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

## TL;DR

This study shows that new tRNA synthetase inhibitors improve health and lifespan in worms by boosting autophagy, a process linked to cellular cleanup.

## Contribution

The paper identifies four new tRNA synthetase inhibitors that extend both healthspan and lifespan in C. elegans.

## Key findings

- REP8839, REP3123, LysRS-In-2, and halofuginone extend healthspan and lifespan in C. elegans.
- These compounds increase autophagy at lifespan-extending doses.
- The effects partially depend on the transcription factor ATF-4.

## Abstract

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.