Fasting and low-calorie diets have long been praised for their potential to delay age-related diseases and extend lifespan. However, a new study from MIT researchers uncovers a darker side to these benefits: while fasting boosts the intestine’s ability to heal by enhancing stem cell regeneration, it may also increase the risk of cancer. In research conducted on mice, the team at MIT identified a crucial pathway that becomes active during the "refeeding" phase following a fast. This pathway significantly amplifies the regenerative capacity of intestinal stem cells, allowing the intestine to recover from injuries or inflammation.
But the study also highlights a significant downside, if cancerous mutations occur during this heightened regenerative state, there’s a greater likelihood of developing early-stage intestinal tumors. “More stem cell activity is good for regeneration, but too much of a good thing over time can have unfavorable consequences,” explains Omer Yilmaz, an MIT associate professor of biology and a member of MIT’s Koch Institute for Integrative Cancer Research, who is the senior author of the study published in Nature.
The mechanisms behind fasting and regeneration
The research builds on previous findings from Yilmaz’s lab, which showed that fasting enhances the regenerative abilities of intestinal stem cells by switching their energy source from carbohydrates to lipids. This shift helps the cells survive and maintain function during periods of nutrient scarcity.
The new study sought to answer unresolved questions: What exactly triggers this boost in regeneration, and when does it occur? The researchers found that while stem cell activity is suppressed during fasting, it surges during the refeeding phase when nutrients become available again. This increase in activity is driven by the mTOR signaling pathway, which regulates cell growth and protein synthesis.
To test this, the researchers divided mice into three groups: one fasted for 24 hours, another fasted for 24 hours followed by a 24-hour refeeding period, and a control group that ate freely throughout the study. The results were striking: intestinal stem cells showed the highest levels of proliferation at the end of the refeeding period, significantly more than in the mice that hadn’t fasted at all.
“We think that fasting and refeeding represent two distinct states,” says Shinya Imada, one of the study’s lead authors. “During fasting, cells adapt to use lipids as an energy source to survive. But it’s the refeeding that really drives the regeneration, activating stem cells to build new cellular mass and repopulate the intestinal lining.”
The risks of enhanced regeneration
While this regenerative boost can be beneficial for healing, it also carries risks. Intestinal stem cells, which are among the most rapidly dividing cells in the body, are often the origin of precancerous cells. The study found that when cancer-linked mutations occurred during the refeeding period, the mice were much more likely to develop precancerous polyps than if those mutations occurred during fasting or in mice that did not fast at all.
This suggests that the very process that makes fasting beneficial could also create a more favorable environment for cancerous mutations to take hold and proliferate. “I want to emphasize that this was all done in mice, using very well-defined cancer mutations,” Yilmaz cautions. “In humans, the situation is likely to be much more complex, but these findings do suggest a potential risk when re-feeding after fasting, especially if exposure to a mutagen like charred meat occurs.”
Implications for human health and future research
The study raises important questions about the safety of fasting as a therapeutic strategy, particularly in environments where there may be exposure to cancer-causing agents. While fasting’s regenerative benefits are clear, the potential for increased cancer risk must be carefully considered. Yilmaz notes that the findings could have significant implications for people undergoing treatments like radiation, which can damage the intestinal lining. His lab is now exploring whether polyamine supplements might stimulate similar regenerative effects without the need for fasting, potentially offering a safer alternative.
“This fascinating study provides insights into the complex interplay between food consumption, stem cell biology, and cancer risk,” says Ophir Klein, a professor of medicine at the University of California, San Francisco, who was not involved in the study. “It suggests that careful consideration is needed when planning diet-based strategies for regeneration to avoid increasing cancer risk. ”As researchers continue to explore these complex mechanisms, the study lays the groundwork for future investigations into how diet, stem cell activity, and cancer risk are interconnected and how we might harness the benefits of fasting while minimizing the risks.
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