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Study Detects Shifts in Brain Gene Dynamics With Age

NEW YORK (GenomeWeb) – A team from the US and Canada has tracked brain gene expression dynamics in individuals over the span of a day and across different age groups, demonstrating that circadian patterns in the brain may shift with age.

Using array-based gene expression profiling, the researchers assessed two prefrontal cortex samples per person in almost 150 deceased individuals. By combining information on each individual's age with his or her time of death, they were able to detect age-related differences in the expression of circadian clock-related genes.

The findings, set to appear online this week in the Proceedings of the National Academy of Sciences, indicated that new transcripts take on daily expression rhythms in older individuals, while some of the genes that are expressed on a circadian cycle in younger individuals lose their rhythmic expression with age.

"As we expected, younger people had that daily rhythm in all the classic 'clock' genes," senior author Colleen McClung, a psychiatry researcher at the University of Pittsburgh, said in a statement. "But there was a loss of rhythm in many of these genes in older people, which might explain some of the alterations that occur in sleep, cognition, and mood in later life."

For their analysis, McClung and her colleagues used the Affymetrix Human Gene 1.1 ST array to profile gene expression patterns in post-mortem brain samples from 146 individuals who donated to a University of Pittsburgh brain tissue donation program.

Each individual was tested at two prefrontal cortex sites involved in attention, executive function, and depression that are known from prior studies to show variable gene expression at different times of day: one called Brodmann's area 11 and another known as Brodmann's area 47.

Along with approaches for normalizing each individual's time of death, the team considered prefrontal cortex expression patterns in the context of age, comparing samples from individuals younger than 40 years old, those older than 60, or individuals in between.

Overall, the researchers uncovered almost 2,500 genes with expression that varied with time of day in Brodmann's area 11 and more than 1,600 circadian rhythm-related genes in Brodmann's area 47.

In particular, they saw a core set of 235 genes that showed rhythmic — and largely similar — expression patterns in both brain areas. These included known circadian genes as well as transcripts suspected of showing rhythmic expression in the brain that have not been implicated in circadian cycles in other parts of the body.

And not all of the genes showed the same rhythmicity over time. Instead, the team's results pointed to 1,186 genes that had age-related changes in the rhythm of their expression in Brodmann's area 11. Almost 1,600 genes had age-related rhythm changes in Brodmann's area 47.

In Brodmann's area 11, for example, the researchers saw some genes that lost their rhythmic expression or showed a shift in the timing of this regulation. Conversely, some new genes started showing circadian expression in older individuals but did not seem to have rhythmic expression in the prefrontal cortexes of younger individuals.

The findings seem to fit with past studies that have described declining performance on complex cognitive tasks later in the day in older individuals, who tend to be more cognitively sharp in the morning, McClung said. Likewise, she noted that older individuals also display circadian rhythm-related changes affecting body systems outside the brain.

"We know also that the circadian rhythm changes with aging, leading to awakening earlier in the morning, fewer hours of sleep, and less robust body temperature rhythms," she said in a statement.