In the last ten years, the discovery of neuronal DNA postmitotic instability has changed the theoretical landscape in neuroscience and, more broadly, biology. In 2003, A. M. Olovnikov suggested that neuronal DNA is the "initial substrate of aging". Recent experimental data have significantly increased the likelihood of this hypothesis. How does neuronal DNA accumulate damage and in what genome regions? What factors contribute to this process and how are they associated with aging and lifespan? These questions will be discussed in the review. In the course of Metazoan evolution, the instability of neuronal DNA has been accompanied by searching for the pathways to reduce the biological cost of brain activity. Various processes and activities, such as sleep, evolutionary increase in the number of neurons in the vertebrate brain, adult neurogenesis, distribution of neuronal activity, somatic polyploidy, and RNA editing in cephalopods, can be reconsidered in the light of the trade-off between neuronal plasticity and DNA instability in neurons. This topic is of considerable importance for both fundamental neuroscience and translational medicine.
Keywords: DNA repair; epigenetics; evolution of the nervous system; lifespan; nervous system; neuronal DNA; postmitotic mutagenesis.