A new study done in mice suggests that a calorie-restricted diet before radiation boosts cell regeneration through the increased survival of reserve stem cells that can quickly rebuild intestinal tissue. These findings shed light on the mechanisms behind the benefits of calorie restriction and align with observations by oncologists that short-term fasting before chemotherapy can lessen the severity of gastrointestinal destruction. The findings were published today in Stem Cell Reports.
The study was done by scientists at the University of Pennsylvania who were examining reserve stem cells, which they had previously shown to normally reside in a dormant state and thus be protected from chemotherapy and radiation. Upon a strong injury that kills active cells, reserve stem cells “wake up” to regenerate tissue.
To investigate how these reserve stem cells are affected by calorie restriction, the scientists fed mice a diet reduced in calories by 40% from normal. Under these conditions, the researchers observed reserve intestinal stem cells to expand five-fold. Deleting the reserve stem cells in calorie-restricted mice cut their intestinal regeneration capabilities in half, indicating these cells have an important role in carrying out the benefits of calorie restriction.
Next, the researchers compared genes that were turned on in normal versus calorie-restricted animals to determine the mechanism by which the cells were acting. They found that reserve stem cells were repressing pathways regulated by the protein complex mTOR, which is a known nutrient-sensing complex.
While lower mTOR activity correlates with resistance to injury, mTOR activation is also known to drive dormant cells out of quiescence, which is needed for regeneration.
"Curiously, we see that, when they're injured, the calorie-restricted mice were actually better able to activate mTOR than their counterparts," explained Christopher Lengner, an associate professor in Penn's School of Veterinary Medicine. "So somehow, even though mTOR is being suppressed initially, it's also better poised to become activated after injury. That's something we don't fully understand."
In the future, the researchers plan to further explore these mechanisms to see what type of signaling molecules can modulate the activation of reserve stem cells.
Image: When mice were allowed to eat without limit and were then exposed to radiation, their intestinal cells' (in red) regeneration was limited (left). Mice fed a calorie-restricted diet showed a greatly enhanced regenerative capacity in their intestinal tissue (right). Image courtesy of the University of Pennsylvania.