Drug synergy slows ageing and improves healthspan through IGF and SREBP lipid signaling

Pharmacological interventions directly modulating ageing would extend human healthspan, resulting in dramatic medical and economic benefits. Such interventions should be efficacious in adults and ideally repurpose drugs known to be safe. Here we show that dramatic lifespan extension can be achieved by targeting multiple, evolutionarily conserved ageing pathways using drugs already used in humans. Using this approach in C. elegans, we were able to slow ageing, improve healthspan and minimize trade-offs. We show that daf-2, daf-7 and sbp-1 (mammalian SREBP-1c) interact upstream of changes in lipid metabolism, resulting in increased monounsaturated fatty acid content and lifespan extension. For one combination, we observed evolutionary conservation in fruit flies. To the best of our knowledge, this is the largest lifespan effect ever reported for any adult-onset drug treatment in C. elegans. Drug repurposing approaches, by leveraging drugs already approved for humans, could lead to rapid translation of experimental results to clinical applications. Overall design: A total of 53 samples are sequenced in three lanes. Lane one contains from sample 1 to sample 17 which includes all single drugs in triplicates and control in duplicate. Lane two contains from sample 18 to sample to sample 37 which includes six drug combinations in triplicates and control in duplicate. The third lane contains from sample 38 to sample 53 which includes three drug combinations in triplicates, one drug combination in duplicate, eat-2 mutants in triplicates and control in duplicate.

53