Department of Molecular Pathology, Oncode Institute, Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Molecular Cancer Research, Center for Molecular Medicine, Oncode Institute, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands.
Department of Molecular Pathology, Oncode Institute, Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
Cell Rep. 2020 Jul 21;32(3):107937. 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.
热量限制（CR）通过多种细胞内机制延长寿命，包括增加 DNA 修复，从而减少导致与年龄相关的病理的 DNA 突变。然而，目前尚不清楚 CR 如何作用于组织水平的突变保留。在这里，我们使用 Cre 介导的 confetti 报告基因的 DNA 重组作为中性突变的替代物，并通过活体显微镜来确定 CR 如何影响肠道中突变的保留。我们发现，CR 导致更多具有功能的 Lgr5 干细胞的产生，这些干细胞竞争龛位占据，导致干细胞竞争更慢但更强。因此，携带中性或 APC 突变的干细胞遇到更多的野生型竞争细胞，从而增加了它们从龛位中被取代并随着时间的推移丢失的机会。因此，我们的数据表明，CR 不仅影响突变的获得，而且还导致肠道中突变的保留率降低。
