肠干细胞老化是由mTORC1通过p38MAPK-p53途径驱动的

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

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|核心内容：

营养物质只被肠道绒毛吸收。

这种器官的老化会导致吸收不良和相关疾病，但其老化机制尚不清楚。

在这里，我们发现衰老引起的肠道绒毛结构和功能下降是由mTORC1调节的，mTORC1是一种营养物质和生长因子的感受器，在老年小鼠的肠道干细胞和祖细胞中高度激活。(#节食在一定程度上可以让其适当降温)

这些衰老表型在肠道干细胞特异性TSC1基因敲除小鼠中重复出现。

机制上，mTORC1的激活增加了MKK6的蛋白质合成，增强了p38MAPK-p53通路的激活，导致肠干细胞的数量和活性以及绒毛的大小和密度减少。

靶向p38MAPK或p53可以预防或挽救ISC和绒毛老化以及营养吸收缺陷。

这些发现揭示了mTORC1通过增强肠道干细胞中一个重要的应激反应途径来驱动衰老，并将p38MAPK确定为mTORC1下游的一个抗衰老靶点。

原文摘要：

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.

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参考文献：https://sci-hub.se/10.1038/s41467-019-13911-x

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