The ACE-inhibitor drug captopril inhibits ACN-1 to control dauer formation and aging

Egan, B. M.; Pohl, F.; Anderson, X.; Williams, S. C.; Adodo, I. G.; Hunt, P.; Wang, Z.; Chiu, C.-H.; Scharf, A.; Mosley, M.; Kumar, S.; Schneider, D. L.; Fujiwara, H.; Hsu, F.-F.; Kornfeld, K.

doi:10.1101/2023.07.17.549402

bioRxiv · 10.1101/2023.07.17.549402

The ACE-inhibitor drug captopril inhibits ACN-1 to control dauer formation and aging

Egan, B. M.·Pohl, F.·Anderson, X.·Williams, S. C.·Adodo, I. G.·Hunt, P.·Wang, Z.·Chiu, C.-H.·Scharf, A.·Mosley, M.·Kumar, S.·Schneider, D. L.·Fujiwara, H.·Hsu, F.-F.·Kornfeld, K.

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Abstract

The renin-angiotensin-aldosterone system (RAAS) plays a well-characterized role regulating blood pressure in mammals. Pharmacological and genetic manipulation of the RAAS has been shown to extend lifespan in C. elegans, Drosophila, and rodents, but its mechanism is not well defined. Here we investigate the angiotensin-converting enzyme (ACE) inhibitor drug captopril, which extends lifespan in worms and mice. To investigate the mechanism, we performed a forward genetic screen for captopril hypersensitive mutants. We identified a missense mutation that causes a partial loss-of-function of the daf-2 receptor tyrosine kinase gene, a powerful regulator of aging. The homologous mutation in the human insulin receptor causes Donohue syndrome, establishing these mutant worms as an invertebrate model of this disease. Captopril functions in C. elegans by inhibiting ACN-1, the worm homolog of ACE. Reducing the activity of acn-1 via captopril or RNAi promoted dauer larvae formation, suggesting acn-1 is a daf gene. Captopril-mediated lifespan extension xwas abrogated by daf-16(lf) and daf-12(lf) mutations. Our results indicate that captopril and acn-1 control aging by modulating dauer formation pathways. We speculate that this represents a conserved mechanism of lifespan control. Summary StatementCaptopril and acn-1 control aging. By demonstrating they regulate dauer formation and interact with daf genes, including a new DAF-2(A261V) mutant corresponding to a human disease variant, we clarified the mechanism.

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Egan, B. M., Pohl, F., Anderson, X., Williams, S. C., Adodo, I. G., Hunt, P., Wang, Z., Chiu, C.-H., Scharf, A., Mosley, M., Kumar, S., Schneider, D. L., Fujiwara, H., Hsu, F.-F., Kornfeld, K.. 2023-07-19. The ACE-inhibitor drug captopril inhibits ACN-1 to control dauer formation and aging. https://doi.org/10.1101/2023.07.17.549402

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