Use of GRADE grid to reach decisions on clinical practice guidelines when consensus is elusive
2008; BMJ; Volume: 337; Issue: jul31 1 Linguagem: Inglês
10.1136/bmj.a744
ISSN0959-8138
AutoresRoman Jaeschke, Gordon Guyatt, Phillip Dellinger, Holger J. Schünemann, Mitchell Levy, Regina Kunz, Susan L. Norris, Julian Bion,
Tópico(s)Climate Change and Health Impacts
ResumoAbstract 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.
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