Scientists may have discovered why the brain’s higher information-processing center slows down in old age, affecting everything from language, to vision, to motor skills. The findings may also point toward drugs for reversing the process.
A brain chemical called GABA helps neurons stay finicky about which signals they respond to – a must for the brain to function at its peak. Certain neurons in very old macaque monkeys lose their pickiness, researchers have found, seemingly because they don’t get enough GABA. These results appear in the journal Science, published by the American Association for the Advancement of Science (AAAS).
If a lack of GABA is indeed responsible for the old neurons’ indiscriminate firing, this problem may be simple enough to treat. Existing drugs, such as Xanax, increase GABA production, according to author Audie Leventhal of the University of Utah School of Medicine. These drugs haven’t been carefully tested on the elderly, though.
"The good news is there are a lot of drugs around that can facilitate GABA-ergic function and maybe some of them will help," said Leventhal.
Leventhal and his colleagues studied visual function in monkeys he believes are the oldest in the world. The monkeys live in a colony in Kunming, China, established as part of a Chinese and Russian experimental program in the 1950s. At 30 years old (around 90 in people years), these animals have lived around twice as long as they do in the wild.
“They really do sort of look like grandpa. They have thinning hair and wrinkles,” Leventhal said.
In monkeys, as well as humans, visual function declines with age. While the eye itself does degenerate, this decline also involves the vision-related section of the cerebral cortex, which is responsible for many “higher-order” brain functions.
What the researchers discovered about the visual system likely applies to age-related declines in other parts of the cerebral cortex, according to Leventhal,
"If it's going on in the visual cortex, it's probably going on in other parts of the cortex," he said.
In the visual cortex, each so-called “V1 neuron” responds only to the sight of objects at a specific orientation or moving in a certain direction. GABA probably restricts the V1 neurons from responding to any other types of stimuli. This process helps the brain make sense out of the vast quantities of visual information coming in through the eyes.
"It’s like New York City or Boston during a blackout,” Leventhal said, describing what would happen if neurons weren’t restricted to specific responses. “With all the gating mechanisms like the stoplights out, you’d think traffic would move faster. But it doesn’t."
The researchers recorded the activity of individual neurons in the visual cortex of old and young macaque monkeys, while showing the monkeys various images on a computer screen. The devices that monitored the neurons also held small glass tubes of substances that could be released directly onto the neurons. The substances were GABA, a GABA-enhancing compound called muscimol, and a GABA-blocking compound called bicuculline.
The GABA blocker made the neurons less selective in the young monkeys, but had no significant effect in old monkeys. Presumably, that’s because the older neurons had already lost much of their selectivity, according to the researchers.
GABA and the GABA-enhancer had a relatively small effect in the young monkeys, moderately increasing the percentage of cells that were selective for particular orientations and directions. In the old monkeys, however, GABA and the GABA-enhancer had a much stronger effect, significantly increasing the percentage of highly selective cells.
Thus, the visual cortex of the older monkeys seemed to function less effectively, because GABA wasn’t limiting the neurons to specific responses. Exactly how this change occurred isn’t completely clear. In their Science paper, the researchers speculate that perhaps GABA production decreases in older brains.
Leventhal is hoping that more researchers will begin study aging in monkeys.
“It’s absolutely remarkable to me that my lab is the only lab in the world studying higher brain function in old monkeys. Old monkeys are rare, but the world is full of old human primates,” Leventhal said. “Hopefully we can drum up a little interest, and encourage other people who are trying to figure out how come their kids are smarter than they are now.”
The effect lasted only as long as GABA levels were maintained. When the chemical was removed, the brains of the old monkeys reverted to their aged confusion within a few minutes, Leventhal said. Added GABA appeared to have no effect on the young.
"It may be that already approved GABA (boosting drugs) have a positive effect on mental decline in the brains of older adults, but nobody has ever looked," he told Reuters Health.
The next logical step is to test the effects of known GABA-increasing drugs on older brains.
Dr Richard Harvey of the UK's Alzheimer's Society says new drugs with fewer side-effects may need to be developed to make best use of this discovery.
"The benzodiazepines, which include Xanax (alprazolam) and Valium (diazepam) affect the GABA system in the brain. "However they are highly addictive, and any benefits you might get from enhancing GABA are mitigated by the significant problems of physical and psychological dependence.
"Brain function gets worse as we get older, pure and simple. It's not whether it will get worse, it's a matter of how much worse it will get," Leventhal said. "The ramifications of this are to correct brain degradation in the elderly. That is significant to every human being."
What will be interesting to discover is why GABA levels decline with age. Do GABA-producing cells die off? Or are there signals that inhibit the production or release of GABA in aged brains? Or do old cells have insufficient energy output from their mitochondria to support the production of GABA?
Leventhal believes the aging phenomenon that causes these results is happening throughout the brain.
Leventhal believes a lack of GABA as people age will not just affect vision but all higher brain functions.
The boosting of GABA with drugs will not be as safe and effective as the natural production of GABA by young healthy nerve cells. Still, this discovery points the way for drug development and further research into how the brain ages. This research brings closer the day when we know how to slow and even reverse brain aging.
Update: Leventhal learned about the Rhesus Macaque monkeys in China during a sabbatical in China.
He also is an honorary professor at the University of Science and Technology in Anhui, China, a connection that came about because a number of his graduate students have been Chinese and he did a sabbatical there.
|Share |||Randall Parker, 2003 May 02 06:15 PM Aging Reversal|