Intestinal stem cells are responsible for maintaining the lining of the intestine, which typically renews itself every 5 days. When an injury or infection occurs, stem cells are key to repairing any damage. As we age, the regenerative abilities of our intestinal stem cells decline. According to the findings of a MIT-led study published in the journal Cell Stem Cell, this age-related loss of function can be reversed by a 24-hour fast.
Mihaylova et al show that short-term fasting promotes intestinal stem and progenitor cell function in young and aged mice by inducing a robust fatty acid oxidation (FAO) program; PPAR (peroxisome proliferator-activated receptor) agonists emulate these effects, showing that fatty acid metabolism has positive effects on young and old intestinal stem cells. Image credit: Mihaylova et al, doi: 10.1016/j.stem.2018.04.001.
“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,” said co-lead author Dr. Omer Yilmaz, of MIT.
“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.”
“Our study provided evidence that fasting induces a metabolic switch in the intestinal stem cells, from utilizing carbohydrates to burning fat,” added MIT Professor David Sabatini, co-lead author of the study.
“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 years, researchers have known that low caloric intake is linked with enhanced longevity in humans and other organisms.
The MIT-led team was interested in exploring how fasting exerts its effects at the molecular level, specifically in the intestine.
“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,” Dr. Yilmaz said.
“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, the researchers removed intestinal stem cells and grew them in a culture dish, allowing them to determine whether the cells can give rise to ‘mini-intestines’ known as organoids.
They found that stem cells from the fasting mice doubled their regenerative capacity.
“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,” said first author Dr. Maria Mihaylova, from Whitehead Institute for Biomedical Research and the David H. Koch Institute for Integrative Cancer Research at MIT.
“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 sequencing the messenger RNA of stem cells from the mice that fasted, revealed that fasting induces cells to switch from their usual metabolism, which burns carbohydrates such as sugars, to metabolizing fatty acids.
This switch occurs through the activation of PPARs (peroxisome proliferator-activated receptors), which turn on many genes that are involved in metabolizing fatty acids.
The scientists found that if they turned off this pathway, fasting could no longer boost regeneration.
They now plan to study how this metabolic switch provokes stem cells to enhance their regenerative abilities.
They also found that they could reproduce the beneficial effects of fasting by treating mice with a molecule that mimics the effects of PPARs.
“That was also very surprising. Just activating one metabolic pathway is sufficient to reverse certain age phenotypes,” said co-author Dr. Chia-Wei Cheng, also from the David H. Koch Institute for Integrative Cancer Research at MIT.
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Maria M. Mihaylova et al. 2018. Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging. Cell Stem Cell 22 (5): 769-778; doi: 10.1016/j.stem.2018.04.001
