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Gerosuppression by pan-mTOR inhibitors.

Olga V Leontieva1, Mikhail V Blagosklonny1

  • 1Department of Cell Stress Biology, Roswell Park Cancer Institute, Elms and Carlson Streets, Buffalo, NY 14263, USA.

Aging
|January 13, 2017
PubMed
Summary

Dual mTOR inhibitors, unlike rapamycin, effectively suppress cellular aging markers and enhance chronological lifespan. These compounds show promise as novel anti-aging therapeutics at lower, non-cancerous doses.

Keywords:
agingcancerdual mTORC1/C2 inhibitorsrapalogssenescencesirolimus

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Area of Science:

  • Cellular senescence
  • Aging research
  • Molecular biology

Background:

  • Rapamycin extends lifespan and delays age-related diseases by inhibiting mTOR.
  • Rapalogs and pan-mTOR inhibitors suppress cellular senescence.
  • Pan-mTOR inhibitors target both mTORC1 and mTORC2 complexes.

Purpose of the Study:

  • To investigate the optimal gerosuppressive concentrations of various pan-mTOR inhibitors.
  • To compare the efficacy of pan-mTOR inhibitors against rapamycin in suppressing senescence.
  • To explore the potential of pan-mTOR inhibitors as anti-aging drugs.

Main Methods:

  • Determined optimal gerosuppressive concentrations for Torin1, Torin2, AZD8055, PP242, KU-006379, and GSK1059615.
  • Assessed inhibition of senescence-associated hypertrophy, lysosomal accumulation (SA-beta-Gal), lipid accumulation (Oil Red), and loss of re-proliferative potential (RPP).
  • Analyzed the pS6K/pS6 axis and rapamycin-insensitive mTOR functions.

Main Results:

  • Identified optimal concentrations for pan-mTOR inhibitors, with Torin1 and Torin2 at 30 nM.
  • Pan-mTOR inhibitors effectively reduced senescence-associated hypertrophy, with IC50s as low as 15 nM for AZD8055.
  • These inhibitors preserved RPP, inhibited the pS6K/pS6 axis, and outperformed rapamycin in suppressing senescence markers and increasing chronological lifespan.

Conclusions:

  • Pan-mTOR inhibitors are superior to rapamycin in combating cellular aging phenotypes.
  • Inhibition of rapamycin-insensitive mTOR functions contributes to anti-aging effects.
  • Pan-mTOR inhibitors represent a promising new class of anti-aging drugs at sub-anticancer concentrations.