Calorie restriction governs intestinal epithelial regeneration through cell autonomous regulation of mTORC1 in reserve stem cells

Here, we show that CR enhances regenerative capacity of the intestinal epithelium as a result of increased number of reserve ISCs. We observe that precise regulation of mechanistic target of Rapamycin complex 1 (mTORC1) signaling plays a significant role in regulation of sensitivity of reserve intestinal stem cells to injury and that premature activation of mTORC1 signaling through nutrient modulation, at the time of damage, leads to poor regeneration outcome. These data delineate a critical role for mTORC1 signaling in epithelial regeneration and inform clinical strategies based on nutrient modulation of mTORC1 activity. mRNA-Sequencing of FACS sorted murine intestinal reserve stem cells (Hopx-CreER) or active stem cells (Lgr5-eGFP-CreER) isolated from mice fed ad libitium or under calorie restriction. Cells were isolated in 5 batches from 10 different animals.