Aging may trigger a previously underrecognized change in the brain’s immune system, with protective cells in the hippocampus declining and being increasingly replaced by cells that carry stronger inflammatory signals, according to new research.
The study, funded by the National Institutes of Health and published in the journal Science, examined postmortem brain tissue from 40 neurologically healthy adults aged 20 to 95.
Researchers from the University of California, San Diego, the New York Genome Center, and the University of California, Irvine found that the shift becomes particularly apparent beginning around age 50. The findings could provide new clues about why the risk of neuroinflammation, dementia, and other neurodegenerative diseases rises with age.
Immune Cells Change During Midlife
The researchers focused on the hippocampus, a brain region that plays a central role in learning and memory.
Microglia, the brain’s primary resident immune cells, normally help protect neural tissue by clearing debris and responding to injury. The study found that these cells gradually decline from about age 50 through age 75.
At the same time, they appear to be increasingly replaced by immune cells with characteristics resembling cells that originate in the bloodstream.
“The most striking change was that after about age 50, the brain’s resident immune cells, called microglia, appear to be increasingly replaced by immune cells that enter from the bloodstream,” said Nathan Zemke, Ph.D., first author of the study and a principal investigator at the UC San Diego Center for Epigenomics, according to Fox News Digital.
“Microglia normally protect the brain by clearing debris and responding to injury, but the incoming cells carry stronger inflammatory signals.”
The discovery challenges the long-held understanding that microglia remain in the brain throughout life and continually replenish themselves.
NIH researchers said the findings could help explain how normal aging creates an environment associated with persistent inflammation and increased vulnerability to neurodegenerative disease.
Advanced Testing Reveals Cell Origins
The research team combined several advanced single-cell techniques to examine the aging brain.
In addition to measuring gene activity, researchers examined the three-dimensional organization of the genome and epigenetic changes, which can preserve clues about a cell’s identity and origin.
“Gene expression tells us what a cell is doing today, but epigenetic signatures preserve information about where a cell came from,” Zemke said, per Science Daily.
Researchers said combining the methods allowed them to detect changes in immune-cell identity and lineage that might not have been apparent from gene activity alone.
Bing Ren, Ph.D., a corresponding author of the study and scientific director and CEO of the New York Genome Center, said aging was associated with widespread changes in the physical organization of the genome across multiple types of brain cells.
Blood-Brain Barrier Also Shows Signs Of Aging
The study identified another age-related change involving the blood-brain barrier. The barrier serves as a protective boundary between the bloodstream and brain, helping regulate which substances can enter brain tissue.
Researchers found signs of deterioration in cells involved in maintaining that barrier as people age. The findings raise the possibility that changes to the blood-brain barrier could be among the factors involved in allowing blood-derived immune cells to enter the aging brain.
However, researchers do not yet know what initiates the process.
Possible Implications for Alzheimer’s and Dementia
Aging is the largest known risk factor for dementia, but scientists are still working to understand the biological processes that connect aging with diseases such as Alzheimer’s.
The newly identified immune-cell transition could offer another avenue for research.
“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,” Ren said, Science Daily reported.
Researchers said future studies will need to determine whether the loss of resident microglia and influx of blood-derived immune cells directly contribute to Alzheimer’s disease or other neurological conditions.
Xiangmin Xu, Ph.D., a corresponding author and professor and director of the Center for Neural Circuit Mapping at UC Irvine, said that understanding these cellular changes could eventually help researchers identify interventions designed to preserve brain function and reduce vulnerability to neurodegenerative disease.
New Treatment Possibilities Remain Experimental
One potentially significant aspect of the findings is that the newly identified immune cells appear to originate in the blood.
That could make them more accessible to future therapies than cells located deep within the brain.
“It may eventually be possible to modify blood-derived immune cells so that they are more protective and less inflammatory when in the brain,” Zemke said, per Fox.
Such an approach could eventually offer a way to influence the brain’s immune environment without directly manipulating cells within the central nervous system.
However, that possibility remains speculative. The researchers emphasized that the current study does not establish a treatment or show that changing these immune cells would prevent dementia or Alzheimer’s disease.
Study Has Important Limitations
The research examined tissue collected after death from 40 different people rather than following the same individuals over decades.
That means the study can identify strong age-related patterns but cannot establish how an individual person’s brain changes throughout life or prove that the observed immune-cell changes cause cognitive decline or Alzheimer’s disease.
“We also do not yet know what triggers the influx of blood-derived immune cells into the brain,” Zemke said, Fox reported.
Researchers said future work will need to examine whether changes in the blood-brain barrier, inflammation, genetics, lifestyle or other factors initiate the process.
The study also focused exclusively on the hippocampus, meaning the findings may not represent immune changes occurring throughout the entire brain.
The timing and extent of the changes varied considerably among individuals, suggesting that brain aging may not follow exactly the same pattern in everyone.
“The next challenge is to understand what drives that variation and whether some of those factors can be modified,” Zemke said.
