Scientists used to think that physical malfunctions due to aging were caused by a decline in all cells, but newer views suggest that this isn't the case. Rather, the aging process appears to trigger some definite genetic changes in the brain, said Andrej Rotter, the study's lead author and a professor of both pharmacology and neuroscience at Ohio State University.
"That's really the great advantage of SAGE," Rotter said. "If we don't find an entry for a tag sequence on the NIH database, then we may have found an unknown gene that could be important in some process."
He and his colleagues compared genes expressed in the cerebellum the area of the brain that controls posture, balance and muscle movement of adult and aged mice.
"A number of elderly people die each year from injuries related to falling," Rotter said. "Falling down implies a loss of both motor control and sense of balance, properties that are both associated with the cerebellum. We think there may be specific genes involved in this loss of function."
While the researchers are just beginning to uncover the differences between genes expressed in the cerebella of young and old mice, they're surprised with what they've found so far.
For instance, they found sizable decreases in the expression of genes that produce growth hormone, which is key to growth and development, and in prolactin, a hormone that stimulates milk production and also helps maintain the immune system. Growth hormone gene expression was nearly 10 times higher in the young mouse cerebellum, while prolactin gene expression was nearly 15 times higher in young mice.
"We don't know what role either hormone plays in the cerebellum, but the fact that there was such a drastic decrease in the hormones between the young and old mice means they represent genes that should be studied further," Rotter said.
The researchers presented their results on November 9 in New Orleans at the annual Society for Neuroscience meeting.
They analyzed gene expression in the mouse cerebellum using serial analysis of gene expression (SAGE), a powerful tool that lets researchers count the number of times a gene tag, or short sequence of DNA, appears in a given tissue. The more often a tag appears, the more that particular gene is expressed in the tissue. The researchers then compared these tags to a database of mouse cerebellum tags run by the National Institutes of Health.
Unlike other DNA analysis techniques that are useful only for analyzing known genes, SAGE quantifies known and unknown genes.
"That's really the great advantage of SAGE," Rotter said. "If we don't find an entry for a tag sequence on the NIH database, then we may have found an unknown gene that could be important in some process.
"We're trying to find some of the fundamental, specific changes that could underlie some of the defects associated with aging," he said. "Cerebellar function decreases as we age, but no one has really been able to figure out what the basis of these changes may be.
Rotter and his colleagues are going further with their studies of gene expression in mice. They are currently looking at the effects that low-calorie diets have on gene expression in the mouse cerebellum. Research in worms, yeast, mice and even monkeys has suggested that caloric restriction may lead to a longer life.
"We want to see if caloric restriction prevents a drop-off in prolactin and growth hormone," Rotter said. "If it does, that would imply that the genetic pathways for making these hormones is somehow involved in an increased lifespan."
Rotter conducted the study with Adrienne Frostholm, an adjunct associate professor of pharmacology; Katarzyna Rejniak, a postdoctoral researcher at Ohio State; and Magdalena Popescu, Julie Besco and, both doctoral students at Ohio State.
This work was funded by grants from the National Institutes of Health.