Gut stem cell aging is driven by mTORC1 via a p38 MAPK-p53 pathway

Dan He, Hongguang Wu, Jinnan Xiang, Xinsen Ruan, Peike Peng, Yuanyuan Ruan, Ye-Guang Chen, Yibin Wang, Qiang Yu, Hongbing Zhang, Samy L. Habib, Ronald A. Pinho, Huijuan Liu () and Baojie Li ()
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Dan He: Shanghai Jiao Tong University
Hongguang Wu: Shanghai Jiao Tong University
Jinnan Xiang: Shanghai Jiao Tong University
Xinsen Ruan: Shanghai Jiao Tong University
Peike Peng: Fudan University
Yuanyuan Ruan: Fudan University
Ye-Guang Chen: Tsinghua University
Yibin Wang: University of California
Qiang Yu: A-STAR Genome Institute of Singapore
Hongbing Zhang: Chinese Academy of Medical Sciences and Peking Union Medical College
Samy L. Habib: University of Texas Health Science Center at San Antonio
Ronald A. Pinho: University of Texas MD Anderson Cancer Center
Huijuan Liu: Shanghai Jiao Tong University
Baojie Li: Shanghai Jiao Tong University

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract 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 aging-caused 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.

Date: 2020
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DOI: 10.1038/s41467-019-13911-x

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