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

Brian M. Egan, Franziska Pohl, Xavier Anderson, Shoshana C. Williams, Imienreluefe Gregory Adodo, Patrick Hunt, Zuoxu Wang, Chen Hao Chiu, Andrea Scharf, Matthew Mosley, Sandeep Kumar, Daniel L. Schneider, Hideji Fujiwara, Fong Fu Hsu, Kerry Kornfeld

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1-16
Number of pages16
JournalDevelopment (Cambridge)
Volume151
Issue number3
DOIs
StatePublished - 2024

Keywords

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

Fingerprint

Dive into the research topics of 'The ACE inhibitor captopril inhibits ACN-1 to control dauer formation and aging'. Together they form a unique fingerprint.

Cite this