title: Dual mTORC1/C2 inhibitors: gerosuppressors with potential anti-aging effect.
abstract: Over the past decade, our understanding of the molecular and cellular mechanisms presiding over cellular and tissue decline with aging has greatly advanced. Classical hallmarks of aging cell include increasing levels of reactive oxygen species, DNA damage and senescence entry, which disrupt tissue architecture and function. Tissue dysfunction with aging has been shown to correlate with a cellular switch from a G0 reversible quiescence state into a G0 irreversible senescence state (geroconversion), causing a permanent proliferative block. The TOR (target of rapamycin) kinase has been shown to promote geroconversion. Rapamycin and other rapalogs specifically suppress activity of the mammalian TOR (mTOR) complex 1 (mTORC1) -but not mTOR complex 2 (mTORC2)- and decrease senescence entry, thus preserving proliferative potential. In this perspective, we briefly comment recent progress of Leontieva and colleagues showing a new class of non-rapalog drugs that target simultaneously mTORC1 and mTORC2 and prevent geroconversion in a more efficient way than rapamycin. Its potential future use as rejuvenating, anti-aging therapeutics is therefore proposed.
authors.affiliation: Buck Institute for Research on Aging, Novato, CA, USA.|Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative Diseases (CIBERNED), and ICREA, Barcelona, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Sousa-Victor
authors.affiliation: Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative Diseases (CIBERNED), and ICREA, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: García-Prat
authors.affiliation: Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative Diseases (CIBERNED), and ICREA, Barcelona, Spain.
authors.forename: Pura
authors.initials: P
authors.lastname: Muñoz-Cánoves
mesh_terms: D000375:Aging / Q000187:drug effects*; D000818:Animals; D001798:Blood Proteins / Q000737:chemistry*; D016922:Cellular Senescence / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D011687:Purines / Q000737:chemistry*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D001798:Blood Proteins; D007211:Indoles; D046912:Multiprotein Complexes; D011687:Purines; C031024:torin; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; C572919:PP242
keywords: aging; geroconversion; mTOR; quiescence; senescence