New research reveals profound immune shifts in the brain that start around age 50, potentially linked to neurodegenerative diseases.
A recent NIH-funded study highlights a remarkable transformation in the immune environment of the hippocampus, a brain region essential for learning and memory, with implications for understanding age-related cognitive decline. Researchers found that this immune remodeling begins in midlife, contributing to chronic brain inflammation observed in neurodegenerative conditions.
“Aging is the single largest risk factor for dementia, but our understanding of how it drives disease is still incomplete,” remarked Richard Hodes, M.D., director of the NIH’s National Institute on Aging (NIA). This newly uncovered microglial shift could provide crucial insights into the aging process and its impacts on brain health.
The collaboration among scientists at the University of California, San Diego, the New York Genome Center, and the University of California, Irvine employed advanced single-cell analysis techniques. They examined postmortem hippocampal tissue from 40 neurologically healthy adults aged 20 to 95.
The findings revealed a gradual decline in microglia, the brain's primary immune cells, starting around age 50 and lasting until age 75. These cells are replaced by others exhibiting heightened inflammatory characteristics and attributes similar to immune cells that originate from peripheral blood.
This research challenges a long-held belief about microglia, which are understood to develop during embryonic growth and maintain their populations through self-renewal over a person's lifetime.
To achieve a detailed examination of how aging affects the human brain, the research team integrated standard gene activity measurements with advanced methodologies for mapping the genome's three-dimensional structure and its epigenetic modifications.
“While gene expression reveals current cellular activity, epigenetic signatures retain historical data about a cell's origins,” stated first author Nathan Zemke, Ph.D., director of single-cell genomics at the UC San Diego Center for Epigenomics. This combination of approaches unveiled significant shifts in immune cell identity and lineage that gene expression alone would not have exposed.
The study also uncovered signs of age-related deterioration in cells responsible for maintaining the blood-brain barrier, a crucial protective layer that regulates substances entering the brain from the bloodstream.
Aging was found to be associated with extensive changes in the structural organization of the genome across various brain cell types. “The progressive structural disruptions were closely linked to shifts in gene regulation and cell identity, highlighting a fundamental aspect of aging in the human brain,” said Bing Ren, Ph.D., corresponding author of the study and scientific director and CEO of the New York Genome Center.
Future research aims to understand the reasons behind the loss of resident microglia with age and whether these newly identified immune transitions are directly implicated in Alzheimer's disease and other aging-related neurological disorders.
“Grasping these cellular transitions may open up new pathways for developing interventions that safeguard brain function and mitigate the risk of neurodegenerative ailments,” noted Xiangmin Xu, Ph.D., professor and director of the Center for Neural Circuit Mapping at UC Irvine.
This study received NIH support through NIA grants R01AG067153 and R01AG082127, along with funding from the NIH Common Fund for the 4D Nucleome (4DN) program grant 1U01DA052769. These findings are part of an ongoing series of studies backed by 4DN, as presented in journals like Science and Science Advances, that explore how the 3D organization of the genome influences human development, aging, and various diseases.
Materials provided by NIH/Office of the Director. Note: Content may be edited for style and length.
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