Targeting Age-related LINE-1 Activation Alleviates Cardiac Aging

Cardiac aging is a key contributor to cardiovascular diseases and associated mortality, yet effective therapeutic strategies remain limited due to the complexity and gradual nature of aging. While LINE-1 retrotransposons are known to drive cellular senescence, their role in cardiac aging remains poorly understood. Here, we showed that LINE-1 ORF1p and ORF2p expression significantly increased in the heart with age. To investigate the role of LINE-1 in cardiac aging, we generated cardiomyocyte-specific Mov10 knockout mice (Mov10-cKO), given its role in suppressing LINE-1 retrotransposition. These mice exhibited LINE-1 derepression and cardiac dysfunction at three months of age, along with premature aging phenotypes and cGAS-STING activation. Further in vitro analysis showed that pharmacological inhibition of LINE-1 reverse transcription (using 3TC) or STING signaling (using H-151) suppressed cGAS-STING activation and attenuated cellular senescence in Mov10-knockout cardiomyocytes. Notably, either of these pharmacological interventions similarly improved cardiac function and reduced cardiac inflammation and senescence phenotypes in naturally aged mice. Taken together, our findings establish LINE-1 as a driver of cardiac aging via cGAS-STING activation. This work not only elucidates a novel mechanism of retrotransposon-mediated cardiac aging but also provides evidence for targeting LINE-1 or its downstream effectors to mitigate age-related cardiac dysfunction.