Age-Related Changes in mTORC1-Related Nutrient Sensing Degrade Intestinal Stem Cell Function

Dysregulation of nutrient sensing is one of the hallmarks of aging, and the work here illustrates that this dysregulation has downstream consequences to stem cell function in at least intestinal tissues. That said, it seems unlikely that this disruption of nutrient sensing in later life, in part caused by increased levels of the mTORC1 complex, is close to the root causes of aging. One might expect rejuvenation therapies targeting forms of damage and dysfunction that are closer to the causes of aging to result in restoration of more youthful nutrient sensing.

The adult intestine is a regionalized organ, whose size and cellular composition are adjusted in response to nutrient status. This involves dynamic regulation of intestinal stem cell (ISC) proliferation and differentiation. How nutrient signaling controls cell fate decisions to drive regional changes in cell-type composition remains unclear. Here, we show that intestinal nutrient adaptation involves region-specific control of cell size, cell number, and differentiation.

We uncovered that activation of mTOR complex 1 (mTORC1) increases ISC size in a region-specific manner. mTORC1 activity promotes Delta expression to direct cell fate toward the absorptive enteroblast lineage while inhibiting secretory enteroendocrine cell differentiation. In aged flies, the ISC mTORC1 signaling is deregulated, being constitutively high and unresponsive to diet, which can be mitigated through lifelong intermittent fasting. In conclusion, mTORC1 signaling contributes to the ISC fate decision, enabling regional control of intestinal cell differentiation in response to nutrition.


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