Fasting has been trending for a while, although it is not a diet per se. Science is also very interested as the numerous health benefits of low-calorie diets and intermittent fasting have been demonstrated, such as delaying the onset of some age-related diseases and extending life. However, the processes are very complex, and researchers continue to analyze the molecular mechanisms behind the reactions caused by fasting.
The Massachusetts Institute of Technology (MIT) is one of the organizations that deeply studies this phenomenon and, for example, has shown that one way fasting exerts its beneficial effects is by enhancing the regenerative capacity of intestinal stem cells, which helps the intestine recover from injuries or inflammations.
In a new study with mice, MIT has now identified the pathway that allows this enhanced regeneration, which is activated once the animals start "refeeding" after fasting. They also found a drawback of this regeneration: 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 an excess of a good thing over time can have less favorable consequences," says Omer Yilmaz, associate professor of Biology at MIT, member of the Koch Institute for Integrative Cancer Research at MIT, and lead author of this study published in Nature.
Yilmaz adds that more studies are needed before reaching any conclusion about whether fasting has a similar effect in humans. "We still have much to learn, but it is interesting to see that being in a fasting or refeeding state when exposed to a mutagen can have a profound impact on the likelihood of developing cancer in these well-defined mouse models," he says.
Is it fasting or the post-feeding?
Yilmaz's laboratory has been investigating how fasting and low-calorie diets affect intestinal health for some time. Thus, in 2018, they observed that during fasting, intestinal stem cells begin to use lipids as an energy source, instead of carbohydrates. They also demonstrated that this process led to a significant increase in the regenerative capacity of stem cells. However, some questions remained unanswered, such as how fasting triggers this increase in regenerative capacity and when regeneration begins.
"Since that article, we have focused on understanding what drives regeneration during fasting: Is it fasting itself that drives regeneration or is it the feeding afterwards?" Yilmaz questions.
In this new study, researchers discovered that the regeneration of stem cells is suppressed during fasting, but then increases during the refeeding period. They followed three groups of mice: one that fasted for 24 hours, another that fasted for 24 hours and then was allowed to eat whatever it wanted during a 24-hour refeeding period, and a control group that ate freely throughout the experiment.
They analyzed the proliferation capacity of intestinal stem cells at different times and found that they showed the highest levels at the end of the 24-hour refeeding period. They were also more proliferative than intestinal stem cells of mice that had not undergone fasting.
"We believe that fasting and refeeding represent two distinct states. In the fasting state, the cells' ability to use lipids and fatty acids as an energy source allows them to survive when nutrients are low. And then it is the post-fasting refeeding state that truly drives regeneration. When nutrients are available, these stem cells and progenitor cells activate programs that allow them to generate cell mass and repopulate the intestinal lining," explains Shinya Imada, postdoctoral researcher at MIT and another lead author of the study.
It was observed in further studies that these cells activate a cellular signaling pathway known as mTOR, which is involved in cell growth and metabolism. One of mTOR's functions is to regulate messenger RNA translation into protein, so when activated, cells produce more protein. This protein synthesis is essential for stem cells to proliferate. The researchers demonstrated 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 refeeding state, there is more proliferation, and it is necessary to generate cell mass. This requires more proteins to generate new cells, and these stem cells continue to generate more differentiated cells or specialized intestinal cell types that line the intestine," explains Saleh Khawaled, another lead author.
However, researchers also found that when stem cells are in this highly regenerative state, they are more likely to become cancerous. Intestinal stem cells are one of the most actively dividing cell types in the body, as they help renew the intestine lining completely every five to 10 days. By dividing so frequently, they are the most common source of precancerous cells in the intestine.
In this study, researchers observed that if they activated a cancer-causing gene in mice during the refeeding stage, they were much more likely to develop precancerous polyps than if the gene was activated during the fasting state. Cancer-related mutations that occurred during the refeeding state also had a much higher likelihood of producing polyps than mutations that occurred in mice that did not go through the fasting and refeeding cycle.
"I want to emphasize that all of this was done in mice, using very well-defined cancer mutations. In humans, it will be much more complex," says Yilmaz. "But it leads us to the next notion: fasting is very healthy, but if you are unlucky enough to refeed after fasting and expose yourself to a mutagen, such as a charred steak or something like that, you could actually be increasing your chances of developing an injury that can lead to cancer."
Yilmaz also points out that the regenerative benefits of fasting could be significant for people undergoing radiation treatments, which can damage the intestinal lining, or for other types of intestinal injuries. His laboratory is now studying whether polyamine supplements could help stimulate this type of regeneration without the need for fasting.
"The study reveals that, in mice, refeeding after fasting increases the proliferation of intestinal stem cells and enhances tissue regeneration. However, this also increases the risk of tumor formation, especially when the tumor suppressor gene APC is lost. The study identifies that the activation of mTORC1 during that return to feeding causes these changes through a greater protein synthesis via polyamine metabolism," indicates Nabil Djouder, who heads the Growth Factors, Nutrients, and Cancer Group at the Spanish National Cancer Research Centre (CNIO).
According to Djouder, "the work presents a novel and interesting discovery, especially because dietary habits that can lead to inflammatory bowel disease (IBD) are significant risk factors for colorectal cancer (CRC), however, the mechanisms governing the relationship between nutrients, IBD, and CRC remain unclear."
The CNIO researcher recalls that in light of these findings, in his laboratory they previously demonstrated, as published in Cell Metabolism (Brandt et al., 2018), that the inactivation of mTORC1 is beneficial for APC-dependent colorectal cancer. "This suggests that mTORC1 inhibition could mitigate colorectal cancer in patients with APC mutations. On the other hand, we also saw that mTORC1