Brain immune cells during human aging
A single-cell study in Science reveals major shifts in immune cells, genome organization and gene regulation in the aging human hippocampus. These findings offer critical insights into brain aging with major implications for age-related dementias
Researchers have discovered that the human brain undergoes widespread age-related changes in genome regulation beginning in midlife that may help explain why aging is the greatest risk factor for neurodegenerative diseases such as Alzheimer’s.
In a new study published in Science, researchers used cutting-edge single-cell technologies to profile gene regulation and three-dimensional genome architecture in individual cells from the human hippocampus, the brain region critical for learning and memory. By examining brain samples across the adult lifespan, the team generated one of the most comprehensive views to date of how genome regulation changes during brain aging.
One of the study’s most striking findings was a dramatic shift in microglia, the brain’s immune cells, between approximately ages 50 and 75. Microglia that originate during embryonic development declined substantially and were replaced by cells with molecular signatures that resemble immune cells from the blood. This finding challenges the longstanding view that microglia established during embryonic development persist throughout the human lifespan.
These replacement microglia-like cells exhibited elevated inflammatory signatures, suggesting they may contribute to chronic neuroinflammation in the aging human brain. The scientists also observed a substantial decline in cell populations important for maintaining the blood-brain barrier, which protects the brain from harmful substances in the bloodstream.
“Microglia are critical for maintaining brain homeostasis,” said a corresponding author of the study. “When these cells fail to perform their housekeeping duties, toxic materials accumulate that can trigger inflammatory processes that may contribute to neurodegenerative diseases.”
Across multiple brain cell types, researchers also observed a global erosion of three-dimensional genome architecture, suggesting that structural breakdown of the genome may be a fundamental hallmark of brain aging. “This work represents a major step forward in understanding how aging reshapes the human genome in brain cells,” said another author. “These findings demonstrate a critical need for studying gene regulation and genome organization to gain a mechanistic understanding of the aging process.”
“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 another co-corresponding author of the study.
