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The Brain Starts to Change at Age 40

By Cheryl Simon Silver

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If you’re middle aged, there’s a good reason why you can’t beat your child at games like “Memory” and “Concentration.” Scientists report that after age 40, brain tissue shows genetic changes that may contribute to the aging process, including cognitive decline.

Researchers at Children’s Hospital in Boston and at Harvard Medical School report a genetic signature revealed in post mortem tissues of individuals between 26 and 106 years old. They looked at tissue from the prefrontal region of the brain, the locus of higher level functions such as long-term planning and executive function.

Bruce Yankner, lead author of the study, says aging brains show significant differences in the behavior of several groups of genes that are important for brain function and that may contribute to the aging process. One group of the genes plays a role in what researchers call synaptic plasticity—the ability of the brain to make new connections so critical to learning and memory.

It may be that DNA damage in the brain is reversible. --Bruce Yankner, Harvard Medical School
Another group of genes, involved in processes such as responses to stresses and defense against damaging oxidants such as free radicals, are turned on in the aging brain. The researchers found that regions of particular genes are quite vulnerable to DNA damage in the aging brain.

“These regions appear to be quite vulnerable to DNA damage—they are chemically sensitive, and they are not repaired easily,” Yankner says. The findings appear this week as an advance online publication in Nature.

The research team performed a statistical analysis to 11,000 genes for the study, and compared the rates of change over time. The changes in genes of individuals younger than 40 years were quite similar, and the genes of the oldest individuals were also similar. However, the individuals between ages 40 and 73—the middle years—aged at strikingly different rates, with some gene patterns resembling those of the young group, while others had gene patterns more like those of the older group.

Once they zeroed in on the groups of genes, the researchers conducted laboratory tests in which they exposed brain cells to agents such as free radicals and environmental toxins. The results mimic the changes seen in the tissue of aging brains.

On the bright side, when the researchers duplicated the scenario in the lab, and genetically manipulated the cells to produce proteins to repair the damage, the function of the damaged genes was restored, and more copies were made.

“It may be that DNA damage, once it occurs in the brain, is reversible,” Yankner says.

Once the damage is reversed, it might be possible to extend the duration of cognitive function, or to delay the onset of age-related diseases such as Alzheimer’s disease or Parkinson’s. This will be a goal of future research.

“There is certainly evidence that DNA damage can underlie a large part of the aging process in humans,” Yankner says. “My feeling is that the process of maintaining the integrity of the genome is going to be very important in understanding the aging process. Whether it explains the entire spectrum of the aging process, or a part of it, remains to be seen.”

Lu, T. et al. Gene regulation and DNA damage in the ageing human brain. Published online in Nature (June 9, 2004).

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