FMO rewires metabolism to promote longevity throughtryptophan and one carbon metabolism
Choi, H. S.; Bhat, A.; Howington, M. B.; Schaller, M. L.; Cox, R.; Huang, S.; Beydoun, S.; Miller, H. A.; Tuckowski, A. M.; Mecano, J.; Dean, E. S.; Jensen, L.; Beard, D. A.; Evans, C. R.; Leiser, S. F.
Show 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.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- PQM-1 controls hypoxic survival via regulation of lipid metabolism 97%
- The 18S rRNA Methyltransferase DIMT-1 Regulates Lifespan in the Germline Later in Life 97%
- Systems biology and machine learning approaches identify metabolites that influence dietary lifespan and healthspan responses across flies and humans. 96%
Similar papers in this journal
- fmo-4 promotes longevity and stress resistance via ER to mitochondria calcium regulation in C. elegans 97%
- Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing neuronal human amyloid-β 97%
- Overexpression of Ssd1 and calorie restriction extend yeast replicative lifespan by preventing deleterious age-dependent iron uptake 96%
Similar papers in this journal
- Serotonin signaling modulates aging-associated metabolic network integrity in response to nutrient choice 97%
- Gut microbiota-mediated lipid accumulation as a driver of evolutionary adaptation to blue light toxicity in Drosophila 94%
- Lifespan prolonging mechanisms and insulin upregulation without fat accumulation in long-lived reproductives of a higher termite 94%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.