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

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. Flavin containing monooxygenase 2 (FMO-2) is known to increase lifespan under dietary restriction through incompletely understood mechanisms. Here the authors report that FMO-2 modifies tryptophan and methionine metabolic pathways to enhance stress resistance and slow aging in C. elegans.

Automated summary

This study reveals that FMO-2 modifies endogenous metabolism through changes in one carbon metabolism, leading to increased lifespan and healthspan in C. elegans. Decreased methylation is identified as the major flux modified by FMO-2, which is sufficient to recapitulate its longevity benefits. It is also found that tryptophan, a validated substrate for FMO-2, is decreased in multiple mammalian FMO overexpression models. The study highlights the importance of FMOs in promoting health and longevity through metabolic remodeling.