The cause for aging’s telltale slowing in memory and cognition remains unclear, and the molecular drivers are even more unknown. Now, a study in mice suggests that the most pronounced changes that occur over time are in the white matter—neurons that are integral to transmitting signals across the brain. The research also examined how two anti-aging treatments—caloric restriction and infusions of plasma from young mice—affect different regions of the brain. Which one slowed age-related decline the best? The young plasma.

The results offer insight into the cognitive decline of normal aging, as well as the way aging contributes to neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases and multiple sclerosis.

This research is published in Cell, in the paper, “Atlas of the aging mouse brain reveals white matter as vulnerable foci.

“I saw this study as a way to explain that somewhat mysterious regional vulnerability,” said Tony Wyss-Coray, PhD, professor of neurology and neurological sciences at Stanford Medicine and the director of the Phil and Penny Knight Initiative for Brain Resilience at Stanford’s Wu Tsai Neurosciences Institute.

The researchers profiled 1,076 samples from 15 regions in both hemispheres of the brains of 59 female and male mice across seven ages (from 3 to 27 months.) They identified and ranked the top genes expressed by cells found in each region of the brain. They identified 82 genes that are frequently found and vary in concentration in 10 or more regions.

The findings suggest that the white matter, which is found deep in the brain and contains nerve fibers protected by white-colored myelin, showed the earliest and most pronounced changes in gene expression for mice 12 and 18 months old.

More specifically, the authors write that they identified a “brain-wide gene signature of aging in glial cells, which exhibited spatially defined changes in magnitude.” By integrating spatial and single-nucleus transcriptomics, they found that glial aging “was particularly accelerated in white matter compared with cortical regions, whereas specialized neuronal populations showed region-specific expression changes.”

“We cannot definitively say how gene expression changes in white matter affect memory and cognition. That would require more genetic manipulation and neurobiology work,” Wyss-Coray said. “But we know white matter is the wiring that connects the different brain regions together.”

Past work has shown that aging disrupts an otherwise stable gene expression pattern in the brain, turning on genes that regulate inflammation and the immune response, and turning off genes responsible for protein and collagen synthesis. The inflammation and immune response affect the integrity of the myelin sheath, the insulation layer around nerves responsible for transmitting signals across the brain.

“White matter has been a rather neglected area in aging research, which usually focuses on the neuron-dense regions like the cortex or hippocampus,” said Oliver Hahn, PhD, formerly a postdoctoral fellow in the Wyss-Coray lab and now a principal investigator at Calico Life Sciences. “The fact that white matter is emerging in our data as an area of particular vulnerability to aging opens up new and intriguing hypotheses.”

During the study, the team explored two interventions—caloric restriction and injections of plasma from young mice—to evaluate whether they protected against the region-specific shifts in gene expression. Each intervention began when the mice were 19 months old and lasted four weeks.

The researchers found that caloric restriction caused genes associated with circadian rhythms to turn on, while the plasma intervention turned on genes involved in stem cell differentiation and neuronal maturation that led to selective reversal of age-related gene expression.

“The interventions appeared to act on very different regions in the brain and [induce] strikingly different effects,” Hahn said. “This suggests that there are multiple regions and pathways in the brain that have the potential to improve cognitive performance at old age.”

The team also examined age-related changes in genes associated with three neurodegenerative diseases—Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis—that typically affect specific regions of the brain. The expression distribution for each gene had changed in older animals and occurred in regions of the brain that are not typically associated with a particular neurodegenerative condition. This finding could offer insight into the vast number of patients who have neurodegenerative diseases without a firm genetic link.

“The individual gene changes observed in the mouse may not directly translate to humans,” Wyss-Coray said. “But we believe the vulnerability of white matter to aging probably does.”

The study could also offer new opportunities to explore treatments and interventions by using the gene expression data to zero in on the cell populations vulnerable to aging. Future studies could explore how gene expression leads to functional changes in neuronal activity and structure.

Graphical abstract Hahn et al.
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