It has been established that the gut renews itself constantly, and its stem cells accumulate age-related molecular changes that alter how genes are switched on and off. A paper recently published in Nature Aging describes finding an epigenetic drift follows clear patterns and appears in aging intestines as well as most colon cancers.
Additionally, some regions age more quickly than others, forming a patchwork of weakened tissues that are more prone to degeneration. However, the researchers suggest that the drift can be slowed and partly reversed by restoring iron levels or key cellular signals.
Cells in the human gut are replaced every few days, faster than any other tissue in the body. These fresh cells are produced by specialized stem cells that keep the intestinal lining healthy, but over time, they begin to accumulate epigenetic changes. These changes follow a clear pattern rather than at random, according to the researchers led by Prof. Francesco Neri of the University of Turin in Italy.
The researchers identified a process they called ACCA (Aging- and Colon Cancer-Associated) Drift, a gradual shift in epigenetic markers that becomes stronger as people age. “We observe an epigenetic pattern that becomes increasingly apparent with age,” says Prof. Neri, formerly a group leader at the Leibniz Institute on Aging — Fritz Lipmann Institute in Jena.
Aging Pattern Link to Risk of Cancer
Genes that help maintain normal tissue balance are those most affected by the newly discovered drift, with most being involved in renewing the intestinal lining through the Wnt signaling pathway, which, when altered, causes the gut’s ability to self-repair begin to weaken.
This same drifting pattern was also found to appear in aging intestinal tissue as well as in nearly all colon cancer samples the researchers analyzed. Suggesting that the aging stem cells may create certain conditions that make cancer more likely to develop.
Aging Inside the Gut
One of the striking findings was that aging does not affect the intestines evenly. The human gut is made from tiny structures called crypts, which are formed from a single stem cell, and if that stem cell develops epigenetic changes, every cell within the crypt will inherit them.
This results in the intestines of older people becoming a mix of younger and older crypts, with some regions being relatively healthy and others being more likely to produce damaged cells that increase the risk of cancer growth.
“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,” explains Dr. Anna Krepelova.
Iron Loss and DNA Repair
According to the researchers, as intestinal cells age, they take in less iron while releasing more of it, reducing the amount of iron that is available in the cell nucleus. Iron is essential for TET enzymes to function properly, which typically helps remove excess DNA methylation. When iron levels drop, the enzymes do not work effectively, leading to excess DNA methylations remaining rather than being broken down, resulting in the epigenetic drift occurring.
“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,” says Dr. Anna Krepelova. “As TET activity declines, DNA methylations build up, key genes are switched off, and they ‘fall silent.’ This chain reaction further speeds up epigenetic drift.”
Inflammation Accelerates Aging
Age-related inflammation in the gut adds to the problem. In fact, even mild-grade inflammatory signals were found to disrupt the iron balance inside the cells, placing additional stress on metabolism. The negative action occurs at the same time Wnt signaling is weakening, further reducing the stem cell’s abilities to stay active and healthy.
Inflammation and iron imbalance, along with reduced Wnt signaling, act as an accelerator for the epigenetic drift. This is why aging in the intestines may begin as well as progress faster than previously believed, according to the researchers.
Slowing Gut Aging
While this is a complex process, there is some hope. Experiments using organoid intestinal model cultures grown from stem cells experienced a slowed or partly reversed epigenetic drift, which was achieved by restoring iron uptake or by directly boosting Wnt signaling. Both of these methods reactivated the TET enzymes, which allowed the cells to begin clearing excess DNA methylation again.
“This means that epigenetic aging does not have to be a fixed, final state,” Dr. Anna Krepelova says. “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.”
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