New data from a National Institutes of Health-funded study reveals that midlife brings substantial remodeling to the immune cell landscape of the human hippocampus, pointing to a potential mechanism behind chronic neuroinflammation in neurodegenerative diseases. Scientists analyzed postmortem hippocampal tissue from 40 neurologically healthy adults aged 20 to 95 years old, as detailed in a paper published in Science titled “Epigenetic and 3D genome reprogramming during the aging of human hippocampus.”
Collaborative Research Uncovers Major Shifts in Brain Immune Cells
The study was conducted by a team of researchers from the University of California, San Diego, the New York Genome Center, and the University of California, Irvine. To uncover these cellular changes, the scientists moved beyond traditional gene expression measurements. They integrated advanced techniques to analyze the genome’s 3D architecture alongside the epigenome.
“Gene expression tells us what a cell is doing today, but epigenetic signatures preserve information about where a cell came from,” according to Nathan Zemke, PhD, director of single-cell genomics at the UC San Diego Center for Epigenomics and first author on the study. Zemke noted that combining these approaches exposed a major shift in the identity and lineage of immune cells within the aging human brain that standard gene expression data could not reveal.
Decline of Resident Microglia and Blood-Brain Barrier Deterioration
Researchers observed that the brain’s primary immune cells progressively decline between the ages of 50 and 75. These resident cells are replaced by cells carrying elevated inflammatory signatures that closely resemble peripheral blood-derived immune cells. This finding questions the long-held belief that microglia, which emerge during embryonic development, necessarily renew throughout the entire human lifespan.
Additionally, the data demonstrated that cells responsible for maintaining the protective blood-brain barrier deteriorate with age. Across multiple brain cell types, aging coincided with a widespread and coordinated disruption of genome architecture.
“The progressive structural disruptions were closely linked to shifts in gene regulation and cell identity, potentially revealing a fundamental feature of aging in the human brain,” according to Bing Ren, PhD, scientific director and CEO of the New York Genome Center, and professor of genetics and development at Columbia University. Ren served as a corresponding author on the study.
Future Directions in Neurodegenerative Disease Research
Future studies will investigate the exact mechanisms driving the loss of resident microglia. Researchers also aim to determine whether this newly identified immune-cell transition contributes directly to the onset of Alzheimer’s disease and other age-related neurological disorders. Insights from this study may eventually support the development of targeted therapies to preserve cognitive function and reduce vulnerability to neurodegeneration.
Frequently Asked Questions
What did the new NIH-funded study discover about the aging brain?
According to the study published in Science, the immune cell landscape of the human hippocampus undergoes substantial remodeling during midlife. Researchers found that primary brain immune cells decline between ages 50 and 75 and are replaced by cells with inflammatory signatures resembling peripheral blood-derived immune cells.
Who led the research on hippocampal aging?
The collaborative work was conducted by scientists from the University of California, San Diego, the New York Genome Center, and the University of California, Irvine, utilizing postmortem hippocampal tissue from 40 neurologically healthy adults.
Why are microglia important in neurodegenerative disease research?
Understanding how they decline or transform during midlife helps scientists explore mechanisms behind chronic neuroinflammation and age-related conditions like Alzheimer’s disease.
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