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NEUROSCIENCE
Secrets of Brain Aging RevealedAdvice from Experts: Protect Your Genome
Along with failing eyesight and impaired hearing, for many people old age brings the frustration of diminishing mental abilities. For scientists who study aging and neurodegeneration, the Holy Grail has been to identify the molecular changes underlying this seemingly inevitable decline in brain power.
In studying the aging brain, Bruce Yankner (right), Tao Lu, and colleagues have discovered a possible link between DNA damage and neurodegenerative diseases like Alzheimer's and Parkinson's. (Photo by Jeff Cleary) Now, researchers at HMS and Children's Hospital Boston have identified a group of genes whose activity decreases with age in the human brain. The decline, starting as early as 40, results from damage to the brain's DNA and progresses at varying rates in different individuals. "We found that genes that play a role in learning and memory were among those most significantly reduced in the aging human cortex. These include genes that are required for communication between neurons," said Bruce Yankner, HMS professor of neurology at Children's and senior author of the study, which appears in the June 24 Nature. The results suggest that aging starts early in adult life, and they raise the possibility that protecting against DNA damage could delay aging and age-related neurodegenerative conditions like Alzheimer's disease. Yankner and his colleagues used gene chip technology to measure the expression levels of 11,000 genes, or nearly half the genome, in postmortem brain tissue from the frontal cortex of 30 normal subjects ranging in age from 26 to 106. They found that four percent of the genes changed in expression between the young and old brains. By comparing gene expression patterns between different subjects, the researchers found that gene activity was similar among all the young adults and was uniformly changed among the over-70 subjects. But the middle-age group between 40 and 70 years old showed much more variability. "Some of those individuals looked more like the young group, while the transcriptome patterns of others looked more like the old group," Yankner explained. "It's a case where science validates several thousand years of common sense by suggesting that people age at different rates." Brain PowerThe brain does not passively submit to the passage of years, however. The genome analysis identified increases in a group of protective genes that defend tissues against oxygen damage. The increase in antioxidant genes, DNA repair genes, and stress-response genes suggested to Yankner and his colleagues that the aging brain might be fighting increased oxidative stress. These observations also led the researchers to hypothesize that some of the genes that were less active in the aging brain might be disproportionately affected by oxidative DNA damage.To look at DNA damage in brain tissue, Tao Lu, a research fellow in neurology in Yankner's lab, devised a method that first cleaved DNA specifically at sites of damage, then measured how much intact DNA was left in any particular gene by quantitative polymerase chain reaction. "Developing this assay really opened a door for us," Yankner said, "because it enabled us to resolve oxidative DNA damage to any sequence in the genome." They used the assay to look at 30 different genes and saw damage in some genes after age 40 and in all genes after age 70. The researchers found that damage was most common in the promoter regions of genes. This made sense since promoters tend to be high in guanine and cytosine, bases that are most sensitive to oxidative damage. DNA damage that occurs in these regions is not repaired during normal gene activity, but only gets reversed when cells divide. Since neurons do not divide, promoter damage can accumulate and, the researchers reasoned, could lead to the depressed gene activity detected in aging brains. That's exactly what seems to happen, the researchers found. They discovered that the genes that were downregulated with aging accumulated greater damage than genes whose expression was stable or increased. Using neuron cells in culture and even by damaging the DNA in a test tube, the researchers showed that age-sensitive genes are more susceptible to oxidative damage and less amenable to repair than the genes that do not change with age. Some of the DNA damage could be repaired in culture, suggesting that not all aging-related changes are irreversible. DNA Damage and DegenerationThe link between normal aging, DNA damage, and neurodegenerative disease is of particular interest for Yankner, who has studied Alzheimer's disease for many years. While the role of DNA damage in cancer has long been appreciated, before now it was not widely thought to play a role in neurodegenerative diseases, Yankner said. His group is interested in figuring out why some gene sequences are more vulnerable to DNA damage than others and whether the changes of normal aging might trigger the molecular cascades that underlie degenerative diseases of aging like Alzheimer's and Parkinson's.One promising avenue for future work is whether measures to protect the genome early in adult life will pay off by slowing brain aging. "Together with recent work in nematodes and drosophila, this human study suggests that some of what happens later in the brain starts early in adult life," Yankner said. This raises the possibility that enhancing DNA repair or preventing damage with antioxidants could protect brain function later in life and perhaps slow the onset of neurodegenerative disease. It is too early to tell whether gobbling vitamins or other antioxidants will protect the brain, but Yankner looks forward to testing these ideas in aging animal models using the gene damage assay. In the short term, the researchers are looking forward to completing their gene profiling of the aging brain using chips that cover the entire genome. Even then, Yankner says, the work has just begun. "I see the gene expression profile not as a definitive indicator of what has gone wrong, but as a first step in providing a hypothesis that will be pursued by many labs to understand the biology of the aging brain." --Pat McCaffrey |
