New research published in Nature Aging and Nature Cell Biology challenges the long-held belief that gut deterioration is an unavoidable outcome of aging. A collaborative effort between researchers at the University of Turin and the Leibniz Institute on aging – Fritz Lipmann Institute in Germany has uncovered key mechanisms driving gut aging, revealing potential targets for intervention and prevention. The studies pinpoint epigenetic and proteomic changes in intestinal stem cells as critical factors, offering new hope for mitigating age-related risks like colon cancer and impaired tissue repair.
New research suggests that the aging of the gut isn’t an inevitable process and can be actively countered. Two recently published studies in Nature Aging and Nature Cell Biology, a collaboration between the University of Turin and the Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) in Jena, Germany, have revealed unprecedented details about the mechanisms driving gut aging and propose concrete strategies to combat it. The research indicates that epigenetic and proteomic changes in intestinal stem cells can increase the risk of colon cancer and the loss of regenerative capacity associated with aging, potentially opening avenues for prevention or reversal.
As we age, the gut—one of the most dynamic tissues in the human body—progressively loses efficiency, becoming more susceptible to inflammation, infection, and cancer. Researchers led by Professor Francesco Neri, who previously worked at FLI and now at the University of Turin, conducted two investigations that explain how this process unfolds and how it might be influenced. Understanding these changes is crucial as gut health plays a significant role in overall well-being.
The Two Studies
The first study describes a specific form of epigenetic aging in intestinal stem cells, termed “Acca drift” (Aging- and colon cancer-associated drift). With age, cells accumulate DNA hypermethylation, which silences key genes, particularly those regulating the Wnt signaling pathway—essential for maintaining tissue balance. This epigenetic drift creates a “mosaic” of young and very aged intestinal crypts, which expand over time and exhibit characteristics similar to those observed in colon tumor lesions.
The research team, with Dr. Anna Krepelova as first author, identified the factors triggering this phenomenon: alterations in iron metabolism, which reduce the activity of Tet enzymes responsible for removing excess methylation; chronic, low-grade inflammation typical of aging; and a weakening of the Wnt signal. Restoring iron import or boosting the Wnt signal in intestinal organoid models slowed or reversed the drift, demonstrating that epigenetic aging can be modulated.
“These studies, also funded by a call for excellence in research, open up new concrete perspectives for the prevention and treatment of some of the most common age-related diseases,” said Massimo Segre, president of the Molinette Research Foundation, which provided a grant to Professor Francesco Neri. “Publication in two prestigious scientific journals is both recognition of the extraordinary work done and a boost towards the practical application of the discoveries. This is precisely the mission of the Molinette Research Foundation: to transform every donation into concrete results for our community and shared scientific knowledge.”
The second study, conducted in collaboration with Dr. Alessandro Ori and researchers Alberto Minetti and Omid Omrani, focused on the gut’s regenerative capacity. In older mice, tissue repair was compromised due to an alteration in proteostasis—the system that ensures the proper functioning of cellular proteins. Researchers discovered that, after injury, older intestines delayed the production of polyamines—small molecules like spermidine and putrescine, crucial for cell growth and proteostasis. Reactivating this metabolism early, through short periods of caloric restriction followed by refeeding or oral supplementation, restored the regenerative capacity of the epithelium. This suggests that aged tissue retains a potential for self-healing that can be stimulated with targeted interventions.
Key Takeaway: Gut Aging Isn’t Inevitable
The two studies converge on a key message: gut aging isn’t an inevitable process, but one that can be modulated. Understanding how iron, inflammation, the Wnt pathway, and polyamines interact opens new opportunities for: preventing or slowing intestinal aging; reducing the risk of age-related colon cancer; improving healing after chemotherapy, infections, or surgery in older adults; and extending these approaches to other aging tissues, such as skin or liver.
“These results confirm that the Foundation is achieving its objectives of promoting excellence in research by selecting projects and researchers truly capable of producing impact, with direct repercussions on improving the quality of life of the elderly,” said Professor Emilio Hirsch, scientific director of the Molinette Research Foundation and director of the Center for Molecular Biotechnology in Turin. “The results stem from years of scientific collaboration between the University of Turin and the Leibniz Institute on Aging – FLI, a European reference institute for the study of aging, with which UniTo has established an International Research Cooperation Agreement for five years. The research was made possible thanks to funding from the AIRC Foundation – Grandi Donatori and the Molinette Research Foundation, which decisively supported the development of the projects.”
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