Nucleic acids such as DNA and RNA should in the normal course of events largely remain localized within the cell nucleus and mitochondria, the locations of the nuclear genome and mitochondrial genomes respectively. Changes that take place with age disrupt everything, however, and this disruption includes the mislocalization of DNA and RNA fragments into the body of the cell. One of the many lines of defense against infectious pathogens such as viruses and bacteria deployed by cells takes the form of sensor proteins that detect inappropriate DNA and RNA in the cytosol of the cell, and then trigger inflammatory signaling and potentially even cell death. Thus a sizable portion of the chronic inflammation characteristic of later life is a maladaptive reaction to some aspects of the poor state of structural organization within aged cells.
Today's open access paper reviews these mechanisms, with a particular emphasis on the connection between age-related chronic inflammation and increased tendency towards an inappropriate coagulation response in the aging vasculature, the cause of thrombosis. An important facet of present research into immune aging is the effort to find ways to interfere in chronic inflammatory signaling without disabling necessary inflammatory responses. This has so far proven to be challenging, as all inflammation runs through much the same triggers and regulatory systems. The only alternative is to remove the underlying damage of aging that causes maladaptive inflammatory responses, but at present that is not the primary focus of the research community.
Misplaced nucleic acids as a trigger of Coagul-Aging
Aging is characterized by a gradual decline in tissue homeostasis and regenerative capacity, accompanied by the emergence of a chronic, low-grade inflammatory state termed inflammaging. This sterile inflammation stems from the accumulation of cellular and molecular damage, defective clearance of self-derived debris, and persistent activation of innate immune pathways. Inflammaging plays a central role in the development of age-related pathologies, including cardiovascular and thrombotic diseases.
One of the major vascular consequences of inflammaging is the establishment of a prothrombotic phenotype, referred here to as coagul-aging. This state results from endothelial dysfunction, platelet hyperreactivity, and altered hemostatic balance. Importantly, inflammation and coagulation are not isolated processes but are functionally intertwined through the concept of thrombo-inflammation, a coordinated response originally evolved to contain infection and repair tissue damage. When chronically activated, however, this crosstalk becomes maladaptive, sustaining vascular injury and thrombotic risk.
Emerging evidence suggests that misplaced nucleic acids, including extracellular or cytosolic DNA, RNA, and RNA:DNA hybrids, act as molecular triggers of both innate immune activation and coagulation. These nucleic acids, often derived from endogenous retroelements or senescence-associated damage, are sensed by pattern recognition receptors such as cGAS-STING, TLR9, and RIG-I-like receptors, promoting type I interferon responses, cytokine release, and tissue factor expression. In parallel, they may directly activate the contact pathway of coagulation via factor XII, providing a non-inflammatory route to thrombin generation.
In this review, we examine the role of nucleic acid accumulation and dysregulation in linking inflammaging to coagul-aging. We propose that extracellular nucleic acids act as central effectors of age-associated thrombo-inflammatory circuits, not only by sustaining chronic immune activation, but also by directly triggering coagulation, potentially bypassing classical inflammatory pathways. These properties position nucleic acids as both mechanistic drivers and potential therapeutic targets in vascular aging.
View the full article at FightAging
