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

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 takeaways The most effective known geroprotectors act by polypharmacological mechanisms. Graph neural networks predicted polypharmacological geroprotectors with a hit rate of 70%. The predicted polypharmacological geroprotectors are exceptionally effective. The predicted polypharmacological mechanism was experimentally confirmed. Rationally designing polypharmacological compounds results in geroprotectors with exceptional efficacy.