Targeting age-related LINE-1 activation alleviates cardiac aging.

Area of Science:

• Cardiology
• Molecular Biology
• Aging Research

Background:

• Cardiac aging contributes significantly to cardiovascular diseases and mortality.
• The role of long interspersed nuclear element-1 (LINE-1) retrotransposons in cardiac aging is not well understood.
• LINE-1 elements are known to induce cellular senescence.

Purpose of the Study:

• To investigate the role of LINE-1 retrotransposons in cardiac aging.
• To explore the potential therapeutic targets for age-related cardiac dysfunction.

Main Methods:

• Generated cardiomyocyte-specific Mov10-knockout mice to study LINE-1 regulation in the heart.
• Assessed cardiac function, aging phenotypes, and cGAS-STING pathway activation.
• Utilized pharmacological inhibitors of LINE-1 reverse transcription (3TC) and STING (H-151) in cell and animal models.

Main Results:

• LINE-1 expression increased with age in the heart.
• Mov10-knockout mice exhibited LINE-1 derepression, cardiac dysfunction, and premature cardiac aging.
• Inhibition of LINE-1 or STING attenuated senescence and improved cardiac function in both cell and aged mouse models.
• cGAS-STING activation was identified as a key mediator in LINE-1-induced cardiac aging.

Conclusions:

• LINE-1 retrotransposons are a significant driver of cardiac aging via cGAS-STING pathway activation.
• Targeting LINE-1 and its downstream effectors presents a promising therapeutic strategy for age-related cardiac dysfunction.