Signalling responses to escalating doses of metabolic stress will be investigated in CRA1. Four sub-projects (SP) will focus on the functional patterns of energy availability and signalling responses derived thereof as essential mediators of stress responses. Signalling pathways and factors to be analysed include insulin and phosphoinositide 3-kinase (PI3K) signalling, AMP-activated kinase (AMPK), the deacetylase SIRT1, p38 MAP kinase, redox regulator kinases and the transcription factors NRF-2 and FoxO1. Taken together, all SPs of CRA1 are focused on the role of energy availability as putative metabolic stressor that induces and employs intracellular second messengers (ROS, ATP/ADP/AMP, NADH/NAD+, Acetyl-CoA) and secondary responses, which ultimately culminate in increased stress resistance and survival. Moreover, CRA1 is linked to a wide range of topics described in the other CRAs since mediators of inflammatory and genotoxic stress such as PI3K and nuclear hormone receptors (e.g. PPARs, T3R, glucocorticoid receptor) also act as important metabolic regulators.