The aging of the intestine, foundational to the development of significant diseases such as colon cancer, is not an unavoidable process, but it can be modulated, even halted. By acting on certain factors responsible for cellular alteration and degeneration that reduce the regenerative capacity of intestinal stem cells: among them, iron homeostasis and inflammation.
Two major studies conducted by researchers at the University of Turin and the Leibniz Institute on Aging—Fritz Lipmann Institute (FLI) in Jena, Germany, published in Nature Aging and Nature Cell Biology, suggest this. Understanding these risk elements, “tumor generators” of colon cancer, serves as both a means and a strategy to counteract their emergence.
Factors and Trigger Mechanisms of Aging and Intestinal Disease
A key role in intestinal aging is attributed to epigenetic and proteomic alterations in intestinal stem cells, changes that trigger an increased risk of colon cancer as regenerative capacity wanes with age. Looking more closely: epigenetic drift is substantially linked to age-related diseases, such as various cancers, yet the underlying molecular mechanisms remain unclear.
A first hypothesis proposed by the Nature Aging study, which analyzed DNA methylation data and gene expression from samples of healthy human colon tissue and cancerous tissue, points to a drift in DNA methylation (DNAm) and the tight link between aging and colon cancer.
Experimental investigations have observed how this drift is conserved in the mouse intestinal epithelium, in which intestinal stem cells appear to be characterized by intrinsic, non-dividing particularities, and whose expansion seems to be regulated by crypt clonality and fission.
This specific form of epigenetic aging of intestinal stem cells has been defined as Acca drift (Aging- and colon cancer-associated drift) and would explain how, with age, cells accumulate DNA hypermethylation that silences key genes, including those responsible for regulating the Wnt signaling pathway, which is essential for maintaining tissue balance. This epigenetic drift would thus generate a complex and intricate architecture of young and highly aged intestinal crypts that progressively expand, taking on features similar to those observed in colon tumor lesions.
This drift process is governed by inflammation related to aging and diminished Wnt signaling, which disrupt iron metabolism, thereby compromising the activity of Tet enzymes, which are responsible for removing excessive methylation, with important consequences.
Among these consequences is the development of chronic, low-grade inflammation typical of aging and a weakened Wnt signal. Here another key factor comes into play: iron. Restoring homeostasis and iron import or boosting Wnt signaling appears to be crucial: intestinal organoid models have shown that targeting this component can slow down or even reverse the drift, demonstrating that epigenetic aging can be modulated.
The Regenerative Capacity of the Intestine
Aging reduces the regenerative potential of the intestinal epithelium across species, including humans, though the precise causes remain only partly understood. Some evidence from the Nature Cell Biology study put forward a preliminary hypothesis: experiments in aged mice indicate that tissue repair is impaired due to a disruption of proteostasis, the cellular system that ensures correct protein function.
The researchers pursued this by mapping the temporal dynamics of regeneration after damage induced by 5-fluorouracil, a chemotherapy agent routinely used in cancer treatment, using proteomic and metabolomic tissue profiles alongside functional assays. Comparing regeneration dynamics in mice of different ages revealed that proteostasis stress and elevated polyamine levels follow injury, but only in aged epithelia. In essence, this suggests that delayed regeneration is an intrinsic characteristic of aging epithelial cells that exhibit reduced protein synthesis and accumulation of ubiquitinated proteins. Supporting experiments show that inhibiting the polyamine pathway in vivo can further delay regeneration in old mice, while activating it—for example, via dietary intervention such as brief periods of caloric restriction followed by refeeding—or oral polyamine supplementation could improve the regenerative capacity of mature intestines. These results point toward promising epithelial targets for shaping strategies against aging-related declines in tissue repair mechanisms, helping aged tissues preserve a latent capacity for self-healing.
In short, these newly uncovered aspects revealed by the recent studies may chart a path toward novel, potentially integrative interventions to prevent or reverse the processes leading to colon cancer development. This disease often depends on aging in addition to lifestyle factors. Across both studies, the interplay among iron balance, inflammation, the Wnt pathway, and polyamines appears to offer a viable strategy to prevent or slow intestinal aging, lower age-associated colon cancer risk, and improve healing after chemotherapy, infections, or surgical procedures in older individuals. There is also potential to extend these approaches to other aging tissues, such as skin or liver.
Fonti
Krepelova A, Rasa M, Annunziata F et al. Iron homeostasis and cell clonality drive cancer-associated intestinal DNA methylation drift in aging. Nature Aging, 2025, 5(12):2432-2448. Doi: 10.1038/s43587-025-01021-x.
Minetti A, Omrani O, Brenner C et al. Polyamines sustain epithelial regeneration in aged intestines by modulating protein homeostasis.Nature Cell Biology, 2025, 27(12):2063-2077. Doi: 10.1038/s41556-025-01804-9
Abbonati a Karla Miller
