The circadian rhythm of gene activity changes with age, according to new study at the University of Pittsburgh School of Medicine that examined thousands of genes from nearly 150 human brains. The findings also suggest that a novel biological clock emerges in the older brain.
Nearly all brain and body processes, such as the sleep/wake cycle, metabolism, alertness and cognition, are controlled by a 24-hour circadian rhythm. These daily activity patterns are regulated by certain genes that are found in almost all cells, but have rarely been studied in the human brain.
“Studies have reported that older adults tend to perform complex cognitive tasks better in the morning and get worse through the day,” said senior investigator Colleen McClung, Ph.D.
“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.”
The presence of gene changes or “molecular aging” in the brain had been previously shown by senior co-investigator Etienne Sibille, Ph.D.
For the study, the scientists examined the effects of normal aging on molecular rhythms in the human pre-frontal cortex, an area of the brain involved in learning, memory and other aspects of cognitive performance.
The researchers looked at brain samples of 146 people with no history of mental health or neurological problems whose families had donated their remains for medical research and for whom the time of death was known. They categorized the brains depending on whether they had come from a person younger than 40 or older than 60, and then analyzed two tissue samples from the pre-frontal cortex for rhythmic activity, or expression, of thousands of genes.
They identified 235 core genes that make up the molecular clock in this part of the brain.
“As we expected, younger people had that daily rhythm in all the classic ‘clock’ genes,” Dr. McClung said. “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.”
To their surprise, the team also found a set of genes that gained rhythmicity in older individuals.
The findings could contribute to the development of treatments for cognitive and sleep problems in older people, as well as a potential treatment for “sundowning,” a condition in which older dementia patients become agitated, confused and anxious in the evening.
“Since depression is associated with accelerated molecular aging, and with disruptions in daily routines, these results also may shed light on molecular changes occurring in adults with depression,” said Sibille.
In future research, the scientists plan to explore the function of the brain’s circadian-rhythm genes in lab and animal models, as well as see if they are altered in people who have psychiatric or neurological illnesses.
The findings are published online in the Proceedings of the National Academy of Sciences.