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Published on: November 26, 2017
Targeting age-related LINE-1 activation alleviates cardiac aging
Chaofan Yang1,2,3, Heng Du1,2,3, Siqi Liu1,2,3
1State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Insights
Long interspersed nuclear element-1 (LINE-1) retrotransposons drive cardiac aging and dysfunction through cGAS-STING activation. Inhibiting LINE-1 or STING shows therapeutic potential for age-related heart conditions.
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.
Abstract:
Cardiac aging is a major driver of cardiovascular diseases and associated mortality, yet its therapeutic options are limited. While long interspersed nuclear element-1 (LINE-1) retrotransposons are known to drive cellular senescence, their role in cardiac aging is poorly defined. Here we showed that LINE-1 expression increased in the heart with age. To investigate their role in cardiac aging, we generated cardiomyocyte-specific Mov10-knockout mice, which failed to suppress LINE-1. These mice developed LINE-1 derepression, cardiac dysfunction and premature cardiac aging by 3 months of age, accompanied by cGAS-STING activation. Pharmacological inhibition of LINE-1 reverse transcription (with 3TC) or STING (with H-151) suppressed cGAS-STING activation and attenuated senescence in Mov10-knockout H9C2 cells. Notably, both inhibitors improved cardiac function and reduced cardiac inflammation and senescence phenotypes in naturally aged mice. Together, our findings establish LINE-1 as a driver of cardiac aging via cGAS-STING activation, highlighting LINE-1 and its downstream effectors as therapeutic targets for age-related cardiac dysfunction.
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