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The ACE inhibitor captopril inhibits ACN-1 to control dauer formation and aging.
- Source :
-
Development (Cambridge, England) [Development] 2024 Feb 01; Vol. 151 (3). Date of Electronic Publication: 2024 Feb 12. - Publication Year :
- 2024
-
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 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 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 RNA interference promoted dauer larvae formation, suggesting that acn-1 is a daf gene. Captopril-mediated 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.<br />Competing Interests: Competing interests The authors declare no competing or financial interests.<br /> (© 2024. Published by The Company of Biologists Ltd.)
- Subjects :
- Animals
Humans
Mice
Caenorhabditis elegans metabolism
Angiotensin-Converting Enzyme Inhibitors pharmacology
Angiotensin-Converting Enzyme Inhibitors metabolism
Aging
Longevity physiology
Receptor, Insulin metabolism
Mutation genetics
Mammals metabolism
Captopril pharmacology
Captopril metabolism
Caenorhabditis elegans Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1477-9129
- Volume :
- 151
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Development (Cambridge, England)
- Publication Type :
- Academic Journal
- Accession number :
- 38284547
- Full Text :
- https://doi.org/10.1242/dev.202146