Extracellular vesicle–derived genetic material triggers inflammation via cGAS–STING pathway, offering promising therapeutic targets

A new study has identified long interspersed nuclear element-1 (LINE-1) RNA as a potent systemic factor that promotes neuroinflammation and cognitive impairment during aging. The findings illuminate a previously unclear molecular link between peripheral aging processes and central nervous system dysfunction, and point to promising new therapeutic strategies.

Aging is widely characterized by chronic, low-grade inflammation and progressive cognitive decline. However, the biological mechanisms that connect age-related changes in peripheral tissues to brain dysfunction have remained elusive. The new research reveals that LINE-1 RNA, delivered to the brain via circulating extracellular vesicles (EVs)—acts as a key trigger of inflammation and neuronal damage.

LINE-1 elements are retrotransposons that make up a substantial portion of the human genome. Thought to be remnants of ancient viral infections, they have the ability to copy and insert themselves into DNA. While normally kept under tight epigenetic control, LINE-1 elements become increasingly active with age as genomic regulation deteriorates. In addition to potentially damaging DNA through insertion events, LINE-1 RNA can provoke immune responses by mimicking viral genetic material.

Cells rely on innate immune sensors such as cGAS (cyclic GMP-AMP synthase) to detect foreign or misplaced DNA and activate inflammatory signaling through STING (stimulator of interferon genes). While this pathway evolved to combat pathogens, age-related cellular dysfunction can lead to inappropriate activation.

The study demonstrates that plasma EV–derived LINE-1 RNA levels rise significantly with age and correlate strongly with established biomarkers of brain aging, including neurofilament light chain (NFL). Using mouse models, researchers found that EVs from aged individuals cross the blood-brain barrier and deliver LINE-1 RNA directly to microglia, the brain’s resident immune cells. This activates the cGAS–STING pathway, triggering neuroinflammation, neuronal damage, and measurable cognitive deficits.

Importantly, pharmacological interventions showed therapeutic potential. Treatment with 3TC (lamivudine), which blocks LINE-1 reverse transcription, or H151, an inhibitor of STING signaling, significantly reduced neuroinflammation and improved cognitive performance in aged models.

The research further identifies aged peripheral tissues, particularly the brain and lung, as major sources of pro-aging EVs enriched in LINE-1 RNA. This discovery reveals a novel mechanism of inter-organ communication that drives systemic aging effects on the brain.

Together, these findings position EV-derived LINE-1 RNA and its downstream cGAS–STING signaling pathway as critical systemic contributors to brain aging. Targeting this pathway may offer new therapeutic avenues to mitigate cognitive decline and combat age-related neurodegenerative diseases.