Epigenetic and 3D genome reprogramming during the aging of human hippocampus [CUT&Tag]

Age-related cognitive decline in humans is associated with altered physiology of the hippocampus, a region critical for memory consolidation and spatial navigation. While changes in gene expression have been observed in aging brain cells, our understanding of the regulatory mechanisms underlying these changes and their connection to chromatin structure remains limited. To unravel these complexities, we have applied a comprehensive multi-omics approach, integrating single-nucleus gene expression, chromatin accessibility, DNA methylation, and 3D chromatin architecture data obtained from hippocampal tissues of 40 neurotypical human donors spanning the adult lifespan. We observed a striking loss of astrocytes during aging, including the subset of astrocytes that play a role in maintaining and regulating synaptic transmission. In individuals aged 50-75 years, microglia undergo a dramatic switch from a predominantly homeostatic state to an epigenetically primed inflammatory state that coincides with reprogramming of their DNA methylomes. In the aged cells, we detected erosion of the 3D genome architecture, where local chromatin domains are diminished, trans-chromosomal interactions are strengthened, and CTCF DNA binding is reduced. Importantly, age-related changes in chromatin folding have high correspondence with the aging transcriptome and epigenome in multiple cell types. Our data identifies age-associated changes in cell types/states and gene regulatory features that provide insight into the loss of synapses and cognitive decline that occurs in the human brain during aging.