Brain evolution and lifespan regulation: conservation of signal transduction pathways that regulate energy metabolism.

Mechanisms for sensing, acquiring, storing and using energy are fundamental to the survival of organisms at all levels of the phylogenetic scale. Single-cell organisms evolved surface receptors that sense an energy source and, via signal transduction pathways that couple the receptors to the cell cytoskeleton move towards the energy source. Mutlicellular organisms evolved under conditions that favored species that developed complex mechanisms for obtaining food, with nervous systems being critical mediators of energy acquisition and regulators of energy metabolism. A conserved signaling system involved in regulating cellular and organismal energy metabolism, and in sensing and responding to energy/food-related environmental signals, involves receptors coupled to the phosphatidylinositol-3-kinase-Akt signaling pathway. Prominent activators of this pathway are insulin, insulin-like growth factors and brain-derived neurotrophic factor (BDNF). Recent studies in diverse organisms including nematodes, flies and rodents have provided evidence that insulin-like signaling in the nervous system can control lifespan, perhaps by modulating stress responses and energy metabolism. Interestingly, the lifespan-extending effect of dietary restriction in rodents is associated with increased BDNF signaling in the brain, and a related increase of peripheral insulin sensitivity, suggesting a mechanism whereby the brain can control lifespan. Thus a prominent evolutionarily conserved function of the nervous system is to regulate food acquisition and energy metabolism, thereby controlling lifespan.