Colorectal cancer is strongly linked to aging, yet we still do not understand how the aging intestine becomes more vulnerable to tumor formation. At the center of intestinal health are stem cells that constantly renew the gut lining and protect it from damage. With age, these stem cells decrease both in number and function while the surrounding tissue environment becomes increasingly inflamed. This chronic low-grade inflammation, also called “inflammaging”, may quietly undermine the intestine’s natural defenses, allowing precancerous cells to gain a foothold. Although medications such as low-dose aspirin are known to reduce colorectal cancer risk, recent clinical trials suggest their benefits may differ in older adults, raising critical unanswered questions. Determining how aging alters the stem cell ecosystem of the colon and whether these changes can be reversed represents an important opportunity to refine cancer prevention strategies for the growing aging population.
This project will integrate aged mouse models with human cohort studies and a randomized clinical trial to define how aging reshapes the intestinal stem cell niche and influences colorectal cancer risk. The research will focus on specialized fibroblasts that support stem cell function and on inflammatory signaling pathways, such as prostaglandin and interferon responses, that intensify with age. Using single-cell and spatial transcriptomic technologies, the team will map how these cellular interactions change over time and assess whether low-dose aspirin can restore a healthier, more resilient stem cell environment. Parallel analyses of colon biopsies and circulating biomarkers from younger and older trial participants will identify molecular signatures of “colon aging” that predict aspirin responsiveness. Together, these insights will enable more precise use of preventive therapies, identify biomarkers of cancer risk, and inform personalized strategies to protect the aging colon from tumor initiation.