes Longevity

Cell Rep. 2019 Jul 23;28(4):1050-1062.e6. doi: 10.1016/j.celrep.2019.06.078.


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 (UPRmt), 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 UPRmt 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 UPRmt 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.

Keywords: AMPK; C. elegans; UPR(mt); aging; daf-2 rsks-1; germline; mRNA translation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Down-Regulation / genetics
  • Enzyme Activation
  • Genes, Helminth
  • Genome
  • Germ Cells / metabolism
  • Longevity / physiology*
  • Mitochondria / metabolism*
  • Mitochondrial Dynamics
  • Mutation / genetics
  • Organ Specificity
  • Protein Biosynthesis*
  • Signal Transduction
  • Stress, Physiological*
  • Unfolded Protein Response


  • Caenorhabditis elegans Proteins
  • AMP-Activated Protein Kinases