The ACE Inhibitor Captopril Inhibits ACN-1 To Control Dauer Formation And Aging

Abstract

The renin-angiotensin-aldosterone system (RAAS) plays a wellcharacterized role regulating blood pressure in mammals. Pharmacological and genetic manipulation of the RAAS has been shown to extend lifespan in Caenorhabditis 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 inworms andmice. To investigate themechanism, 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 thesemutant 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 RNA interference promoted dauer larvae formation, suggesting that acn-1 is a daf gene. Captoprilmediated lifespan extension was abrogated by daf-16(lf) and daf-12(lf) mutations. Our results indicate that captopril and acn-1 influence lifespan by modulating dauer formation pathways. We speculate that this represents a conserved mechanism of lifespan control.

Department(s)

Biological Sciences

Comments

National Institutes of Health, Grant 5T32GM007067-44

Keywords and Phrases

acn-1; Aging; C. elegans; Captopril; daf-2; Dauer

International Standard Serial Number (ISSN)

1477-9129; 0950-1991

Document Type

Article - Journal

Document Version

Final Version

File Type

text

Language(s)

English

Rights

© 2024 The Authors, All rights reserved.

Publication Date

01 Jan 2024

PubMed ID

38284547

Link to Full Text

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