Cell-based screen identifies translation state modulators that extend lifespan in D. melanogaster and C. elegans - PubMed
4 hours ago
- #phenotypic screening
- #translational regulation
- #lifespan extension
- Dietary restriction (DR) and cold-induced longevity (CHIL) inhibit global protein synthesis but selectively enhance translation of proteins that support mitochondrial function, stress resistance, and lifespan extension.
- A cell-based phenotypic screen was developed to identify compounds that mimic DR/CHIL by reporting on mRNA translation based on 5'-UTR length.
- The screen identified compounds, including known lifespan-extenders like curcumin and rapamycin, that preferentially increase expression of mRNAs with short 5'-UTRs.
- Fluspirilene, a novel candidate, extended lifespan in Drosophila melanogaster and Caenorhabditis elegans and mitigated age-related locomotor decline in female flies.
- Fluspirilene's longevity effects in C. elegans required DAF-16/FOXO, HLH-30/TFEB transcription factors, and the autophagy gene atg-18, indicating an autophagy-dependent mechanism.
- Fluspirilene's pro-longevity effects are constrained by evolutionary divergence and nutrient status, as it failed to extend lifespan in other Caenorhabditis species and flies on a high-yeast diet.
- The study supports drug discovery efforts targeting translation state modulation as a therapeutic strategy for healthy aging.