Scholars@Duke

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

Publication ,  Journal Article
He, D; Wu, H; Xiang, J; Ruan, X; Peng, P; Ruan, Y; Chen, Y-G; Wang, Y; Yu, Q; Zhang, H; Habib, SL; De Pinho, RA; Liu, H; Li, B
Published in: Nat Commun
January 2, 2020
Published version (DOI) Link to item

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.

Duke Scholars

Yibin Wang
Author Yibin Wang Medicine, Cardiology
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Published In

Nat Commun

DOI

10.1038/s41467-019-13911-x

EISSN

2041-1723

Publication Date

January 2, 2020

Volume

11

Issue

1

Start / End Page

37

Location

England

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Tumor Suppressor Protein p53
  • Tuberous Sclerosis Complex 1 Protein
  • Tamoxifen
  • Stem Cells
  • Sirolimus
  • Signal Transduction
  • Receptors, G-Protein-Coupled
  • Mitogen-Activated Protein Kinase 14
  • Mice, Knockout
 

Citation

APA
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ICMJE
MLA
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He, D., Wu, H., Xiang, J., Ruan, X., Peng, P., Ruan, Y., … Li, B. (2020). Gut stem cell aging is driven by mTORC1 via a p38 MAPK-p53 pathway. Nat Commun, 11(1), 37. https://doi.org/10.1038/s41467-019-13911-x
He, Dan, Hongguang Wu, Jinnan Xiang, Xinsen Ruan, Peike Peng, Yuanyuan Ruan, Ye-Guang Chen, et al. “Gut stem cell aging is driven by mTORC1 via a p38 MAPK-p53 pathway.” Nat Commun 11, no. 1 (January 2, 2020): 37. https://doi.org/10.1038/s41467-019-13911-x.
He D, Wu H, Xiang J, Ruan X, Peng P, Ruan Y, et al. Gut stem cell aging is driven by mTORC1 via a p38 MAPK-p53 pathway. Nat Commun. 2020 Jan 2;11(1):37.
He, Dan, et al. “Gut stem cell aging is driven by mTORC1 via a p38 MAPK-p53 pathway.” Nat Commun, vol. 11, no. 1, Jan. 2020, p. 37. Pubmed, doi:10.1038/s41467-019-13911-x.
He D, Wu H, Xiang J, Ruan X, Peng P, Ruan Y, Chen Y-G, Wang Y, Yu Q, Zhang H, Habib SL, De Pinho RA, Liu H, Li B. Gut stem cell aging is driven by mTORC1 via a p38 MAPK-p53 pathway. Nat Commun. 2020 Jan 2;11(1):37.

Published In

Nat Commun

DOI

10.1038/s41467-019-13911-x

EISSN

2041-1723

Publication Date

January 2, 2020

Volume

11

Issue

1

Start / End Page

37

Location

England

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Tumor Suppressor Protein p53
  • Tuberous Sclerosis Complex 1 Protein
  • Tamoxifen
  • Stem Cells
  • Sirolimus
  • Signal Transduction
  • Receptors, G-Protein-Coupled
  • Mitogen-Activated Protein Kinase 14
  • Mice, Knockout