In a new study published in Science, scientists used advanced single-cell methods to examine gene regulation and the three-dimensional organization of the genome in individual cells of the human hippocampus, a brain region essential for learning and memory. By analyzing samples from adults across a wide range of ages, the researchers created one of the most detailed pictures yet of how genomic regulation changes as the brain ages.

Brain immune cells undergo major changes in midlife

One of the most notable changes appeared in microglia, immune cells that help maintain and protect the brain. The researchers found that between about ages 50 and 75, there is a sharp decline in microglia that develop during embryonic development. At the same time, those cells were increasingly replaced by cells with molecular characteristics similar to immune cells found in the blood.

The results challenge the long-held assumption that microglia established early in development remain in the brain throughout life. The replacement microglia-like cells also showed stronger signs of inflammation, raising the possibility that they contribute to chronic inflammation in the aging brain.

The researchers also detected a significant decrease in the number of cells that help maintain the blood-brain barrier. This protective barrier helps shield the brain from potentially harmful substances circulating in the bloodstream.

“Microglia are critical to maintaining brain homeostasis,” said Bing Ren, Ph.D., corresponding author of the study, scientific director and CEO of the New York Genome Center, professor of genetics and development, biochemistry and molecular biophysics, and systems biology at Columbia University, and associate director of the Vagelos Institute for Basic Biomedical Sciences at Columbia University VP&S. “When these cells are no longer able to fulfill their housekeeping role, the accumulation of toxic substances can trigger inflammatory processes and contribute to neurodegenerative diseases.”

The 3D structure of the genome also deteriorates with age

The changes were not limited to immune cells. The researchers observed widespread erosion of three-dimensional genome structure across several types of brain cells.

Inside cells, DNA is not randomly packed into the nucleus. It folds into highly organized three-dimensional structures that help control which genes are turned on or off. The researchers found that this organization becomes less ordered with age, suggesting that deterioration of genome structure may be a fundamental feature of brain aging.

“This study is a major step forward in understanding how the human genome changes in brain cells as we age,” said Nathan Zemke, director of single-cell genomics at the Epigenomics Center at the University of California, San Diego. “These findings demonstrate the critical need to study gene regulation and genome organization to understand the mechanisms of the aging process.”

Aging may require systemic remodeling

The findings suggest that brain aging is more complex than a simple, steady decline. Instead, multiple systems appear to change simultaneously, including immune cells, blood vessels, neurons, and genome organization.

“Importantly, this study reveals that aging is not simply a gradual decline, but involves coordinated and dynamic remodeling of the immune, vascular, and nervous systems. These findings open the door to the identification of new therapeutic targets aimed at preserving circuit integrity and brain function throughout the lifespan,” said Xiangmin Xu, Ph.D., Chancellor’s Professor and director of the Center for Neural Circuit Mapping at the University of California, Irvine, and a co-corresponding author of the study.

Part of a 10-year genome-mapping effort

This research was conducted through the National Institutes of Health’s 4D Nucleome (4DN) Common Fund Program. This decade-long effort was created to map how genomes are organized in space and how that organization changes over time.

From 2015 to 2025, the 4D Nucleome Program brought together interdisciplinary research teams from across the United States to investigate how the spatial arrangement of the genome influences biological processes. In addition to this study, Dr. Ren contributed as a co-corresponding author or co-author on three other studies examining genome structure across different cell types and time scales.

Together, these studies will generate important new resources for researchers and create new opportunities to investigate how changes in genome organization contribute to development, aging, and disease, including neurodegenerative diseases.