Chronic low-grade inflammation is one of the most reliable biological signatures of aging, yet its molecular ignition points remain poorly mapped. A newly identified mechanism connecting nuclear RNA-DNA hybrid structures to the inflammatory secretions of aged cells offers a potential druggable target — one that could reshape how we approach inflammaging and age-related disease.
When cells enter senescence, they don't simply stop dividing — they transform into inflammatory signaling hubs that flood surrounding tissue with cytokines and proteases through the senescence-associated secretory phenotype (SASP). This study pinpoints R-loops — three-stranded nucleic acid structures formed when nascent RNA hybridizes back onto template DNA — as previously underappreciated SASP drivers. In senescent cells, R-loops enriched in alpha-satellite repeat sequences accumulate in the cytoplasm via active nuclear export. This export depends on a complex between the helicase DDX1 and the nuclear transport protein exportin-1 (XPO1). Once cytoplasmic, these R-loops concentrate in cytoplasmic chromatin fragments, which then activate the cGAS-STING innate immune pathway — the same inflammatory sensor implicated in COVID-19 severity, lupus, and cancer immunotherapy. Critically, pharmacological inhibition of XPO1 using KPT-330 (selinexor) suppressed R-loop export, reduced SASP output, attenuated age-associated inflammation, and extended healthspan in model organisms.
This finding reframes R-loops from primarily a DNA-damage and cancer-biology concern into a core aging mechanism. The cGAS-STING axis has already attracted significant senolytic and anti-inflammatory drug development attention, but upstream nodes like XPO1 have been underexplored in aging contexts. Selinexor is an FDA-approved oncology drug, which raises the possibility of repurposing studies in aging, though its toxicity profile in healthy populations is a serious practical constraint. The research is mechanistically rigorous, but whether R-loop export causally drives inflammaging in humans — rather than correlating with it — will require longitudinal human tissue data. This is an incrementally paradigm-shifting finding that meaningfully expands the SASP molecular map.
