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 Caenorhabdtitis 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.
Highlights
Animal aging is characterized by progressive, degenerative changes of tissue structure and function
We discovered that reducing the activity of acn-1 caused a robust extension of lifespan and delayed age-related changes in C. elegans
These results identify a new drug and a new gene that influence aging in C. elegans
Summary
Animal aging is characterized by progressive, degenerative changes of tissue structure and function. A growing number of interventions have been demonstrated to delay age-related degeneration and extend lifespan in model animals such as worms, flies and mice [1]. These interventions include dietary changes such as caloric restriction, genetic changes such as reducing the activity of the insulin/insulin-like growth factor-1 (IGF-1) signaling pathway, and drugs such as rapamycin. These studies indicate that pathways that influence aging have been conserved during animal evolution [1]. Model organisms are promising systems to identify and characterize interventions that promote healthy aging and may be beneficial in humans
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