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Comments on Allen, Parker et al. (2021) International Worm Meeting "Role of the conserved cholinesterase family member CEST-1.1 and its modular metabolite products in life span control" (0)
Overview
Allen, Parker, Hu, Patrick, Schroeder, Frank, Wrobel, Chester, Curtis, Brian, Kruempel, Joseph, & Higgins-Chen, Albert (2021). Role of the conserved cholinesterase family member CEST-1.1 and its modular metabolite products in life span control presented in International Worm Meeting. Unpublished information; cite only with author permission.
Although the role of the C. elegans FoxO transcription factor DAF-16 in promoting longevity is well established, how DAF-16/FoxO extends life span remains poorly understood. While the identities of thousands of DAF-16/FoxO target genes are known, mechanistic links between DAF-16/FoxO-dependent regulation of specific genes and DAF-16/FoxO-dependent life span extension are lacking. We have discovered that a conserved cholinesterase family member encoded by the DAF-16/FoxO target gene cest-1.1 is required for full life span extension in the context of reduced DAF-2 insulin-like signaling and sufficient to extend life span when expressed in a wild-type background. A functional CEST-1.1::GFP fusion protein is expressed specifically in the intestine and localizes to the apical plasma membrane. Comparative metabolomic analysis using HPLC-high resolution mass spectrometry revealed that CEST-1.1 is required for the biosynthesis of two structurally novel nucleoside-like ascarosides termed uglas#1 and uglas#11. These surprising findings support a role for an unprecedented class of metabolites in life span control and orthogonally expand the landscape of biogenic small molecules that may influence aging.
Affiliations:
- University of Michigan Medical School, Ann Arbor, MI
- Yale School of Medicine, New Haven, CT
- Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY
- Vanderbilt University Medical Center, Nashville, TN