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.
Highlights
Cellular senescence is a hallmark of aging [1] and senescent cells accumulate with age in vivo in mammals [2, 3]; this is thought to drive aging by limiting tissue replicative capacity and causing tissue dysfunction
We first set out to test the impact of AZD8055 treatment on cell morphology, as this represents a very useful biomarker of cellular senescence in fibroblasts [31]
We report that short-term inhibition of mTORC1 and mTORC2 by administration of AZD8055 can reverse morphological and biochemical phenotypes of senescence in near-senescent human fibroblasts, including reduction in cell size and granularity, loss of SA-β-gal staining and reacquisition of fibroblastic spindle morphology
Summary
Cellular senescence is a hallmark of aging [1] and senescent cells accumulate with age in vivo in mammals [2, 3]; this is thought to drive aging by limiting tissue replicative capacity and causing tissue dysfunction (reviewed in [4]). Senescent cells can be characterized by significant alterations in phenotype: they exhibit a large, flat, vacuolated and granular morphology with accumulation of lipid droplets and visible stress fibers, together with increased lysosomal content [5]. Deletion of the p21 gene can prolong lifespan in telomerase-null mice [10] and clearance of p16-expressing senescent cells in vivo can rejuvenate aged mice [11]. Telomerase reactivation suppresses premature aging phenotypes in telomerase knock-out mice [12,13,14]. Taken together these key findings strongly support the argument that senescent cells are detrimental in older animals. Developing strategies to delay the onset of senescence or remove senescent cells may provide a route to preventing age-related disease
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