mTORC1 in Intestinal Stem Cell Aging

Researchers here investigate the relationship between the protein complex mTORC1 and the aging of intestinal stem cells, leading to loss of function in the intestine. mTORC1 signaling increases with age in intestinal tissue and leads to exhaustion of the stem cell pool, as downstream mechanisms are triggered to suppress proliferation of these cells. Naturally, mTOR or mTORC1 inhibitors are capable of reducing this effect, though one should always compare all things related to mTOR with the effects of calorie restriction before becoming too excited by new findings. Calorie restriction acts to inhibit mTOR signaling, and the size of the health benefits that it provides should guide expectations as to the bounds of the possible for therapies that inhibit mTORC1.

Nutrient malabsorption is common among the elderly, and often causes anemia and other illnesses. Nutrients are absorbed by the intestinal villi, which are composed of a layer of intestinal epithelial cells (IECs) and the lamina propria, and the absorption activity is affected by the size and density of villi. The epithelial layer is renewed every 4-5 days by intestinal stem cells (ISCs), which generate transient amplifying (TA) progenitor cells that later differentiate into absorptive or secretory cells. It has been reported that the number and regenerative activities of ISCs are decreased in 17 to 24-month-old mice, yet whether aging affects villus function and how villus aging is controlled remain less well understood.

mTOR, a sensor of nutrients and growth factors, is a central regulator of aging and a target for lifespan and healthspan extension. mTOR forms mTORC1 and mTORC2 complexes, and mTORC1 activation promotes cell proliferation by increasing global protein synthesis and other anabolic processes. mTORC1 signaling has been shown to be required for IEC proliferation during homeostasis and regeneration, including regeneration mediated by quiescent ISCs. In addition, several studies have shown that diet restriction promotes ISC expansion via mTORC1 signaling, although conflicting results have been reported regarding the exact roles played by mTORC.

The current genetic study reveals that mTORC1, which is hyperactivated in IECs, especially ISCs and TA cells of aged mice, drives villus aging by inhibiting ISC and progenitor cell proliferation through amplifying the MKK6-p38-p53 stress response pathway. This leads to ISC exhaustion and decreases in villus size and density. The natural function of the mTOR-MKK6-p38 MAPKs-p53 pathway may be to balance mTORC1-induced overgrowth and protect cells from runaway proliferation and oncogenic transformation, which is consistent with the concept that aging acts as an anti-hyperplasia mechanism.

Targeting p38 MAPK or p53 prevents or rescues ISC and villus aging and nutrient absorption defects. Inhibition of mTORC1 with rapamycin for only 1.5 months partially restored the structure and function of intestinal villi in old mice. 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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