Research reveals the benefits and harms of fasting

Low-calorie diets and intermittent fasting have been shown to have numerous health benefits: they can delay the onset of certain age-related diseases and extend lifespan, not only in humans but also in many other organisms.

There are many complex mechanisms underlying this phenomenon. Previous work from MIT has shown that one way fasting exerts its beneficial effects is by stimulating the regenerative capacity of intestinal stem cells, helping the intestine 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 once the mice begin “refeeding” after fasting. They also discovered a downside to this regeneration: when cancer 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 can have less beneficial effects over time,” says Omer Yilmaz, an associate professor of biology at MIT and a member of the Koch Institute for Integrative Cancer Research at MIT, and the senior author of the new study.

Yilmaz adds that further research is needed before a conclusion can be drawn as to whether fasting has a similar effect in humans.

“We still have a lot to learn, but it is interesting that fasting or refeeding when mutagen exposure occurs can have a profound impact on the likelihood of developing cancer in these well-defined mouse models,” he says. say.

MIT postdocs Shinya Imada and Saleh Khawaled are the lead authors of the paper to appear in Nature.

Drive regeneration

Yilmaz’s laboratory has been studying how fasting and low-calorie diets affect intestinal health for several years. In a 2018 study, his team reported that intestinal stem cells begin using lipids as an energy source instead of carbohydrates during a fast period. They also showed that fasting led to a significant increase in the regenerative capacity of stem cells.

However, unanswered questions remained: How does fasting cause this boost in regenerative capacity, and when does regeneration begin?

“Since that article, we’ve really focused on understanding what it is about fasting that stimulates regeneration,” says Yilmaz. ‘Is it the fasting itself that stimulates regeneration, or is it eating after fasting?’

In their new study, the researchers found that stem cell regeneration is suppressed during fasting, but then increases during the refeeding period. The researchers followed three groups of mice: one that fasted for 24 hours, another 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 for the entire period. experiment.

The researchers analyzed the ability of intestinal stem cells to multiply at different times and found that the stem cells showed the highest proliferation levels 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.

“We think that fasting and refeeding represent two different states,” says Imada.

“In the fasting state, the ability of cells to use lipids and fatty acids as an energy source allows them to survive when nutrients are low. And then it’s the post-fast refeeding state that really stimulates regeneration. When nutrients become available , these stem and progenitor cells activate programs that allow them to build cellular mass and repopulate the intestinal wall.”

Further studies have shown that these cells activate a cellular 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 it is activated, cells produce more proteins. This protein synthesis is essential for the proliferation of stem cells.

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 referred state you have more proliferation and you have to build up cellular mass. That requires more proteins to build new cells, and those stem cells go on to build more differentiated cells or specialized intestinal cell types that line the intestine,” says Khawaled.

Too much of a good thing

The researchers also found that when stem cells are in this highly regenerative state, they are more susceptible to cancer. Intestinal stem cells are among the most actively dividing cells in the body because they cause the lining of the intestine to completely change every five to ten days. Because they divide so frequently, these stem cells are the most common source of precancerous cells in the intestine.

In this study, the researchers found that if they turned on a cancer-causing gene in the mice during the refeeding phase, they were much more likely to develop precancerous polyps than if the gene was turned on during fasting. Cancer-related mutations that occurred during refeeding 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 all this happened in mice, using very well-defined cancer mutations. In humans it will be a much more complex situation,” says Yilmaz.

“But it does lead us to this idea: fasting is very healthy, but if you’re unlucky and you’re feeding again after fasting, and you’re exposed to a mutagen, like a charred steak or something, it might could increase your chances of developing a lesion that could cause cancer.”

Yilmaz also noted that the regenerative benefits of fasting can be significant for people undergoing radiation treatment, which can damage the intestinal lining, or other forms of intestinal damage. His laboratory is now investigating whether polyamine supplements can help stimulate this type of regeneration, without the need to fast.

This story is republished courtesy of MIT News (web.mit.edu/newsoffice/), a popular site covering news about MIT research, innovation, and education.