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<p>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 <i>Mov10</i>-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 <i>Mov10</i>-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.</p>

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Targeting age-related LINE-1 activation alleviates cardiac aging

  • 期刊论文

  • 发表日期：

    2026年1月22日

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  • Chaofan Yang,
  • Heng Du,
  • Siqi Liu,
  • Pengfei Xu,
  • Yuhan Wang,
  • Yanan Zhou,
  • Hailong Yuan,
  • Yujing Li,
  • Jianghua Shen,
  • Xiaosu Yuan,
  • Mei Li,
  • Chuting He,
  • Jiahe Zhang,
  • Yi Xiao,
  • Jinmiao Bi,
  • Yu Hou,
  • Jingyi Zang,
  • Zeyu Gao,
  • Moshi Song

摘要

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.