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

Abstract

AbstractThe 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 inC. 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 thedaf-2receptor 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 inC. elegansby inhibiting ACN-1, the worm homolog of ACE. Reducing the activity ofacn-1via captopril or RNAi promoted dauer larvae formation, suggestingacn-1is adafgene. Captopril-mediated lifespan extension xwas abrogated bydaf-16(lf)anddaf-12(lf)mutations. Our results indicate that captopril andacn-1control aging by modulating dauer formation pathways. We speculate that this represents a conserved mechanism of lifespan control.Summary StatementCaptopril andacn-1control aging. By demonstrating they regulate dauer formation and interact withdafgenes, including a new DAF-2(A261V) mutant corresponding to a human disease variant, we clarified the mechanism.