Gut stem cell aging is driven by mTORC1 via a p38 MAPK-p53 pathway.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31896747.
- Also identified by DOI 10.1038/s41467-019-13911-x and PMC identifier 6940394.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Intestines
- Mechanistic Target of Rapamycin Complex 1
- Stem Cells
- Tumor Suppressor Protein p53
- p38 Mitogen-Activated Protein Kinases