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The role of circulating anti-aging αKlotho in cardiac aging

Dong I Lee1, Dao-Fu Dai2

  • 1Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Cell Signaling
|September 2, 2025
PubMed

Insights

The anti-aging hormone α-Klotho, when supplemented, improves heart function in aged mice by enhancing diastolic function and reducing cardiac damage. This highlights the Klotho-Sirtuin1 pathway as a potential therapeutic target for age-related heart failure.

Area of Science:

  • Cardiology
  • Gerontology
  • Molecular Biology

Background:

  • Aging significantly impairs cardiac function, increasing heart failure prevalence, particularly heart failure with preserved ejection fraction (HFpEF) in the elderly.
  • HFpEF is a major cause of morbidity and mortality in older adults, necessitating novel therapeutic strategies.
  • The anti-aging hormone α-Klotho's role in cardiac health is an emerging area of research.

Purpose of the Study:

  • To investigate the therapeutic potential of soluble Klotho (sKL) in ameliorating age-related cardiac diastolic dysfunction.
  • To elucidate the molecular mechanisms underlying sKL's cardioprotective effects, focusing on the Sirtuin1 (Sirt1) pathway.
  • To assess the impact of sKL on cardiac structure and vascularization in aged hearts.

Main Methods:

  • Utilized aged and Klotho-deficient mouse models to study the effects of aging on cardiac function.
  • Administered soluble Klotho (sKL) supplementation to aged mouse models.
  • Assessed cardiac diastolic function, left ventricular hypertrophy, fibrosis, and capillary density.
  • Investigated the role of Sirtuin1 (Sirt1) in mediating sKL's effects on DNA damage and protein acetylation.

Main Results:

  • Supplementation with soluble Klotho (sKL) significantly improved cardiac diastolic function in aged mice.
  • sKL treatment led to reduced left ventricular hypertrophy and cardiac fibrosis.
  • sKL administration increased capillary density in the aged heart.
  • The cardioprotective effects of sKL were dependent on Sirt1-mediated regulation of DNA damage pathways and cardiac protein acetylation.

Conclusions:

  • Targeting the Klotho-Sirtuin1 axis holds therapeutic promise for treating age-related diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF).
  • Soluble Klotho (sKL) demonstrates significant cardioprotective effects in aged hearts by improving diastolic function and cardiac remodeling.
  • These findings offer new insights into managing cardiovascular diseases associated with aging.

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