Low-calorie diets and intermittent fasting have been reported to have numerous health benefits, including delaying the onset of some age-related diseases and lengthening lifespan, not only in humans but in many other organisms.
Previous work by MIT researchers has shown that one way fasting exerts its beneficial effects is by boosting the regenerative abilities of intestinal stem cells, which helps the intestine recover from injuries or inflammation. Through a newly reported study in mice, MIT researchers have now identified the pathway that enables this enhanced regeneration, which they showed is activated once the animals begin refeeding after the fast. They also found a downside to this regeneration. Their studies showed that when cancerous mutations occurred during the regenerative period, the mice were more likely to develop early-stage intestinal tumors.
“Having more stem cell activity is good for regeneration, but too much of a good thing over time can have less favorable consequences,” said Omer Yilmaz, MD, PhD, an MIT associate professor of biology, and a member of MIT’s Koch Institute for Integrative Cancer Research.
Yilmaz added that further studies are needed before forming any conclusion as to whether fasting has a similar effect in humans. “We still have a lot to learn, but it is interesting that being in either the state of fasting or refeeding when exposure to mutagen occurs can have a profound impact on the likelihood of developing a cancer in these well-defined mouse models.”
Yilmer is senior author of the team’s published study in Nature, titled “Short-term post-fast refeeding enhances intestinal stemness via polyamines.” MIT postdocs Shinya Imada, MD, PhD, and Saleh Khawaled, PhD, are the lead authors of the paper, in which the researchers stated “Collectively, our data indicate that post-fast refeeding leads to a burst in stem-cell-driven regeneration and that these refed stem cells when exposed to genetic alterations have an elevated risk of developing cancers in mouse models …”
For more than a century, fasting interventions, including short-term fasting, intermittent fasting and caloric restriction, have been reported to extend lifespan and enhance tissue regeneration in many species, the authors wrote. “However, how adult stem cells contribute to these organismal benefits, given their importance in tissue regeneration and tumor initiation, has not been fully characterized.”
Yilmaz’s lab has for several years been investigating how fasting and low-calorie diets affect intestinal health. In a previous study the researchers reported that during a fast, intestinal stem cells (ISCs) begin to use lipids as an energy source, instead of carbohydrates. They also showed that fasting led to a significant boost in stem cells’ regenerative ability. “Previously, we and others have reported that a 24-h fast enhances ISC function by activating a fatty acid oxidation program and that the fasted intestine and ISCs are protected from chemo-induced and radiation-induced damage,” the team explained.
However, unanswered questions remained. How does fasting trigger this boost in regenerative ability, and when does the regeneration begin? “Since that paper, we’ve really been focused on understanding what is it about fasting that drives regeneration,” Yilmaz says. “Is it fasting itself that’s driving regeneration, or eating after the fast?”
For their newly reported study the researchers followed three groups of mice—one that fasted for 24 hours, another one that fasted for 24 hours and then was allowed to eat whatever they wanted during a 24-hour refeeding period, and a control group that ate whatever they wanted throughout the experiment.
The team analyzed the ability of the animals’ intestinal stem cells’ to proliferate at different time points, and found that stem cell regeneration is suppressed during fasting but then surges during the refeeding period. The results showed that the 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 at all. “Overall, our data support the notion that many benefits of fasting in the intestine occur during refeeding by stimulating ISCs to generate greater numbers of progeny in homeostasis and injury,” they noted.
“We think that fasting and refeeding represent two distinct states,” Imada said. “In the fasted state, the ability of cells to use lipids and fatty acids as an energy source enables them to survive when nutrients are low. And then it’s the post-fast refeeding state that really drives the regeneration. When nutrients become available, these stem cells and progenitor cells activate programs that enable them to build cellular mass and repopulate the intestinal lining.”
Further studies revealed that these cells activate the mTOR cellular signaling pathway, which is involved in cell growth and metabolism. One of mTOR’s roles is to regulate the translation of messenger RNA into protein, so when it’s activated, cells produce more protein. This protein synthesis is essential for stem cells to proliferate.
The researchers showed that mTOR activation in these stem cells also led to production of large quantities of polyamines—small molecules that help cells to grow and divide. Khawaled commented, “In the refed state, you’ve got more proliferation, and you need to build cellular mass. That requires more protein, to build new cells, and those stem cells go on to build more differentiated cells or specialized intestinal cell types that line the intestine.”
The authors further wrote, “… post-fast refeeding stimulates global protein translation, which is coordinated partly by increased mTORC1 activity and polyamine synthesis.” Their collective results, they noted, “… provide evidence to support the hypothesis that post-fasting refeeding primes ISCs for a robust regenerative response upon nutritional stimulation.”
The researchers also found that when stem cells are in this highly regenerative state, they are more prone to become cancerous. Intestinal stem cells are among the most actively dividing cells in the body, as they help the lining of the intestine completely turn over every five to 10 days. Because they divide so frequently, these stem cells are the most common source of precancerous cells in the intestine. Previous studies have demonstrated that fasting interventions and fasting-mimicking diets mostly inhibit tumor growth, the team noted. “However, these studies mainly focused on the fasted state; they did not delineate the contributions of the refed states on tumour initiation.”
In their newly released study, the researchers discovered that if they turned on a cancer-causing gene in the mice during the refeeding stage, the animals 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 cycle of fasting and refeeding. Outlining the results of their studies in mice, the team stated, “… we conclude that post-fast refeeding augments ISC-initiated tumour formation by engaging an mTORC1–polyamine–protein synthesis axis.”
Yilmaz added, “I want to emphasize that this was all done in mice, using very well-defined cancer mutations. In humans it’s going to be a much more complex state. But it does lead us to the following notion: Fasting is very healthy, but if you’re unlucky and you’re refeeding after a fasting, and you get exposed to a mutagen, like a charred steak or something, you might actually be increasing your chances of developing a lesion that can go on to give rise to cancer.” The authors added, “Given our findings, fast–refeeding cycles must be carefully considered and tested when planning diet-based strategies for regeneration without increasing cancer risk, as post-fast refeeding leads to a burst in stem-cell-driven regeneration and tumorigenicity.”
Yilmaz also noted that the regenerative benefits of fasting could be significant for people who undergo radiation treatment, which can damage the intestinal lining, or other types of intestinal injury. His lab is now studying whether polyamine supplements could help to stimulate this kind of regeneration, without the need to fast.
