Doubling healthy lifespan using drug synergy

Tesfahun Dessale; Krishna Chaithanya Batchu; Diogo Barardo; Ng Li Fang; Vanessa Yuk Man Lam; Linfan Xiao; Markus R. Wenk; Nicholas S. Tolwinski; Jan Gruber

Due to the lack of generally accepted biological markers for ageing [15] [16] [17] , lifespan studies are currently 46 the only way to test the efficacy of ageing interventions 18 . We therefore developed our candidate drug 47 combinations in a short-lived model organism, the nematode Caenorhabditis elegans. Using our 48 approach, we identify two triple drug combinations that extend lifespan and healthspan to an extent 49 greater than any previously reported pharmacological intervention in C. elegans 13 . Our synergistic 50 drug combinations show effect sizes comparable to the classical ageing mutations while avoiding 51 most of the tradeoffs associated with them 19-21 . We find that these interventions actually increase some 52 markers of performance while slowing biological ageing rate. Moreover, we identified TGF as a key 53 contributor and required pathway in mediating these synergistic effects. We also find that worms 54 treated with synergistic drug combinations have higher MUFA:PUFA ratios and a decrease in 55 membrane lipid peroxidation index. Finally, we confirm that this synergistic effect is also present in 56 the fruit fly Drosophila melanogaster. Table S1 ). We chose to target 75 AMP activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), caloric restriction 76 (CR), C-Jun N-terminal kinases (JNK) and mitohormesis/mitochondrial metabolism as primary 77 longevity regulatory pathways. For each pathway, we identified drugs and drug-like molecules 78 reported to extend lifespan in at least one common model organism (nematodes, fruit flies or mice).