Effects of rapamycin on growth hormone receptor knockout mice

Area of Science:

• Gerontology
• Molecular Biology
• Metabolism

Background:

• Inhibition of mechanistic target of rapamycin complex 1 (mTORC1) is known to extend lifespan.
• The role of mechanistic target of rapamycin complex 2 (mTORC2) in longevity remains less understood.
• Growth hormone receptor knockout (GHR-KO) mice exhibit suppressed mTORC1 and elevated mTORC2 signaling.

Purpose of the Study:

• To investigate the impact of concurrently inhibiting both mTORC1 and mTORC2 signaling on lifespan.
• To elucidate the mechanisms by which mTORC2 influences longevity in GHR-KO mice.

Main Methods:

• Rapamycin, an mTOR inhibitor, was administered to control normal (N) mice and GHR-KO mice.
• mTORC1 and mTORC2 signaling were assessed in various tissues.
• Metabolic parameters, immune cell function, and inflammation were evaluated.
• Rictor and Raptor knockdown was performed in GHR-KO mouse embryonic fibroblast (MEF) cells.

Main Results:

• Rapamycin extended lifespan in N mice but shortened it in GHR-KO mice.
• In GHR-KO mice, rapamycin treatment reduced mTORC2 signaling without further inhibiting mTORC1 in key metabolic tissues.
• Rapamycin-treated GHR-KO mice displayed impaired glucose and lipid homeostasis, immune cell dysfunction, and increased inflammation.
• Rictor knockdown in GHR-KO MEF cells reduced mTORC2 signaling, confirming its role.

Conclusions:

• Drastic reduction of mTORC2 signaling significantly impairs longevity in GHR-KO mice.
• Disruption of whole-body homeostasis, including metabolic and immune functions, underlies the observed longevity defect.
• Targeting mTORC1 and mTORC2 simultaneously may have differential effects on lifespan depending on the physiological context.