New study identifies gene 'fingerprint' for brain ageing, sheds light on memory decline

A new study offers insight into the cognitive decline of normal ageing, shedding light on how ageing contributes to neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases.

Most of us who have reached their middle age must have experienced a slowing memory and cognition. Until now, scientists did not have a clear picture of the molecular changes that take place in the brain to cause it.

Now, a study on mice has determined that the most pronounced changes occur in the white matter, a type of nervous system tissue that is integral to transmitting signals across the brain.

The study that identified a gene 'fingerprint' for brain ageing also examined two treatments — caloric restriction and infusions of plasma from young mice — that affect certain regions of the brain, with the plasma appearing to slow the age-related memory decline.

In many neurodegenerative diseases, certain areas of the brain are more vulnerable to damage, but there was a lack of clarity on the exact reason.

“I saw this study as a way to explain that somewhat mysterious regional vulnerability,” said Tony Wyss-Coray, PhD, a neurology professor who led the study that examined gene expression in different regions of the mouse brain as it matures.

This study by Stanford scientists was published on August 16 in Cell journal.

The research team sampled 15 regions in both hemispheres of the brains of 59 female and male mice aged 3 to 27 months. They identified and ranked the top genes expressed by cells found in each region of the brain and identified 82 genes that are found frequently and vary in concentration in 10 or more regions.

The team used these genes to develop a common ageing score, assessing how gene activity in different regions of the brain change with age.

The researchers found that white matter, which is found deep in the brain and contains nerve fibres protected by white-coloured myelin, showed the earliest and most pronounced changes in gene expression for mice 12 and 18 months old. According to Wyss-Coray, these mice are about as old, in mouse years, as a person in their 50s.

Past work has shown that ageing 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 ageing research, which usually focuses on the neuron-dense regions like the cortex or hippocampus,” Hahn said. “The fact that white matter is emerging in our data as an area of particular vulnerability to ageing opens up new and intriguing hypotheses.”

Interventions to slow the genetic shift that leads to the decline in specific regions of the brain could be beneficial in addressing neurodegenerative disease as well as the general decline associated with ageing.

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 the dietary intervention caused genes associated with circadian rhythms to turn on, while the plasma intervention turned on genes involved in stem cell differentiation and neuronal maturation led to 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 said. “This suggests that there are multiple regions and pathways in the brain that have the potential to improve cognitive performance in 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 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 ageing. Future studies could explore how gene expression leads to functional changes in neuronal activity and structure.

Wyss-Coray and colleagues at the Knight Initiative for Brain Resilience aim to expand on this work by building similar genetic atlases of ageing in the human brain.

“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 ageing probably does.”