Metabolic Regulation of Longevity by Flavin-containing Monooxygenase 2
Creators: name: Choi, Christopher
Publisher: name: My University
Year: 2022
Subjects: subject: biogerontology
subject: flavin-containing monooxygenase
subject: one-carbon metabolism
subject: metabolic studies in C. elegans
subject: lipid metabolism
subject: Physiology
subject: FOS: Biological sciences
subject: Health Sciences

description: Aging is the greatest risk factor for multiple leading causes of death, such as heart diseases, multiple types of cancer, and Alzheimer’s disease. Aging is thus a growing economic and health concern worldwide as the number of people over the age of 65 continues to increase. Multiple genetic and environmental pathways that slow aging have been discovered using animal models. However, the mechanisms by which these pathways extend lifespan remain largely unclear. Metabolism is a major regulator of longevity whose perturbation can slow aging and promote healthspan and longevity. Previous studies implicate metabolism in multiple longevity pathways, such as insulin signaling, nutrient sensing, and dietary restriction, across multiple organisms, including C. elegans. These findings make understanding the mechanisms of metabolic regulation of longevity a crucial next step. A major challenge to studying metabolism in C. elegans is its reliance on a live bacterial food source. Bacteria have their own metabolic activity that confounds the metabolic changes in C. elegans. While methods of killing bacteria to stop their metabolic activity exist, they make the bacteria inedible, present additional confounding variables or are not practical to use. Using paraformaldehyde (PFA), a crosslinking chemical, we developed a viable method of killing bacteria and stopping their metabolic activity that 1) is edible for the worms, 2) can be used in a high-throughput manner, and 3) does not substantially affect longevity phenotypes. Thus, PFA treatment is a viable way of preventing bacterial metabolism to study C. elegans metabolism. The PFA treatment allowed us to determine the metabolic changes that occur following the expression of fmo-2, a member of the highly conserved enzyme family flavin-containing monooxygenase and a major longevity regulator downstream of multiple pathways, including dietary restriction. Using metabolomics and RNAi knockdown, we determine that fmo-2 interacts with one carbon metabolism (OCM) to influence longevity and stress resistance. OCM is a metabolic network that has been implicated in multiple longevity pathways and is a crucial intermediate network for processes necessary for survival, including nucleotide synthesis, the transsulfuration pathway, and methylation. Using computational modeling, we identify the flux through methylation processes to be reduced in fmo-2 overexpression animals, suggesting that fmo-2 and reduced methylation flux are in the same functional pathway. Our data also identify tryptophan as an endogenous substrate of FMO-2 and implicate the kynurenine pathway as a target of FMO-2 that is likely linked to changes OCM. A potential downstream consequence of the changes in OCM following fmo-2 expression is the induction of endoplasmic reticulum unfolded protein response (UPRER), which is involved in proteostasis and longevity regulation. A reduction in methylation flux can lead to the reduction of phosphatidylcholine (PC) synthesis, which in turn can activate the UPRER. Our data thus far are consistent with a model where FMO-2 reduces PC synthesis to activate the UPRER, thereby promoting longevity and health. My thesis work furthers our understanding of a highly conserved enzyme family whose member serves as a critical convergence point for multiple longevity pathways. In addition, it also furthers our understanding of the metabolic regulation of the aging process and identifies key regulators that can potentially serve as therapeutic targets to slow aging to promote health and longevity.