Breaking a fast provides more health benefits than the fast itself, a study in mice shows 1. After the mice stopped eating, stem cells to repair damage shot up in their intestines — but only when the mice went back into their food, the study found.

However, this activation of stem cells came at a price: Mice were more likely to develop precancerous polyps in their intestines if they had suffered a cancer-causing genetic change during the post-fasting period than if they had not fasted at all.

These results, on August 21st inNaturepublished show that “regeneration is not free,” says Emmanuelle Passegué, a stem cell biologist at Columbia University Irving Medical Center in New York City who was not involved in the study. “There is a dark side that needs to be considered.”

Fast route to health

Researchers have been studying the potential health benefits of fasting for decades, and there is evidence that the practice may help delay certain diseases and extend life expectancy in rodents. However, the underlying biological mechanisms behind these benefits have been a mystery.

In 2018, Ömer Yilmaz, a stem cell biologist at the Massachusetts Institute of Technology in Cambridge, and his colleagues found that stem cells were likely involved. During fasting, these cells begin burning fats instead of carbohydrates as an energy source, resulting in an increase in their ability to repair damage to the intestines in mice 2.

Yilmaz and his colleagues wanted to understand how and when fasting leads to an increase in stem cell activity and numbers. In their latest work, the researchers examined three groups of mice: animals that fasted for 24 hours, those that fasted for 24 hours and were then allowed to eat for 24 hours, and those that were allowed to eat at any time during the study.

Intestinal stem cells multiplied fastest in the mice that were given food after fasting. These stem cells help repair and regenerate the intestinal wall by producing large amounts of molecules called polyamines, which are important for cell growth and division.

“There's so much emphasis on fasting and how long to fast that we've somehow overlooked this whole other side of the equation: what happens when you're fed,” says Yilmaz.

Downside

Because intestinal stem cells can also be a source of precancerous cells due to their ability to constantly divide, when a cancer-causing gene was activated during the refeeding period, the animals were more likely to develop tumors than those that had not fasted.

It was these additional cancer susceptibilities that pushed the animals over the edge and toward developing tumors, rather than the act of eating itself, says Nada Kalaany, a cancer metabolism specialist at Harvard Medical School in Boston, Massachusetts.

Researchers should always be concerned about anything that could cause cancer, but Valter Longo, a biogerontologist at the University of Southern California in Los Angeles, says that mice with the altered genes were "almost doomed to get cancer" and that the slight increase in risk found in this study may not be broadly applicable. He points to a study he published in 2015 that found a 45% reduction in abnormal cell and tissue growth in mice that fasted compared to animals that didn't.

Longo says instead that the results of theNaturestudy could help identify ways to carry out coordinated cellular regeneration to repair damaged tissues, such as in people with inflamed intestines or Crohn's disease.

It is also unclear whether the results of theNaturestudy applies to humans and if so, how. Yilmaz says he and his colleagues are conducting a clinical trial to find out. But the results show that the refeeding period creates a "vulnerable state" that could require extra caution against anything that could damage cellular DNA, he says.