Unrepaired or inaccurately repaired DNA damage can lead to a range of cell fates, such as apoptosis, cellular senescence or cancer, depending on the efficiency and accuracy of DNA damage repair and ...on the downstream DNA damage signalling. DNA damage repair and signalling have been studied and modelled in detail separately, but it is not yet clear how they integrate with one another to control cell fate. In this study, we have created an integrated stochastic model of DNA damage repair by non-homologous end joining and of gamma irradiation-induced cellular senescence in human cells that are not apoptosis-prone. The integrated model successfully explains the changes that occur in the dynamics of DNA damage repair after irradiation. Simulations of p53/p21 dynamics after irradiation agree well with previously published experimental studies, further validating the model. Additionally, the model predicts, and we offer some experimental support, that low-dose fractionated irradiation of cells leads to temporal patterns in p53/p21 that lead to significant cellular senescence. The integrated model is valuable for studying the processes of DNA damage induced cell fate and predicting the effectiveness of DNA damage related medical interventions at the cellular level.
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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.
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44.
BASIS: an internet resource for network modelling Gillespie, Colin S.; Wilkinson, Darren J.; Shanley, Daryl P. ...
Journal of integrative bioinformatics,
12/2006, Volume:
3, Issue:
2
Journal Article
Peer reviewed
Open access
There is a growing realisation that complex biological processes cannot be understood through the application of ever more reductionist experimental programs alone. Recognising this, we have a ...constructed a flexible web-service based modelling system called BASIS (Biology of Ageing e-Science Integration and Simulation), which facilitates model construction and development. In particular it allows users to store, share and simulate their models. The system is accessed through web-services using any language (e.g. Python or Java) or under any operating system (e.g. Linux or Windows).
Evolution, stress, and longevity KIRKWOOD, THOMAS B. L.; KAPAHI, PANKAJ; SHANLEY, DARYL P.
Journal of anatomy,
November 2000, 2000-Nov, 2000-11-00, 20001101, Volume:
197, Issue:
4
Journal Article
Peer reviewed
Open access
The disposable soma theory suggests that longevity is determined through the setting of longevity assurance mechanisms so as to provide an optimal compromise between investments in somatic ...maintenance (including stress resistance) and in reproduction. A corollary is that species with low extrinsic mortality are predicted to invest relatively more effort in maintenance, resulting in slower intrinsic ageing, than species with high extrinsic mortality. We tested this prediction in a comparative study of stress resistance in primary skin fibroblasts and confirmed that cells from long‐lived species are indeed more resistant to a variant of stressors. A widely studied example of within‐species variation in lifespan is the rodent calorie restriction model. Food‐restricted animals show elevations in a range of stress response mechanisms, and it has been suggested that this is an outcome of natural selection for life history plasticity. We have developed a theoretical model for dynamic optimisation of the allocation of effort to maintenance and reproduction in response to fluctuations in food availability. The model supports the suggestion that the response to calorie restriction may be an evolutionary adaptation, raising interesting questions about the hierarchy of genetic control of multiple stress response systems. The model identifies ecological factors likely to support such an adaptation that may be relevant in considering the likely relevance of a similar response to calorie restriction in other species. Comparative and theoretical studies support the role of somatic maintenance and stress response systems in controlling the rate of ageing.
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The disposable soma theory suggests that aging occurs because natural selection favors a strategy in which fewer resources are invested in somatic maintenance than are necessary for indefinite ...survival. However, laboratory rodents on calorie-restricted diets have extended life spans and retarded aging. One hypothesis is that this is an adaptive response involving a shift of resources during short periods of famine away from reproduction and toward increased somatic maintenance. The potential benefit is that the animal gains an increased chance of survival with a reduced intrinsic rate of senescence, thereby permitting reproductive value to be preserved for when the famine is over. We describe a mathematical life-history model of dynamic resource allocation that tests this idea. Senescence is modeled as a change in state that depends on the resources allocated to maintenance. Individuals are assumed to allocate the available resources to maximize the total number of descendants. The model shows that the evolutionary hypothesis is plausible and identifies two factors, both likely to exist, that favor this conclusion. These factors are that survival of juveniles is reduced during periods of famine and that the organism needs to pay an energetic “overhead” before any litter of offspring can be produced. If neither of these conditions holds, there is no evolutionary advantage to be gained from switching extra resources to maintenance. The model provides a basis to evaluate whether the life-extending effects of calorie-restriction might apply in other species, including humans. Corresponding Editor: D. Roff
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47.
Food restriction, evolution and ageing KIRKWOOD, Thomas B. L; SHANLEY, Daryl P
Mechanisms of ageing and development,
2005, Volume:
126, Issue:
9
Journal Article
Peer reviewed
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A publication by Shanley and Kirkwood attempts to explain data on caloric restriction and life extension in the context of the Disposable Soma theory for the evolution of senescence. The limitations ...of this model are detailed and its special assumptions reviewed.
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