Reversal of phenotypes of cellular senescence by pan-mTOR inhibition

• Published in: Aging (Albany, NY.) NY.), 2016-02, Vol.8 (2), p.231-244
• Main Authors: Walters, Hannah E, Deneka-Hannemann, Sylwia, Cox, Lynne S
• Format: Article
• Language: English
• Subjects: Cell Proliferation - drug effects; Cells, Cultured; Cellular Senescence - drug effects; Cellular Senescence - physiology; Fibroblasts - drug effects; Humans; Immunoblotting; Microscopy, Fluorescence; Morpholines - pharmacology; Phenotype; Research Paper; Skin; TOR Serine-Threonine Kinases - antagonists & inhibitors
• ISSN: 1945-4589; 1945-4589
• DOI: 10.18632/aging.100872

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.