Go hungry before radiotherapy
Scientists from the University of Pennsylvania, working under the guidance of Associate Professor Christopher Lengner, have discovered cells responsible for improving the ability of intestinal tissue to regenerate in a low-calorie diet.
In mice with unlimited access to food, exposure to radiation suppresses (left) the regeneration of intestinal cells (red), while animals on a low-calorie diet demonstrate increased regenerative capacity of intestinal tissues (right).
Animal experiments have long shown that a significant restriction of the caloric content of the diet – 40% below the norm – increases the duration of a healthy life, the duration of the disease-free aging period and even the total life expectancy of almost all animal models used. Further studies have demonstrated that animals kept on a low-calorie diet are also capable of better regeneration of various tissues after damage.
For a long time, specialists have not been able to identify the mechanisms mediating these positive effects. According to one theory, a low-calorie diet slows down age-related degeneration and provides improved regenerative function by increasing the integrity and activity of adult stem cells located in certain tissues and giving rise to different types of cells that form this tissue.
In their earlier work, the authors studied the mechanisms that help intestinal stem cells resist DNA damage. They were led to this by the assumption that a low-calorie diet somehow contributes to this.
More recent studies have been devoted to the study of the effect of a low-calorie diet on active stem cells. These cells are responsible for the daily renewal of tissue, while it is known that they are overly sensitive to DNA damage, including when exposed to ionizing radiation. Therefore, it is very unlikely that these cells mediate increased regeneration in a low-calorie diet.
Instead of studying these cells, the authors turned their attention to another population of intestinal stem cells, known as reserve stem cells. Previously, they, as well as other research groups, have demonstrated that these cells are usually at rest and immune to the effects of chemotherapy and radiation. With severe damage leading to the destruction of active stem cells, these reserve cells "wake up" and regenerate the affected tissues.
In search of confirmation of their hypothesis, the researchers analyzed the reaction of this subpopulation of mouse intestinal stem cells to a low-calorie diet, as well as subsequent irradiation.
When animals were kept on a diet whose caloric content was 40% lower than normal, the population of reserve stem cells increased by 5 times. Paradoxically, according to the observations made, the rate of division of these cells slowed down. The authors plan to search for a solution to this phenomenon in the near future.
With selective destruction of reserve stem cells in the intestines of mice kept on a low-calorie diet, the ability to regenerate decreased by half, which indicates the important role of these cells in the mechanisms underlying the positive effects of a low-calorie diet.
To decipher these mechanisms, the authors compared gene expression in normal animals and mice kept on a low-calorie diet. As expected, the reserve stem cells are characterized by the suppression of many signaling pathways regulated by the protein complex mTOR (mammalian rapamycin target protein), which is best known as a complex that registers nutrients.
Previously, researchers who have studied other types of tissues have demonstrated that activation of mTOR can bring cells out of a state of rest, which is a prerequisite for starting the regeneration process. In their work, the authors found that reserve stem cells have low mTOR activity, which is further reduced in conditions of a low-calorie diet. At the same time, low mTOR activity correlated with damage resistance.
At the same time, after the termination of the damaging effect, the activation of mTOR is necessary to start the regeneration process. An interesting fact is that in mice kept on a low-calorie diet, this activation occurs more efficiently, even despite the initially inactivated state of this protein complex. This phenomenon is not yet completely clear.
To confirm that mTOR regulates the activity of reserve stem cells, the authors conducted experiments with the mTOR–activating amino acid leucine and rapamycin, a drug that inhibits mTOR. As expected, under the influence of leucine, these cells began to actively proliferate, while rapamycin blocked their division.
Pre-enrichment with leucine in the feed of mice made the reserve stem cells of their intestines more sensitive to radiation exposure, while reducing their ability to regenerate tissue after radiation damage, while adding rapamycin to the feed protected the stem cells, keeping them at rest.
However, the authors warn that rapamycin cannot be used as a substitute for a low-calorie diet, as it will continue to block the activation of mTOR even after the damaging effects have ceased, depriving reserve stem cells of the ability to activate and regenerate intestinal tissue. They emphasize that to date there is no drug that fully reproduces the effects of a low-calorie diet, so these effects can only be achieved by reducing calories consumed.
The researchers hope in the near future to understand in more detail the mechanism they discovered and find out which signaling molecules are able to modulate the activation of reserve stem cells.
Article by Maryam Yousefi et al. Calorie Restriction Governs Intestinal Epithelial Regeneration through Cell-Autonomous Regulation of mTORC1 in Reserve Stem Cells is published in the journal Stem Cell Reports.
Evgenia Ryabtseva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of the University of Pennsylvania: Low-calorie Diet Enhances Intestinal Regeneration After Injury.