Fasting Boosts Stem Cells’
Regenerative Capacity
A drug treatment that mimics fasting can
also provide the same benefit, study finds
By Anne Trafton | MIT News Office
A drug treatment that mimics fasting can
also provide the same benefit, study finds
By Anne Trafton | MIT News Office
May 3, 2018 -- 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.
This
age-related loss of stem cell function can be reversed by a 24-hour fast,
according to a new study from MIT biologists. The researchers found that
fasting dramatically improves stem cells’ ability to regenerate, in both aged
and young mice.
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 and the Koch Institute, 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.”
Jared
Rutter, a professor of biochemistry at the University of Utah School of
Medicine, described the findings as “interesting and important.”
“This
paper shows that fasting causes a metabolic change in the stem cells that
reside in this organ and thereby changes their behavior to promote more cell
division. In a beautiful set of experiments, the authors subvert the
system by causing those metabolic changes without fasting and see similar
effects,” says Rutter, who was not involved in the research. “This work fits
into a rapidly growing field that is demonstrating that nutrition and
metabolism has profound effects on the behavior of cells and this can
predispose for human disease.”
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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