Use of GRADE grid to reach decisions on clinical practice guidelines when consensus is elusive

Abstract

<h3>Abstract</h3> Flavin containing monooxygenases (FMOs) are promiscuous enzymes known for metabolizing a wide range of exogenous compounds. In <i>C. elegans</i>, <i>fmo-2</i> expression increases lifespan and healthspan downstream of multiple longevity-promoting pathways through an unknown mechanism. Here, we report that, contrary to its classification as a xenobiotic enzyme, <i>fmo-2</i> expression leads to rewiring of endogenous metabolism principally through changes in one carbon metabolism (OCM). 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 enzymes. 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 critical role in promoting health and longevity through metabolic remodeling.

Keywords

Affiliated Institutions

• Brown University US
• McMaster University CA
• Cooper University Hospital US
• Oregon Health & Science University US
• Queen Elizabeth Hospital Birmingham GB
• University of Birmingham GB

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