DNA Methylation Changes in the Aging Gut May Help Drive Cancer Risk

The human gut is one of the body’s fastest-renewing tissues. Every few days, new cells are produced from intestinal stem cells to help maintain the lining of the gut. However, a study suggests that, with age, some of those stem cells may begin to carry an epigenetic pattern linked to important genes becoming less active.

Researchers from the Leibniz Institute on Aging – Fritz Lipmann Institute in Germany, the Molecular Biotechnology Centre in Turin, and the University of Turin found that a specific form of epigenetic aging, called ACCA drift, short for aging- and colon cancer-associated drift, builds up in intestinal stem cells over time. This drift involves increased DNA methylation, a chemical marking system that can influence whether genes are active or silent.

“We observe an epigenetic pattern that becomes increasingly apparent with age,” said Prof. Francesco Neri, who led the international research team.

The findings, published in Nature Aging, may help explain why the risk of colorectal cancer rises with age. The researchers found that the same epigenetic drift seen in aging gut tissue was also detected in almost all colon cancer samples examined, suggesting that aging stem cells may help create a tissue environment that is more vulnerable to disease.

DNA methylation and Cancer
As we age, DNA methylation patterns can gradually shift through a process known as epigenetic drift. These changes may disrupt normal gene regulation, silence tumor-suppressor genes, or give certain cells a growth advantage. Over time, this can create a more cancer-prone environment, helping explain why cancer risk increases with age and why abnormal DNA methylation is commonly found in tumors.

In previous posts, we explored DNA methylation as a key epigenetic mechanism, highlighted how DNA methylation patterns can be used in epigenetic clocks to estimate biological age, and discussed how abnormal methylation changes are linked to cancer development, particularly in tissues such as the colon.

A Patchwork of Younger and Older Cells

One important finding from the study was that epigenetic aging did not happen evenly across the gut. Instead, the intestine appeared to develop a patchwork pattern.

Each intestinal crypt, a small tube-like structure in the gut lining, comes from a single stem cell. When that stem cell develops age-related epigenetic changes, the entire crypt can carry the same older molecular profile.

“Over time, more and more areas with an older epigenetic profile develop in the tissue,” explained study author Dr. Anna Krepelova. “Through the natural process of crypt division, these regions continuously enlarge and can continue to grow over many years.”

This means that some areas of the aging gut may remain relatively younger at the epigenetic level, while other areas may carry more aged patterns. These older regions may be more likely to produce abnormal or damaged cells, which could contribute to cancer risk.

How Iron, Inflammation, and Wnt Signaling Fit In

The study also points to several factors that may drive this drift. Older intestinal cells appeared to have disrupted iron metabolism, with less available iron inside the cell nucleus. This matters because iron helps support TET enzymes, which are involved in removing or modifying DNA methylation marks.

When TET activity drops, methylation marks may build up. As a result, genes that help maintain healthy tissue renewal can become less active.

“When there’s not enough iron in the cells, faulty markings remain on the DNA. And the cells lose their ability to remove these markings,” said Krepelova.

Age-related inflammation also appeared to make the process worse. At the same time, Wnt signaling, an important pathway that helps intestinal stem cells stay active and functional, became weaker. Together, reduced iron availability, inflammation, and weaker Wnt signaling appeared to accelerate the accumulation of epigenetic drift.

Epigenetic Aging May Not Be Completely Fixed

The researchers also found a hopeful clue. In intestinal organoids, miniature gut-like models grown from stem cells, they were able to slow or partly reverse the drift by restoring iron import or activating Wnt signaling.

“This means that epigenetic aging does not have to be a fixed, final state,” said Krepelova. “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.”

The study does not mean that aging can be simply reversed, or that changing iron levels would prevent cancer. Instead, it shows that some age-related epigenetic changes may be biologically flexible under experimental conditions. More research is needed to understand whether these mechanisms can be safely targeted in humans.

Source: Krepelova, A., Rasa, M., Annunziata, F. et al. Iron homeostasis and cell clonality drive cancer-associated intestinal DNA methylation drift in aging. Nature Aging. November 26, 2025.

Resource:Leibniz Institute on Aging – Fritz Lipmann Institute. As our gut age: New study finds out why important genes “go quiet” as we get older. November 28, 2025.