Immune Cells Enter Aging Brain: New Discovery Challenges Long-Held Beliefs

Stanford researchers have discovered that immune cells from the bloodstream migrate into the aging brain as early as middle age, transforming into microglia and challenging the long-standing belief that these cells remain largely separate from the body’s immune system throughout life.

Cellular Changes in the Aging Brain

Additional findings published in the Journal of Experimental Medicine by researchers at Albany Medical College demonstrate that a specific class of immune cells known as group 2 innate lymphoid cells (ILC2s) also accumulates in older brains. Led by Qi Yang and Kristen L. Zuloaga, the Albany research team examined mouse and human brain tissue to track these shifts.

According to the Albany Medical College study, older mouse brains contained up to five times as many ILC2 cells as younger brains, with large concentrations appearing in the choroid plexus. This structure produces cerebrospinal fluid and sits adjacent to the hippocampus, a brain region that plays a key role in learning and memory. The researchers also identified substantial numbers of ILC2s in the choroid plexus of elderly humans.

Activating Immune Pathways to Restore Cognitive Function

Although ILC2 cells in older brains generally reside in an inactive, or quiescent, state, researchers successfully stimulated them using a cell signaling molecule called IL-33. According to Qi Yang and Kristen L. Zuloaga, IL-33 treatment caused the cells to proliferate and manufacture proteins that encourage neuron formation and survival.

Treating aged mice with IL-33 or injecting them with lab-activated ILC2 cells improved their performance on cognitive tests measuring learning and memory. Furthermore, treatment with IL-5—one of the signaling molecules produced by activated ILC2s—increased new nerve cell formation in the hippocampus while reducing potentially damaging brain inflammation, according to the study data.

Macrophage Performance and Metabolic Health

Parallel research from Stanford Medicine led by Andreasson links aging-associated systemic inflammation to the decline of tissue-resident macrophages. These long-lived immune cells are responsible for clearing senescent cells, including roughly 100 billion neutrophils, produced daily, which start showing signs of senescence within 8 to 12 hours after entering the bloodstream.

According to the Stanford study, a pro-inflammatory signaling molecule called PGE2 increases with age, along with its surface receptor EP2 on tissue-resident macrophages. This unrelenting inflammatory stimulation downshifts the macrophages’ ability to clear senescent neutrophils, causing them to accumulate in organs such as the liver, spleen, and bone marrow.

When researchers genetically deleted the EP2 receptor in tissue-resident macrophages or blocked it with a drug, the decline in macrophage performance stopped. Older mice lacking EP2 retained youthful neutrophil numbers, exhibited lower levels of visceral fat and greater muscle mass, and maintained organ function matching that of younger mice.