The cell’s ability to sense and respond to the availability of nutrients through growth and stasis is one of the hallmarks of aging and associated diseases. mTORC1 (mechanistic target of rapamycin complex 1) is the primary sensor and integrator of the cell’s response to nutrient availability, and dysregulation of mTORC1 activation is at the core of many age-related disease processes.
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The mTORC1 pathway plays a fundamental role in healthy cellular function and growth. mTORC1 integrates multiple signals that arise from dynamic changes in the extracellular environment, many of which are related to the availability of nutrients—particularly amino acids—that are used by the cell’s biosynthetic machinery to grow and function.
Within the mTORC1 pathway, amino acids play a specific and critical signaling role, serving as a fundamental cue that directs the cell either to:
mTORC1 regulates both cell growth and autophagy through its kinase activity, primarily in response to the availability of amino acids.
Nutrient signaling is the cell’s ability to sense and respond to the availability of amino acids, glucose, and other biomolecules to enable normal cell function and survival. In particular, amino acids—the building blocks of proteins—are the nutrients that are most directly linked to cellular growth that is mediated by mTORC1.
Varying availability of nutrients requires cells to sense and communicate with each other and rapidly respond to changes in the environment to enable normal cell function and survival. When nutrients such as amino acids are abundant, cells respond by increasing their capacity for biosynthetic growth, including making proteins and other components required for normal cellular function and/or increasing their size or number. Conversely, when nutrients are scarce, cells respond by turning on their biosynthetic “recycling” process, known as autophagy—a process that degrades cellular structures such as proteins to generate the needed building blocks to maintain cellular survival and function.
mTORC2 is critical for maintaining the sensitivity of cells to growth factors and is the primary mTOR complex that directs the cell’s response to growth factor inputs. However, mTORC1 also integrates signals from growth factors to enable the proper regulation of cell growth and protein synthesis—in fact, growth factor signals, which are transmitted through the tuberous sclerosis complex (TSC) and the GTPase Rheb, are required for the activation of mTORC1 by nutrients or other inputs.
Thus, genetic defects in the growth factor signaling pathway that regulates mTORC1—e.g., in TSC—can cause dysregulation of the mTOR pathway, leading to improper protein expression and cell growth. Patients with tuberous sclerosis have mutations in TSC that hyperactivate the mTORC1 signaling pathway, leading to the development of benign tumors in multiple organ systems and a host of accompanying symptoms that range from mild to severe.