Sci. Aging Knowl. Environ., 7 May 2003
Chip off the Old Brain
Memory-robbing brain changes begin in youth
Key Words: CA1 region neuroglia Morris spatial water maze demyelination synaptic plasticity
The embarrassing memory lapses of old age might stem from changes in gene activity during youth, according to new research that tracked the output of brain genes in rats. The results suggest that slowing brain aging might be possible--if treatment begins long before memory starts to falter.
Aging undermines the brain. Thinking slows, short-term and long-term memory flag, and attention drifts (see "All in Your Mind"). To understand how these changes occur, researchers have used microarrays, or gene chips, to identify age-related perturbations in the activity of brain genes. For example, several studies of rodent brains suggest that aging cranks up genes that orchestrate inflammation and signal oxidative stress, and many scientists blame age-related deterioration on inflammation and oxidative damage. Because gene chips are expensive, most researchers use small numbers of animals--usually fewer than five per age group--in their studies, which weakens their conclusions. Neuroscientist Philip Landfield of the University of Kentucky in Lexington and colleagues designed a statistically stronger, yet pricier, study involving three groups of rats--young, middle-aged, and elderly--each of which contained 10 animals.
The researchers first evaluated memory in the three groups, composed of animals that were 4, 14, and 24 months old. One test gauged the rodents' ability to recall the location of a clear plastic platform in a tank of water. A second test determined whether they could remember whether an object, such as a coffee cup, had been in their cage previously; this assessment was possible because rats spend more time exploring unfamiliar objects than familiar ones. The researchers then used microarrays to profile gene activity in the young, middle-aged, and elderly rats; they tested a portion of the animals' hippocampi, which are crucial for memory and learning. Two hundred thirty-three genes either increased or decreased their activity with age.
To pinpoint memory-undercutting genes, the researchers combined the microarray data from all of the animals and applied statistics to correlate the output of each gene with performance on the recall tests. This analysis connected 161 genes to failing memory. The list included some of the usual suspects in brain aging: Genes involved in inflammation and oxidative stress worked harder, whereas genes that keep the energy-producing mitochondria humming slacked off. However, the method also fingered some conspirators not seen previously, such as genes that regulate production of myelin, the insulation around nerve fibers. The alterations kicked in earlier than the researchers had expected. Although middle-aged rodents still had sharp minds, many of the changes linked to declining memory had already begun. "It's like a 'gene grenade,' " says neuroscientist and study co-author Eric Blalock. "The pin gets pulled in middle age, but it doesn't explode until old age."
Other studies have identified age-related shifts in gene activity, but this work is novel because the team connected these adjustments to weakening memory, says geneticist Tomas Prolla of the University of Wisconsin, Madison. Hindering some of these genetic changes might slow brain aging, Landfield says. Because the genes start to go awry so early in life, such treatment can't wait until someone forgets her daughter's birthday or where she parked her car.
May 7, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150