Abstract
Senescent cells accumulate in several tissues during ageing and contribute to several pathological processes such as ageing and cancer. Senescence induction is a complex process not well defined yet and is characterized by a series of molecular changes acquired after an initial growth arrest. We found that fatty acid synthase (FASN) levels increase during the induction of senescence in mouse hepatic stellate cells and human primary fibroblasts. Importantly, we also observed a significant increase in FASN levels during ageing in mouse liver tissues. To probe the central role of FASN in senescence induction, we used a small-molecule inhibitor of FASN activity, C75. We found that C75 treatment prevented the induction of senescence in mouse and human senescent cells. Importantly, C75 also reduced the expression of the signature SASP factors interleukin 1α (IL-1α), IL-1β and IL-6, and suppressed the secretion of small extracellular vesicles. These findings were confirmed using a shRNA targeting FASN. In addition, we find that FASN inhibition induces metabolic changes in senescent cells. Our work underscores the importance of C75 as a pharmacological inhibitor for reducing the impact of senescent cell accumulation.
Highlights
Accumulation of senescent cells in different tissues during ageing has been extensively reported, especially in cardiovascular and other age-related diseases[1]
We found that senescent hepatic stellate cells (HSCs) displayed a significant increase in the amount of puromycin-labelled peptides compared with control, indicating that global protein synthesis[34] is increased in senescent cells and suggesting an increase in mammalian target of rapamycin (mTOR) activity (Fig. 3a)
Cellular senescence is a well-defined phenotype characterized by a stable cell cycle arrest in response to different stress signals such as oncogene activation and DNA damage, and accompanied by a characteristic secretory phenotype of extracellular vesicles (EVs) and SASP5,6,26,40
Summary
P53 endogenous expression progressively induces senescence in mouse hepatic stellate cells In order to investigate the metabolic adaptation during the activation of senescence, we took advantage of hepatic stellate cells (HSCs) derived from adult mouse liver, previously described by Lujambio et al.[24]. HSCs after Dox removal showed increased SA-β-gal (senescence-associated βgalactosidase) activity (Fig. 1c, e) with reduced cell proliferation, measured by cell number by 4′,6-diamidino-2phenylindole (DAPI) and quantifying cells positive for Ki67 staining (Fig. 1c, f, g). Overall, these results show that after Dox removal HSCs undergo a cell cycle arrest and express different markers of senescence. We observed increased levels of several well-established biomarkers of senescence such as CDKN2A, CDKN1A, IL1A and IL1B in livers from aged mice, suggesting increased senescence in vivo (Fig. 2b).
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