Neural stem cells generate new neurons throughout life in the mammalian hippocampus. This process, called adult neurogenesis, is critically involved in certain forms of learning and memory. In addition, failing or altered neurogenesis has been associated with a number of neuro-psychiatric diseases such as major depression and cognitive aging. We aim to characterize the cellular and molecular mechanisms regulating neural stem cell activity and behavior on a single cell level. Using intravital imaging we identified the behavioral properties of individual neural stem cells in the mouse hippocampus. Here we present novel approaches to study the cellular principles underlying life-long neurogenesis using imaging-based tools and single cell profiling of RNA and protein expression across lifespan and in human models of brain development. The aim of our work is to provide new insights into the cellular principles of life-long neurogenesis and to identify novel mechanisms regulating the behavior of stem cells across lifespan.