Physical and cognitive inactivity as well as metabolic dysfunction are important risk factors for cognitive decline in old age. Very little is unknown about how the benefits of physical and cognitive activity are mechanistically linked to the plastic properties and energy metabolism of the brain nor the extend to which such risks are modifiable to improve cognition in aging. This consortium aims to test hypotheses that focus on the interdependence and interaction of neural plasticity and meta bolic regulatory pathways such as insulin signaling. We also hypothesize that this interaction is modified by individual risk factors such as cerebral amyloidosis found in over 20% of cognitively normal older individuals. We will focus on a specific brain region, the hippocampus, because its dysfunction impairs statial navigation and memory precision. These functions will be boosted through plasticity-related interventions and probed using parallel behavioral assays in animals and humans. In a tightly interconnected effort we aim to relate mechanistic insights at the level of synapses and small synaptic networks, epigenetic processes including histonemodifications and non-coding RNAs, to human aging, its individual variability and scope for plasticity in the face of metabolic dysregulation. Thus the participating groups aim to norrow the existing gaps in our mechanistic and clinical understanding of the crossroads between genetic, neural and metabolic effects of a physically and cognitively active lifestyle. We want to apply the novel insights provided in this consortium to develop scientifically proven novel commercial products for combined physical and cognitive training interventions in humans. Furthermore, we anticipate that mechanistic insights gained will identify novel pharmacological targets for the interaction between metabolic signaling pathways and neural plasticity.