Published on: Nov 28, 2025
Researchers from the Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) in Jena, the Molecular Biotechnology Centre (MBC) in Turin, and the University of Turin have identified a core mechanism that drives aging in the human gut. Their study, published in Nature Aging, reveals that a distinct form of epigenetic aging—called ACCA drift—gradually accumulates in intestinal stem cells, shutting down essential genes through hypermethylation.
Over time, this drift expands across intestinal crypts, fueled by age-related inflammation, weakened Wnt signaling, and disrupted iron metabolism. Together, these changes reduce the activity of DNA-modifying TET enzymes, allowing harmful methylation marks to build up. This not only accelerates cellular aging but also helps explain why the risk of colorectal cancer increases with age.
Although the gut renews itself faster than any other organ, its stem cells accumulate specific epigenetic changes over a lifetime. According to lead author Prof. Francesco Neri, aging in the gut follows a predictable pattern—ACCA drift—rather than occurring randomly. Genes that regulate tissue balance, especially those involved in the Wnt pathway, are particularly affected. The same drift pattern was found in nearly all colon cancer samples, suggesting that aging stem cells may create conditions favorable to tumor development.
The drift also creates a patchwork effect: some intestinal crypts remain young while others age significantly. Because each crypt originates from a single stem cell, epigenetic changes spread as crypts divide, causing aged regions to enlarge over decades.
A key driver is impaired iron metabolism. Older intestinal cells take up less iron and release more, reducing the iron (II) levels needed for TET enzyme activity. Without enough iron, these enzymes can’t remove excess methylation marks, leading to a cascade of gene silencing that accelerates drift.
Mild chronic inflammation and weakened Wnt signaling—both common in aging—further intensify this process.
Despite its complexity, the researchers found reasons for optimism. In intestinal organoid models, restoring iron import or boosting Wnt signaling successfully reactivated TET enzymes and reduced the methylation buildup. This partially reversed epigenetic drift.
These findings show that epigenetic aging may not be irreversible, says Dr. Anna Krepelova. We now see that even deeply embedded molecular aging markers can potentially be adjusted.
The discovery opens new avenues for delaying gut aging and lowering colorectal cancer risk by targeting iron metabolism and key signaling pathways.
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