Fmo induction as a tool to screen for pro-longevity drugs

Area of Science:

• Biochemistry
• Genetics
• Gerontology

Background:

• Dietary restriction (DR) and hypoxia are known longevity pathways in C. elegans.
• These pathways converge on the induction of the flavin-containing monooxygenase gene, fmo-2.
• FMOs are conserved enzymes with potential roles in mammalian longevity.

Purpose of the Study:

• To screen compounds for their ability to induce fmo-2 expression.
• To identify small molecules that activate longevity pathways.
• To investigate the mechanisms of DR- and hypoxia-mediated fmo-2 induction.

Main Methods:

• Utilized an fmo-2 fluorescent transcriptional reporter in C. elegans.
• Screened 80 compounds known to improve stress resistance in mouse fibroblasts.
• Assessed compound effects on fmo-2 induction and C. elegans lifespan.

Main Results:

• 19 out of 80 compounds significantly induced fmo-2 expression.
• 10 compounds induced fmo-2 more than twofold.
• 9 of these compounds also extended lifespan in C. elegans.
• Mitochondrial inhibitors and DRD2 antagonists were identified as inducers of fmo-2, revealing links to hypoxia and dopamine signaling pathways.

Conclusions:

• fmo-2 induction is a viable strategy for identifying potential longevity compounds.
• Nine identified drugs enhance stress resistance, induce fmo-2, and extend lifespan.
• Dopamine signaling plays a role in DR-mediated fmo-2 induction.