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 were interested in drugs that might eventually be tested in humans so we favored drugs with 80 reported efficacy in mammals or that are already approved for human use. Based on these criteria, we 81 initially selected eleven candidate drugs (Supplementary Table S1 ). We added allantoin to our study 82 based on a report showing lifespan effects in C. elegans and a transcriptional analysis suggesting that 83 its mode of action is unusually distinct from other compounds 22 Table 97 S3). While transcriptional analyses revealed significant overlap between affected genes, we also 98 identified sets of genes that were unique to each individual compound (Fig. 2a) . MET shows 99 significant overlap with the other drugs, having the smallest unique set. Almost all genes affected by 100 MET and PSORA were also affected by at least one other drug in the set (Fig. 2a) . ALLAN causes 101 fewer gene-expression changes overall than any of the other compounds, but 48% of the genes 102 affected by ALLAN are unique, that is, not affected by any of the other drugs, while only 17% of the 103 genes affected by MET are unique (Fig. 2a