As Aging Brain's Internal Clock Fades, A New Timekeeper May Kick In

Ever notice the catnaps that older relatives take in the middle of the day? Or how grandparents tend to be early risers?

You're not alone. Colleen McClung did, too. A neuroscientist at the University of Pittsburgh Medical Center, McClung wanted to know what was going on in the brain that changes people's daily rhythms as they age.

We all have a set of so-called clock genes that keep us on a 24-hour cycle. In the morning they wind us up, and at night they help us wind down. A study out Monday in Proceedings of the National Academy of Sciences found that those genes might beat to a different rhythm in older folks.

"When you think about the early bird dinner specials, it sort of fits in with their natural shift in circadian rhythms," says McClung. "There is a core set of genes that has been described in every animal — every plant all the way down from fungus to humans — and they're pretty much the same set of genes."

The genes are the master controllers of a bunch of other genes that control processes ranging from metabolism to sleep. When you woke up this morning, the timekeeping genes told a gland in your brain to give a jolt of the stress hormone cortisol to wake up. Tonight, they'll tell a gland to spit out melatonin, a hormone that makes you sleepy.

"You can think of them as sort of the conductor of an orchestra," says McClung. They make sure all the other genes keep time.

It's been known for a long time that older people experience disruptions in these rhythms. Their orchestras seem to go off the beat, but it isn't known why. So, McClung and her colleagues looked at brain tissue samples from about 150 people — some young, some old — taken immediately after death. The researchers determined which genes were expressed at the time of death in samples of the prefrontal cortex, the part of the brain that sits right behind the forehead and is associated with memory and cognition.

"What we found in this study was that as people get older, they tend to have a loss of rhythmicity in a number of these core clock genes," she says. It's likely throwing their timing out of whack. That finding was expected.

But they also found something else: another set of genes that seemed to pick up a rhythm, but only in older brains. That second set of genes, McClung speculates, might be working like a backup clock that starts ticking when the main one becomes less reliable.

If that's the case, it could be contributing to neurodegenerative and psychiatric diseases that tend to set in later in life, many of which involve changes in the sleep-wake cycle.

"We're particularly interested in a condition called sundowning, where people become agitated and irritable and anxious only in the evening, and this is usually in older people that have dementia," McClung says. Their backup clock genes might not be kicking in correctly, she says.

"You can imagine that things actually get weaker with age, but that things can get stronger with age is really exciting," says Doris Kretzschmar, a neuroscientist with the Oregon Institute of Occupational Health Sciences. She studies circadian rhythms in flies and wasn't involved in the McClung study.

"These mechanisms are really, really well-conserved. In Drosophila and humans, it's the same four genes that regulate the core clock. Even plants have clocks," says Kretzschmar. When they're thrown off, whether it's in humans or animals, all sorts of things can go awry. Digestion can lose its regularity, behavioral patterns can change, and sleep and memory can be disrupted.

"No one really knows why age increases the risk for diseases like Alzheimer's and Parkinson's. This could provide a mechanism for that," says Kretzschmar.

"Right now all we can say is that they become rhythmic, but we don't know if that's important," says McClung.

To find out, McClung and her colleagues will have to figure out what exactly those genes do. For that, they'll need more brains — mouse brains this time.