Format

Send to

Choose Destination
Nat Chem Biol. 2019 May;15(5):453-462. doi: 10.1038/s41589-019-0243-4. Epub 2019 Mar 25.

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

Author information

1
The Skaggs Institute for Chemical Biology, Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
2
Ludwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
3
Department of Molecular Medicine, The Scripps Research Institute, San Diego, CA, USA.
4
Dorris Neuroscience Center, The Scripps Research Institute, San Diego, CA, USA.
5
Department of Chemistry and Biochemistry, Oberlin College, Oberlin, OH, USA.
6
Vividion Therapeutics, San Diego, CA, USA.
7
Department of Molecular Medicine, The Scripps Research Institute, San Diego, CA, USA. pscheck@scripps.edu.
8
Dorris Neuroscience Center, The Scripps Research Institute, San Diego, CA, USA. pscheck@scripps.edu.
9
The Skaggs Institute for Chemical Biology, Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. lbar-peled@mgh.harvard.edu.
10
The Massachusetts General Hospital Cancer Center, Boston, MA, USA. lbar-peled@mgh.harvard.edu.
11
Deparment of Medicine, Harvard Medical School, Boston, MA, USA. lbar-peled@mgh.harvard.edu.
12
The Skaggs Institute for Chemical Biology, Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. cravatt@scripps.edu.

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 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.

PMID:
30911178
DOI:
10.1038/s41589-019-0243-4

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center