Indianapolis, Indiana – Scientists at the Indiana University School of Medicine have uncovered evidence that a little-known blood condition linked to aging may play a significant role in the severity of inflammatory bowel disease, offering a promising new direction for treatment.
The research centers on a condition called clonal hematopoiesis of indeterminate potential, or CHIP. The disorder develops when blood stem cells acquire genetic mutations and begin producing altered blood cells.
CHIP is relatively common among older adults and has previously been associated with a higher risk of blood cancers, cardiovascular disease and kidney problems. Now, researchers say it may also intensify inflammation in the digestive tract.
In a study published in the journal Blood, the Indiana University team found a clear connection between CHIP mutations and worsening gut inflammation tied to conditions such as Crohn’s disease and ulcerative colitis. According to the Centers for Disease Control and Prevention, between 2.4 million and 3.1 million Americans are currently living with inflammatory bowel disease, with the highest prevalence among adults over the age of 45.
To investigate the link, researchers analyzed large datasets from the UK Biobank and the National Institutes of Health’s All of Us Research Program. Their analysis revealed that people with CHIP mutations face a greater risk of developing inflammatory bowel disease.
The association appeared especially strong among women and individuals carrying mutations in the DNMT3A gene, which were linked to a higher likelihood of Crohn’s disease. At the same time, younger individuals with larger mutations in the TET2 gene showed an increased risk of ulcerative colitis.
Laboratory studies helped illuminate how these mutations may influence disease severity. Using mouse models, the scientists observed that blood stem cells carrying CHIP mutations triggered heightened immune activity and more extensive tissue damage within the colon. The team traced much of this inflammatory response to a molecular pathway known as APE1/Ref-1.
By targeting that pathway with a drug called APX3330, researchers were able to dramatically reduce inflammation in their experimental models and restore healthier conditions in the colon. The drug, originally developed by Indiana University scientist Mark Kelley, works without suppressing the immune system. This is an important distinction from many current therapies used to manage inflammatory bowel disease.
Researchers say the findings suggest that although CHIP mutations emerge as part of the aging process, their harmful effects on inflammation may not be permanent. A clinical trial is now being prepared to evaluate APX3330 in people living with inflammatory bowel disease. Scientists also hope to explore whether the same approach could help address inflammation linked to other age-related conditions, including heart and kidney disease.
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