Drug Synergy Slows Aging and Improves Healthspan through IGF and SREBP Lipid Signaling

There is growing interest in pharmacological interventions directly targeting the aging process. Pharmacological interventions against aging should be efficacious when started in adults and, ideally, repurpose existing drugs. We show that dramatic lifespan extension can be achieved by targeting multiple, evolutionarily conserved aging pathways and mechanisms using drug combinations. Using this approach in C. elegans, we were able to slow aging and significantly extend healthy lifespan. To identify the mechanism of these drug synergies, we applied transcriptomics and lipidomics analysis. We found that drug interactions involved the TGF-β pathway and recruited genes related with IGF signaling. daf-2, daf-7, and sbp-1 interact upstream of changes in lipid metabolism, resulting in increased monounsaturated fatty acid content and this is required for healthy lifespan extension. These data suggest that combinations of drugs targeting distinct subsets of the aging gene regulatory network can be leveraged to cause synergistic lifespan benefits. Admasu et al. used drug combinations to test whether lifespan extension in C. elegans may be enhanced by simultaneous targeting of multiple aging pathways. They found that synergistic drug combinations can modulate pathways, such as IGF and SREBP lipid signaling, not impacted by the individual drugs, resulting in significant lifespan extension.