New Epigenetic Aging Pattern Linked to Colon Cancer Risk Discovered in Gut Stem Cells
A recent international study published in Nature Aging has identified an epigenetic aging pattern, termed Aging- and Colon Cancer-Associated (ACCA) drift, in human gut stem cells. This drift, characterized by shifts in DNA methylation, intensifies with age and appears to compromise the gut's self-repair capabilities, potentially increasing the risk of colon cancer by silencing genes crucial for tissue health. Researchers also identified contributing factors and potential methods to slow or partially reverse this process in laboratory settings.
Unveiling ACCA Drift: Epigenetic Aging in Gut Stem Cells
An international research team, led by Professor Francesco Neri of the University of Turin, uncovered a non-random pattern of epigenetic changes in gut stem cells, which they termed Aging- and Colon Cancer-Associated (ACCA) drift. The study describes how these chemical tags, or epigenetic markers, on DNA regulate gene activity and undergo significant shifts as individuals age. These changes involve DNA methylation, which can turn genes on or off without altering the underlying DNA sequence.
How ACCA Drift Progresses
The human gut continuously renews its lining through specialized stem cells located within structures known as crypts. Each crypt originates from a single stem cell, and epigenetic changes within that stem cell are inherited by all cells in its crypt. The ACCA drift involves a gradual accumulation of DNA methylations.
As individuals age, areas with an older epigenetic profile expand through crypt division, leading to a mosaic of crypts with varying epigenetic ages throughout the intestine. Experiments utilizing mouse models and intestinal organoids confirmed the specificity and propagation of this drift within the intestines.
A Precursor to Colon Cancer
Researchers observed that the epigenetic drift pattern identified in aging intestinal tissue is also present in nearly all analyzed colon cancer samples. The drift primarily affects genes critical for maintaining normal tissue balance, particularly those involved in the Wnt signaling pathway, which is vital for intestinal lining renewal.
The gradual silencing of these genes, some of which function as tumor suppressors, is suggested to create conditions within aging stem cells that are conducive to cancer development. This accumulation of risk occurs prior to tumor formation.
Factors Accelerating ACCA Drift
The study identified several factors that accelerate ACCA drift:
- Iron Imbalance: Aging intestinal cells exhibited reduced iron uptake and increased iron release, leading to a decrease in iron (II) availability within the cell nucleus. Iron (II) is essential for TET (ten-eleven translocation) enzymes, which are responsible for removing excess DNA methylations. Impaired TET enzyme function due to low iron (II) contributes to the accumulation of these methylations and the silencing of key genes.
- Inflammation: Age-related gut inflammation was found to exacerbate the issue by disrupting cellular iron balance and imposing metabolic stress.
- Weakened Wnt Signaling: A decline in Wnt signaling further reduces 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.
Hope for Intervention
Laboratory experiments using intestinal organoids demonstrated that epigenetic drift could be slowed or partially reversed. Restoring iron uptake or boosting Wnt signaling both reactivated TET enzymes, enabling cells to clear excess DNA methylations.
Dr. Anna Krepelova, a co-author of the study, stated that these findings suggest epigenetic aging is not an irreversible state and that its molecular parameters can be manipulated.