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December 11, 2017

Inhibiting Key Nutrient Sensing Pathway May Reverse Age-Related Stem-Cell Loss

(Top) Tracheal epithelium after one round of regeneration. (Bottom) Tracheal epithelium after three rounds of regeneration. The stem cells are green (marked with a Trp63 staining), and the nuclei are blue (marked with DAPI). [Samantha Haller, Ph.D.]

  • Researchers from Stanford University, the Buck Institute, Columbia University, and the USCF School of Medicine, report that target of rapamycin (TOR), a nutrient-sensing pathway critical to the aging process, drives the loss of adult stem cells. Treating mice with the TOR inhibitor rapamycin prevented this loss and could reverse age-related loss of stem cells in mouse trachea, say the scientists who published their study (“mTORC1 Activation during Repeated Regeneration Impairs Somatic Stem Cell Maintenance”) in Cell Stem Cell

    “The balance between self-renewal and differentiation ensures long-term maintenance of stem cell (SC) pools in regenerating epithelial tissues. This balance is challenged during periods of high regenerative pressure and is often compromised in aged animals. Here, we show that target of rapamycin (TOR) signaling is a key regulator of SC loss during repeated regenerative episodes. In response to regenerative stimuli, SCs in the intestinal epithelium of the fly and in the tracheal epithelium of mice exhibit transient activation of TOR signaling,” write the investigators.

    “Although this activation is required for SCs to rapidly proliferate in response to damage, repeated rounds of damage lead to SC loss. Consistently, age-related SC loss in the mouse trachea and in muscle can be prevented by pharmacologic or genetic inhibition, respectively, of mammalian target of rapamycin complex 1 (mTORC1) signaling. These findings highlight an evolutionarily conserved role of TOR signaling in SC function and identify repeated rounds of mTORC1 activation as a driver of age-related SC decline.”

    According to the scientists, adult stem cells remain in a quiet state, waiting to be activated in case of infection or injury. In response to such injury, however, stem cells have to be able to divide rapidly, to generate daughter cells that differentiate into cells that repair the tissue. This division has to be asymmetric, i.e., meaning that only one of the two cells generated during the stem cell division goes on to differentiate, while the other cell remains a stem cell.

    Buck Institute professor and senior author Heinrich Jasper, Ph.D., says previous research showed that TOR needs to be maintained at a low level in order to preserve stem cells in a quiet state and prevent their differentiation. But in this study, researchers discovered that TOR signaling becomes activated in many stem cell types when they are engaged in a regenerative response.

    Dr. Jasper, who is now a staff scientist at Genentech, says this activation is important for rapid tissue repair, but at the same time it also increases the probability that stem cells will differentiate, thus losing their stem cell status. Dr. Jasper says this loss— in this case in the fly intestine, mouse muscle, and mouse trachea— is particularly prevalent when the tissue is under heavy or chronic pressure to regenerate, which occurs in response to infections or other trauma to the tissue. During aging, Dr. Jasper says that repeated or chronic activation of TOR signaling contributes to the gradual loss of stem cells. Accordingly, by performing genetic or pharmacological interventions to limit TOR activity chronically, the researchers were able to prevent or reverse stem cell loss in tracheae and muscle of aging mice. 

    "It's all about maintaining a balance between stem cell renewal and differentiation," he said. "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 Institute, led by postdoctoral fellow Samantha Haller, Ph.D., began in the intestines of fruit flies and moved to mouse trachea, tissues that share many similarities. Experiments involving mouse muscle were done at Stanford University. At the Buck Institute, mice were put on differing regimens of rapamycin treatment starting at different stages of life. Dr. Jasper, who says rapamycin was able to rescue stem cells even when given to mice starting at 15 months of age (the human equivalent of 50 years of age), adds that “in every case we saw a decline in the number of stem cells, and rapamycin would bring it back."

    Whether this recovery of tissue stem cell numbers is due to a replenishment of the stem cell pool from more differentiated cells, or due to an increase in "asymmetric" stem cell divisions that allow one stem cell to generate two new ones, remains to be answered, he said.

    Dr. Jasper says TOR can be regulated by a number of stimuli, and researchers are now attempting to better 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?"

    Researchers at the Buck are also testing homologs of rapamycin that are more specifically aimed at TOR Complex 1, a key complex containing TOR that regulates cell growth and metabolism in all complex organisms.

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