fmo-4promotes longevity and stress resistance via ER to mitochondria calcium regulation inC. elegans

Flavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports thatC. elegans fmo-2promotes longevity, stress resistance, and healthspan by rewiring endogenous metabolism. However, there are fiveC. elegansFMOs and five mammalian FMOs, and it is not known whether promoting longevity and health benefits is a conserved role of this gene family. Here, we report that expression ofC. elegans fmo-4promotes lifespan extension and paraquat stress resistance downstream of both dietary restriction and inhibition of mTOR. We find that overexpression offmo-4in just the hypodermis is sufficient for these benefits, and that this expression significantly modifies the transcriptome. By analyzing changes in gene expression, we find that genes related to calcium signaling are significantly altered downstream offmo-4expression. Highlighting the importance of calcium homeostasis in this pathway,fmo-4overexpressing animals are sensitive to thapsigargin, an ER stressor that inhibits calcium flux from the cytosol to the ER lumen. This calcium/fmo-4interaction is solidified by data showing that modulating intracellular calcium with either small molecules or genetics can change expression offmo-4and/or interact withfmo-4to affect lifespan and stress resistance. Further analysis supports a pathway wherefmo-4modulates calcium homeostasis downstream of activating transcription factor-6 (atf-6), whose knockdown induces and requiresfmo-4expression. Together, our data identifyfmo-4as a longevity-promoting gene whose actions interact with known longevity pathways and calcium homeostasis.