R-loops exported from the nucleus drive inflammaging
Senescent cells are known to fuel chronic inflammation, but the precise molecular trigger has been elusive. New research points to RNA-DNA hybrids being actively transported out of the cell nucleus.
When cells stop dividing, they enter a state called senescence. They linger in tissues and release a cocktail of inflammatory signals, a phenomenon known as the SASP (senescence-associated secretory phenotype). This process contributes to age-related diseases. Yet the upstream mechanism that kicks off SASP has remained poorly understood.
R-loops as the ignition switch for inflammation
A study published in Nature Aging now identifies a specific molecular step. The researchers showed that senescent cells accumulate R-loops, structures in which RNA hybridises with the DNA strand inside the nucleus. Normally, these are resolved quickly. In senescent cells, however, a protein complex involving DDX1 and XPO1 actively exports them out of the nucleus.
Once outside the nucleus, these R-loops are detected by the cGAS-STING pathway, a cellular alarm system normally tasked with identifying foreign DNA such as viruses. When erroneously triggered by the cell’s own R-loops, it activates the production of inflammatory molecules that constitute the SASP.
Blocking XPO1 reduces senescence-driven inflammation
The team tested what happens when R-loop export is blocked. Inhibiting the export protein XPO1 reduced cGAS-STING activation and lowered SASP-related inflammation. In animal models, this also extended healthspan.
These are preliminary findings from cell cultures and animal models. Whether the same mechanism operates in humans, and whether XPO1 inhibition is safe and effective as an anti-aging strategy, remains to be established. Notably, XPO1 inhibitors already exist as approved cancer drugs, which may accelerate translational research.
From a longevity perspective, this identifies a concrete upstream target for inflammaging: not the inflammation itself, but the nuclear export step that precedes it.