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

3 Some of the most important findings in biogerontology are the evolutionarily conserved pathways that 34 regulate lifespan 1-6 . In model organisms, mutations affecting these pathways can often extend lifespan 35 by between 30% and 100% 7,8 . Combining different genetic mutations can result in synergistic lifespan 36 extension 9-11 . By contrast, the effect of pharmacological interventions are typically much weaker, even 37 when targeting the same pathways 2,12,13 , but this genetic synergy suggests a potential strategy for the 38 design of novel pharmacological interventions by simultaneously targeting multiple evolutionarily 39 conserved ageing pathways. To date there is little data on synergistic effects of pharmacological 40 interventions on lifespan 14 . Here we report an in vivo approach to design novel multi-drug ageing 41 interventions. We show how multi-drug interventions leverage pathway synergies to maximize effect 42 size, while minimizing side effects and detrimental developmental tradeoffs through targeting distinct 43 but interacting ageing pathways. Our ultimate aim was to design a purely pharmacological, adult-44 onset intervention with lifespan efficacy similar or better than those of canonical aging mutations did.