As the aging population increases, the race to unpack the molecular understanding of aging heats up. The rapamycin (mTOR) complex 1 (mTORC1) is known to be a key component of multiple functions of the body, including metabolism. Now, a new paper finds that when mTOR activity is slightly increased, the lifetime of animals can be shortened by up to 20%.
The findings not only link mildly increased nutrient signaling to limited lifespan in mammals, but the authors add that they also “support a two-component process of parenchymal damage and myeloid inflammation that together precipitate a time-dependent organ deterioration that limits longevity.”
This work is published in Nature Aging in the paper, “A mild increase in nutrient signaling to mTORC1 in mice leads to parenchymal damage, myeloid inflammation, and shortened lifespan.”
The activity of the mTOR protein complex is regulated through signaling by the Rag GTPases according to the amount of nutrients available in the cell. In this study, researchers genetically modified a signal to mTOR to indicate the false presence of an increase of nutrients in the cell by generating mice that endogenously express active mutant variants of RagC.
When cells are signaled to have nutrients in excess, it leads to malfunction and inflammation in organs such as the pancreas, the liver, and the kidneys. Immune cells accumulate and, instead of repairing, trigger inflammation that further increases problems in those organs.
More specifically, the mice exhibited “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.”
In addition, through bone marrow transplantation experiments, the team showed that “myeloid cells are abnormally activated by signals emanating from dysfunctional RagC-mutant parenchyma, causing neutrophil extravasation that inflicts additional inflammatory damage.”
The activity of lysosomes is reduced in both naturally aged and genetically modified animals. “When there is an excess of nutrients it makes sense that the cell shuts down the recycling activity of lysosomes because this recycling operates especially when there are no nutrients,” said lead author Alejo Efeyan, PhD, head of the metabolism and cell signaling group at the National Cancer Research Centre (CNIO) in Madrid, Spain. This decrease in lysosomal activity also occurs in human aging, as verified by researchers who contrasted blood samples from young people and septuagenarians.
Given the central role of mTOR in metabolism, this research provides clues to why aging-related diseases appear or worsen in people with a high body mass index and sheds light on why calorie restriction can promote healthy aging, as certain genes activated by limiting nutrient intake interact with mTOR.
Beyond this paper, Efeyan believes that the new animal model generated in this study offers “ample fertile ground to ask more questions about how nutrient increase, or their signaling, facilitates processes in the different organs that allow us to understand their aging in particular.”
