Researchers at Stanford University have discovered that large numbers of immune cells from the blood cross the blood-brain barrier into the human brain as people age. Published in Nature on July 30, 2026, the findings challenge the long-held view that the brain is a closed immunological system and suggest new ways to deliver therapies for neurological disorders.
For decades, standard medical understanding held that the human brain’s immune defenses operated almost entirely apart from the rest of the body. Specialized resident immune cells called microglia were thought to establish themselves during embryonic development and self-renew throughout a person’s lifespan without any outside contribution. A robust physiological barrier known as the blood-brain barrier guarded against wandering cells and circulating molecules.
New research upends that framework. Scientists demonstrated that peripheral immune cells born in the bone marrow routinely migrate into brain tissue over the course of human aging, eventually accounting for a large share of the total microglia population.
Tracing Bone Marrow Cells Into the Aging Brain
To track the origins of these aging brain cells, an NIH-funded research team leveraged a biological marker. As people age, blood stem cells in the bone marrow acquire unique genetic mutations that are passed along to all the daughter cells they produce. This clonal hematopoiesis acts as a natural genetic barcode.
Further confirming the mechanism, analysis of brain tissue from a study participant who had previously received a bone marrow transplant revealed microglia carrying the exact mutations of the transplanted marrow.
“We usually think of the brain as a closed system,” said Julia Belk, a postdoctoral scholar in pathology at Stanford Medicine and first author on the new study. “What we found is that actually a lot of immune cells enter the human brain during aging.”
Julia Belk, postdoctoral scholar in pathology at Stanford Medicine
The volume of these migrating cells increases noticeably as people grow older. Brain tissue samples from older adults contained more marrow-derived microglia than samples from younger individuals, showing that the accumulation is an ongoing, cumulative process throughout life.
Midlife Shifts and Genomic Overhauls
The discovery aligns with broader single-cell investigations into the human hippocampus. A separate study reported that the cellular landscape of the brain’s memory region undergoes a coordinated overhaul between the ages of 50 and 75. During this midlife phase, embryonic microglia decline sharply while blood-derived replacements carrying stronger inflammatory signatures take their place, coinciding with a drop-off in cell populations that maintain the blood-brain barrier.
“Unlike most immune cells, which are continuously replenished by blood stem cells from the bone marrow, immune cells in the brain were presumed to renew themselves throughout the lifespan without contribution from outside the brain,” said Jaiswal. “Our first study showed that this might not always be the case.”
Siddhartha Jaiswal, associate professor of pathology at Stanford Medicine
In earlier genetic work supported in part by a Knight Initiative Innovation Award from the Wu Tsai Neurosciences Institute, the team noted that individuals carrying specific immune cell clones produced by mutated blood stem cells exhibited a much lower likelihood of developing Alzheimer’s.
Therapeutic Implications for Neurological Diseases
The revelation that peripheral immune cells can naturally cross into the brain opens new avenues for medical interventions. Because the blood-brain barrier routinely blocks many therapeutic molecules from reaching brain tissue, harnessing bone marrow pathways could provide a delivery route for treatments.
“We have discovered a massive influx of immune cells from the blood into the human brain during aging,” Belk says. “Our findings suggest new opportunities to engineer peripheral immune cells to treat or prevent neurological diseases.”
Julia Belk, Stanford Medicine
