Klotho enhances diastolic function in aged hearts through Sirt1-mediated pathways

Area of Science:

• Cardiovascular Biology
• Aging Research
• Molecular Mechanisms of Disease

Background:

• Aging causes cardiac functional decline, increasing heart failure with preserved ejection fraction (HFpEF) risk.
• α-Klotho is an anti-aging hormone with potential roles in cardiovascular health.
• Diastolic dysfunction is a key feature of HFpEF, often associated with aging.

Purpose of the Study:

• To investigate the impact of α-Klotho on age-related cardiac diastolic dysfunction.
• To explore the downstream molecular mechanisms, particularly the Sirtuin1 (Sirt1) pathway, linking Klotho to cardiac function.
• To assess the therapeutic potential of soluble α-Klotho (sKL) supplementation in an aging mouse model.

Main Methods:

• Aged wild-type and Klotho-deficient mice were treated with daily sKL injections for 10 weeks.
• Cardiac function was comprehensively evaluated using echocardiography, intracardiac pressure catheterization, and exercise tolerance tests.
• Proteomic and acetylomic analyses were employed to identify molecular changes in cardiac proteins, focusing on DNA damage and acetylation patterns.

Main Results:

• Klotho deficiency exacerbated cardiac hypertrophy, diastolic dysfunction, and exercise intolerance in aged mice.
• sKL treatment ameliorated these age-associated cardiac abnormalities and improved capillary density.
• sKL supplementation restored Sirtuin1 (Sirt1) expression, mitigated DNA damage response, and reduced hyperacetylation of key cardiac proteins, including contractile elements.

Conclusions:

• Klotho deficiency impairs cardiac diastolic function, partly through Sirt1 deficiency and increased protein hyperacetylation, contributing to HFpEF.
• Soluble α-Klotho (sKL) supplementation demonstrates therapeutic potential by attenuating age-dependent cardiac dysfunction and DNA damage.
• sKL may represent a promising therapeutic strategy for combating age-related HFpEF.