TY - JOUR T1 - Doubling healthy lifespan using drug synergy JF - bioRxiv DO - 10.1101/153205 SP - 153205 AU - Tesfahun Dessale AU - Krishna Chaithanya Batchu AU - Diogo Barardo AU - Ng Li Fang AU - Vanessa Yuk Man Lam AU - Linfan Xiao AU - Markus R. Wenk AU - Nicholas S. Tolwinski AU - Jan Gruber Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/08/01/153205.abstract N2 - Pharmacological interventions that target human ageing would extend individual healthspan and result in dramatic economic benefits to rapidly ageing societies worldwide. For such interventions to be contemplated they need to comprise drugs that are efficacious when given to adults and for which extensive human safety data are available. Here we show that dramatic lifespan extension can be achieved in C.elegans by targeting multiple, evolutionarily conserved ageing pathways using drugs that are already in human use. By targeting multiple synergistic ageing pathways, we are able to slow ageing rate, double lifespan and improves healthspan while minimize developmental and fitness trade-offs. Moreover, we established that there is no synergistic benefit in a daf-2 or daf-7 background, implying the involvement of the TGFβ and IGF pathways in this synergy. Employing lipidomics and transcriptomics analysis we found lipid metabolism to be affected resulting in increased monounsaturated fatty acids (MUFA) and decrease membrane peroxidation index. Our best drug combination showed a conserved lifespan extension 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. This drug-repurposing approach, using drugs already approved for humans to target multiple conserved aging pathways simultaneously, could lead to interventions that prevent age-related diseases and overall frailty in a rapidly ageing population. ER -