How does the brain control lifespan?

There is generally a positive correlation between brain/body size ratio and lifespan, particularly among mammals, suggesting a role for the brain in determining lifespan. Recent studies in diverse organisms including nematodes, flies and rodents have provided evidence that, indeed the brain may control lifespan. Signaling pathways involved in both central nervous system and peripheral stress responses and regulation of energy metabolism may play important roles in lifespan determination. Indeed, genetic and environmental manipulations of these systems can greatly affect lifespan by changing levels of hormones that modulate energy metabolism, stress resistance and regenerative capacity of cells throughout the body. A signal transduction pathway in neurons involving receptors coupled to phosphatidylinositol-3-kinase, Akt and glycogen synthase kinase-3beta appears to play a key role in regulation of longevity by the brain. Mutations in genes that encode proteins in the insulin signaling pathway can increase lifespan in C. elegans and Drosophila, this signaling pathway in neurons in the brain may be particularly important in limiting lifespan. Dietary restriction results in the upregulation of brain-derived neurotrophic factor (BDNF) in the brain, which may increase the resistance of neurons to aging. Interestingly, BDNF signaling in the brain can increase peripheral insulin sensitivity, suggesting a mechanism whereby the brain can control lifespan. We speculate that during evolution the brain took on the task of monitoring and controlling peripheral energy metabolism, and thereby regulating lifespan in the context of food availability. Roles for other evolutionarily conserved brain signaling pathways in lifespan determination are likely to be discovered in the near future.