Regulation of mTOR complexes in long-lived growth hormone receptor knockout and Snell dwarf mice

Area of Science:

• Aging research
• Molecular biology
• Genetics

Background:

• Downregulation of mechanistic target of rapamycin (mTOR) signaling is linked to lifespan extension across species.
• Growth hormone receptor knockout (GHRKO) and Snell dwarf mice exhibit significantly increased lifespans and reduced mTORC1 function.

Purpose of the Study:

• To investigate the molecular mechanisms underlying reduced mTORC1 function in long-lived GHRKO and Snell dwarf mice.
• To identify alterations in mTORC1 components and upstream regulators contributing to extended lifespan.

Main Methods:

• Analysis of mTORC1 components (DEPTOR, PRAS40) and upstream regulators (TSC1, TSC2) in liver, kidney, and skeletal muscle tissues.
• Western blotting to assess protein levels and phosphorylation status of TSC2.
• Fibroblast studies involving TSC2 knockdown to evaluate its role in mTORC1 regulation.

Main Results:

• Reduction of DEPTOR and PRAS40 in the liver of long-lived mice, contrary to expected changes for reduced mTORC1 activity.
• Elevated levels of TSC1 and TSC2 in multiple tissues of GHRKO and Snell mice.
• Decreased phosphorylation of TSC2, indicating increased activity of the TSC1/TSC2 complex.
• Reversal of GHRKO-associated mTORC1 changes upon TSC2 knockdown.

Conclusions:

• Increased levels of active, unphosphorylated TSC1/TSC2 complex contribute to the reduced mTORC1 function observed in long-lived GHRKO and Snell dwarf mice.
• The TSC1/TSC2 pathway represents a significant factor in the lifespan extension observed in these mouse models.
• Findings provide insights into the molecular basis of aging and potential targets for interventions.