Cell nonautonomous activation of flavin-containing monooxygenase promotes longevity and health span

Abstract

Stabilization of the hypoxia-inducible factor-1 (HIF-1) increases lifespan and healthspan in nematodes through an unknown mechanism. We report that neuronal stabilization of HIF-1 mediates these effects in C. elegans through a cell non-autonomous signal to the intestine resulting in activation of the xenobiotic detoxification enzyme flavin-containing monooxygenase-2 (FMO-2). This pro-longevity signal requires the serotonin biosynthetic enzyme TPH-1 in neurons and the serotonin receptor SER-7 in the intestine. Intestinal FMO-2 is also activated by dietary restriction (DR) and necessary for DR-mediated lifespan extension, suggesting that this enzyme represents a point of convergence for two distinct longevity pathways. FMOs are conserved in eukaryotes and induced by multiple lifespan-extending interventions in mice, suggesting that these enzymes may play a critical role in promoting health and longevity across phyla.

NHR‐49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

“…Here, we show that NHR‐49 is also vital for an adaptive transcriptional response to the organic peroxide tBOOH. This response includes the induction of the flavin‐containing monooxygenase fmo‐2 , which is important for dietary restriction‐induced longevity and resistance to several stresses (Leiser et al., 2015), and two other genes, K05B2.4 and sodh‐1 , that we reveal here to be important for resistance to organic peroxide. Moreover, we find that nhr‐49 is also required for the induction of tBOOH‐induced genes by acute fasting.…”

“…Lastly, hlh‐30 ( tm1978 ) mutation only weakly reduced fmo‐2 induction by tBOOH (statistically not significant, Figures 3e and S3b–d). In contrast, hlh‐30 was partially required for fmo‐2 induction by fasting, as reported (Leiser et al., 2015), and for sodh‐1 expression, under both stress and non‐stress conditions (Figures 3e and S3b–d). These data suggest that NHR‐49 and HLH‐30 act in parallel, or that NHR‐49 acts downstream of HLH‐30, to promote the transcriptional response to organic peroxide.…”

“…NHR‐49 and MDT‐15 regulate lipid metabolism and are needed to induce several lipid metabolism genes in fasted worms (Taubert et al., 2006; Van Gilst et al., 2005; Van Gilst, Hadjivassiliou & Yamamoto, 2005). As fmo‐2 is also induced by fasting (Leiser et al., 2015), we tested whether nhr‐49 is required for fmo‐2 induction in fasted worms. Real‐time quantitative PCR (qPCR) analysis showed that fmo‐2 mRNA levels are strongly induced by tBOOH and by fasting, and this induction was blocked in nhr‐49 ( nr2041 ) null mutants (Figure 1c,d).…”

“…The intestinal induction of fmo‐ 2 by fasting or hypoxia requires the transcription factors hlh‐30/TFEB and hif‐1/HIF (Leiser et al., 2015), master regulators of C. elegans autophagy, and hypoxia gene programs, respectively (Lapierre et al., 2013; O'Rourke & Ruvkun, 2013; Powell‐Coffman, 2010). Moreover, hlh‐30 is required for the long lifespan of glp‐1 ( e2141 ) mutants (Nakamura et al., 2016).…”

“…One of the most highly tBOOH‐induced, mdt‐15 ‐dependent, skn‐1 ‐independent genes is the flavin‐containing monooxygenase fmo‐2 , whose HIF‐1‐dependent induction in response to hypoxia and dietary restriction (DR) is important for the associated increase in lifespan. Indeed, fmo‐2 is induced in several C. elegans longevity paradigms (Bennett et al., 2017; Leiser et al., 2015). Elucidating how fmo‐2 and other genes induced under these conditions are regulated is important to understand how these responses become defective during aging or in disease (Hekimi et al., 2011; Hetz et al., 2013; Lin & Beal, 2006; Shore & Ruvkun, 2013).…”