The aging human brain may be far less sealed off from the rest of the body than long believed. Stanford Medicine researchers have found that large numbers of immune cells originating in the blood begin crossing into the brain as early as middle age, where they take up residence and behave like the brain's own resident immune cells.
The finding challenges a decades-old assumption that the blood-brain barrier keeps circulating immune cells almost entirely out of neural tissue, protecting it as an "immune-privileged" organ. Researchers led by postdoctoral scholar Julia Belk, with senior authors Siddhartha Jaiswal and Howard Chang, instead found substantial numbers of blood-derived cells inside brain tissue from middle-aged and older adults.
To trace the cells' origin, the team relied on a natural genetic tagging system called clonal hematopoiesis, in which blood stem cells in the bone marrow pick up random mutations as a person ages and pass those mutations to all their descendant cells. By comparing DNA from a person's blood with DNA extracted from their post-mortem brain tissue and looking for matching mutations, the researchers could tell, cell by cell, whether an immune cell in the brain had been born in the bone marrow rather than in the brain itself. "What we found is that actually a lot of immune cells enter the human brain during aging," the researchers reported.
Cells that become microglia
Once inside the brain, the migrating blood cells appeared to transform into microglia, the brain's own specialized immune cells, which normally arise during embryonic development and were thought to renew themselves locally throughout life without outside help. The Stanford team's analysis, described August 14 in the journal Nature, found this replenishment from blood becomes substantial by middle age and continues into old age. Notably, the same process does not appear to occur in mice or non-human primates, meaning it may be a distinctly human feature of brain aging that animal models have missed.
The researchers also found a possible clinical hook: people carrying certain mutated blood stem cell clones that contributed heavily to this brain infiltration showed a lower risk of Alzheimer's disease, according to a summary of the findings from the National Institutes of Health. That raises the possibility that peripheral immune cells could eventually be engineered or recruited to help clear the amyloid and tau protein buildups associated with neurodegenerative disease.
Outside scientists say the work reframes how researchers should think about neuroinflammation, long treated as an internal brain process, as something shaped continuously by the body's circulating immune system. The Stanford group is now working to determine what draws these cells into the brain in the first place, whether a weakening blood-brain barrier with age is the trigger, and whether the process could be encouraged or blocked therapeutically as a new avenue against dementia and other age-related brain diseases.
