DURHAM, N.C. – Researchers have discovered a potential reason why learning and memory function declines with age: aging brains produce lower levels of critical growth factors that fuel the birth of new neurons in the hippocampus, the brain’s learning and memory center, according to a study in rats.
The researchers said their findings suggest that drugs to enhance such growth factors, or other preventive therapies, might sustain neuronal growth and thus maintain learning and memory in older people.
The production of new neurons in the hippocampus was known to slow dramatically by middle age in rats — the equivalent of 45 to 50 years in humans — said the researchers from Duke University Medical Center and the Durham Veterans Affairs Medical Center (VAMC). But the molecular basis for this decline has remained a mystery, they said.
In the Aug. 15, 2005, issue of the journal GLIA, published early on line, the Duke/VAMC team reported that the levels of three critical growth factors — fibroblast growth factor-2 (FGF-2), insulin-like growth factor -1 (IGF-1) and vascular endothelial growth factor (VEGF) — decline dramatically in the middle-aged hippocampus of rats. These growth factors are secreted mostly by supporting cells in the brain, called astrocytes, and they are critical for enabling stem cells to produce new neurons.
Their results illuminate the mechanism behind the declining production of new neurons in the dentate gyrus region of the hippocampus, where learning and memory occur, said Dr. Ashok K. Shetty, a Research professor of neurosurgery and lead author of the study. Co-authors are Bharathi Hattiangady (Ph.D.) and Geetha Shetty (M.S.).
Scientists had previously speculated that newly born cells in the aging hippocampus were failing to reach their potential for one of three reasons: they were differentiating into mostly non-neuronal cells; they were not migrating to the proper brain regions; or they were failing to survive long enough. However, the Duke/VAMC team showed in an earlier study that newly born cells in middle-aged and aged rats demonstrated none of these defective behaviors. They reported these initial results in the January 15, 2005, issue of the European Journal of Neuroscience.
"We determined that there is no major, fundamental defect in how newly born cells behave in the aging hippocampus," said Shetty. "There is simply less of the growth factors that drive stem cells to produce new neurons. This is encouraging news because it means we can employ strategies to increase the levels of these growth factors and see whether an increased production of new neurons can be sustained in the aging hippocampus."
For example, regular physical exercise and exposure to enriching environments have both been shown to boost new neuron production in the hippocampus, said Shetty. While these strategies will not halt the decline, they may slow it considerably, he said.
Young adult rat brains (equivalent to 20-35 years of age in humans) produce approximately 2,000-3,000 new neurons per day in the hippocampus. In contrast, by middle age (45-50 years of age), only 500-700 new neurons are born each day. From that point on there is little decline in neuron production, the study showed.
However, the numbers of supporting "astrocytes" that produce the growth factor FGF-2 continue to decline with advancing age, the study showed. Moreover, a fraction of newly born neurons in older brains show retarded growth of dendrites – the tentacle-like structures that reach out to and connect with other neurons to exchange messages. Such changes in new neuron numbers and growth may contribute to delayed memory processes as the brain ages, said Shetty.
Shetty said his research is the first to examine long-term survival of newly born neurons in aging brains. Most studies have focused on the production of new neurons at a specific age rather than neuronal behavior over a period of time.
In their study, Shetty’s team tracked new neurons in young, middle-aged and old rats for five months as the cells divided, matured, differentiated and migrated. They observed the neurons’ behavior and measured the levels of growth factors at each age to determine how new neuron production and development progressed in each age group.
Future studies will focus on developing strategies to sustain increased neuron production in the aged brain and examining whether increased production of new neurons in the senescent hippocampus will improve learning and memory function in the aged.
Their research was supported by a grant from the National Institute for Aging of the National Institutes of Health.
Duke University Medical Center. August 2005.