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Preserved cardiac function by vinculin enhances glucose oxidation and extends health- and life-span.

ABSTRACT: Despite limited regenerative capacity as we age, cardiomyocytes maintain their function in part through compensatory mechanisms, e.g., Vinculin reinforcement of intercalated discs in aged organisms. This mechanism, which is conserved from flies to non-human primates, creates a more crystalline sarcomere lattice that extends lifespan, but systemic connections between the cardiac sarcomere structure and lifespan extension are not apparent. Using the rapidly aging fly system, we found that cardiac-specific Vinculin-overexpression [Vinculin heart-enhanced (VincHE)] increases heart contractility, maximal cardiac mitochondrial respiration, and organismal fitness with age. Systemic metabolism also dramatically changed with age and VincHE; steady state sugar concentrations, as well as aerobic glucose metabolism, increase in VincHE and suggest enhanced energy substrate utilization with increased cardiac performance. When cardiac stress was induced with the complex I inhibitor rotenone, VincHE hearts sustain contractions unlike controls. This work establishes a new link between the cardiac cytoskeleton and systemic glucose utilization and protects mitochondrial function from external stress.

SUBMITTER: Sessions AO

PROVIDER: S-EPMC6086353 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Preserved cardiac function by vinculin enhances glucose oxidation and extends health- and life-span.

Sessions Ayla O AO Min Peter P Cordes Thekla T Weickert Barry J BJ Divakaruni Ajit S AS Murphy Anne N AN Metallo Christian M CM Engler Adam J AJ

APL bioengineering 20180717 3

Despite limited regenerative capacity as we age, cardiomyocytes maintain their function in part through compensatory mechanisms, e.g., Vinculin reinforcement of intercalated discs in aged organisms. This mechanism, which is conserved from flies to non-human primates, creates a more crystalline sarcomere lattice that extends lifespan, but systemic connections between the cardiac sarcomere structure and lifespan extension are not apparent. Using the rapidly aging fly system, we found that cardiac- ...[more]

PMID: 30105314

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Project description: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.

Dataset Information

Preserved cardiac function by vinculin enhances glucose oxidation and extends health- and life-span.

Publications

Preserved cardiac function by vinculin enhances glucose oxidation and extends health- and life-span.

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