Researchers from the Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) in Germany, together with colleagues from the Molecular Biotechnology Centre and the University of Turin in Italy, have identified a key mechanism that makes the aging intestine more susceptible to cancer. Their study, published in Nature Aging, details how a specific form of epigenetic change called ACCA drift accumulates in intestinal stem cells over time.
Epigenetic changes are chemical markers on DNA that regulate gene activity. In the gut, these changes build up as people age, especially in genes responsible for maintaining tissue health through pathways such as Wnt signaling. According to Prof. Francesco Neri from the University of Turin, "We observe an epigenetic pattern that becomes increasingly apparent with age." The study found that this ACCA drift is not random but follows a clear pattern and can be detected in both aging intestines and colon cancer samples.
The process affects individual intestinal crypts—small tubular structures originating from single stem cells. When these stem cells undergo epigenetic changes, entire crypts reflect these modifications. Dr. Anna Krepelova explained: "Over time, more and more areas with an older epigenetic profile develop in the tissue. Through the natural process of crypt division, these regions continuously enlarge and can continue to grow over many years."
The research shows that iron metabolism plays a crucial role in this process. Older intestinal cells absorb less iron while releasing more at the same time, reducing available iron (II) in cell nuclei. This impairs TET enzymes responsible for preventing excess DNA methylation. When TET enzyme activity drops due to insufficient iron, DNA methylations accumulate and silence important genes.
Inflammation linked to aging further aggravates this situation by disrupting iron distribution and weakening Wnt signaling—a pathway essential for keeping stem cells active. The combination of iron deficiency, inflammation, and loss of Wnt signaling accelerates epigenetic drift throughout the intestine.
The team also demonstrated potential interventions using organoid cultures derived from intestinal stem cells. By restoring iron import or activating Wnt signaling pathways, they were able to slow down or partially reverse epigenetic drift. This led to increased TET enzyme activity and reduced DNA methylation levels. Dr. Krepelova noted: "This means that epigenetic aging does not have to be a fixed, final state. For the first time, we are seeing that it is possible to tweak the parameters of aging that lie deep within the molecular core of the cell."
These findings provide new insights into why colorectal cancer risk increases with age and highlight possible avenues for future therapies targeting molecular processes involved in gut aging.
