Novel tRNA Synthetase Inhibitors Increase Healthspan, Lifespan, and Autophagic Flux in C. elegans

We previously demonstrated that the tRNA synthetase inhibitors mupirocin and borrelidin extend lifespan in C. elegans and S. cerevisiae and that tRNA synthetase inhibition enhances autophagy in mammalian cells. In this study, we identify four additional tRNA synthetase inhibitors, REP8839, REP3123, LysRS-In-2, and halofuginone, that extend both healthspan and lifespan in C. elegans. 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.