A drug treatment that mimics fasting can also provide the same benefit, study finds....
As people age, their intestinal stem cells begin to lose their ability to regenerate. These stem cells are the source for all new intestinal cells, so this 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, a change that stimulates the stem cells to become
more regenerative. The researchers found that they could also boost
regeneration with a molecule that activates the same metabolic switch. Such an
intervention could potentially help older people recovering from GI infections
or cancer patients undergoing chemotherapy, the researchers say.
"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, a member of the Koch
Institute for Integrative Cancer Research, 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."
David Sabatini, an MIT professor of biology and
member of the Whitehead Institute for Biomedical Research, is also a senior
author of the paper, which appears in the May 3 issue of Cell Stem Cell.
"This study provided evidence that fasting
induces a metabolic switch in the intestinal stem cells, from utilizing
carbohydrates to burning fat," Sabatini says. "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."
The paper's lead authors are Whitehead Institute
postdoc Maria Mihaylova and Koch Institute postdoc Chia-Wei Cheng.
Boosting regeneration
For many decades, scientists have known that low
caloric intake is linked with enhanced longevity in humans and other organisms.
Yilmaz and his colleagues were interested in exploring how fasting exerts its
effects at the molecular level, specifically in the intestine.
Intestinal stem cells are responsible for
maintaining the lining of the intestine, which typically renews itself every
five days. When an injury or infection occurs, stem cells are key to repairing
any damage. As people age, the regenerative abilities of these intestinal stem
cells decline, so it takes longer for the intestine to recover.
"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, 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.
The researchers 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," Mihaylova says. "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."
Metabolic switch
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 transcription factors called PPARs, which turn on many genes that are
involved in metabolizing fatty acids.
The researchers 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," Cheng says.
"Just activating one metabolic pathway is sufficient to reverse certain
age phenotypes."
The findings suggest that drug treatment could
stimulate regeneration without requiring patients to fast, which is difficult
for most people. One group that could benefit from such treatment is cancer
patients who are receiving chemotherapy, which often harms intestinal cells. It
could also benefit older people who experience intestinal infections or other
gastrointestinal disorders that can damage the lining of the intestine.
The researchers plan to explore the potential
effectiveness of such treatments, and they also hope to study whether fasting
affects regenerative abilities in stem cells in other types of tissue.
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