New research from a collaborative international team is shedding light on the fundamental biological processes driving age-related increases in colorectal cancer risk. Scientists have identified a specific pattern of epigenetic changes, dubbed “ACCA drift,” within intestinal stem cells that appears to contribute to gene silencing adn cellular dysfunction. The findings, published in Nature Aging, suggest that interventions targeting iron metabolism and inflammation may offer potential avenues for slowing or even reversing this process, offering a new direction in the fight against this common and often deadly cancer.
A new study has identified a fundamental mechanism of aging within the intestinal tract, potentially explaining why the risk of colorectal cancer increases with age. Researchers from the Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) in Jena, Germany, the Molecular Biotechnology Center (MBC) in Turin, and the University of Turin, Italy, discovered that a specific form of epigenetic aging – termed “ACCA drift” – accumulates in intestinal stem cells, leading to the silencing of crucial genes.
The human intestine is unique in its rapid rate of renewal, generating new cells from specialized stem cells every few days. However, as we age, these stem cells accumulate epigenetic changes – chemical markers on DNA that act as switches, controlling which genes are active. Understanding these changes is critical for developing strategies to maintain gut health and prevent age-related diseases.
The research, recently published in Nature Aging, reveals that these changes aren’t random. Led by Professor Francesco Neri of the University of Turin, Italy, the international team found a distinct pattern developing with age, which they’ve named ACCA drift (Aging- and Colon Cancer-Associated). “We observe an epigenetic pattern that becomes increasingly apparent with age,” explained Professor Neri, formerly a group leader at the Leibniz Institute on Aging – Fritz Lipmann Institute in Jena.
Genes responsible for maintaining healthy tissue balance are particularly vulnerable, including those controlling intestinal renewal through the Wnt signaling pathway. This “drift” isn’t limited to aging intestines; it was also detected in nearly all colon cancer samples examined, suggesting that aging stem cells create an environment conducive to cancer development.
Aging as a Mosaic: Different Tissue Areas are Affected Differently
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Remarkably, the ACCA drift isn’t evenly distributed throughout the intestine. Each intestinal crypt – a small, tube-like section of the intestinal lining – originates from a single stem cell. When that stem cell undergoes epigenetic changes, the entire crypt reflects those changes. “Over time, more and more areas with an older epigenetic profile develop within the tissues,” explained Dr. Anna Krepelova. “Through the natural process of crypt division, these regions continually expand and can continue to grow for many years.”
This explains why older intestines contain a patchwork of crypts – some remaining youthful while others have significantly aged – and why certain areas are more prone to producing dysfunctional cells, potentially fueling cancer growth.
Disrupted Iron Metabolism Halts Repair Systems
Researchers discovered that older intestinal cells absorb less iron while simultaneously releasing more, reducing the amount of iron (II) available in the cell nucleus. This iron is a crucial component of TET enzymes, which normally protect against excessive DNA methylation. When iron levels are insufficient, TET enzymes can’t function properly, and excessive DNA methylation accumulates.
When there isn’t enough iron in the cells, faulty markings remain on the DNA. And the cells lose their ability to remove these markings.”
Dr. Anna Krepelova, Leibniz Institute on Aging – Fritz Lipmann Institute (FLI)
This creates a domino effect: as TET activity declines, more DNA methylation builds up, silencing important genes. This can further accelerate epigenetic drift.
Inflammation and Impaired Wnt Signaling Accelerate Aging
The research team also found that mild inflammatory processes in the aging intestine exacerbate this mechanism. Inflammatory signals alter iron distribution within the cell and put stress on metabolism. Simultaneously, Wnt signaling – a critical pathway for maintaining active and functional stem cells – weakens.
This combination of iron deficiency, inflammation, and impaired Wnt signaling acts as an “accelerator” for epigenetic drift, suggesting the aging process in the intestine may begin earlier and spread more rapidly than previously understood.
Aging Drift Can Be Influenced
Despite the complexity of the mechanism, the study offers encouraging results. Researchers were able to partially slow or reverse 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 interventions led to increased TET enzyme activity and allowed cells to begin breaking down methylation again. “This means that epigenetic aging doesn’t necessarily have to be a definitive and fixed state,” emphasized Dr. Anna Krepelova. “For the first time, we are seeing that it is possible to modify aging parameters that lie deep within the molecular core of the cell.”
