Scientists have not just uncovered a new way that aging cells drive inflammation, but they've also blocked this pathway with an existing Food and Drug Administration-approved medicine. This opens the door to an entirely new way to shield the body from age-related health decline.
Researchers from the University of Texas' MD Anderson Cancer Center (UT MD Anderson) have discovered a new cellular cause of age-related inflammation, or inflammaging – a leading driver of chronic disease, weight gain, muscle loss and declining health overall.
“Chronic, widespread inflammation is a driving factor in many age-related diseases, including cancer, and our research has discovered one reason why this happens,” says corresponding author Rugang Zhang, PhD, professor and chair of Experimental Therapeutics at UT MD Anderson.
As our cells age, some stop dividing and become senescent – remaining alive but dysfunctional, and releasing inflammatory molecules that can contribute to chronic inflammation. These markers of inflammation then promote the production of R-loops.
An R-loop is a temporary three-stranded nucleic acid structure formed during gene transcription. Without getting too deep into it, these structures help regulate functions such as gene expression and DNA repair.
However, too many R-loops forming or those that stick around too long after they've done their job can lead to DNA damage and exacerbate inflammaging. This has already been linked to the inflammation that can activate the growth of cancer cells.
In healthy cells, R-loops are normally confined to the nucleus. In senescent cells, however, R-loops are able to cross the nuclear envelope and move out into the cytoplasm, where they attach themselves to pieces of DNA debris. The immune system then perceives this coupling as a threat, triggering a response that drives chronic inflammation.
“Understanding the cause is the first step toward developing treatments," says Zhang.
During this process, the researchers also found that two proteins – DDX1 and XPO1 – facilitated this new inflammatory process. XPO1 enabled the transport of R-loops across the nuclear envelope into the cytoplasm, and DDX1 appears to escort R-loops to DNA debris to attach to.
This is important, because the inflammatory immune response only occurred when DNA debris and R-loops connected in this space outside the nucleus.
So, the team thought, perhaps blocking one of these proteins could prevent R-loops from reaching the chromatin fragments. Which would, potentially, silence the inflammation-driving immune cell response.
Researchers looked to the FDA-approved drug KPT-330 (selinexor), traditionally used to treat multiple myeloma, a rare blood cancer, by preventing nuclear export. Selinexor also blocked XPO1 production, preventing R-loops from being exported.
In preclinical mouse models, selinexor kept R-loops contained to the nucleus. This resulted in meaningful improvements in inflammation markers linked to liver damage, fat gain, muscle loss and lifespan.
In mice, scientists observed that blocking this export suppressed inflammaging and even reversed age-related body composition changes.
"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," Zhang adds.
Scientists have become increasingly interested in the role that R-loops play in age-related inflammation. This new discovery from Zhang and his colleagues not only identifies a new inflammatory pathway but proposes a way to block it.
Future research looking into why cells export R-loops, and targeting DDX1 instead of XPO1, is expected to shed more light on senescent cell behavior – and how we can target it to combat chronic disease tied to aging.
The study was published in the journal Nature Aging.
Source: UT MD Anderson via EurekAlert!
