title: Angiotensin Converting Enzyme (ACE) Inhibitor Extends Caenorhabditis elegans Life Span.
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.
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Dietrich
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Kerry
authors.initials: K
authors.lastname: Kornfeld
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000235:genetics; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D002216:Captopril / Q000494:pharmacology*; D014450:Electron Transport Complex III / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics; D008136:Longevity; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D034622:RNA Interference; D011972:Receptor, Insulin / Q000235:genetics; D037761:Sirtuins / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D029742:Caenorhabditis elegans Proteins; D002216:Captopril; D014450:Electron Transport Complex III; D051858:Forkhead Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D037761:Sirtuins; C481274:ACN-1 protein, C elegans; C108831:daf-16 protein, C elegans; C443102:Isp-1 protein, Caenorhabditis elegans; C100662:AGE-1 protein, C elegans; C107483:DAF-2 protein, C elegans; C507014:SIR-2.1 protein, C elegans