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

Nat Commun. 2020 Jan 2;11(1):37. doi: 10.1038/s41467-019-13911-x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Animals
  • Cell Proliferation
  • Cellular Senescence
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism
  • Intestines / cytology*
  • Intestines / physiology
  • MAP Kinase Kinase 6 / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 14 / genetics
  • Mitogen-Activated Protein Kinase 14 / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Signal Transduction
  • Sirolimus / pharmacology
  • Stem Cells / cytology
  • Stem Cells / physiology*
  • Tamoxifen / pharmacology
  • Tuberous Sclerosis Complex 1 Protein / genetics
  • Tuberous Sclerosis Complex 1 Protein / metabolism
  • Tumor Suppressor Protein p53 / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • Lgr5 protein, mouse
  • Receptors, G-Protein-Coupled
  • Trp53 protein, mouse
  • Tsc1 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Protein p53
  • Tamoxifen
  • Mechanistic Target of Rapamycin Complex 1
  • Mitogen-Activated Protein Kinase 14
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 6
  • Map2k6 protein, mouse
  • Sirolimus