Targeting age-related LINE-1 activation alleviates cardiac aging

  • Nat Aging. 2026 Feb;6(2):414-429. doi: 10.1038/s43587-025-01056-0.
Chaofan Yang  #  1  2  3 ,  Heng Du  #  1  2  3 ,  Siqi Liu  1  2  3 ,  Pengfei Xu  1  2  3 ,  Yuhan Wang  1  2  3 ,  Yanan Zhou  1  2  3 ,  Hailong Yuan  1  2  3 ,  Yujing Li  1  2  3 ,  Jianghua Shen  1  2  3 ,  Xiaosu Yuan  1  2  3 ,  Mei Li  1  2  3 ,  Chuting He  1  2  3 ,  Jiahe Zhang  1  2  3 ,  Yi Xiao  1  2 ,  Jinmiao Bi  1  2  3 ,  Yu Hou  4 ,  Jingyi Zang  1  2 ,  Zeyu Gao  1  2 ,  Moshi Song  5  6  7
Affiliations
  • 1. State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
  • 2. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.
  • 3. University of Chinese Academy of Sciences, Beijing, China.
  • 4. Department of Radiological Medicine, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, China.
  • 5. State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. [email protected].
  • 6. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. [email protected].
  • 7. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 41571992 DOI: 10.1038/s43587-025-01056-0
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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