Reversal of phenotypes of cellular senescence by pan-mTOR inhibition

Area of Science:

• Cellular and Molecular Biology
• Aging Research
• Gerontology

Background:

• Cellular senescence, a state of irreversible proliferation arrest, acts as a tumor suppressor but contributes to aging and tissue dysfunction when accumulated.
• The mechanistic target of rapamycin (mTOR) pathway is a key regulator of cellular processes implicated in aging.

Purpose of the Study:

• To investigate if acute inhibition of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) can reverse senescence phenotypes in near-senescent human fibroblasts.
• To explore the potential of mTOR inhibition as a therapeutic strategy for age-related cellular changes.

Main Methods:

• Treatment of human skin fibroblasts nearing replicative senescence with AZD8055, a low-dose ATP-mimetic pan-mTORC inhibitor.
• Assessment of senescence-associated phenotypes including cell size, granularity, SA-β-gal staining, cell morphology, and actin cytoskeleton organization.
• Evaluation of the drug's effect on cell proliferation control throughout the fibroblast lifespan.

Main Results:

• AZD8055 treatment reversed multiple senescence phenotypes: reduced cell size and granularity, decreased SA-β-gal activity, and restored fibroblastic spindle morphology.
• The drug induced actin cytoskeleton rearrangement, suggesting a potential mechanism for the observed rejuvenation.
• Short-term AZD8055 exposure did not impair the fibroblasts' ability to control proliferation over their lifespan.

Conclusions:

• Acute, short-term inhibition of both mTORC1 and mTORC2 can effectively reverse key features of senescence in human fibroblasts.
• This approach offers a promising strategy to counteract the development of senescence-associated characteristics in aging cells.
• Targeting mTOR may represent a viable therapeutic avenue for mitigating age-related functional decline.