Calorie Restriction Increases the Number of Competing Stem Cells and Decreases Mutation Retention in the Intestine

• Published in: Cell reports (Cambridge) 2020-07, Vol.32 (3), p.107937-107937, Article 107937
• Main Authors: Bruens, Lotte, Ellenbroek, Saskia Inge Johanna, Suijkerbuijk, Saskia Jacoba Elisabeth, Azkanaz, Maria, Hale, Alexander James, Toonen, Pim, Flanagan, Dustin James, Sansom, Owen James, Snippert, Hugo Johannes, van Rheenen, Jacco
• Format: Article
• Language: English
• Subjects: Adenomatous Polyposis Coli Protein - deficiency; Adenomatous Polyposis Coli Protein - metabolism; Animals; Caloric Restriction; calorie restriction; Cell Competition; Cell Count; Cell Lineage; competition; diet; Female; intestine; Intestines - cytology; Intravital Microscopy; Lgr5; Male; Mice, Inbred C57BL; Mutation - genetics; mutation retention; stem cells; Stem Cells - cytology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.107937

Calorie restriction (CR) extends lifespan through several intracellular mechanisms, including increased DNA repair, leading to fewer DNA mutations that cause age-related pathologies. However, it remains unknown how CR acts on mutation retention at the tissue level. Here, we use Cre-mediated DNA recombination of the confetti reporter as proxy for neutral mutations and follow these mutations by intravital microscopy to identify how CR affects retention of mutations in the intestine. We find that CR leads to increased numbers of functional Lgr5+ stem cells that compete for niche occupancy, resulting in slower but stronger stem cell competition. Consequently, stem cells carrying neutral or Apc mutations encounter more wild-type competitors, thus increasing the chance that they get displaced from the niche to get lost over time. Thus, our data show that CR not only affects the acquisition of mutations but also leads to lower retention of mutations in the intestine. [Display omitted] •Calorie restriction increases stem cell numbers in intestinal crypts•Increased stem cell numbers per crypt strengthen stem cell competition•Mutant stem cells encounter more wild-type competitors upon calorie restriction•More wild-type competitors reduce retention of mutant stem cells in the intestine Calorie restriction increases the number of stem cells in intestinal crypts. Bruens et al. show that this increase results in stronger stem cell competition. Consequently, mutated stem cells encounter more wild-type competitors, which decreases the chance that these mutated stem cells are retained in the intestinal epithelium.