Clay, K. J. | bioRxiv Science

bioRxiv2024

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 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

pharmacology and toxicology↗

bioRxiv2022

Proteostasis is differentially modulated by inhibition of translation initiation or elongation

Recent work has revealed an increasingly important role for mRNA translation in maintaining proteostasis. Inhibiting translation protects from various proteostatic insults, including heat, expression of aggregation-prone proteins, or aging. However, multiple studies have come to differing conclusions about the mechanisms underlying the protective effects of translation inhibition. Here, we systematically lower translation either by pharmacologically inhibiting translation initiation or elongation and show that each step activates distinct protective responses in Caenorhabditis elegans. Targeting initiation triggers an HSF-1 dependent mechanism that protects from heat and age-associated protein misfolding but not from proteotoxicity caused by proteasome dysfunction. Conversely, targeting elongation triggers an HSF-1 independent mechanism that protects from heat and proteasome dysfunction but not from age-associated protein aggregation. Furthermore, while inhibiting translation initiation increases lifespan in wild-type worms, inhibiting translation elongation only extends lifespan when the animals exhibit preexisting proteotoxic stress--either as a result of aggregation-prone protein expression or hsf-1 deficiency. Together our findings suggest that organisms evolved complementary mechanisms that the mRNA translation machinery can trigger to restore proteostasis.

biochemistry↗