Scientists Find Immune Cells Enter Aging Brains Earlier Than Expected
Inside tissue taken from aged human brains, scientists have found evidence of a cellular migration that challenges one of the longstanding assumptions about how the brain maintains its immune defenses.
The cells are not neurons or the brain’s long-established resident immune cells alone. They are descendants of blood-forming cells in the bone marrow, and researchers found evidence that they had moved into the brain and taken on characteristics remarkably similar to microglia, the immune cells that help maintain and protect neural tissue. The finding, published in Nature on July 30, suggests that the adult human brain is more dynamically connected to the immune system than scientists once believed.
For Julia Belk, a Stanford University postdoctoral researcher who led the study, the question grew from an earlier discovery that had already unsettled conventional thinking.
In 2023, Belk and colleagues studying age-related genetic changes in blood cells found that some of those cells appeared in the brains of older people. The researchers were particularly interested in clonal hematopoiesis, a condition in which blood-forming stem cells acquire mutations and certain clones begin producing a disproportionate share of blood cells. Stanford researchers found that people carrying some of these mutations appeared to have a lower risk of developing Alzheimer’s disease.
“The result was so surprising that we didn’t believe it at first,” Siddhartha Jaiswal, a Stanford pathologist and senior researcher on that work, said in 2023. After checking the findings, he said, the team became confident that people with the mutations were less likely to develop Alzheimer’s.
That observation raised a basic biological question: How could cells originating in the blood influence an organ long thought to maintain a largely separate immune environment?
The answer emerging from the new study is that the boundary is more permeable, and the exchange more extensive, than previously understood.
Researchers examined brain tissue from 20 aged individuals and used accumulated somatic mutations as natural cellular “barcodes.” Because mutations acquired by a cell and its descendants can be inherited within a cellular clone, the researchers could use those genetic marks to trace whether brain immune cells originated from long-lived cells established early in life or from blood-forming cells in the bone marrow.
They found evidence of an influx of marrow-derived cells in every one of the 20 individuals examined. Single-cell analyses, including lineage tracing based on mitochondrial DNA variants, showed that the incoming cells closely resembled microglia and could constitute a substantial portion of the microglial population.
That finding matters because microglia have traditionally been understood as a special population of immune cells established in the developing brain. In mice, they seed the brain during embryonic development and can maintain themselves for much of the animal’s life with relatively little contribution from adult blood-forming cells. The origins of human microglia, however, have proved less straightforward.
The new evidence does not simply overturn that biology. Rather, it points to an additional source of immune cells entering the human brain during aging and becoming integrated into the existing microglial population.
The distinction is important. The researchers are not reporting that ordinary circulating white blood cells are constantly flooding a healthy brain. They are describing a population of myeloid cells derived from the bone marrow that enters the brain and adopts a microglia-like identity. The study therefore adds a new layer to the relationship between blood, bone marrow and the aging nervous system.
The work also builds on an unexpected observation from the Stanford team’s earlier Alzheimer’s research. In that study, people with clonal hematopoiesis were about 30% to 40% less likely to develop Alzheimer’s disease in one analysis, with a similar association found in a separate cohort of more than 1,000 people. The researchers then detected bone-marrow-derived cells carrying those mutations in postmortem brain tissue.
Julia Belk described the technical challenge of that earlier investigation as requiring “a technical trick” and sophisticated computational analysis because the RNA normally used to identify cell types had not survived the freezing process used to preserve the brain samples. By examining DNA modifications instead, the researchers were able to identify the cells as microglia.
The latest study takes that observation further by looking beyond people carrying particular mutations. Its central finding is that marrow-derived immune cells appear to enter the brains of aged people broadly, rather than representing an unusual consequence of one genetic condition.
That does not establish that the cells protect against Alzheimer’s disease. The Nature study reports an association between most types of clonal hematopoiesis and lower Alzheimer’s risk, but it does not prove that the incoming cells cause that protection. Nor does it establish that the process is beneficial in every circumstance.
Microglia can perform essential housekeeping functions, including responding to damaged tissue and helping clear unwanted material. But immune activity in the aging brain can also contribute to inflammation and neural damage. Stanford researchers have described this dual role as an important unresolved problem: understanding how to preserve the protective functions of microglia while limiting harmful ones.
The question is now becoming more specific. If blood-derived cells are entering the brain as people age, what determines when they cross the boundary? Which cells are able to establish themselves? Do they behave differently from the microglia already present? And, most importantly, do some of them help preserve brain function while others contribute to disease?
Those questions have implications beyond Alzheimer’s. Scientists studying Parkinson’s disease and other age-related neurological disorders are increasingly examining the immune system as part of the biology of brain aging. Stanford researchers are already investigating whether the properties of particular immune-cell populations might eventually be used to promote resilience against neurodegenerative disease.
For now, the significance of the new finding is more fundamental than therapeutic. The aging human brain is not an isolated biological compartment whose immune population was fixed at the beginning of life. The evidence suggests that, over time, cells originating in the bone marrow can enter that environment, resemble its resident immune cells and become part of its cellular landscape.
The researchers have therefore turned an old question about where brain immune cells come from into a broader one about how the aging body and brain communicate. And in that exchange, cells once thought to belong primarily to the blood may have a much larger role in the aging brain than scientists had recognized.
