Research into the biochemistry of longevity does not proceed at a rapid pace, even now that the field has become popular. Much of this research takes the form of first discovering longevity-enhancing mutations in short-lived species and then painstakingly tracing chains of cause and effect from protein to protein and interaction to interaction. Since cellular metabolism is by no means fully understood, even in the extremely well studied nematode worm C. elegans, this takes a long time. For example, we can see that is has taken thirty years or so to move from the first C. elegans longevity-enhancing mutation to the discovery of many more, and now here finding that some of these mutations converge on the activity of the FMO-2 gene. This slow pace of increased understanding is one of the reasons why manipulating the operation of cellular metabolism to slow the pace of aging seems a poor choice of primary goal for research and development, versus the alternative approach of finding specific forms of damage and attempting to repair them.
A mild impairment of mitochondrial function activates the hypoxia inducible factor (HIF-1)-mediated hypoxia stress response pathway leading to a HIF-1-dependent increase in lifespan. Lifespan extension resulting from HIF-1 stabilization is dependent on activation of flavin-containing monooxygenase-2 (FMO-2). In this work, we explored the role of fmo-2 in the long lifespan of genetic mitochondrial mutants in C. elegans. We found that fmo-2, but not other fmo genes, are specifically upregulated in the long-lived mitochondrial mutants clk-1, isp-1, and nuo-6. Disruption of fmo-2 through RNA interference or genetic mutation shortens the lifespan of these mitochondrial mutants indicating that fmo-2 is required for lifespan extension in these worms.
Moreover, signaling molecules that have been shown to be involved in upregulation of fmo-2 are also required for the long life of clk-1, isp-1, and nuo-6 mutants including HLH-30, NHR-49, and MDT-15. Finally, we examined the effect of multiple lifespan-promoting pathways in clk-1 mutants on the expression of fmo-2. We found that in all cases, genes required for clk-1 longevity are also required for the upregulation of fmo-2 in clk-1 worms. These genes included DAF-16, PMK-1, SKN-1, CEH-23, AAK-2, HIF-1 and ELT-2. Combined, this work advances our understanding of the molecular mechanisms contributing to longevity in the long-lived mitochondrial mutants and identifies FMO-2 as a common downstream effector of multiple pathways that modulate longevity.
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