The human intestine replaces its cells faster than any other tissue in the body. Every few days, new cells are produced by specialized stem cells that keep the intestinal lining healthy. However, over time, these stem cells begin to accumulate epigenetic changes. These are chemical tags attached to DNA that function like on/off switches, controlling which genes stay on and which are turned off.
A new study published in Natural aging shows that these changes follow a clear pattern rather than appearing randomly. The international research team was led by Professor Francesco Neri from the University of Turin in Italy. Scientists have identified a process they call ACCA (Aging- and Colon Cancer-Associated) drift, a gradual change in epigenetic markers that becomes stronger as people age. “We observe an epigenetic pattern that becomes more and more apparent with age,” explains Professor Neri, former group leader at the Leibniz Institute on Aging – Fritz Lipmann Institute in Jena.
Aging patterns linked to cancer risk
The genes most affected by this drift are those which contribute to the maintenance of normal tissue balance. Many of them participate in the renewal of the intestinal mucosa via the Wnt signaling pathway. When these genes are changed, the gut’s ability to repair itself begins to weaken.
The researchers found that the same pattern of drift appears not only in aging intestinal tissue, but also in almost all of the colon cancer samples they analyzed. This overlap suggests that aging stem cells may create conditions that make cancer more likely to develop.
A patchwork of aging inside the gut
A striking finding is that aging does not affect the gut uniformly. The intestine is made up of tiny structures called crypts, each formed from a single stem cell. If this stem cell develops epigenetic changes, each cell in the crypt inherits them.
Dr. Anna Krepelova explains how this process takes place. “Over time, more and more areas with an older epigenetic profile develop in the tissues. Through the natural process of crypt division, these regions continually expand and can continue to grow for many years.”
As a result, the intestines of older people become a mixture of younger and much older crypts. Some areas remain relatively healthy, while others are more likely to produce damaged cells, increasing the chances of cancer growth.
Iron loss disrupts DNA repair
Researchers have also discovered why this epigenetic drift occurs. As intestinal cells age, they absorb less iron while releasing more. This reduces the amount of iron (II) available in the cell nucleus. Iron(II) is essential for the proper functioning of TET (ten-eleven translocation) enzymes, which normally help remove excessive DNA methylations.
When iron levels drop, these enzymes no longer work effectively. As a result, excessive DNA methylations remain in place instead of being broken down.
“When there is not enough iron in cells, defective markings remain on the DNA. And cells lose their ability to remove these markings,” explains Dr. Anna Krepelova. As TET activity decreases, DNA methylations accumulate, key genes are turned off, and they “go silent.” This chain reaction further accelerates epigenetic drift.
Inflammation accelerates the aging process
Age-related intestinal inflammation makes the problem worse. The team showed that even mild inflammatory signals can disrupt the iron balance inside cells and place additional stress on metabolism. At the same time, Wnt signaling weakens, reducing the ability of stem cells to remain active and healthy.
Together, iron imbalance, inflammation, and reduced Wnt signaling act as an accelerator of epigenetic drift. For this reason, aging in the gut may begin earlier and progress more quickly than scientists previously thought.
Can intestinal aging be slowed down?
Despite the complexity of these processes, the results offer some hope. In laboratory experiments using organoid cultures, miniature intestinal models grown from stem cells, researchers were able to slow or partially reverse epigenetic drift. They achieved this by restoring iron absorption or directly stimulating Wnt signaling.
Both approaches reactivated TET enzymes and allowed cells to start removing excess DNA methylations again. “This means that epigenetic aging does not have to be a fixed end state,” explains Dr. Anna Krepelova. “For the first time, we see that it is possible to modify the parameters of aging that lie deep in the molecular core of the cell.”
