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

By targeting multiple overlapping ageing and longevity-related pathways we succeeded in designing 299 synergistic pharmacological interventions that, even when only applied to animals from adult age, 300 more than doubled healthy lifespan in C. elegans. This effect size is comparable to that of the classical 301 ageing mutations and, to the best of our knowledge, is the largest reported for any adult-onset 302 pharmacological intervention 13 . However, unlike in ageing mutations we detect very limited 303 detrimental evolutionary or fitness tradeoffs associated with this lifespan extension by drug synergies 304 19 . In particular, we did not detect any decrease in oxygen consumption or total fecundity. The latter 305 result is consistent with a previous study showing benefits of an adult-onset intervention using 306 resveratrol without reduced fecundity 56 . These data suggest that there is significant post-9 controls (Fig. 5g) . Mortality analysis suggests that one synergistic drug treatment slows basic 311 biological ageing rate by ~20% (Extended data Fig. 10 ). To test for evolutionary conservation, we 312 determined lifespan benefits in the fruit fly Drosophila melanogaster, confirming qualitative 313 conservation for two of the four synergistic drug combinations. Nematodes are evolutionarily more 314 distant from fruit flies than they are from mammals 57 , making mechanisms and pathways conserved 315 between flies and nematodes ancient, and tracing this synergy back to a common ancestor of all three 316 clades.