“Aging is the single largest risk factor for dementia, but our understanding of how it drives disease is still incomplete,” said Richard Hodes, M.D., director of NIH’s National Institute on Aging (NIA). “This previously hidden microglial shift, now uncovered by innovations in technology and thinking, may be an important clue to help us complete the puzzle.”

Brain Immune Cells Begin Changing in Midlife

Researchers from the University of California, San Diego, the New York Genome Center and the University of California, Irvine used advanced single-cell methods to study postmortem hippocampal tissue from 40 neurologically healthy adults between the ages of 20 and 95.

Their analysis found that microglia, the brain’s main immune cells, gradually decline from about age 50 to age 75. At the same time, they appear to be replaced by cells with stronger inflammatory signals and other traits similar to immune cells that originate in peripheral blood.

The discovery challenges a long-standing assumption about microglia. These cells first develop during embryonic growth, and scientists have generally believed that they remain in the brain and continually renew themselves throughout a person’s life.

Advanced Tools Reveal Cell Origins

To examine the effects of aging on the human brain in exceptional detail, the team combined standard measurements of gene activity with newer methods that map the genome’s 3D structure and its chemical modifications, known as the epigenome.

“Gene expression tells us what a cell is doing today, but epigenetic signatures preserve information about where a cell came from,” said first author Nathan Zemke, Ph.D., director of single-cell genomics at the UC San Diego Center for Epigenomics. “By combining these approaches, we uncovered a major shift in the identity and lineage of immune cells in the aging human brain’s immune cells that gene expression data alone would not have revealed.”

These combined methods allowed the researchers to identify changes in immune cell identity and origin that would have remained hidden if they had examined gene activity alone.

Aging Also Affects the Blood-Brain Barrier

The study also found signs of age-related decline in cells that help maintain the blood-brain barrier, the protective boundary that controls what can pass from the bloodstream into the brain.

Across many kinds of brain cells, aging was also associated with widespread and coordinated changes in the genome’s physical organization.

“The progressive structural disruptions were closely linked to shifts in gene regulation and cell identity, potentially revealing a fundamental feature of aging in the human brain,” said Bing Ren, Ph.D., a corresponding author of the study, scientific director and CEO of the New York Genome Center, and professor of genetics and development at Columbia University.

Possible Links to Alzheimer’s Disease

Future research will examine why resident microglia are lost with age and whether the newly identified immune cell transition directly contributes to Alzheimer’s disease and other neurological conditions associated with aging.

“Understanding these cellular transitions may provide new opportunities to develop interventions that preserve brain function and reduce vulnerability to neurodegenerative disease,” said Xiangmin Xu, Ph.D., professor and director of Center for Neural Circuit Mapping at UC Irvine, and a corresponding author of the study.

NIH supported this research through NIA grants R01AG067153 and R01AG082127 and the NIH Common Fund 4D Nucleome (4DN) program grant 1U01DA052769. The work is part of a collection of studies supported by 4DN and published in Science and Science Advances. Together, these papers provide new insight into how the genome’s 3D organization shapes human development, aging, and numerous diseases.