Angiotensin Converting Enzyme (ACE) Inhibitor Extends Caenorhabditis elegans Life Span

PLoS Genet. 2016 Feb 26;12(2):e1005866. doi: 10.1371/journal.pgen.1005866. eCollection 2016 Feb.

Abstract

Animal aging is characterized by progressive, degenerative changes in many organ systems. Because age-related degeneration is a major contributor to disability and death in humans, treatments that delay age-related degeneration are desirable. However, no drugs that delay normal human aging are currently available. To identify drugs that delay age-related degeneration, we used the powerful Caenorhabditis elegans model system to screen for FDA-approved drugs that can extend the adult lifespan of worms. Here we show that captopril extended mean lifespan. Captopril is an angiotensin-converting enzyme (ACE) inhibitor used to treat high blood pressure in humans. To explore the mechanism of captopril, we analyzed the acn-1 gene that encodes the C. elegans homolog of ACE. Reducing the activity of acn-1 extended the mean life span. Furthermore, reducing the activity of acn-1 delayed age-related degenerative changes and increased stress resistance, indicating that acn-1 influences aging. Captopril could not further extend the lifespan of animals with reduced acn-1, suggesting they function in the same pathway; we propose that captopril inhibits acn-1 to extend lifespan. To define the relationship with previously characterized longevity pathways, we analyzed mutant animals. The lifespan extension caused by reducing the activity of acn-1 was additive with caloric restriction and mitochondrial insufficiency, and did not require sir-2.1, hsf-1 or rict-1, suggesting that acn-1 functions by a distinct mechanism. The interactions with the insulin/IGF-1 pathway were complex, since the lifespan extensions caused by captopril and reducing acn-1 activity were additive with daf-2 and age-1 but required daf-16. Captopril treatment and reducing acn-1 activity caused similar effects in a wide range of genetic backgrounds, consistent with the model that they act by the same mechanism. These results identify a new drug and a new gene that can extend the lifespan of worms and suggest new therapeutic strategies for addressing age-related degenerative changes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / drug effects*
  • Aging / genetics
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology*
  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans / drug effects*
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / antagonists & inhibitors
  • Caenorhabditis elegans Proteins / genetics*
  • Captopril / pharmacology*
  • Electron Transport Complex III / genetics
  • Forkhead Transcription Factors / genetics
  • Longevity
  • Mutation
  • Phosphatidylinositol 3-Kinases / genetics
  • RNA Interference
  • Receptor, Insulin / genetics
  • Sirtuins / genetics
  • Stress, Physiological / genetics

Substances

  • ACN-1 protein, C elegans
  • Angiotensin-Converting Enzyme Inhibitors
  • Caenorhabditis elegans Proteins
  • Forkhead Transcription Factors
  • daf-16 protein, C elegans
  • Captopril
  • Isp-1 protein, Caenorhabditis elegans
  • AGE-1 protein, C elegans
  • DAF-2 protein, C elegans
  • Receptor, Insulin
  • SIR-2.1 protein, C elegans
  • Sirtuins
  • Electron Transport Complex III