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The role of ribosomal protein S6 kinases in cellular senescence, ageing and fatty liver disease

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Title: The role of ribosomal protein S6 kinases in cellular senescence, ageing and fatty liver disease
Authors: Gallage, Suchira Upeksha
Item Type: Thesis or dissertation
Abstract: The world’s elderly population is growing rapidly, and ageing is the largest risk factor for the predominant killer diseases, including cancer, cardiovascular disease and dementia. Ageing and metabolic dysfunction are tightly linked, and there is a need to understand the underlying mechanisms driving these complex processes for therapeutic interventions. Deregulated nutrient sensing, particularly mechanistic target of rapamycin (mTOR) signalling, and cellular senescence are hallmarks of ageing. Previous studies have shown that deletion of ribosomal protein S6 kinase 1 (S6K1), a downstream effector of mTOR, in mice prolongs lifespan and protects from obesity. Given the recent evidence implicating mTOR signalling in cellular senescence and the senescence-associated secretory phenotype (SASP), we hypothesised that a decelerated senescence and SASP response may underlie, at least partially, the health improvements in S6K1-/- mice. 600-day-old S6K1-/- mice displayed normal levels of senescence in the liver but showed a significant attenuation in age-related induction of SASP markers, inflammation and immune infiltration. Experiments performed in mouse embryonic fibroblasts isolated from S6K1 and/or S6K2 knockout mice or depletion of S6 kinases in human primary fibroblasts confirmed that S6 kinases regulate a proinflammatory SASP subset without affecting the senescence growth arrest. The diminution in age-related inflammation may in part be responsible for the improved healthspan observed in S6K1-/- mice. Given the close link between ageing, obesity and cancer, we also studied whether S6 kinases (S6K1 and S6K2) play a causal role in a diet-induced model of non-alcoholic steatohepatitis (NASH). We observed that liver-specific deletion of S6K1 and S6K2 induces a sexually dimorphic phenotype with males showing a beneficial response whilst females showing a worsened outcome, suggesting that gender disparity is an important factor for metabolic and cancer therapy. In summary, we demonstrated that S6 kinases play an important role in the regulation of the proinflammatory SASP and fatty liver disease.
Content Version: Open Access
Issue Date: Sep-2017
Date Awarded: Dec-2017
URI: http://hdl.handle.net/10044/1/75114
DOI: https://doi.org/10.25560/75114
Copyright Statement: Creative Commons Attribution Non-Commercial No Derivatives licence.
Supervisor: Gil, Jesús
Withers, Dominic
Sponsor/Funder: Medical Research Council (Great Britain)
Wellcome Trust (London, England)
Department: Institute of Clinical Sciences
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Department of Clinical Sciences PhD Theses