A Study Finds Genomic ‘fingerprint’ for Brain Aging

While most of us who have reached middle age have seen a decline in memory and cognition, scientists are still unsure of the exact molecular changes that lead to brain aging. The most noticeable changes, according to a recent mouse study, are found in the white matter, a type of nervous system tissue that is crucial for signal transmission throughout the brain. The study also looked at two therapies that target specific brain regions: caloric restriction and injections of young mouse plasma, with the plasma appearing to delay the aging process.

The findings shed light on how aging affects neurological illnesses like Alzheimer’s, Parkinson’s, and multiple sclerosis as well as the cognitive decline that comes with normal aging.

Certain parts of the brain are more susceptible to injury in many neurodegenerative illnesses, although it is unclear why this is the case.

I saw this study as a way to explain that somewhat mysterious regional vulnerability,”said Tony Wyss-Coray, Ph.D., a professor of neurology and neurological sciences and the study’s lead author.

The senior author of a paper outlining the findings is Wyss-Coray, the D.H. Chen Professor II at Stanford Medicine and the director of the Phil and Penny Knight Initiative for Brain Resilience at Stanford’s Wu Tsai Neurosciences Institute. The paper’s lead author is Oliver Hahn, a former postdoctoral fellow in the Wyss-Coray lab who is currently a principle investigator at Calico Life Sciences. Cell released the study on August 16.

Different genes were discovered in various locations

The researchers took 15 brain samples from 59 female and male mice ranging in age from 3 to 27 months. They discovered and rated the top genes expressed by brain cells in each location. They discovered 82 genes that are often detected and vary in concentration in at least ten different areas.

The researchers utilized these genes to create a common aging score, which assessed how gene activity in different areas of the brain changes with age.

The white matter, which is found deep in the brain and contains nerve fibers coated by white-colored myelin, revealed the earliest and most dramatic changes in gene expression for mice aged 12 and 18 months. According to Wyss-Coray, these mice are about the same age as a person in their 50s in mouse years.

“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 mentioned.  But we know white matter is the wiring that connects the different brain regions together.

Previous research has demonstrated that aging disturbs an otherwise steady gene expression pattern in the brain, turning on genes that regulate inflammation and the immunological response while turning down genes responsible for protein and collagen synthesis. The inflammation and immunological reaction compromise the integrity of the myelin sheath, the insulation layer around nerves that transmits messages 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,” Hahn added. “The fact that white matter is emerging in our data as an area of particular vulnerability to aging opens up new and intriguing hypotheses.”

Intervention trials

Interventions to halt the genetic shift that leads to decrease in specific brain regions could be useful in addressing neurodegenerative illness as well as the general decline associated with age.

During the investigation, the researchers looked into two interventions: caloric restriction and injections of young mouse plasma to see if they could protect against region-specific changes in gene expression. Each intervention lasted four weeks and began when the mice were 19 months old.

The researchers discovered that the dietary intervention activated genes involved in circadian rhythms, whereas the plasma intervention activated genes involved in stem cell differentiation and neural development, resulting in a 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 added. “This suggests that there are multiple regions and pathways in the brain that have the potential to improve cognitive performance at old age.

The researchers also looked at age-related alterations in genes linked to three neurodegenerative diseases: Alzheimer’s, Parkinson’s, and multiple sclerosis, which all impact different parts of the brain. In older animals, the expression distribution of each gene had changed, and this occurred in areas of the brain that are not generally associated with a specific neurodegenerative disorder. This discovery could shed light on the large number of patients suffering from neurodegenerative diseases who lack a clear genetic link.

The discovery may also open up new avenues for investigating therapies and interventions by focusing on cell types prone to aging using gene expression data. Future research could look into how gene expression affects neural activity and structure. Wyss-Coray and her Knight Initiative colleagues.

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

The study was co-authored by researchers from New York University Langone Health, Saarland University, the Helmholtz-Centre for Infection Research, the Max Planck Institute for Biology of Ageing, Alkahest Inc., and University College London.

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