FMO rewires metabolism to promote longevity through tryptophan and one carbon metabolism in C. elegans

Hyo Sub Choi, Ajay Bhat, Marshall B. Howington, Megan L. Schaller, Rebecca L. Cox, Shijiao Huang, Safa Beydoun, Hillary A. Miller, Angela M. Tuckowski, Joy Mecano, Elizabeth S. Dean, Lindy Jensen, Daniel A. Beard, Charles R. Evans and Scott F. Leiser ()
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Hyo Sub Choi: University of Michigan
Ajay Bhat: University of Michigan
Marshall B. Howington: University of Michigan
Megan L. Schaller: University of Michigan
Rebecca L. Cox: University of Michigan
Shijiao Huang: University of Michigan
Safa Beydoun: University of Michigan
Hillary A. Miller: University of Michigan
Angela M. Tuckowski: University of Michigan
Joy Mecano: University of Michigan
Elizabeth S. Dean: University of Michigan
Lindy Jensen: University of Michigan
Daniel A. Beard: University of Michigan
Charles R. Evans: University of Michigan
Scott F. Leiser: University of Michigan

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Flavin containing monooxygenases (FMOs) are promiscuous enzymes known for metabolizing a wide range of exogenous compounds. In C. elegans, fmo-2 expression increases lifespan and healthspan downstream of multiple longevity-promoting pathways through an unknown mechanism. Here, we report that, beyond its classification as a xenobiotic enzyme, fmo-2 expression leads to rewiring of endogenous metabolism principally through changes in one carbon metabolism (OCM). These changes are likely relevant, as we find that genetically modifying OCM enzyme expression leads to alterations in longevity that interact with fmo-2 expression. Using computer modeling, we identify decreased methylation as the major OCM flux modified by FMO-2 that is sufficient to recapitulate its longevity benefits. We further find that tryptophan is decreased in multiple mammalian FMO overexpression models and is a validated substrate for FMO-2. Our resulting model connects a single enzyme to two previously unconnected key metabolic pathways and provides a framework for the metabolic interconnectivity of longevity-promoting pathways such as dietary restriction. FMOs are well-conserved enzymes that are also induced by lifespan-extending interventions in mice, supporting a conserved and important role in promoting health and longevity through metabolic remodeling.

Date: 2023
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DOI: 10.1038/s41467-023-36181-0

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