A phenotypic cell-based screen designed to detect compounds that shift mRNA translation toward short 5'-UTR transcripts — mimicking dietary restriction and cold-induced longevity — identified fluspirilene, an antipsychotic drug, as a novel lifespan-extending agent. The screen's validity was confirmed by its enrichment of known longevity compounds including rapamycin and curcumin. Fluspirilene significantly extended lifespan in both Drosophila melanogaster and C. elegans, reduced age-related locomotor decline in female flies, and required DAF-16/FOXO, HLH-30/TFEB, and the autophagy gene atg-18 for its effects in worms. Crucially, it failed to extend lifespan in flies on high-yeast diets or in two other Caenorhabditis species, revealing meaningful boundary conditions.
The 4E-BP/eIF4E translational axis has been a compelling but pharmacologically underexplored longevity target. What distinguishes this work is the upstream screening logic: rather than targeting individual genes, the assay captures the functional translation-state shift that DR produces systemically. That's a more physiologically meaningful filter than conventional target-based screens. Fluspirilene's established safety profile in humans — it's a diphenylbutylpiperidine antipsychotic — lowers the translational barrier to follow-up studies, though its psychiatric mechanism (dopamine receptor blockade) raises obvious confound concerns for mammalian longevity studies. The nutrient-dependence of its effects is a critical caveat, suggesting Western dietary contexts could blunt efficacy. This is incremental-to-solid preclinical work; the screen design itself may prove more durable than fluspirilene specifically.
