CONICET | Buscador de Institutos y Recursos Humanos

Cognitive decline is a hallmark of the aging nervous system, characterized by increas‐ing memory loss and a deterioration of mental capacity, which in turn creates a favora‐ble context for the development of neurodegenerative diseases. One of the mostdetrimental alterations that occur at the molecular level in the brain during aging is themodification of the epigenetic mechanisms that control gene expression. As a result ofthese epigenetic‐driven changes in the transcriptome most of the functions of thebrain including synaptic plasticity, learning, and memory decline with aging. The epige‐netic mechanisms altered during aging include DNA methylation, histone modifica‐tions, nucleosome remodeling, and microRNA‐mediated gene regulation. In this review,we examine the current evidence concerning the changes of epigenetic modificationstogether with the molecular mechanisms underlying impaired neuronal gene transcrip‐tion during aging. Herein, we discuss the alterations of DNA methylation pattern thatoccur in old neurons. We will also describe the most prominent age‐related histoneposttranslational modifications in the brain since changes in acetylation and methyla‐tion of specific lysine residues on H3 and H4 are associated to functional decline in theold. In addition, we discuss the role that changes in the levels of certain miRNAs wouldplay in cognitive decline with aging. Finally, we provide an overview about the mecha‐nisms either extrinsic or intrinsic that would trigger epigenetic changes in the agingbrain, and the consequences of these changes, i.e., altered transcriptional profile andreactivation of transposable elements in old brain.