A calorie-restricted diet is often said to enhance longevity. Less frequently discussed, and poorly understood, is why fasting should slow aging or delay the loss of tissue function associated with aging. To better understand how fasting confers its putative benefits, MIT biologists studied a kind of tissue renewal, the maintenance of the lining of the intestine. To renew itself every five days, the lining depends on the regenerative capacity of stem cells, which declines as we age.
Fasting, the MIT biologists found, dramatically improves stem cells’ ability to regenerate. In studies of both aged and young mice, the researchers determined that even a 24-hour fast can reverse the age-related loss of stem cell function.
Details of the study appeared May 3 in the journal Cell Stem Cell, in an article entitled “Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging.” In fasting mice, the article maintains, cells begin breaking down fatty acids instead of glucose, a change that stimulates the stem cells to become more regenerative.
“We show that a 24-hour fast augments intestinal stem cell (ISC) function in young and aged mice by inducing a fatty acid oxidation (FAO) program,” the article’s authors wrote, “and that pharmacological activation of this program mimics many effects of fasting.”
Both real fasting and pharmacologically simulated fasting, the researchers found, activate the same metabolic switch. This finding suggests 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.
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. Then 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,” said Maria Mihaylova, Ph.D., one of the study’s lead authors and a researcher at MIT’s Whitehead Institute. “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 mRNA 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 peroxisome proliferator-activated receptors (PPARs), which turn on many genes that are involved in metabolizing fatty acids.
“Acute genetic disruption of Cpt1a, the rate-limiting enzyme in FAO, abrogates ISC-enhancing effects of fasting but long-term Cpt1a deletion decreases ISC numbers and function, implicating a role for FAO in ISC maintenance,” the Cell Stem Cell article detailed. “These findings highlight a role for FAO in mediating pro-regenerative effects of fasting in intestinal biology and may represent a viable strategy for enhancing intestinal regeneration.”
The researchers found that if they turned off the FAO pathway, fasting could no longer boost regeneration. They now plan to study how this metabolic switch provokes stem cells to enhance their regenerative abilities.
“This study provided evidence that fasting induces a metabolic switch in the intestinal stem cells, from utilizing carbohydrates to burning fat,” asserted David Sabatini, M.D., Ph.D., a senior author of the paper and an MIT professor of biology and member of the Whitehead Institute. “Interestingly, switching these cells to FAO enhanced their function significantly. Pharmacological targeting of this pathway may provide a therapeutic opportunity to improve tissue homeostasis in age-associated pathologies.”
“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,” added Ömer Yilmaz, M.D., Ph.D., another senior author and an MIT assistant professor of biology and a member of the Koch Institute for Integrative Cancer Research.
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.