Multiple Targets, One Goal: Compounding life-extending effects through Polypharmacology

Abstract

Analysis of lifespan-extending compounds suggested the most effective geroprotectors target multiple biogenic amine receptors. To test this hypothesis, we used graph neural networks to predict such polypharmacological compounds and evaluated them in C. elegans. Over 70% of the selected compounds extended lifespan, with effect sizes in the top 5% compared to the DrugAge database. This reveals that rationally designing polypharmacological compounds enables the design of geroprotectors with exceptional efficacy. Key takeawaysO_LIThe most effective known geroprotectors act by polypharmacological mechanisms. C_LIO_LIGraph neural networks predicted polypharmacological geroprotectors with a hit rate of 70%. C_LIO_LIThe predicted polypharmacological geroprotectors are exceptionally effective. C_LIO_LIThe predicted polypharmacological mechanism was experimentally confirmed. C_LIO_LIRationally designing polypharmacological compounds results in geroprotectors with exceptional efficacy. C_LI