Researchers have found that the human brain begins undergoing broad changes in the way its genome is regulated starting in midlife. The findings may help explain why age is the strongest risk factor for neurodegenerative conditions such as Alzheimer’s disease.
In a new study published in Science, scientists used advanced single-cell methods to examine gene regulation and three-dimensional genome organization in individual cells from the human hippocampus, a brain region essential for learning and memory. By analyzing samples from adults across a wide range of ages, the team created one of the most detailed pictures yet of how genome regulation shifts as the brain grows older.
Brain Immune Cells Undergo a Major Midlife Shift
One of the most notable changes appeared in microglia, the immune cells that help maintain and protect the brain. Between approximately ages 50 and 75, the researchers found a sharp decline in microglia that originate during embryonic development. At the same time, those cells were increasingly replaced by cells whose molecular features resembled immune cells found in the blood.
That result challenges a long-standing assumption that microglia established early in development remain in the brain for a person’s entire life. The replacement microglia-like cells also showed stronger inflammatory signatures, raising the possibility that they could contribute to chronic inflammation in the aging brain.
The researchers also detected a substantial decline in cell populations 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 for maintaining brain homeostasis,” said Bing Ren, PhD, a 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 in the Vagelos Institute for Basic Biomedical Science (Vagelos Institute) in VP&S, Columbia University, “When these cells fail to perform their housekeeping duties, toxic materials accumulate that can trigger inflammatory processes that may contribute to neurodegenerative diseases.”
The Genome’s 3D Structure Also Deteriorates With Age
The changes were not limited to immune cells. Across several types of brain cells, the researchers observed a broad erosion of three-dimensional genome architecture.
Inside a cell, DNA is not simply packed randomly into the nucleus. It is folded into a highly organized three-dimensional structure that helps control which genes are switched on or off. The researchers found that this organization became less orderly with age, suggesting that deterioration in genome structure could be a fundamental feature of brain aging.
“This work represents a major step forward in understanding how aging reshapes the human genome in brain cells,” said Nathan Zemke, Director of Single-cell Genomics at the Center for Epigenomics at UC San Diego. “These findings demonstrate a critical need for studying gene regulation and genome organization to gain a mechanistic understanding of the aging process.”
Aging May Involve Coordinated Remodeling
The findings suggest that brain aging is more complicated than a simple, steady decline. Instead, multiple systems appear to change together, 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 immune, vascular, and neuronal systems. These findings open the door to identifying new therapeutic targets aimed at preserving circuit integrity and brain function across the lifespan,” said Xiangmin Xu, PhD, 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 Decade-Long Genome Mapping Effort
The research is one of six papers published in Science through the National Institutes of Health’s 4D Nucleome (4DN) Common Fund program. The decade-long initiative was created to map how the genome is 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 genome’s spatial arrangement influences biological processes. In addition to this study, Dr. Ren contributed as a co-corresponding author or co-author on three other Science papers examining genome architecture across different cell types and timescales.
Together, the studies create a major new resource for researchers and provide fresh opportunities to investigate how changes in genome organization contribute to development, aging, and disease, including neurodegenerative disorders.
