Genes help solve age-old questions


June 10, 2004
In the first genetic analysis of the aging human brain, Harvard scientists have identified hundreds of genes tied specifically to aging - genes that begin to change at the ripe middle-age of 40.

"This finding gives new meaning to reaching 40," said Ann Graybiel, a professor of brain science at the Massachusetts Institute of Technology in Cambridge who was not involved in the research. "It is a heroic effort to determine which genes are particularly vulnerable as we age."
Also of consequence is a finding of great variability in the aging status of these genes among individuals between 40 and 70. These age-related genes looked like those of young adults in some people in their 50s, while others at that age had the genetic patterns of people in their 80s, said Dr. Bruce Yankner, lead investigator of the study, which appears this week in the journal Nature.
Yankner, a professor of neurology and neuroscience at Harvard Medical School and Children's Hospital in Boston, and his colleague, Tao Lu, collected brain tissue from 30 unidentified people who died between ages 26 and 106. These were so-called "normal" brains, with no signs of injury or disease. Tissue came from brain banks around the country.

According to Yankner, about 4 percent of the 11,000 genes identified were significantly changed over the life span and linked to the aging process.

The frontal lobe is a uniquely human tissue that regulates ability to carry out tasks, organize, plan, judge and analyze information. The scientists took snippets of frontal lobe brain tissue and placed them in lab dishes filled with thousands of gene markers, so-called gene chip analysis. This allows scientists to identify specific genes active at a particular time.

The Harvard scientists discovered that many of the genes associated with aging play a role in the functioning of the synapse, the gap between neurons where communication takes place. There are billions of neurons in the human brain. Learning and memory are tied to the strength and number of the synapses made by these brain cells. The genes most altered by the aging process govern several neurotransmitters that are involved with learning and memory. Activity of these genes is significantly decreased with advancing age, Yankner and his colleagues found.

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They also found genes that did just the opposite; these genes worked harder as the person grew older. These include genes that repair brain proteins, genes that repair damaged genes, and genes that protect against free radical damage. Free radicals are toxic molecules that damage cells, and have been the targets for prevention and treatment studies with antioxidant compounds like vitamin E. Yankner suspects that these increases in activity are part of a compensatory effort to protect the brain against damage.

Yankner said variability in middle-age of the status of these genes could begin to explain why some people seem younger for their age, and some much older. He said the finding proves that there are genes that are more vulnerable to damage than others. And it seems that these age-related genes are damaged by free radical molecules. "It does raise the possibility that this kind of damage is reversible," Yankner said.

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