FMO rewires metabolism to promote longevity through tryptophan and one carbon metabolism
FMO rewires metabolism to promote longevity through tryptophan and one carbon metabolism
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, contrary to its classification as a xenobiotic enzyme, fmo-2 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.
Choi Hyo Sub、Howington Marshall B.、Schaller Megan L.、Huang Shijiao、Miller Hillary A.、Evans Charles R.、Mecano Joy、Dean Elizabeth S.、Cox Rebecca、Bhat Ajay、Jensen Lindy、Beydoun Safa、Beard Daniel A.、Leiser Scott F.、Tuckowski Angela M.
Department of Molecular and Integrative Physiology, University of MichiganCellular and Molecular Biology Program, University of MichiganDepartment of Molecular and Integrative Physiology, University of MichiganDepartment of Molecular and Integrative Physiology, University of MichiganCellular and Molecular Biology Program, University of MichiganDepartment of Internal Medicine, University of MichiganDepartment of Molecular and Integrative Physiology, University of MichiganDepartment of Molecular and Integrative Physiology, University of MichiganDepartment of Molecular and Integrative Physiology, University of MichiganDepartment of Molecular and Integrative Physiology, University of MichiganDepartment of Molecular and Integrative Physiology, University of MichiganDepartment of Molecular and Integrative Physiology, University of MichiganDepartment of Molecular and Integrative Physiology, University of MichiganDepartment of Molecular and Integrative Physiology, University of Michigan||Department of Internal Medicine, University of MichiganCellular and Molecular Biology Program, University of Michigan
基础医学生物化学分子生物学
agingmetabolismflavin containing monooxygenaseone carbon metabolismtryptophankynureninestress resistancelifespan
Choi Hyo Sub,Howington Marshall B.,Schaller Megan L.,Huang Shijiao,Miller Hillary A.,Evans Charles R.,Mecano Joy,Dean Elizabeth S.,Cox Rebecca,Bhat Ajay,Jensen Lindy,Beydoun Safa,Beard Daniel A.,Leiser Scott F.,Tuckowski Angela M..FMO rewires metabolism to promote longevity through tryptophan and one carbon metabolism[EB/OL].(2025-03-28)[2025-05-09].https://www.biorxiv.org/content/10.1101/2021.06.18.449022.点此复制
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