Reversal of phenotypes of cellular senescence by pan-mTOR inhibition

Journal article

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: Cox, L; Deneka-Hannemann, S; Walters, H

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Impact Journals
• Journal: Aging
• Publication date: 2016-02-05
• ISSN: 1945-4589
• Keywords: cellular senescence; mTORC2; mTORC1; AZD8055; rapamycin; aging