title: Dynamic modelling of pathways to cellular senescence reveals strategies for targeted interventions.
abstract: Cellular senescence, a state of irreversible cell cycle arrest, is thought to help protect an organism from cancer, yet also contributes to ageing. The changes which occur in senescence are controlled by networks of multiple signalling and feedback pathways at the cellular level, and the interplay between these is difficult to predict and understand. To unravel the intrinsic challenges of understanding such a highly networked system, we have taken a systems biology approach to cellular senescence. We report a detailed analysis of senescence signalling via DNA damage, insulin-TOR, FoxO3a transcription factors, oxidative stress response, mitochondrial regulation and mitophagy. We show in silico and in vitro that inhibition of reactive oxygen species can prevent loss of mitochondrial membrane potential, whilst inhibition of mTOR shows a partial rescue of mitochondrial mass changes during establishment of senescence. Dual inhibition of ROS and mTOR in vitro confirmed computational model predictions that it was possible to further reduce senescence-induced mitochondrial dysfunction and DNA double-strand breaks. However, these interventions were unable to abrogate the senescence-induced mitochondrial dysfunction completely, and we identified decreased mitochondrial fission as the potential driving force for increased mitochondrial mass via prevention of mitophagy. Dynamic sensitivity analysis of the model showed the network stabilised at a new late state of cellular senescence. This was characterised by poor network sensitivity, high signalling noise, low cellular energy, high inflammation and permanent cell cycle arrest suggesting an unsatisfactory outcome for treatments aiming to delay or reverse cellular senescence at late time points. Combinatorial targeted interventions are therefore possible for intervening in the cellular pathway to senescence, but in the cases identified here, are only capable of delaying senescence onset.
authors.affiliation: Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom; Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Piero
authors.initials: P
authors.lastname: Dalle Pezze
authors.affiliation: Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom; Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Glyn
authors.initials: G
authors.lastname: Nelson
authors.affiliation: Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom; Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Elsje G
authors.initials: EG
authors.lastname: Otten
authors.affiliation: Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom; Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Viktor I
authors.initials: VI
authors.lastname: Korolchuk
authors.affiliation: Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom; Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Thomas B L
authors.initials: TB
authors.lastname: Kirkwood
authors.affiliation: Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom; Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: von Zglinicki
authors.affiliation: Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom; Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Daryl P
authors.initials: DP
authors.lastname: Shanley
mesh_terms: D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology*; D003198:Computer Simulation; D004249:DNA Damage / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D049490:Systems Biology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D014157:Transcription Factors; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases