Phenotypic screening has identified small-molecule modulators of aging, but the mechanism of compound action often remains opaque due to the complexities of mapping protein targets in whole organisms. Here, we combine a library of covalent inhibitors with activity-based protein profiling to coordinately discover bioactive compounds and protein targets that extend lifespan in Caenorhabditis elegans. We identify JZL184—an inhibitor of the mammalian endocannabinoid (eCB) hydrolase monoacylglycerol lipase (MAGL or MGLL)—as a potent inducer of longevity, a result that was initially perplexing as C. elegans does not possess an MAGL ortholog. We instead identify FAAH-4 as a principal target of JZL184 and show that this enzyme, despite lacking homology with MAGL, performs the equivalent metabolic function of degrading eCB-related monoacylglycerides in C. elegans. Small-molecule phenotypic screening thus illuminates pure pharmacological connections marking convergent metabolic functions in distantly related organisms, implicating the FAAH-4/monoacylglyceride pathway as a regulator of lifespan in C. elegans.
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We are grateful to M. Hansen, J. Chang, X. She, and G. Solis for discussions and technical expertise in C. elegans, D. Sabatini for the pRK5 vector, and the Caenorhabditis Genetics Center for strains. This work was supported by the NIH (DA033760, CA215249, GM074215), the Damon Runyon Cancer Research Foundation, and Abide Therapeutics.
Supplementary Tables 1–6, Supplementary Figures 1–12
List of predicted C. elegans SHs, FP-enriched SHs, and gene expression data, related to Fig. 1.
Proteomic data, related to Figs. 3 and 4 and Supplementary Figure 7.
Proteomic data, related to Figs. 3 and 4 and Supplementary Table 7.
Proteomic data, related to Fig. 3.
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Nature Chemical Biology (2019)