Aging represents the principal risk factor for neurodegenerative diseases and is associated with a progressive decline in cognitive function. Although numerous studies have documented age-related changes in gene expression, the epigenetic and structural mechanisms underlying these changes remained unclear.
To delve into these aspects, a group of researchers characterized the human hippocampus across the entire adult lifespan using a single-cell multi-omics approach. The study, published in Science, analyzed postmortem brain tissues from 40 neurotypical individuals (20 women and 20 men) aged between 20 and 100 years, integrating data from transcriptomics, chromatin accessibility, DNA methylation, and three-dimensional genome organization.
The study
The results indicate that, starting in midlife, profound changes occur in the cellular regulatory programs of the hippocampus. Among the most notable changes is a reduction in the population of embryonically derived microglia, accompanied by the emergence of immune cells with molecular characteristics similar to monocytic cells derived from the blood compartment. These cells show increased activation of genes associated with the inflammatory response.
Concurrently, a decrease in astrocytes and endothelial cells was observed, accompanied by alterations in cellular metabolic programs, with reduced expression of genes involved in mitochondrial function and an increase in molecular signatures associated with cellular stress.
The research also documents a progressive loss of the three-dimensional organization of the genome across the different cellular populations. Aging is thus associated with a reduction in the integrity of chromatin domains and a broader reorganization of genomic architecture, phenomena that correlate with widespread epigenetic and transcriptional changes.
Overall, the data suggest that aging of the human hippocampus is characterized by a deep remodeling of both cellular composition and the mechanisms that regulate gene expression. While the study does not establish direct causal relationships, it provides a detailed map of the biological processes that accompany brain aging and that could contribute to increased vulnerability to neurodegenerative diseases.
Study
Zemke NR, Lee S, Mamde S, et al. Epigenetic and 3D genome reprogramming during the aging of the human hippocampus. Science. 2026; doi: 10.1126/science.adt8307.
Abbonati a Karla Miller
