Scientists from the Massachusetts Institute of Technology (MIT), US, found that fasting significantly improves the regenerative function of stem cells in both aged and young mice. The results, published on May 3 in Cell Stem Cell, will help restore intestinal cells in cancer patients undergoing chemotherapy, as well as in aged people suffering from age-related diseases.
In the process of aging, the stem cells of the intestine gradually lose their regenerative abilities. Since these stem cells are the source of all new intestinal cells, decline can make it more difficult to recover from gastrointestinal infections or other conditions that affect the intestine.
In fasting mice, cells begin breaking down fatty acids instead of glucose, which leads to an increase in the regenerative functions of stem cells. Scientists have discovered that it is also possible to stimulate regeneration with a molecule that activates the metabolic switch responsible for this mechanism. Researchers argue that this discovery can potentially help older people recovering from GI infections or cancer patients receiving chemotherapy that destroys intestinal cells.
“Fasting has many effects in the intestine, which include boosting regeneration as well as potential uses in any type of ailment that impinges on the intestine, such as infections or cancers”, – says Omer Yilmaz, an MIT assistant professor of biology and one of the senior authors of the study.
“Understanding how fasting improves overall health, including the role of adult stem cells in intestinal regeneration, in repair, and in aging, is a fundamental interest of my laboratory”.
“This study provided evidence that fasting induces a metabolic switch in the intestinal stem cells, from utilizing carbohydrates to burning fat”, – says David Sabatini, an MIT professor of biology and a senior author of the paper.
“Interestingly, switching these cells to fatty acid oxidation enhanced their function significantly. Pharmacological targeting of this pathway may provide a therapeutic opportunity to improve tissue homeostasis in age-associated pathologies”.
For many decades, scientists have known that low caloric food is associated with enhanced longevity in humans and other organisms. Yilmaz and his colleagues decided to study the effect of starvation at the molecular level, especially in the intestines.
Stem cells of the intestine are responsible for maintaining of the epithelial lining of the intestinal, which typically renews itself every five days. This stem cells are a key factor in recovery from trauma or infectious diseases.
As with the age of the regenerative capacity of these stem cells are reduced, so the recovery of the intestine takes more time.
“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. Notably, during aging, intestinal stem function declines, which impairs the ability of the intestine to repair itself after damage”, – Yilmaz says.
“In this line of investigation, we focused on understanding how a 24-hour fast enhances the function of young and old intestinal stem cells.”
After mice fasted for 24 hours, intestinal stem cells were collected and were grown in a culture dish that stimulates the formation of “mini-intestines” known as organoids. Researchers found that the stem cells from the fasting mice doubled the regenerative properties.
“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 postdoc Maria Mihaylova, one of the lead author of the paper. “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”.
Further studies, including the sequencing messenger RNA of stem cells from fasting mice, have shown that fasting changes the cellular metabolism, in which carbohydrates such as sugars are usually broken down and causes cells to actively burn fatty acids. Such switching occurs through activation of PPAR transcription factors, which turn on many genes that are involved in metabolizing fatty acids.
The researchers found that when this mechanism was turned off, fasting could no longer boost regeneration.
Now they have to find out how this metabolic switch stimulates the regenerative capacity of stem cells. Scientists also found that they could reproduce the beneficial effects of starvation by acting on mice with a molecule that mimics the effects of PPAR.
“That was also very surprising”, – says postdoc Chia-Wei Cheng, the paper’s co-author. “Just activating one metabolic pathway is sufficient to reverse certain age phenotypes”.
The findings suggest that therapy with certain drugs can stimulate regeneration without requiring the patients to fast, which is hard for most people. One of the target groups of such treatment are patients with cancer, receiving chemotherapy, often detrimental to intestinal cells. Also, this method can help the elderly people, suffering from intestinal infections and other gastrointestinal disorders, which can destroy the epithelial lining of the intestinal.
Scientists plan to investigate the potential effectiveness of such treatments, and hope to explore whether fasting affects regenerative capacity in stem cells in other types of tissues.