MD Anderson researchers traced one driver of inflammaging — the chronic background inflammation tied to frailty and higher disease risk — and showed that selinexor, an FDA approved cancer drug, can interrupt it in mice.
Why does getting older mean living with low-grade, chronic inflammation? Researchers at MD Anderson Cancer Center have now mapped a specific molecular step they say drives it. Short RNA-DNA hybrids called R-loops, which normally live inside the nucleus, leak out into the body of senescent cells and trigger an immune response that becomes louder as a person ages. In mouse experiments, blocking that leak with selinexor, a drug already approved to treat multiple myeloma, cut markers of age-related inflammation and reversed some of the body-composition changes that come with aging.
The work, published June 18 in Nature Aging, centers on cells that have stopped dividing but refuse to die, a population known as senescent cells. Senescent cells accumulate with age and are notorious for spewing a brew of inflammatory signals known as the senescence-associated secretory phenotype, or SASP. That steady secretion is one of the main ingredients in so-called inflammaging, the background inflammation that tracks with frailty, muscle loss, fatty liver, and higher risk of cancer and chronic disease. The MD Anderson team, led by Rugang Zhang, chair of Experimental Therapeutics, wanted to know what specifically turns SASP on inside these cells.
Their answer involves an export complex made of two proteins, DDX1 and XPO1, that ferries R-loops out of the nucleus, where they glom onto fragments of DNA left behind by damaged nuclei and trip an innate immune alarm. Once the R-loops reach the cytoplasm, the cell's sensors read them as foreign, and SASP revs up. It is the first time the R-loop pathway, previously studied mostly for its role in transcription and DNA repair, has been tied to SASP and to inflammaging as a whole, according to the authors.
Selinexor is a selective inhibitor of nuclear export that locks XPO1 in place. It is already approved by the FDA for multiple myeloma, and researchers have been testing whether its mechanism could be repurposed against other diseases. By keeping R-loops inside senescent cell nuclei, the team reports, selinexor dialed down SASP markers in aged mice, eased liver damage and fat accumulation, and reduced muscle loss compared with untreated controls. None of those experiments involved people.
That distinction matters. Refractor, the science-news outlet that summarized the work on June 21, describes the drug as "blocking" an aging pathway, but the underlying evidence is preclinical. The same compound, used chronically in older adults without cancer, would carry known on-target toxicities from its oncology use, including low blood counts and gastrointestinal side effects. Inflammaging itself is also one driver among several. Mitochondrial dysfunction, accumulation of senescent cells themselves, and changes in the gut microbiome all contribute, and blocking a single export step will not turn off the rest.
The paper points instead to a sharper set of follow-up questions. The first is whether the DDX1 side of the export complex can be targeted directly, which might let researchers block R-loop leakage without engaging the rest of XPO1's nuclear-export machinery, a route that could be cleaner than repurposing a cancer drug. The second is whether short pulses of selinexor, rather than continuous dosing, would be enough to dampen SASP in older adults. The third is whether the same pathway shows up in human senescent cells from aged tissue, something the mouse model cannot answer. Until those questions are answered in people, the most accurate framing is the one the MD Anderson team itself uses: there is now a concrete, targetable step in inflammaging, and a drug that already exists happens to hit it.