Cellular Senescence | Chemotherapy | Cancer | Molecular Pharmacology | Biomarkers | Therapeutics | Mitochondria

Cellular Senescence | Cancer | Ageing | Epigenetics | Mitochondria | Metabolism |Inflammation

THESIS TITLE'The role of telomeric DNA damage, mitochondria biogenesis and mTOR signalling in cellular senescence'THESIS ABSTRACTCellular senescence is a state of enduring cell-cycle arrest characterised by a persistent DNA damage response, elevated Reactive Oxygen Species (ROS), mitochondrial dysfunction and a senescence-associated secretome. Senescence impacts in vivo not only by acting as a tumour suppressor mechanism but also hindering tissue repair and regeneration. Senescent cells build-up with age in many tissues from humans, baboons and mice, and clearance of senescent cells in mice has been demonstrated to ameliorate age-related pathologies.The mTOR (mechanistic target of rapamycin) is a primeval and conserved pathway among eukaryotes. Inhibition of the mTOR pathway has been shown to extend lifespan of model organisms, to be beneficial against cancer progression and to ameliorate several age-related diseases. While reportssuggest that mTOR plays a role in cellular senescence, it is still incompletely understood how it contributes to the phenotype.Mitochondria sit on the crossroad of many cell fate decisions including apoptosis, differentiation and metabolism. Despite requirement for the aforementioned processes, the role of this organelle in cellular senescence has not been fully elucidated.In this thesis, I describe potential mechanisms by which mTOR may impact on cellular senescence, given its roles in regulating the DNA damage response and mitochondrial homeostasis. Additionally, I inspect the role of mitochondrial biogenesis during induction and maintenance of cellular senescence. Finally, I study the impact of mTOR inhibition by rapamycin and, the effects of compromised mitochondrial biogenesis in liver senescence with age in mice.KEYWORDSAgeingCellular SenescenceMitochondriamTOR pathwayTelomeresDNA damage response (DDR)Reactive Oxygen Species (ROS)