Researchers at the Buck Institute for Research on Aging, USA, found that treating mice with the TOR-inhibitor rapamycin prevented the loss of adult stem cells and could reverse age-related loss of stem cells in mouse trachea. The results of the study were published on December 7, 2017 in Cell Stem Cell.
Stem cells replace dying cells, regenerate damaged tissues and restore the body tissues throughout the whole life. However, with age, the number of stem cells decreases, and their regenerative potential also losses.
American researchers found that the protein TOR (Target of Rapamycin), which plays one of the leading roles in the aging mechanism, also controls the loss of stem cells with age. Treatment of mice with rapamycin, a TOR inhibitor, could stopped and reverse age-related process in the trachea of experimental animals.
In most tissues, mature stem cells hang out in a quiet state. They are activated in case of injury or infection, quickly dividing, creating daughter cells that differentiate into the necessary cells to repair damaged tissue. This division has to be “asymmetric”, i.e. only one of the two cells formed during cell division goes on to differentiate, while the other remains a stem cell.
Professor and a senior author of the study Heinrich Jasper, says previous research showed that TOR needs to be maintained at a low level for the preservation of stem cells in a quiet state and prevent their differentiation.
However, in a new work, Buck researchers found that the TOR signaling becomes activated in many types of stem cells involved in the regenerative response.
Jasper says that this activation is important for the rapid recovery of tissues, but at the same time it increases the probability that stem cells will differentiate, thus losing the status of stem cells.
Such a loss, the scientist continues, in this case – in the fly intestine, mouse muscle and mouse trachea – is especially common with active regeneration, which is caused by chronic infections or tissue traumas.
During aging, repeated or chronic activation of the TOR signaling contributes the gradual loss of stem cells. Based on this, using genetic or pharmacological restriction of chronic TOR activity, the researchers were able to prevent and reverse the loss of stem cells in the trachea and muscles of aging mice.
“It’s all about maintaining a balance between stem cell renewal and differentiation”,- said Jasper. “It’s easy to see how a loss of adult stem cells might accrue over a lifetime and accelerate with aging. We are excited to have a means of rescuing stem cells, boosting their ability to maintain healthy tissue.”
The work at the Buck, led by postdoctoral fellow Samantha Haller, PhD, began by studying the intestines of fruit flies and moved to mouse trachea – tissues that share many similarities. Experiments with muscle tissue of mice were performed at Stanford University.
At the Buck the mice were put on differing regimens of rapamycin treatment starting at different stages of life cycle. Jasper notes that rapamycin was able to save stem cells even when given to mice starting at 15 months of age, the human equivalent of 50 years of age.
“In every case we saw a decline in the number of stem cells, and rapamycin would bring it back.”
Whether this is the result of replenishment of the stem cell pool from more differentiated cells or the consequence of an increase in the number of “asymmetrical” divisions that allow one stem cell to produce two new ones remains to be answered, he said.
Jasper says TOR can be regulated by a number of stimuli, and now scientists are trying to understand how the activity of this signaling pathway is controlled in stem cells.
“Is there a chronic increase in TOR over a lifetime, or is activation stronger in aging animals? What happens downstream of TOR?”, – Jasper says researchers at the Buck are also testing rapamycin homologs that will target TOR Complex 1, a key complex that regulates cell growth and metabolism in all complex organisms.