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

We then systematically determined the efficacy of all ten possible pairs out of the five candidate drugs 121 (Extended data Fig. 2a-i) . For these trials we define synergy based on the Higher Single Activity 122 (HSA) model 28 ; Drug combinations are considered synergistic if the combinatorial effect is 123 significantly larger than any of the combination's single drug effect at the same (ideal) concentrations 124 as in the combination. Using this definition, we identified two synergistic combinations out of the ten 125 pairs tested (Fig. 2c, 170 Several of the drugs tested have previously been reported to be CR mimetics 17,32-34 . We therefore 171 tested each synergistic combination and its constituent compounds in a C. elegans model of CR (eat-2 172 mutants). We found that only RIF among the single drug treatments further extended lifespan in eat-2 Table S3 ). First we explored the transcriptomics data for changes that 223 might affect lipid composition and found that synergistic drug combinations indeed resulted in a 224 significant up regulation of the C. elegans SREBP-1c homologsbp-1, a master transcription factor 225 controlling several lipogenic genes, and genes coding for "desaturases" responsible for MUFA 226 synthesis 38-40 (Fig. 4c ,e). We then employed an MS-based lipidomics assay to determine changes in 227 lipid compositions that might result from these drug treatments. Worms that were exposed to the 228 synergistic drug combinations have a significant rise in TAG reserves ( lifespan in the optimal (best) health category while nematodes exposed to the RIF+PSORA+ALLAN 253 and RAP+RIF+ALLAN spent 57% and 63%, respectively, of their already extended lifespan in 254 optimal health (Fig. 5d, Extended data 9c ). This means that their health span was significantly 255 extended both in absolute and relative terms. Indeed, more than half of the treated animals were still 256 in optimal health even after the last control animal had died (Fig. 5d, Extended data Fig. 9c ).