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Title: The role of ribosomal protein S6 kinases in cellular senescence, ageing and fatty liver disease
Author: Gallage, Suchira Upeksha
ISNI:       0000 0004 8504 4079
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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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.
Supervisor: Gil, Jesús ; Withers, Dominic Sponsor: Medical Research Council ; Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral