The human brain’s aging process is intriguing; it shows improvement in some areas with age, yet discussions often focus on its decline. This focus is understandable given the prevalence of neurodegenerative diseases many seek to avoid.
Research indicates that declines in brain health, usually evident in individuals in their 70s and 80s, begin in midlife. These declines are influenced by genetic factors that increase inflammation and reduce synaptic function, affecting how the brain processes information.
A recent study reveals that genetic changes also reshape the immune cell landscape in the brain, transitioning from one cell type to another. Researchers employed a unique combination of genetic, epigenetic, and three-dimensional genome mapping to scrutinize nearly 320,000 cells from the hippocampus—essential for memory, learning, and navigation—collected from 40 individuals aged 20 to 95.
The findings indicate that aging isn’t merely about genes becoming more or less active; it involves orchestrated modifications in the molecular systems governing these genes.
A notable discovery from the study focuses on microglia, the brain’s immune cells. Previously, scientists thought these cells developed before birth and remained throughout life. However, recent evidence suggests that between ages 50 and 75, many microglia are replaced by monocytes, which likely originate in the bloodstream. (Monocytes are large white blood cells that clear debris and fight germs.)
While researchers couldn’t confirm these new cells originated from bone marrow, their DNA methylation—chemical markers that retain a cell’s developmental memory—was similar to blood monocytes and distinct from original microglia.
By age 80, these monocyte-like cells were the predominant population in most examined brains. These replacement cells exhibit stronger inflammatory markers, possibly explaining why chronic brain inflammation rises with age and is linked to conditions like Alzheimer’s disease.
Another key finding involved astrocytes, star-shaped cells that support neurons, regulate neurotransmitters, and maintain the blood-brain barrier. Their numbers declined steadily with age in the hippocampus, which was unexpected. Surviving astrocytes appeared to struggle, with reduced activity in ATP production genes—the cell’s main energy source—and increased activity in cellular recycling genes.
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These findings suggest that aging astrocytes may face an “energy crisis” leading to their decline. Researchers also observed that aging affects the genome’s physical organization. Inside cell nuclei, DNA forms a complex three-dimensional structure that influences gene interactions. This structure deteriorated with age across nearly every cell type examined.
Chromosomal neighborhoods became less distinct, and DNA-binding proteins were less effective. These “progressive structural disruptions were closely linked to shifts in gene regulation and cell identity,” according to Bing Ren, a geneticist at Columbia University and a corresponding author of the study, as stated in a release.
Many changes occurred at a distinct tipping point around age 50, when gene activity and epigenetic markers shifted significantly. Similar midlife inflection points have been observed in other organs, suggesting biological aging may accelerate in phases rather than gradually declining.
The researchers also examined differences between men and women. Although aging patterns were similar, molecular changes correlated more strongly with age in men across most cell types. The study didn’t explore the reasons for these differences, but it suggests that the aging hippocampus might follow different trajectories in males and females.
Given the constraints of research timelines, scientists couldn’t measure the brains of the same individuals at different life stages. They used postmortem brain tissue, offering snapshots from people with varied lives and genetics. Nevertheless, this study suggests that our brains experience more cellular remodeling during aging than previously understood.
Related: Humans Age Faster at 2 Sharp Peaks, Research Shows
The study raises questions about how to maintain brain health throughout life. According to Xiangmin Xu, a neuroscientist and study author from UC Irvine, “Understanding these cellular transitions may provide new opportunities to develop interventions that preserve brain function and reduce vulnerability to neurodegenerative disease,” as mentioned in a release.
The findings were published in Science.
This article was fact-checked by Fiona MacDonald and edited by Rebecca Dyer. While we pride ourselves on our process, we are only human. If you spot a mistake, please let us know.
