Regulation of Longevity by Flavin-Containing Monooxygenases
Creators: name: Howington, Marshall
Publisher: name: My University
Year: 2022
Subjects: subject: biogerontology
subject: aging
subject: stress resistance
subject: longevity
subject: flavin-containing monooxygenases
subject: Molecular, Cellular and Developmental Biology
subject: Science

description: As the average age of the world’s population skews older, improving human healthspan and lifespan has become a priority. To that end, biogerontology focuses on identifying the genes and pathways that influence aging using model animals, such as mice and the nematode, Caenorhabditis elegans, with the ultimate goal of identifying therapeutic targets to extend lifespan and healthspan. Our previous work established C. elegans flavin-containing monooxygenase-2 (fmo-2) as 1) necessary and sufficient to increase lifespan downstream of dietary restriction and hypoxia-mediated longevity and 2) sufficient to increase resistance to many toxic stresses. fmo-2 encodes for a protein that is most likely an ER transmembrane protein, like mammalian FMOs, and shares ~88% of its catalytic residues with mammalian FMO5 and C. elegans FMO-1 and FMO- 4. Consequently, our central hypothesis is that the regulation of stress resistance and longevity is a conserved property of C. elegans and mammalian FMOs. To that end, we initially hypothesized that overexpression of mouse FMOs in mammalian cell lines would also convey stress resistance. We find that mouse FMO overexpression conveys broad stress resistance against heavy metal, oxidative, ER, and UV stresses. We further find that FMO overexpression results in a shift from carbohydrate metabolism to mitochondrial metabolism and that FMOs regulate multiple endogenous metabolic pathways, including central carbon metabolism, essential amino acid metabolism, and energy metabolism. These data establish a conserved stress resistance role for FMOs. Since mammalian FMO overexpression regulates cellular metabolism, we hypothesized that nematode fmo-2 overexpression would regulate endogenous metabolism and that one or more of these metabolic pathways would be required for fmo-2-mediated longevity. We find that fmo-2 interacts with one carbon metabolism to regulate longevity through modulations of the transmethylation pathway. We also find that fmo-2 interacts with tryptophan metabolism and the kynurenine pathway to regulate longevity as well. Last, due to one carbon metabolism and the kynurenine pathway regulating stress and longevity differently, we conclude that fmo-2 likely regulates longevity and stress resistance through separable pathways. Ultimately, we determine that fmo-2 regulates endogenous metabolism to affect stress resistance, like mammalian FMOs, and that these metabolic effects are also required for longevity. C. elegans have two other fmos that encode for ER transmembrane proteins, fmo-1 and fmo-4. Since these are induced similarly to fmo-2 in multiple longevity pathways (e.g dietary restriction and hypoxia), we hypothesized that these fmos would also be necessary and sufficient to increase longevity downstream of these pathways. Interestingly, we find that both fmo-1 and fmo-4 are required multiple longevity pathways, including sDR, IF, and fmo-2 overexpression-mediated longevity. When overexpressed, fmo-1 and fmo-4 are sufficient to increase longevity, and fmo-4 is sufficient to increase oxidative stress resistance. Nematode fmos regulate multiple overlapping and distinct metabolic pathways with mammalian Fmos, such as glutathione metabolism, cysteine and methionine metabolism, and energy metabolism. We conclude that fmo-1 and fmo-4 function downstream of fmo-2 in regulation longevity and stress resistance, but the exact genetic and metabolic mechanisms of these pathways remain under investigation. Collectively, these findings enhance our understanding of conserved FMO roles, including stress resistance and regulation of endogenous metabolic pathways. Further, these findings establish FMOs as regulators of C. elegans longevity with future work aiming to determine if this role also extends to mammalian FMOs with the long-term goal of identifying therapeutic targets that increase human healthspan and lifespan.