For decades, microglia have been viewed as the brain’s permanent immune residents: cells that arrive during embryonic development, settle into the central nervous system, and renew themselves locally for the rest of an individual’s life. That model is well established in mice, where microglia are seeded before birth and generally remain distinct from blood-forming cells produced in the adult bone marrow. A new study published in Nature challenges the assumption that the same arrangement applies to humans, revealing evidence that bone-marrow-derived myeloid cells enter the aging human brain and can become a substantial part of the microglial population.
The research, led by Belk, Zhang, Reilly and colleagues, used the natural record of genetic change accumulated during a person’s lifetime to reconstruct the history of brain immune cells. Every time a cell divides, it can acquire small, harmless mutations in its DNA. Most of these alterations have no effect on cell function, but they can act as molecular barcodes. If a mutation is inherited by the descendants of one cell, researchers can use it to identify a cellular clone and determine whether cells from different tissues share a common ancestor.
This strategy is particularly valuable in humans, where conventional lineage-tracing experiments are impossible. Scientists cannot label embryonic cells and follow them over decades as they can in laboratory animals. Instead, the study examined naturally occurring somatic mutations—genetic changes present in some cells but not in the germline—to compare populations of immune cells in the blood, bone marrow and brain. Shared mutation patterns can reveal whether cells belong to the same developmental family, while distinct patterns can indicate separate origins.
The team applied this approach to samples from 20 aged individuals and found evidence of marrow-derived cells in the brain of every person examined. The result suggests that the movement of blood-forming cells into the human brain is not an exceptional event restricted to a rare disease or unusual medical history. Rather, it may be a widespread feature of human aging. These cells appeared in brain regions where microglia normally reside, raising the possibility that they enter the central nervous system and adapt to the local environment instead of remaining conventional circulating immune cells.
Single-cell analyses provided a more detailed view of this process. By measuring gene activity and other molecular characteristics in individual cells, the researchers found that the infiltrating marrow-derived cells shared many features with microglia. Microglia are not defined only by their location; they also possess distinctive transcriptional programs that support immune surveillance, debris removal and communication with neurons. The incoming cells appeared to acquire at least some of these microglia-like properties after reaching the brain, suggesting that the tissue environment can reshape their identity.
The study also used mitochondrial DNA variants for single-cell lineage tracing. Mitochondria carry their own small genomes, and mutations arising in mitochondrial DNA can be passed to daughter cells. Because these variants can be detected in individual cells, they provide another way to connect cells within a clone and distinguish populations with different origins. The mitochondrial evidence supported the conclusion that some cells occupying the microglial niche were descendants of marrow-associated progenitors rather than exclusively of the embryonic cells traditionally considered the source of human microglia.
The scale of the contribution was one of the study’s most striking findings. In some individuals, marrow-derived cells appeared capable of making up a large fraction of the microglial pool. This does not necessarily mean that embryonically derived microglia disappear, or that all microglia in older people originate from bone marrow. Instead, the findings point to a mixed system in which long-lived resident cells coexist with later-arriving myeloid cells. The balance between these populations may vary widely among individuals, potentially reflecting age, inflammation, genetics, blood-cell dynamics or the condition of the blood–brain barrier.
The researchers then examined whether this biology might relate to neurodegenerative disease. Using human cohort data, they reported a protective association between most forms of clonal hematopoiesis and Alzheimer’s disease. Clonal hematopoiesis occurs when a blood-forming stem cell acquires a mutation that gives it a growth advantage, allowing its descendants to expand within the blood system. Although clonal hematopoiesis has been linked to several age-related disorders, including cardiovascular disease and some cancers, the new analysis suggests that certain expanded blood-cell clones may be associated with a lower risk of Alzheimer’s disease. The observation is statistical rather than proof of causation, but it raises the possibility that genetically distinct immune-cell populations entering the brain could influence disease-related inflammation or the clearance of pathological material.
The findings could reshape how scientists think about human brain immunity. Mouse studies remain essential, but human microglial biology may differ in a fundamental way because human beings live much longer, experience more cumulative inflammation and possess a distinct history of blood and immune-cell exposure. The arrival of marrow-derived cells may provide a form of immune replacement or adaptation during aging, but it could also have different consequences depending on the cells involved. Some incoming populations might support tissue maintenance, while others could intensify damaging inflammation under particular conditions. The study does not establish which signals permit entry, how frequently these cells cross into the brain, or whether their effects are beneficial in every context. It does, however, provide a powerful new framework for answering those questions. By treating somatic mutations as a permanent cellular trail, the researchers reveal that the aging human brain is more immunologically dynamic than previously thought—and that its resident immune landscape may be continually reshaped by cells born in the marrow.
Subject of Research: The origin, lineage and aging-related replacement of human microglia by marrow-derived myeloid cells.
Article Title: Somatic mutations reveal the ontogeny of microglia in human aging
Article References: Belk, J.A., Zhang, Y., Reilly, E.E. et al. “Somatic mutations reveal the ontogeny of microglia in human aging.” Nature (2026). https://doi.org/10.1038/s41586-026-10939-0
Image Credits: AI Generated
DOI: 10.1038/s41586-026-10939-0
Keywords: microglia, human aging, somatic mutations, mitochondrial DNA, clonal hematopoiesis, bone marrow, brain immunity, Alzheimer’s disease, neuroinflammation, single-cell lineage tracing
