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Dual mTORC1/C2 inhibitors suppress cellular geroconversion (a senescence program)

Olga V Leontieva1, Zoya N Demidenko1, Mikhail V Blagosklonny1

  • 1Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.

Oncotarget
|July 16, 2015
PubMed

Insights

Dual mTOR inhibitors, like Torin1 and PP242, prevent cell cycle arrest from becoming permanent senescence. These compounds preserve cells' ability to proliferate, suggesting potential anti-aging applications.

Area of Science:

  • Cellular senescence
  • Molecular biology
  • Aging research

Background:

  • Mammalian target of rapamycin (mTOR) pathway regulates cell growth and proliferation.
  • Cellular senescence is a state of irreversible cell cycle arrest.
  • mTOR activity drives the conversion of reversible cell cycle arrest into senescence (geroconversion).

Purpose of the Study:

  • To investigate the effect of ATP-competitive mTOR kinase inhibitors on geroconversion.
  • To determine if these inhibitors can preserve re-proliferative potential in arrested cells.
  • To explore the potential of dual mTOR inhibitors as anti-aging therapeutics.

Main Methods:

  • Utilized p21-arrested cells to study geroconversion.
  • Administered ATP-competitive mTOR inhibitors Torin1 and PP242 at varying concentrations.
  • Assessed geroconversion suppression, re-proliferative potential (RP), senescent morphology, hypertrophy, and phosphorylation of S6 kinase (S6K) and S6.
  • Investigated inhibition of both mTOR complex 1 (mTORC1) and mTOR complex 2 (TORC2).

Main Results:

  • Torin1 and PP242 significantly suppressed geroconversion in a dose-dependent manner.
  • Near-maximal gerosuppression correlated with inhibition of p-S6K(T389) and p-S6(S235/236).
  • Dual mTOR inhibitors prevented the development of senescent morphology and cellular hypertrophy, preserving re-proliferative potential.

Conclusions:

  • ATP-competitive mTOR inhibitors effectively suppress geroconversion, offering an alternative to rapalogs.
  • These inhibitors maintain re-proliferative potential in arrested cells, counteracting senescence.
  • Low-dose dual mTOR inhibitors represent a promising new class of drugs for anti-aging strategies and delaying age-related diseases.
Keywords:
GerotargetPathology Sectionagingpan-mTOR inhibitorsrapalogsrapamycinsenescence

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