mTORC1 Pathway and Biology

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 and fundamental cellular function and growth

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:

  • grow (when nutrient levels are abundant), or
  • begin a well-controlled and systematic process of autophagy—i.e., recycling (during a scarcity of nutrients), whereby certain cellular components are broken down into basic building blocks, including amino acids, to maintain the biosynthetic integrity of the cell

mTORC1 regulates both cell growth and autophagy through its kinase activity, primarily in response to the availability of amino acids.

mTORC1 and Nutrient Signaling

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.

mTORC1 and Growth Factor Signaling

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.

The signals that regulate the mTORC1 pathway can be excessively activated or suppressed below healthy levels, thereby contributing to the genesis and progression of a range of diseases.
  • Excessive activation of mTORC1 activity in response to increased availability of nutrients or as a result of genetic errors in the mTORC1 activation pathway—and subsequent increased biosynthetic activity, including protein synthesis—have been linked to a wide range of age-related diseases, including metabolic, autoimmune, and neurodegenerative diseases, as well as suppressed immune function and several rare disorders.
  • Reduced mTORC1 activity has been connected to diseases of aging that involve skeletal muscle growth and function, including age-related muscle loss, or sarcopenia; cachexia associated with age-related diseases such as cancer; chronic obstructive pulmonary disease (COPD); and heart failure in which the breakdown of muscle exceeds its growth.