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Calorie Restriction Promotes Intestinal Regeneration by Reserve Intestinal Stem Cells

Review of “Calorie Restriction Governs Intestinal Epithelial Regeneration through Cell-Autonomous Regulation of mTORC1 in Reserve Stem Cells” from Stem Cell Reports by Stuart P. Atkinson

Long-term calorie restriction (CR) represents an effective means of prolonging healthy lifespan in many different species and may function by preserving tissue-resident stem and progenitor cell function. While long-term CR is “unappetizing” for many, studies in young and healthy animals have established that shorter-term CR enhances recovery from injuries to tissues such as the intestine [1, 2]. However, the specific stem cell-types involved in CR-promoted intestinal regeneration remained unidentified until the publication of a new Stem Cell Reports study by researchers from the laboratory of Christopher J. Lengner (University of Pennsylvania, Philadelphia, PA, USA) [3]. 

Yousefi et al. discovered that reduced calorie provision in a mouse model (by 40% for a period of 4–6 weeks starting at two months of age) enhanced regeneration of the intestinal epithelium in response to DNA-damaging injury via the expansion of an injury-resistant “reserve ISC” pool. Previous studies described reserve ISCs as non-cycling, label-retaining, secretory progenitor cells that possess stem cell activity [4, 5]. Interestingly, the ablation of these reserve ISCs abrogated the pro-regenerative effects of CR, although the study found no alterations to normal epithelial homeostasis.

To understand the mechanisms at play, the authors next RNA-sequenced reserve ISCs from control and CR mice, discovering that CR suppressed the activity of mechanistic target of rapamycin complex 1 (mTORC1) signaling in reserve ISCs. While low mTORC1 activity in reserve ISCs protected the intestinal epithelium from DNA-damaging injury, subsequent intestinal regeneration required the upregulation of mTORC1 signaling. Importantly, stimulation of mTORC1 (genetically or through nutrient sensing) before DNA-damaging injury produced the opposite effect on reserve ISCs and compromised the regeneration of the epithelium.

Overall, this exciting new study demonstrates that reserve ISCs functionally contribute to epithelial regeneration following DNA-damaging injury in CR mice in an mTORC1-dependent manner. The authors hope that this information may allow a better understanding of intestinal epithelium regeneration following DNA damage from radiation exposure, chemotherapy, microbiome dysbiosis, and ischemia-reperfusion injury.

For more on the advantages of calorie restriction and stem-cell mediated intestinal regeneration, stay tuned to the Stem Cells Portal.


  1. Cerletti M, Jang Young C, Finley Lydia WS, et al., Short-Term Calorie Restriction Enhances Skeletal Muscle Stem Cell Function. Cell Stem Cell;10:515-519.
  2. Yilmaz ÖH, Katajisto P, Lamming DW, et al., mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 2012;486:490.
  3. Yousefi M, Nakauka-Ddamba A, Berry CT, et al., Calorie Restriction Governs Intestinal Epithelial Regeneration through Cell-Autonomous Regulation of mTORC1 in Reserve Stem Cells. Stem Cell Reports;10:703-711.
  4. Buczacki SJA, Zecchini HI, Nicholson AM, et al., Intestinal label-retaining cells are secretory precursors expressing Lgr5. Nature 2013;495:65.
  5. Li N, Nakauka-Ddamba A, Tobias J, et al., Mouse Label-Retaining Cells Are Molecularly and Functionally Distinct From Reserve Intestinal Stem Cells. Gastroenterology 2016;151:298-310.e7.