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

Author

Listed:
  • 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
    Chengdu University of Traditional Chinese Medicine)

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.

Suggested Citation

  • 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 & Baojie Li, 2020. "Gut stem cell aging is driven by mTORC1 via a p38 MAPK-p53 pathway," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-13911-x
    DOI: 10.1038/s41467-019-13911-x
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    Cited by:

    1. Eun-Jung Kang & Jae-Hoon Kim & Young Eun Kim & Hana Lee & Kwang Bo Jung & Dong-Ho Chang & Youngjin Lee & Shinhye Park & Eun-Young Lee & Eun-Ji Lee & Ho Bum Kang & Moon-Young Rhyoo & Seungwoo Seo & Soh, 2024. "The secreted protein Amuc_1409 from Akkermansia muciniphila improves gut health through intestinal stem cell regulation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Omid Omrani & Anna Krepelova & Seyed Mohammad Mahdi Rasa & Dovydas Sirvinskas & Jing Lu & Francesco Annunziata & George Garside & Seerat Bajwa & Susanne Reinhardt & Lisa Adam & Sandra Käppel & Nadia D, 2023. "IFNγ-Stat1 axis drives aging-associated loss of intestinal tissue homeostasis and regeneration," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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