Stem cells supply the specialized cells that make up our tissues and organs; every time existing cells are lost for whatever reason, stem cells that can differentiate into that particular type of cell jump into action to compensate for the loss. However, this ability declines over time as aging progresses; indeed, stem cell exhaustion is one of the hallmarks of aging, and it affects our body by decreasing the regenerative capacity of its tissues, leading to immune dysfunction, muscle wasting, and even neurodegenerative diseases.

The lining of your intestine suffers from this problem as well. It consists of a fast-renewing tissue that typically renews itself entirely in a handful of days, and it is responsible for absorbing nutrients as well as keeping away unwanted substances; maintaining its regenerative abilities is therefore important for everyone, old or young; however, for older people, this is more challenging. However, a relatively easy way to boost intestinal stem cell (ISC) function might simply be fasting, according to a new study by a team of MIT biologists [1].

The study

The fact that caloric restriction yields health and longevity benefits in different kinds of organisms, possibly including humans, has already been known for a while. However, it is as of yet unclear what mechanisms cause this effect and to what extent people may benefit from it.

MIT researchers, including Maria Mihaylova, David Sabatini, and Chia-Wei Cheng, wanted to find out how fasting affects intestinal cells in particular. To this end, they set up an experiment in which murine intestinal stem cells were extracted from the animals after a mere 24-hour fast; the regenerative capacity of these cells was subsequently put to the test in a petri dish, where the scientists observed their ability to grow intestines as organoids, which are simplified and smaller versions of actual, full-size organs and are grown in vitro rather than in vivo. As it turned out, ISCs from fasting mice had twice the regenerative capacity of cells coming from controls, and the effect was observed both in young and elderly mice.







Once the effect was observed, the scientists tried to figure out exactly why fasting caused it. According to their analysis, fasting activates PPAR (peroxisome proliferator-activated receptor) transcription factors in ISCs, which switch on several genes that change ISC metabolism. Under these conditions, ISCs switch from metabolizing carbohydrates—which is what they would normally do—to metabolizing fatty acids instead. Suspecting that PPARs were connected to the observed benefits, the scientists repeated the experiment in mice in which the PPAR pathway was turned off and noticed that fasting didn’t help in this case; therefore, it seems that the positive effects of fasting on ISCs are due to its action on PPARs. Why this change enhances ISCs’ regenerative abilities is not yet clear, but this is what the scientists plan to find out next.

Interestingly, the MIT team managed to obtain the same effect without a need for fasting. They administered a molecule that mimicked the PPAR effects to non-fasting mice, and it gave them the same regenerative boost to their ISCs. This means that a drug to induce enhanced ISC regeneration in human patients might be possible without the patients having to go through the trouble of fasting, which can be difficult or simply not an option in certain cases. This type of drug would be especially useful for patients with impaired ISC regeneration, such as elderly people who suffer from intestinal infections or oncological patients undergoing chemotherapy—a side effect of which may, indeed, be damage to intestinal cells.

In addition to finding out how exactly the PPAR switch enhances ISC regeneration, the researchers would like to study whether the same beneficial effects of fasting can be obtained in different types of stem cells as well.

Literature

[1] Mihaylova M. M., Cheng C., Cao A. Q., …, Katajisto P., Sabatini D. M., Yilmaz O. H. Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging, Cell Stem Cell, Cell Press.





