title: Reversal of phenotypes of cellular senescence by pan-mTOR inhibition.
abstract: Cellular senescence, a state of essentially irreversible proliferation arrest, serves as a potent tumour suppressor mechanism. However, accumulation of senescent cells with chronological age is likely to contribute to loss of tissue and organ function and organismal aging. A crucial biochemical modulator of aging is mTOR; here, we have addressed the question of whether acute mTORC inhibition in near-senescent cells can modify phenotypes of senescence. We show that acute short term treatment of human skin fibroblasts with low dose ATP mimetic pan-mTORC inhibitor AZD8055 leads to reversal of many phenotypes that develop as cells near replicative senescence, including reduction in cell size and granularity, loss of SA-β-gal staining and reacquisition of fibroblastic spindle morphology. AZD8055 treatment also induced rearrangement of the actin cytoskeleton, providing a possible mechanism of action for the observed rejuvenation. Importantly, short-term drug exposure had no detrimental effects on cell proliferation control across the life-course of the fibroblasts. Our findings suggest that combined inhibition of both mTORC1 and mTORC2 may provide a promising strategy to reverse the development of senescence-associated features in near-senescent cells.
authors: Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, United Kingdom.
authors: Hannah E
authors: HE
authors: Walters
authors: Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, United Kingdom.|Current address: Oxford BioMedica Plc, Oxford, OX4 6LT, United Kingdom.
authors: Sylwia
authors: S
authors: Deneka-Hannemann
authors: Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, United Kingdom.
authors: Lynne S
authors: LS
authors: Cox
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects* / Q000502:physiology*; D005347:Fibroblasts / Q000187:drug effects*; D006801:Humans; D015151:Immunoblotting; D008856:Microscopy, Fluorescence; D009025:Morpholines / Q000494:pharmacology*; D010641:Phenotype; D012867:Skin; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D009025:Morpholines; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: AZD8055; aging; cellular senescence; mTORC1; mTORC2; rapamycin