Calorie Restriction Governs Intestinal Epithelial Regeneration through Cell-Autonomous Regulation of mTORC1 in Reserve Stem Cells

Abstract

Summary: Aging is a complex process associated with a decline in functionality of adult stem cells affecting tissue homeostasis and regeneration. Calorie restriction (CR) is the only experimental manipulation known to extend lifespan and reduce the incidence of age-related disorders across numerous species. These benefits are likely mediated, at least in part, through the preservation of stem cell function. Here, we show that CR enhances the regenerative capacity of the intestinal epithelium through preservation of an injury-resistant reserve intestinal stem cell (ISC) pool. Cell-autonomous activity of mechanistic target of rapamycin complex 1 (mTORC1) governs the sensitivity of reserve ISCs to injury. CR inhibits mTORC1 in these cells, protecting them against DNA damage, while mTORC1 stimulation, either genetically or through nutrient sensing, sensitizes reserve ISCs to injury, thus compromising regeneration of the epithelium. These data delineate a critical role for mTORC1 in epithelial regeneration and inform clinical strategies based on nutrient modulation. : In this study, Yousefi et al. identify reserve intestinal stem cell-autonomous suppression of mTORC1 activity in response to calorie restriction as the basis for enhanced regeneration of the intestinal epithelium after DNA-damaging injury. Conversely, the authors demonstrate that acute nutrient-based stimulation of mTORC1 prior to injury results in reserve stem cell apoptosis and intestinal regenerative failure. Keywords: calorie restriction, radiation injury, reserve intestinal stem cells, intestine, stem cells, mTORC1 signaling, radiosensitivity, regeneration