Pharmacological convergence reveals a lipid pathway that regulates C. elegans lifespan

Abstract

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 monoacylg-lycerol 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.

Publisher

Nature Publishing Group

Publication Date

5-1-2019

Publication Title

Nature Chemical Biology

Department

Chemistry and Biochemistry

Document Type

Article

DOI

https://dx.doi.org/10.1038/s41589-019-0243-4

Keywords

Molecular characterization, Endocannabinoid system, Caenorhabdits-Elegans, Stem-cells, Longevity, Lipase, Enzyme, Identification, Biosynthesis, Cannabinoids

Language

English

Format

text

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