Reactive Oxygen Species damage
ROS damage activates an array of stress responsive signalling pathways that coordinate the cell’s response to damage by: (i) initiating cell cycle arrest (so that damaged DNA is not propagated in daughter cells); (ii) driving the expression of detoxifying enzymes and chaperones; (iii) coordinating changes in protein synthesis and turnover/autophagy and (iv) in the most extreme cases eliciting cell death.
Ageing and stress resistance are inextricably linked; interventions that confer lifespan extension invariably confer stress-resistance and vice versa. For example, activation of the JNK signalling pathway or the anti-oxidant transcription factor Nrf2 increase oxidative stress resistance and extend lifespan in Drosophila.
Oxidative damage (including protein damage that causes ER stress) activates the ERK1/2, JNK and p38 pathways; however, their role in stress resistance is complex and context-dependent.
For example, ERK1/2 signalling protects against ER stress-induced death (SC lab) and it can also promote Nrf2-dependent gene expression (Sykiotis et al. Sci Signal. 2010; 3 re3); conversely, ERK1/2 activation can induce ROS production, cell cycle arrest and senescence and is reduced in long-lived mice strains.
Similarly, JNK can promote cell death but also increases Drosophila lifespan. We need to resolve these paradoxes and define the role these pathways play in stress resistance and cell longevity.