Chromatin pieces with TRF2 in the cell fluid trigger cGAS-STAT1 inflammation during cell aging

Senescent cells accumulate TRF2-enriched cytoplasmic chromatin fragments (CCFs) associated with persistent DNA damage.

• CCFs co-localize with markers of DNA damage but lack DNA repair proteins, suggesting unrepaired damage.
• Nuclear instability, caused by inflammatory stress and certain mutations, leads to the extrusion of DNA fragments into the cytoplasm.
• The presence of TRF2-enriched CCFs activates the cGAS-STAT1 pathway, which may sustain inflammation associated with cellular senescence.
• Inhibition of the JAK-STAT pathway or treatment with metformin reduces the accumulation of TRF2-enriched CCFs and DNA damage markers.
• The findings propose a link between damaged telomeric DNA in the cytoplasm and chronic immune activation, which is associated with accelerated aging.

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