'Arc'-hitecture of normal cognitive aging

Arc is an effector immediate-early gene that is critical for forming long-term memories. Since its discovery 25 years ago, it has repeatedly surprised us with a number of intriguing properties, including the transport of its mRNA to recently-activated synapses, its master role in bidirectionally regulating synaptic strength, its evolutionary retroviral origins, its ability to mediate intercellular transfer between neurons via extracellular vesicles (EVs), and its exceptional regulation-both temporally and spatially. The current review discusses how Arc has been used as a tool to identify the neural networks involved in cognitive aging and how Arc itself may contribute to cognitive outcome in aging. In addition, we raise several outstanding questions, including whether Arc-containing EVs in peripheral blood might provide a noninvasive biomarker for memory-related synaptic failure in aging, and whether rectifying Arc dysregulation is likely to be an effective strategy for bending the arc of aging toward successful cognitive outcomes.