Increased mTORC1 Nutrient Sensing Shortens Life Span in Mice
The mTOR protein forms complexes, of which mTORC1 is involved in nutrient sensing. Inhibiting mTORC1 mimics some of the effects of a low calorie diet, meaning cells will undertake greater maintenance and repair while also reducing activities that tend to produce molecular damage. The result of either low calorie intake or mTORC1 inhibition is a modestly slowed pace of aging, lesser degrees of dysfunction, lower chronic inflammation in later life, and so forth. Researchers here demonstrate that this can work in the other direction as well. They stimulate the activity of mTORC1 via RagC, producing the same downstream signaling that would occur with in response to a high calorie diet. This intervention reduces life span in mice via inflammatory mechanisms, one more piece of evidence pointing to the importance of inflammation in the processes of aging.
The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) controls cellular anabolism in response to growth factor signaling and to nutrient sufficiency signaled through the Rag GTPases. Inhibition of mTOR reproducibly extends longevity across eukaryotes. Here we report that mice that endogenously express active mutant variants of RagC exhibit multiple features of parenchymal damage that include senescence, expression of inflammatory molecules, increased myeloid inflammation with extensive features of inflammaging and a ~30% reduction in lifespan.
Through bone marrow transplantation experiments, we show that myeloid cells are abnormally activated by signals emanating from dysfunctional RagC-mutant parenchyma, causing neutrophil extravasation that inflicts additional inflammatory damage. Therapeutic suppression of myeloid inflammation in aged RagC-mutant mice attenuates parenchymal damage and extends survival. Together, our findings link mildly increased nutrient signaling to limited lifespan in mammals, and support a two-component process of parenchymal damage and myeloid inflammation that together precipitate a time-dependent organ deterioration that limits longevity.