The mechanisms that extend lifespan in humans are poorly understood. Here we show that extended longevity in humans is associated with a distinct transcriptome signature in the cerebral cortex characterized by downregulation of genes related to neural excitation and synaptic function. In the model system C. elegans, neural excitation increases with age and inhibition of excitation globally, or in glutamatergic or cholinergic neurons, increases longevity. Furthermore, longevity is dynamically regulated by the excitatory-inhibitory balance of neural circuits. The REST transcription factor is upregulated in humans with extended longevity and represses excitationrelated genes. Notably, REST-deficient mice exhibit increased cortical activity and neuronal excitability during aging. Similarly, loss-of-function mutations in the C. elegans REST orthologs Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: