Editors' ChoiceAging

TOR at the core of impaired regeneration

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Science Translational Medicine  03 Jan 2018:
Vol. 10, Issue 422, eaar7508
DOI: 10.1126/scitranslmed.aar7508

Abstract

Repeated activation of target of rapamycin (TOR) signaling during tissue regeneration results in impaired stem cell maintenance and promotes aging.

Losses in stem cell numbers, self-renewal capacity, and/or differentiation into functional and correct daughter cells result in impaired tissue function and declines in organismal health. This is born from repeated macromolecular damages from exogenous and endogenous sources and ultimately drives the aging phenotype across evolutionary boundaries. Protecting the fidelity of stem cell pools and promoting proper self-renewal and daughter cell differentiation is thus a potential target for anti-aging and tissue regenerative interventions. However, understanding the basic molecular and biochemical underpinnings of how stem cells—both generally and in a tissue-specific manner—react to genotoxic and replicative stress is necessary to develop such therapies.

Central to cellular nutrient-sensing, growth, and anabolic related pathways is the target of rapamycin (TOR). Stem cells from a variety of organisms and tissues rely on TOR, and specifically on its functional unit mammalian TOR complex 1 (mTORC1), for regulatory signaling. Nevertheless, it is not well understood how mTORC1, which is classically viewed as having pro-aging and oncogenic potential when constitutively active, impacts stem cell maintenance in the face of repeated regeneration demands. In the recent study by Haller et al., the authors use stem cell model systems in the fruit fly intestinal epithelium and mouse tracheal epithelium and muscle to characterize TOR’s role in stem cell maintenance and tissue regeneration during repeated insults and aging-related strains on these tissue systems.

Haller et al. found that TOR signaling was transiently increased upon regenerative stimuli and required for rapid stem cell proliferation. On the other hand, they found that recurring tissue injury and repeated TOR activation led to stem cell loss and declines in tissue homeostasis, most likely due to improper stem cell differentiation and loss of self-renewal. Inhibition of mTORC1 activity with the drug rapamycin dampened and delayed these age- and stress-related failures in stem cell homeostasis. Thus, modulating mTORC1 activity appears to be a promising therapeutic target to counteract aging and injury associated changes in stem cell function. Additional preclinical and clinic studies are needed to move mTORC1-based therapies forward for improvement in human health.

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