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.

From Ancient Pathways to Aging Cells—Connecting Metabolism and Cellular Senescence

“…Given the complexities of metabolism in general, and the role of metabolism in regulating both the causes and consequences of the senescence response, the field is ripe for applications of systems biology approaches. Indeed, this approach was recently taken to not only understand the dynamics of the senescence response but also to identify therapeutic targets for ameliorating its deleterious effects (Dalle Pezze et al, 2014). …”

Inhibition of DRP-1-Dependent Mitophagy Promotes Cochlea Hair Cell Senescence and Exacerbates Age-Related Hearing Loss

“…The inhibition of mitophagy results in mitochondrial dysfunction and cellular senescence (García-Prat et al, 2016). On the other hand, an increase in mitophagy repairs cellular injury and delays the process of senescence (Dalle Pezze et al, 2014;Manzella et al, 2018).…”

Nutrient sensing, growth and senescence

“…Similarly, expression of mitophagy‐promoting protein kinase PINK1 becomes reduced with aging, suppressing mitophagy and enhancing the probability of senescence transition . Finally, it has been observed that in senescent cells the mitochondrial network becomes hyperfused which prevents damaged mitochondria being engulfed by autophagosomes . Overall, an accumulation of dysfunctional mitochondria as a result of mitophagy impairment may lead to an increase in intracellular ROS and contribute to the senescence phenotype as has been recently demonstrated for muscle stellate cells.…”