Low-calorie diets and intermittent fasting may improve intestinal regeneration, but restarting eating after fasting could increase the risk of developing intestinal tumors in the case of cancerous mutations.
Low-calorie diets and intermittent fasting have been shown to have numerous health benefits, such as delaying the onset of some age-related diseases and prolonging life, not only in humans but in many other organisms. Now, a group of scientists from the Massachusetts Institute of Technology (MIT) has discovered one of the mechanisms that explain these advantages, but has also found that intermittent fasting can have a counterproductive impact, as it leads to an increased risk of cancer in mice.
Previous MIT research has shown that one way fasting exerts its beneficial effects is by increasing the regenerative capacity of intestinal stem cells, which helps the gut recover from injury or inflammation. In a study in mice, MIT researchers have now identified the pathway that enables this enhanced regeneration, which is activated when mice begin to “refeed” after fasting.
However, they also discovered a downside to this regeneration: When cancerous mutations occur during the regeneration period, the mice are more likely to develop intestinal tumors at early stages. “Having more stem cell activity is positive for regeneration, but too much stem cell activity can have less favorable consequences over time,” says Omer Yilmaz, an MIT associate professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and senior author on the new study.
Yilmaz adds that further studies are needed before a conclusion can be drawn on whether fasting has a similar effect in humans: “We still have a lot to learn, but it is interesting to know that being in a fasted or refed state when exposure to a mutagen occurs can have a profound impact on the likelihood of developing cancer in these well-defined mouse models,” he says.
Fasting is healthy, but with nuances
For several years, Yilmaz’s lab has been investigating how fasting and low-calorie diets affect gut health. In a 2018 study, his team reported that during fasting, intestinal stem cells begin using lipids as an energy source instead of carbohydrates. They also showed that fasting leads to a significant increase in the regenerative capacity of stem cells.
However, unanswered questions remained: How does fasting trigger this increase in regenerative capacity, and when does regeneration begin? “Since that study, we have focused on understanding what drives regeneration during fasting,” Yilmaz explains. “Is it the fasting itself that drives regeneration, or is it the process of eating after fasting?”
In their new study, the researchers found that stem cell regeneration is suppressed during fasting but markedly increased during the refeeding period. The researchers followed three groups of mice: one that fasted for 24 hours, one that fasted for 24 hours and then was allowed to eat freely during a 24-hour refeeding period, and a control group that ate normally throughout the experiment.
The researchers analyzed the proliferation capacity of intestinal stem cells at different time points and found that stem cells showed the highest levels of proliferation at the end of the 24-hour refeeding period. These cells were also more proliferative than intestinal stem cells from mice that had not fasted.
“We think that fasting and refeeding represent two distinct states,” said Shinya Imada, one of the authors of the paper published in Nature. “In the fasted state, the cells’ ability to use lipids and fatty acids as an energy source allows them to survive when nutrients are scarce. And then, it’s the post-fasting refeeding state that really drives regeneration. When nutrients become available, these stem cells and progenitor cells activate programs that allow them to build cell mass and repopulate the intestinal lining.”
“Fasting is very healthy, but if you are unlucky enough to be in a refeeding state after a fast and you are exposed to a mutagen, such as charred steak, you could increase your chances of developing cancer.”
Further studies revealed that these cells activate a cell signaling pathway known as mTOR, which is involved in cell growth and metabolism. One of mTOR’s roles is to regulate the translation of messenger RNA into proteins, so when activated, cells produce more proteins. This protein synthesis is essential for stem cells to proliferate.
The researchers showed that mTOR activation in these stem cells also led to the production of large amounts of polyamines, small molecules that help cells grow and divide. “In the feedback state, there is more proliferation, and you need to build cell mass. That requires more proteins to form new cells, and those stem cells go on to form more differentiated cells or specialized intestinal cell types that line the gut,” explains Saleh Khawaled, another of the authors of the paper.
Researchers also found that when stem cells are in this highly regenerative state, they are more likely to become cancerous. Intestinal stem cells are some of the most rapidly dividing cells in the body, helping to renew the lining of the gut every five to 10 days. Because they divide so frequently, these stem cells are the most common source of precancerous cells in the gut.
In this study, the researchers found that if they turned on a cancer-causing gene in mice during the refeeding stage, they were much more likely to develop precancerous polyps than if the gene was turned on during the fasting state. Cancer-linked mutations that occurred during the refeeding state were also much more likely to produce polyps than mutations that occurred in mice that did not undergo the fasting-refeeding cycle.
“I want to emphasize that this was all done in mice, using well-defined cancer mutations. In humans, it will be a much more complex state,” Yilmaz stresses. “But this brings us to the next notion: Fasting is very healthy, but if you are unlucky enough to be in a refeeding state after a fast and you are exposed to a mutagen, like a charred steak or something similar, you could be increasing your chances of developing a lesion that can lead to cancer.”
Yilmaz also noted that the regenerative benefits of fasting could be significant for people undergoing radiation treatment, which can damage the gut lining, or other types of intestinal injury. His lab is now studying whether polyamine supplements could help stimulate this type of regeneration, without the need for fasting.
“This fascinating study provides insight into the complex interplay between dietary intake, stem cell biology, and cancer risk,” says Ophir Klein, a professor of medicine at the University of California, San Francisco and Cedars-Sinai Medical Center, who was not involved in the study. “Their work lays the groundwork for testing polyamines as compounds that may enhance intestinal repair after injury, and suggests that careful consideration should be given when planning regeneration-based dietary strategies to avoid increasing cancer risk.”
