Persistent mTORC1 signaling in cell senescence results from defects in amino acid and growth factor sensing

Area of Science:

• Cellular senescence
• Molecular biology
• Aging research

Background:

• Mammalian target of rapamycin complex 1 (mTORC1) and cell senescence are linked to organismal aging.
• mTORC1 inhibition extends lifespan, and senescent cell clearance improves health.
• Enhanced mTORC1 activity drives senescence phenotypes, but mechanisms are unclear.

Purpose of the Study:

• Investigate the mechanisms driving constitutive mTORC1 activity in senescent human fibroblasts.
• Determine the role of persistent mTORC1 signaling in senescent cell survival.

Main Methods:

• Induction of senescence in human fibroblasts via stress, replicative exhaustion, or oncogene activation.
• Analysis of mTORC1 activity, plasma membrane potential, primary cilia, and intracellular amino acid levels.
• Assessment of senescent cell response to interventions targeting mTORC1 signaling.

Main Results:

• Senescent human fibroblasts exhibit constitutively active mTORC1, resistant to starvation.
• Plasma membrane depolarization causes primary cilia defects, impairing growth factor signaling inhibition.
• Increased autophagy and intracellular amino acids support mTORC1 activity during starvation.
• Interventions correcting these defects restore mTORC1 pathway sensitivity and induce cell death.

Conclusions:

• Constitutive mTORC1 activation is a key feature of cellular senescence.
• Plasma membrane depolarization and associated defects contribute to mTORC1 dysregulation.
• Persistent mTORC1 signaling is essential for senescent cell survival.