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Scientists have uncovered a gut-specific epigenetic aging mechanism that links inflammation and iron imbalance to cancer risk and may be reversible.
Scientists have uncovered a core biological process that drives aging in the gut.
Their work shows that a distinct form of epigenetic aging known as ACCA drift builds up in intestinal stem cells, shutting down important genes through excessive DNA methylation. This process is fueled by age-related inflammation, reduced Wnt signaling, and disrupted iron metabolism, and it spreads through intestinal tissue in a way that may help explain the growing risk of colorectal cancer with age.
Rapid Renewal Meets Gradual Decline
The human gut replaces its cells more rapidly than any other tissue in the body, generating new cells from specialized stem cells every few days. Over time, however, these stem cells accumulate epigenetic changes. These changes are chemical markers attached to DNA that function like switches, controlling which genes are turned on or off.
The study, recently published in Nature Aging, was led by Prof. Francesco Neri of the University of Turin, Italy, in collaboration with scientists from the Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) in Jena, Germany, as well as researchers at the Molecular Biotechnology Centre Turin. The findings show that aging-related changes in the gut follow a clear and consistent pattern rather than occurring at random. The researchers call this pattern ACCA (Aging- and Colon Cancer-Associated) drift.
“We observe an epigenetic pattern that becomes increasingly apparent with age,” explains Prof. Neri, former group leader at the Leibniz Institute on Aging – Fritz Lipmann Institute in Jena.
Genes that are essential for maintaining healthy tissue are especially affected by this drift, including those involved in renewing the intestinal lining through the Wnt signaling pathway.
The same epigenetic changes appear not only in aging intestinal tissue but also in nearly all colon cancer samples that were analyzed. This overlap suggests that aging stem cells may create conditions that make cancer more likely to develop.
Patchwork of aging: Different areas of tissue are affected differently
One striking aspect of ACCA drift is that it does not spread evenly across the intestine. Each intestinal crypt, a small tubular structure within the intestinal lining, originates from a single stem cell. When that stem cell undergoes epigenetic alterations, the changes are passed on to all cells within the crypt. Dr. Anna Krepelova describes how this unfolds: “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.”
This explains why the intestines of older people contain a veritable patchwork of crypts that have remained young and others that have aged significantly, and why certain regions are particularly susceptible to producing more degenerated cells, which promotes cancer growth.
Impaired iron metabolism shuts down repair systems
Why does this drift occur? Researchers have shown that older intestinal cells absorb less iron but release more iron at the same time. This reduces the amount of available iron (II) in the cell nucleus, which serves as a cofactor for the TET (ten-eleven translocation) enzymes. These enzymes normally protect from the excess DNA methylations, but if the cell doesn’t have enough iron, they can’t do their job properly. Excess DNA methylations are no longer broken down.
“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,“ explains Dr. Anna Krepelova. This has a kind of domino effect: as the TET activity decreases, more and more DNA methylations accumulate, and important genes are switched off; they ”fall silent.” This can further accelerate epigenetic drift.
Inflammation and impaired Wnt signaling accelerate aging
The research team was also able to demonstrate that mild inflammatory processes in the gut associated with aging further reinforce this mechanism. Inflammatory signals alter iron distribution in the cell and put strain on the metabolism. At the same time, Wnt signaling also weakens—a signaling pathway that is important for keeping stem cells active and functional.
This combination of iron deficiency, inflammation, and Wnt signaling loss acts as an “accelerator” of epigenetic drift. As a result, the aging process in the intestine can begin earlier and spread faster than previously thought.
Aging drift can be influenced
Despite the complexity of the mechanism, the study also provides encouraging results. The researchers succeeded in slowing down or partially reversing epigenetic drift in organoid cultures—miniature intestinal models grown from intestinal stem cells—by restoring iron import or specifically activating the Wnt signaling pathway.
Both measures led to the TET enzymes becoming more active again and the cells starting to break down the methylations once more. “This means that epigenetic aging does not have to be a fixed, final state,” emphasizes Dr. Anna 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.”
Reference: “Iron homeostasis and cell clonality drive cancer-associated intestinal DNA methylation drift in aging” by Anna Krepelova, Mahdi Rasa, Francesco Annunziata, Jing Lu, Chiara Giannuzzi, Omid Omrani, Elisabeth Wyart, Paolo Ettore Porporato, Ihab Ansari, Dor Bilenko, Yehudit Bergman and Francesco Neri, 26 November 2025, Nature Aging.
DOI: 10.1038/s43587-025-01021-x
This work was supported by funding from Sofja Kovalevskaja Award starting grant from the von Humboldt Foundation (ITA1164767SKP), the Leibniz Institute on Aging (FLI), the Associazione Italiana per la Ricerca sul Cancro (MFAG 2021 ID 26038) and the Fondazione Ricerca Molinette.
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