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Lookup NU author(s): Dr Piero Dalle Pezze, Dr Glyn NelsonORCiD, Gisela Otten, Professor Viktor KorolchukORCiD, Emeritus Professor Thomas Kirkwood, Professor Thomas von Zglinicki, Dr Daryl Shanley
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Dalle Pezze P, Nelson G, Otten EG, Korolchuk VI, Kirkwood TBL, von Zglinicki T, Shanley DP
Publication type: Article
Publication status: Published
Journal: PLoS Computational Biology
Year: 2014
Volume: 10
Issue: 8
Online publication date: 28/08/2014
Acceptance date: 04/06/2014
Date deposited: 20/11/2014
ISSN (print): 1553-734X
ISSN (electronic): 1553-7358
Publisher: Public Library of Science
URL: http://dx.doi.org/10.1371/journal.pcbi.1003728
DOI: 10.1371/journal.pcbi.1003728
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