Gut Cell Replacement and Epigenetic Changes
The human gut features rapid cell replacement driven by specialized stem cells. These cells ensure the intestinal lining remains healthy. Over time, these stem cells accumulate epigenetic changes, which are chemical tags attached to DNA that regulate gene activity.
Aging- and Colon Cancer-Associated (ACCA) Drift Identified
A new study published in Nature Aging, led by Prof. Francesco Neri of the University of Turin, identified a non-random pattern for these epigenetic changes. This process, termed ACCA (Aging- and Colon Cancer-Associated) drift, involves a gradual shift in epigenetic markers that intensifies with age.
Link to Cancer Risk
Genes crucial for maintaining normal tissue balance, particularly those involved in intestinal lining renewal through the Wnt signaling pathway, are significantly affected by ACCA drift. Alterations in these genes compromise the gut's self-repair capabilities. The same epigenetic drift pattern observed in aging intestinal tissue also appears in nearly all analyzed colon cancer samples, suggesting that aging stem cells may foster conditions conducive to cancer development.
Uneven Aging in the Intestine
Aging does not uniformly affect the intestine. The gut is composed of crypts, each originating from a single stem cell. Epigenetic changes in a stem cell are inherited by all cells within its crypt. Dr. Anna Krepelova explained that over time, areas with an older epigenetic profile expand through crypt division, leading to a mosaic of younger and older crypts in older adults. This results in regions with a higher propensity for damaged cells and increased cancer risk.
Mechanism: Iron Loss and DNA Repair Disruption
Researchers discovered that aging intestinal cells exhibit reduced iron uptake and increased iron release, decreasing iron (II) availability in the cell nucleus. Iron (II) is vital for TET (ten-eleven translocation) enzymes, which remove excess DNA methylations. A decline in iron (II) impairs TET enzyme function, leading to the accumulation of DNA methylations and the silencing of key genes, thus accelerating epigenetic drift.
Inflammation Accelerates Aging
Age-related gut inflammation exacerbates the issue by disrupting cellular iron balance and imposing metabolic stress. Concurrently, Wnt signaling weakens, reducing the vitality of stem cells. The combination of iron imbalance, inflammation, and reduced Wnt signaling accelerates epigenetic drift, potentially causing intestinal aging to begin earlier and progress faster than previously understood.
Potential to Slow Gut Aging
Laboratory experiments using intestinal organoids demonstrated that epigenetic drift could be slowed or partially reversed by restoring iron uptake or boosting Wnt signaling. Both methods reactivated TET enzymes, enabling cells to clear excess DNA methylations. Dr. Anna Krepelova stated that these findings suggest epigenetic aging is not irreversible and can be manipulated at a molecular level.