Novel tRNA Synthetase Inhibitors Increase Healthspan, Lifespan, and Autophagic Flux in <i>C. elegans</i>.

We previously demonstrated that the tRNA synthetase inhibitors mupirocin and borrelidin extend lifespan in <i>C. elegans</i> and <i>S. cerevisiae</i> and that tRNA synthetase inhibition enhances autophagy(definition) in mammalian cells. In this study, we identify four additional tRNA synthetase inhibitors, REP8839, REP3123, LysRS-In-2, and halofuginone, that extend both healthspan(definition) and lifespan in <i>C. elegans</i>. These compounds also trigger a significant upregulation of autophagy, specifically at their lifespan-extending doses. These phenotypes partially depend on the conserved transcription factor ATF-4. Our findings further establish tRNA synthetase inhibition as a conserved mechanism for promoting increased lifespan and now healthspan, with potential implications for therapeutic interventions targeting age-related decline in humans.