Study suggests a novel biological clock starts ticking in late life

Toronto, ON – As we age, the genes that regulate our daily biological rhythms appear to change how they function, which could explain the changes in sleep patterns, cognition and mood that can occur in late life, according to a first-of-its-kind study by researchers at the University of Pittsburgh School of Medicine and Centre for Addiction and Mental Health (CAMH).

This finding, based on analyzing thousands of genes from nearly 150 brains, has implications for clinical care for age-related problems associated with these daily rhythms.  

The research, published online last month in the Proceedings of the National Academy of Sciences, also suggests that a novel biological clock begins ticking only in the older brain.

A 24-hour circadian rhythm controls nearly all brain and body processes, such as the sleep/wake cycle, metabolism, alertness and cognition, said senior investigator Dr. Colleen McClung, associate professor psychiatry, Pitt School of Medicine. 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,” Dr. McClung said. “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 Dr. Etienne Sibille, Campbell Family Chair in Clinical Neuroscience at CAMH’s Campbell Family Mental Health Research Institute.

Both teams decided to look at the effects of normal aging on biological rhythms in the human prefrontal cortex, an area of the brain involved in learning, memory and other aspects of cognitive performance.

The researchers examined donated brain samples of 146 people with no history of mental health or neurological problems, for whom the time of death was known. They categorized the brains by age, and analyzed two tissue samples from the prefrontal cortex for rhythmic activity, or expression, of thousands of genes. Using the information on time of death, 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.

This information could ultimately be useful in the development of treatments for cognitive and sleep problems that can occur with aging, as well as a possible treatment for “sundowning,” a condition in which older individuals with dementia become agitated, confused and anxious in the evening.  

“Since depression is associated with accelerated molecular aging, and with disruptions in daily routines, these results may also shed light on molecular changes occurring in adults with depression,” said Dr. Sibille.

In next steps, the researchers will explore the function of the brain’s circadian-rhythm genes in lab and preclinical models, as well as see if they are altered in people who have psychiatric or neurological illnesses.

This work was supported by grants from the U.S. National Institute of Mental Health.