MULTIOMIC profiling reveals how hippocampal epigenetic reprogramming alters cellular lineage and 3D genome architecture during aging. Analyzing postmortem human hippocampal tissue across the adult lifespan, investigators mapped single-nucleus transcriptomes, chromatin accessibility, DNA methylation, and higher-order chromatin structure. Microglial Lineage Shifts via Hippocampal Epigenetic ReprogrammingA central finding is the progressive replacement of resident brain immune cells. At the structural level, hippocampal epigenetic reprogramming accompanies a global erosion of three-dimensional genome architecture across multiple cell types. Together, these findings offer a comprehensive cellular and molecular framework for understanding cognitive vulnerability and synaptic dysfunction in the aging human brain.