Misplaced nucleic acids as a trigger of coagul-aging

Aging is associated with a persistent, sterile inflammatory state called inflammaging, which contributes to endothelial dysfunction, immune dysregulation, and a gradual shift toward a procoagulant phenotype known as coagul-aging. Inflammation and coagulation are now understood as interconnected processes, linked by innate immune activation and thrombin production. Recent evidence highlights the vital role of endogenous nucleic acids, especially cytosolic and extracellular DNA, RNA, and RNA:DNA hybrids, as key mediators at the intersection of these systems. These nucleic acids, often originating from senescent cells and endogenous retroelements, accumulate due to impaired degradation and are detected by pattern recognition receptors such as cGAS-STING, RIG-I, and TLR9. Besides promoting inflammatory cytokine release and tissue factor expression, certain nucleic acid species, particularly when unencapsulated, can directly activate the contact pathway via factor XII (FXII), contributing to thrombin production independently of traditional inflammatory pathways. This dual role makes nucleic acids central players in the convergence of inflammaging and coagul-aging. In this review, we examine the sources, topological forms, and immunothrombotic functions of misplaced nucleic acids in aging. We propose that a cumulative nucleic acid burden acts as a molecular trigger for thrombo-inflammatory responses, offering new insights into age-related vascular risk and novel targets for therapeutic intervention, including the development of biomarker-based risk stratification approaches and novel strategies targeting upstream thromboinflammatory pathways.