Brain aging found to start at 40

Genes can begin to fail early

By William J. Cromie
Harvard News Office

Bruce Yankner, a professor of neurology at Harvard Medical School, is

Two elderly Chinese men play chess under a 1,000-year-old tree (a Chinese symbol of longevity). Insert at lower left shows how the function of certain genes decrease with age in a sample of people ranging in age from 26 to 106 years. (Illustration courtesy of www.yutopian.com.)

investigating how human brains change between ages 26 and 106. If you are more than 40 years old, the news may not be good.

He and his colleagues at Children's Hospital in Boston and Harvard searched brain tissue from 30 people for changes in genes involved in learning and memory, and for damage to these genes caused by the normal stresses of living. From ages 26 to 40 years, their brains show similar patterns of wear and tear and low levels of gene damage. Brains 73 years and older exhibited more damage, as expected.

A big surprise, however, came in the middle ages. Some people between 40 and 70 had gene patterns more like younger people, and some like older people. "In other words, people in their middle-age years show variable rates of brain aging," says Yankner, who is 50.

These results suggest that deleterious changes can occur much earlier than expected. But that's not necessarily true for everyone. The data also indicate that our brains contain protective and repair mechanisms that can compensate for gene damage. "Thus, our findings raise the exciting possibility that drugs or lifestyle changes in young adults could delay cognitive declines and protect against the onset of brain diseases in later years," Yankner concludes.

The research team can already mimic this pattern of gene damage to some extent by growing human brain cells in the lab and exposing them to the kinds of stresses involved in aging. They have also prevented gene damage and restored their function by manipulating repair proteins in the cells. However, doing the same thing in a human brain, Yankner admits, "would require a major leap in medical technology."

A goal of the research is to determine if the gene changes they find raise the risk of brain diseases like Alzheimer's and Parkinson's. If so, it might accelerate the detection and treatment of such infirmities at a time when the population of senior citizens is exploding in the United States and elsewhere.

Tao Lu (left) and Bruce Yankner discuss the possibility that drug or lifestyle changes could delay learning and memory problems and protect against Alzheimer's and other diseases in middle and old age. (Staff photo Rose Lincoln/Harvard News Office)

Aging at different rates

For years, Yankner has been banking brain tissue for the purpose of solving some of the mysteries of normal aging and accelerated aging brought on by Alzheimer's. The tissue comes from both cadavers and from small samples taken during brain surgeries. "Obtaining material from older people has been easy, but collecting it from young brains is very difficult," Yankner observes.

Brain banking and the technology of studying the genes brains contain have evolved together and have now reached the point where evaluating the activity of thousands of genes can be done quickly.

Looking through this technological window, Yankner's team sees negative changes in two groups of genes. "We found genes involved in learning and memory were among those most significantly reduced in the aging human brain," Yankner notes. Other glitches appear in a set of genes that regulate energy protection and transport of proteins in cells, functions vital for normal brain activity and to protect brain cells from damage. Some of these alterations show up in people as young as their 40s.

Younger brains apparently can prevent impairment of these genes. But in middle age, damaging modifications start to creep in. By age 50, gene patterns in some brains look like those of older people, while others resemble those of young adults. They appear to be approaching old age at different speeds. "You can look at middle-aged people on a line at Starbucks and get a good idea of how well their brains are doing," Yankner comments.

Tao Lu, a postdoctoral fellow in Yankner's lab, did much of the work that revealed these variations. The research is described in technical detail in an article published in the June 10 issue of Nature, a British scientific journal.

Promoters demoted

To better understand what's going on, the team aged human cells in test tubes. The cells were challenged by the kind of stresses produced by their own energy-burning activities - the exhaust gases of metabolism. The most vulnerable are so-called promoter regions of the genes, which turn them on and off. Sometimes gene damage is repaired when cells divide, but brain cells don't divide, leaving them more vulnerable to aging. You can think of promoter regions as the engines that drive genes. In brain aging these regions eventually run out of gas.

Alzheimer's disease may involve cases of running out of gas too soon. "An interesting possibility is that Alzheimer's and other brain disorders might represent a poorly suited response to gene damage," Yankner suggests. Comparing gene changes and DNA damage in normal aging and early Alzheimer's may provide the kind of new insight needed to develop better treatments.

A big mystery to solve is whether gene deterioration takes place throughout the brain and body, or only in specific regions. If the same fingerprint of aging can be detected in blood and skin cells, they might make possible simple tests to detect who is at greatest risk for Alzheimer's and other age-related conditions.

Such tests might also reveal whether drugs or lifestyle changes can slow brain aging. For example, antioxidant vitamins, like vitamin E, have been touted as a means to counteract the damage produced by our own cells and by smoke and other pollutants. Gene fingerprinting might reveal if taking such vitamins, drastically cutting calories, or taking certain drugs would encourage good brain health during middle and old age.

If you are in your 40s, should you worry about your brain? Yankner points out that not all middle agers are in the fast-aging lane. "Some of the people 50, 60, and older had remarkably good-looking brains, Yankner points out. That group includes one man in his early 90s. People can take solace from that.