Calorie Restriction Boosts Intestinal Stem Cell Numbers and Improves Regeneration

Researchers here look at the effects of calorie restriction on the stem cell populations that support intestinal tissue. There is plenty of evidence for calorie restriction to improve stem cell activity in other tissues, not to mention aiding many other mechanisms relevant to health. The practice of calorie restriction is very broadly beneficial. It slows aging over the long term, and in the short term improves near all measures of health. Despite the similarities in short term effects between mice and humans, however, it is the case that human life spans are not extended by anywhere near as much as those of mice. The evolutionary argument for this outcome involves the length of seasonal famine in comparison to length of life: the degree to which life spans are plastic in response to circumstances depends on the usual length of adverse circumstances. A mouse requires a much greater proportional extension of life to pass through a seasonal famine into a time of plenty again, and so that greater extension is selected for.

Years of research have demonstrated that existing on a calorie restricted diet can boost healthy lifespan, reducing the risk of heart attack, diabetes, and other age-related conditions. Other, more recent work has shown that calorie-restricted animals regenerate tissue more effectively following injury. "The beneficial effects of calorie restriction are at this point not really up for debate; it's quite clear. But there are all sorts of questions about the cellular and molecular basis to these benefits."

One theory has been that calorie restriction slows age-related degeneration and enables more efficient tissue function by influencing the integrity and activity of adult stem cells, the precursor cells that dwell within specific tissues and give rise to the diversity of cell types that compose that tissue. Recent studies focused on the effects of calorie restriction on the active intestinal stem cells. While these active stem cells bear the burden of daily tissue turnover and act as the workhorses of intestinal function, they are also known to be highly susceptible to DNA damage, such as that induced by radiation exposure, and thus are unlikely to be the cells mediating the enhanced regeneration seen under calorie restriction. Instead of looking at these active stem cells, researchers examined a second population of intestinal stem cells known as reserve stem cells. The team had previously shown that these reserve stem cells normally reside in a dormant state and are protected from chemotherapy and radiation. Upon a strong injury that kills the active cells, these reserve stem cells "wake up" to regenerate the tissue.

To investigate this hypothesis, the scientists focused on how a subpopulation of mouse intestinal stem cells responded under calorie restriction and then when the animals were exposed to radiation. When mice were fed a diet reduced in calories by 40 percent from normal, the researchers observed that reserve intestinal stem cells expanded five-fold. Paradoxically, these cells also seemed to divide less frequently, a mystery the researchers hope to follow up on in later work. When the research team selectively deleted the reserve stem cells in calorie-restricted mice, their intestinal tissue's regeneration capabilities were cut in half, implicating these cells as having an important role in carrying out the benefits of calorie restriction.

"These reserve stem cells are rare cells. In a normal animal they may make up less than half a percentage of the intestinal epithelium and in calorie restricted animals maybe slightly more. Normally, in the absence of injury, the tissue can tolerate the loss, due to the presence of the active stem cells, but, when you injure the animal, the regeneration is compromised and the enhanced regeneration after calorie restriction was compromised in the absence of the reserve stem cell pool. These reserve stem cells that we had shown were important for the beneficial effects of calorie restriction, were repressing many pathways that are all known to be regulated by the protein complex mTOR, which is most well known as being a nutrient-sensing complex. Curiously, we see that, when they're injured, the calorie-restricted mice were actually better able to activate mTOR than their counterparts. 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.

The researchers conducted experiments using leucine, an amino acid that activates mTOR, and rapamycin, a drug which inhibits mTOR, to confirm that mTOR acted within these reserve stem cells to regulate their activity. Reserve stem cells exposed to leucine proliferated, while those exposed to rapamycin were blocked. Pretreating the animals with leucine make the reserve stem cells more sensitive to radiation and less able to regenerate tissue following radiation injury, while rapamycin protected the reserve stem cells as they were more likely to remain dormant. The researchers caution, however, that rapamycin cannot be used as a stand-in for calorie restriction, as it would linger and continue to block mTOR activation even following injury, hindering the ability of the reserve stem cells to spring into action and regenerate intestinal tissue.



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