Future anti-aging drugs could flip a "metabolic switch" to mimic fasting
Fasting has been found to have a range of health benefits, and appears to slow down the aging process. Now, researchers from MIT have found that fasting for just 24 hours is enough to improve the regeneration of a person's intestinal stem cells, which naturally declines with age. Better yet, with the metabolic switch identified, in the future the effect could be mimicked with a drug.
As with stem cells in all parts of the body, intestinal stem cells are in charge of growing new cells in the organ. They maintain the lining of the intestine, which is shed and replaced every few days, fight off infection and repair damage to the tissue. But as is usually the case, these stem cells get less and less effective at their job with age.
Previous research has found that caloric restriction, or continual fasting, has a profound effect on health and longevity. These effects have been seen in mice, rats, monkeys, lemurs, and other animals, and although human studies haven't really been conducted, it seems that we could also benefit from harnessing the diet. So the MIT team set out to study the effects of fasting on intestinal stem cells.
"Intestinal stem cells are the workhorses of the intestine that give rise to more stem cells and to all of the various differentiated cell types of the intestine," says Omer Yilmaz, senior author of the study. "Notably, during aging, intestinal stem function declines, which impairs the ability of the intestine to repair itself after damage. In this line of investigation, we focused on understanding how a 24-hour fast enhances the function of young and old intestinal stem cells."
To test it out, the researchers studied groups of mice, both young and aged, that fasted for a day. Then, the team removed samples of intestinal stem cells from the animals and grew them in culture, where they would develop into organoids, or mini-intestines.
The team found that stem cells from mice that fasted grew more organoids, to the extent that their stem cells had twice the regeneration abilities of control groups of mice that ate normal amounts during the same period. The benefits of fasting applied to both young and old mice.
"It was very obvious that fasting had this really immense effect on the ability of intestinal crypts to form more organoids, which is stem-cell-driven," says Maria Mihaylova, lead author of the study. "This was something that we saw in both the young mice and the aged mice, and we really wanted to understand the molecular mechanisms driving this."
To peer closer at the biological reasons for the health benefits, the researchers then sequenced the messenger RNA from the fasting mice. It turns out that fasting triggered a metabolic switch that lets the animals burn fatty acids instead of the usual carbs. Transcription factors known as PPARs were key, and the team found that switching off this metabolic pathway canceled out the benefits of fasting.
Having pinpointed the pathway responsible, the team was also able to switch it on, mimicking the positive effects. This could potentially lead to drugs and treatments that burn fat and improve longevity without needing to fast at all.
The research was published in the journal Cell Stem Cell.