NATURE COMMUNICATIONS | (2020) 11:37 | https://doi.org/10.1038/s41467-019-13911-x |www.nature.com/naturecommunications
Dan He1,10, Hongguang Wu1,10, Jinnan Xiang1, Xinsen Ruan1, Peike Peng2, Yuanyuan Ruan2, Ye-Guang Chen3, Yibin Wang4, Qiang Yu5, Hongbing Zhang6, Samy L. Habib7, Ronald A. De Pinho8, Huijuan Liu1 & Baojie Li1,9
Nutrients are absorbed solely by the intestinal villi. Aging of this organ causes malabsorption and associated illnesses, yet its aging mechanisms remain unclear. Here, we show that agingcaused intestinal villus structural and functional decline is regulated by mTORC1, a sensor of nutrients and growth factors, which is highly activated in intestinal stem and progenitor cells
in geriatric mice. These aging phenotypes are recapitulated in intestinal stem cell-specific Tsc1 knockout mice. Mechanistically, mTORC1 activation increases protein synthesis of MKK6 and augments activation of the p38 MAPK-p53 pathway, leading to decreases in the number and activity of intestinal stem cells as well as villus size and density. Targeting p38
MAPK or p53 prevents or rescues ISC and villus aging and nutrient absorption defects. These findings reveal that mTORC1 drives aging by augmenting a prominent stress response pathway in gut stem cells and identify p38 MAPK as an anti-aging target downstream of mTORC1.