Age-Related Inflammation Linked to R-Loop Nucleic Acids, Opens Therapies

In a new study published in Nature Aging titled, “Nuclear export of R-loop by the DDX1 and XPO1 complex promotes senescence-associated secretory phenotype and inflammaging,” researchers from the University of Texas (UT) MD Anderson Cancer Center have uncovered a previously unknown connection between R-loop nucleic acid structures and age-related inflammation or inflammaging. The results support new intervention options for chronic inflammation and subsequent health conditions.  

In preclinical models, the administration of KPT-330 (selinexor) prevented export of R-loops and led to significant improvement in inflammation, liver damage, fat gain, muscle loss and overall lifespan.   

“Chronic, widespread inflammation is a driving factor in many age-related diseases, including cancer, and our research has discovered one reason why this happens,” said Rugang Zhang, PhD, professor and chair of Experimental Therapeutics at UT MD Anderson and corresponding author on the study. “Understanding the cause is the first step toward developing treatments. We saw encouraging results using a drug that has already been tested in humans, paving the way for potential clinical use to alleviate age-related conditions.”

Cells begin releasing signals that contribute to chronic inflammation once they enter senescence and stop dividing. Researchers have now pinpointed R-loops as a key component to modulating these inflammatory signals.

An R-loop is a temporary cellular structure created during transcription, when a double strand of RNA and DNA becomes tangled with a third displaced single strand of DNA. While R-loops are traditionally confined to the cell nucleus, the study found that cells in senescence increasingly export R-loops into the cytoplasm. These R-loops attach to fragments of DNA debris to trigger chronic inflammation.

This study identified the two proteins involved in exporting R-loops, DDX1 and XPO1. DDX1 attaches to the R-loop inside the nucleus to facilitate export. XPO1 allows the R-loops to be transported into the cytoplasm by forming a complex with DDX1.

Researchers administered KPT-330, a FDA-approved drug for treating multiple myeloma that blocks nuclear export. The R-loops remain trapped inside the nucleus and could not trigger an inflammatory response.

The study showed that shutting down nuclear export by blocking XPO1 in preclinical mouse models suppressed inflammaging, reduced liver fibrosis, lowered systemic inflammatory markers, and reversed age-related body composition changes.

In a separate experiment, the same inflammatory alarm enabled the immune system to find and eliminate precancerous cells. The authors state that future studies could explore blocking DDX1 specifically, instead of shutting down all nuclear export, to mitigate side effects.

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