Researchers have discovered a signaling pathway in mice that enhances the ability of intestinal stem cells to regenerate after fasting. However, during this recovery phase, if cancerous mutations occur, the mice are at a greater risk for developing early-stage intestinal tumors.
Eating fewer calories and intermittent fasting have been linked to various health advantages, such as delaying the onset of certain age-related diseases and extending lifespan—not just in humans, but across many different species.
There are many intricate mechanisms at play behind this effect. Past research from MIT has indicated that one way fasting provides its health benefits is by enhancing the regenerative capacity of intestinal stem cells, which aids in the intestines’ recovery from injuries or inflammation.
In a recent study involving mice, researchers from MIT pinpointed the pathway responsible for this improved regeneration, which kicks in once the mice start to “refeed” after fasting. They also discovered a downside: Mice experiencing mutations during this regenerative time were more prone to developing early-stage intestinal tumors.
“Increased stem cell activity is beneficial for regeneration, but too much activity over time may lead to unfavorable outcomes,” remarks Omer Yilmaz, an associate professor of biology at MIT, affiliated with MIT’s Koch Institute for Integrative Cancer Research, and the leading author of the new study.
Yilmaz notes that further investigation is necessary before determining if fasting has a similar impact on humans.
“There’s still much to explore, but it is intriguing that being in either a fasting or refeeding state when exposed to mutation-causing agents can significantly affect cancer development in these well-studied mouse models,” he explains.
MIT postdoctoral researchers Shinya Imada and Saleh Khawaled are the primary authors of the upcoming paper in Nature.
Pursuing regeneration
For several years, Yilmaz’s team has been exploring how fasting and reduced-calorie diets influence intestinal health. In a 2018 study, they found that during fasting, intestinal stem cells start utilizing lipids as an energy source rather than carbohydrates, leading to a notable increase in the regenerative capacity of these cells.
Yet, several questions persisted: How does fasting trigger this regenerative boost, and when does this regeneration commence?
“Since that previous paper, our focus has shifted to discerning what aspect of fasting initiates this regeneration,” Yilmaz explains. “Is it the act of fasting itself, or is it the refeeding afterward that prompts regeneration?”
In their latest research, the scientists observed that stem cell regeneration is inhibited during fasting but dramatically increases once refeeding begins. They monitored three groups of mice—one group that fasted for 24 hours, another that fasted for 24 hours and then was allowed to eat freely for another 24 hours, and a control group that ate whatever they wanted the entire time.
By evaluating the intestinal stem cells’ proliferation capabilities at various intervals, the researchers noticed that the stem cells exhibited peak proliferation rates at the end of the 24-hour refeeding phase. Notably, these stem cells showed greater proliferation than those from mice that did not undergo fasting.
“We believe fasting and refeeding are two separate states,” Imada explains. “In the fasting state, cells’ capacity to utilize lipids and fatty acids as energy sources helps them survive during nutrient-scarce times. In contrast, the refeeding state truly stimulates regeneration, allowing these stem cells and progenitor cells to engage in processes that enable them to accumulate cellular mass and regenerate the intestinal lining once nutrients are available.”
Further research revealed that these stem cells activate a cellular signaling pathway known as mTOR, which plays a critical role in cellular growth and metabolism. One of its primary functions is to manage the translation of messenger RNA into proteins, meaning that its activation leads cells to produce more protein. This protein synthesis is essential for stem cells to multiply.
The researchers also discovered that activating mTOR in these stem cells resulted in the production of large amounts of polyamines—small molecules essential for cell growth and division.
“During the refeeding phase, there is an increase in cell proliferation, which requires building cellular mass. This necessitates more protein for new cells, with stem cells progressing to form more specialized intestinal cell types that line the intestine,” Khawaled states.
Too much of a good thing
The team also discovered that when stem cells are in this highly regenerative state, they are more susceptible to becoming cancerous. Intestinal stem cells divide frequently, helping renew the intestinal lining every five to 10 days. Due to their rapid division, these stem cells are often the source of precancerous cells in the intestine.
In this study, researchers observed that activating a cancer-causing gene during the refeeding stage significantly increased the likelihood of developing precancerous polyps compared to activating the gene while fasting. Moreover, mutations linked to cancer that occurred during refeeding were much more likely to lead to polyps than those in mice that did not undergo fasting and refeeding.
“It’s crucial to clarify that this research was conducted on mice with well-defined cancer mutations. In humans, the circumstances will undoubtedly be more complex,” Yilmaz remarks. “But it raises an interesting thought: While fasting is generally healthy, if you’re exposed to a mutagen—like a charred steak—during the refeeding period, you might inadvertently increase your risk of developing lesions that could progress to cancer.”
Yilmaz also highlighted that the regenerative advantages of fasting could be important for individuals undergoing radiation therapy, which can harm the intestinal lining, or other intestinal injuries. His lab is currently researching whether polyamine supplements could stimulate this regeneration without requiring fasting.
This research received funding from the Pew-Stewart Trust Scholar award, the Marble Center for Cancer Nanomedicine, the Koch Institute-Dana Farber/Harvard Cancer Center Bridge Project, and the MIT Stem Cell Initiative.
