QJM · Oct 30, 2026
The Hidden Genome Awakens: LINE-1 Retrotransposons as Emerging Regulators of Cardiac Aging and Inflammation
By Kang S
Cardiac aging is a major determinant of cardiovascular morbidity and mortality, characterized by progressive myocardial fibrosis, impaired contractile function, vascular dysfunction, and reduced regenerative capacity. Although mitochondrial dysfunction, cellular senescence, and chronic inflammation are recognized hallmarks of cardiac aging, the upstream molecular events that coordinate these processes remain incompletely understood. Emerging evidence suggests that endogenous repetitive genomic elements, particularly Long Interspersed Nuclear Element-1 (LINE-1), function as critical regulators of age-associated inflammatory responses. LINE-1 elements are normally maintained in a transcriptionally repressed state through DNA methylation and heterochromatin-associated mechanisms. However, aging-associated epigenetic erosion, loss of heterochromatin integrity, and nuclear structural instability promote LINE-1 derepression and accumulation of LINE-1-derived nucleic acids. These endogenous DNA species activate cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling, triggering chronic type I interferon responses, NF-κB activation, and senescence-associated secretory phenotype (SASP) amplification. In the aging heart, persistent LINE-1/cGAS-STING activation may contribute to cardiomyocyte dysfunction, fibroblast activation, immune remodeling, and progressive myocardial fibrosis. Here, we propose LINE-1 reactivation as a molecular convergence mechanism that integrates several fundamental aging hallmarks, including epigenetic instability, genomic stress, and inflammaging. We discuss the mechanistic basis of LINE-1-driven cardiac aging and evaluate emerging therapeutic strategies targeting LINE-1 reverse transcription, STING signaling, and epigenetic restoration. This framework provides a new perspective for understanding cardiac aging and developing precision interventions for age-related cardiovascular disease.