Knocking down tph-1, the rate-limiting enzyme in serotonin production, inhibits fmo-2 induction (*p<.05 compared to vector DR).
Data from Miller et al. 2017 Aging Cell.
The Leiser lab has previously shown that flavin-containing monooxygenase (fmo)-2 in C. elegans is required downstream of the hypoxic response and dietary restriction (DR) to extend lifespan and improve healthspan. Moreover, fmo-2 induction is sufficient to confer these benefits. As there are five C. elegans FMOs, we were curious to know if any of the other FMOs are also regulators of aging. This project focuses on C. elegans FMO-4 in the context of longevity and stress resistance. FMO-4 is structurally similar to FMO-2, with 88% conservation in catalytic residues, and we have found that it is also required for health benefits in multiple longevity pathways, including DR. Interestingly, fmo-4 is required for fmo-2-mediated longevity and is both required and sufficient to improve stress resistance downstream of fmo-2. However, while fmo-2 is required for the hypoxic response and DR-mediated longevity, fmo-4 is only required for some forms of DR-mediated longevity. Our most recent data show that fmo-4 is required for and downstream of atf-6-mediated longevity, which has implications in stress response and calcium signaling. Taken together, these data lead us to hypothesize that fmo-4 has both overlapping and distinct functions from fmo-2 and predict that fmo-4 promotes healthy aging by regulating calcium signaling and stress response. Going forward, this project will focus on fmo-4 and its interactions with fmo-2 as well as other longevity pathways, the distinct functions of fmo-4, and the downstream metabolic processes being altered by fmo-4 to regulate longevity.