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Microarrays Offer Insight Into Aging, Extended Life Span

By Doug Dollemore

Gene expression microarray technology, a potent tool that is helping clarify what changes occur in cells as they get older, is deepening scientific understanding of how caloric restriction may regulate the aging process in animals, according to Dr. Richard Weindruch, a former National Institute on Aging staff member who delivered the 11th annual Nathan Shock Memorial Lecture in Baltimore recently.

Understanding the cellular and molecular basis of how dietary restriction retards aging in animals may eventually benefit humans, Weindruch said. Scientists may one day develop drugs that safely suppress human appetite over the long term or mimic the beneficial influences of caloric restriction on the body's tissues. These approaches could enable people to continue eating familiar dietary fare, while still reaping the healthful effects of limiting their food consumption.

Dr. Richard Weindruch (r) delivered the 11th annual Nathan Shock Memorial Lecture. He is joined here by Dr. George Roth, a senior guest scientist at NIA.

"We now have, using the microarray approach, an exciting panel of transcriptional markers of the aging process, which will allow us to determine the biological age of tissues. I think this will allow us to see whether an intervention into the aging process has efficacy on a tissue-specific basis," Weindruch told the audience in the Allergy and Asthma Center Auditorium at the Johns Hopkins Bayview Medical Center.

Microarrays, also known as "gene chips," allow researchers to survey the expression of thousands of genes at once, providing an intimate look at the ebb and flow of genetic activity with age. The chips are actually small glass plates containing DNA that has been exposed to messenger RNA (mRNA), a nucleic acid that translates information contained in DNA into proteins. The amount of mRNA that binds to each DNA probe on the chip is an indicator of the activity level of a particular gene.

In his lecture, "Caloric Intake, Oxidative Stress, and Aging," Weindruch, a professor of medicine at the University of Wisconsin at Madison, briefly outlined the history of caloric restriction research, the only intervention that has been shown to increase the maximum lifespan in rodents. He then plunged into his latest work utilizing microarrays.

In these experiments, he and his collaborator Dr. Tomas Prolla profiled the action of 6,347 genes from the gastrocnemius muscles, cerebral cortices and cerebellums of mice that had been on calorie-restricted diets. These mice were allowed to consume a nutrient-dense diet that provided healthful amounts of protein, fat and vitamins and minerals, yet contained about 30 percent fewer calories per week than the diet given to other mice, known as controls, involved in the experiment.

Compared to the control animals, the mRNA extracted from the calorie-restricted mice exhibited numerous differences in activity that might affect critical biological tasks such as cellular response to biologic stress, DNA repair, protein degradation and energy production in brain cells. These observations, published in the Aug. 27, 1999, issue of Science (muscle data) and the July 2000 issue of Nature Genetics (brain data), support the hypothesis that caloric restriction extends survival and vitality in part by limiting injury of cells by free radicals generated by mitochondria, Weindruch said. Many investigators, including Weindruch, suspect that caloric restriction slows aging by keeping free radical production in check.

"It appears that caloric restriction is changing several aspects of energy metabolism in ways that are not fully understood," he said, "but (by) using gene microarrays we have gotten insight into some of those changes."

Weindruch, who was a health scientist administrator at NIA from 1987 to 1990, has devoted his career to the study of caloric restriction and its effects on the body.

"[Weindruch] has published a number of high visibility papers during his career, particularly in the past year, that have highlighted gerontology in general," said Dr. Donald Ingram, chief of the behavioral neuroscience section in NIA's Laboratory of Neurosciences. "These articles have been done with such clarity and such stimulation of thought that he has really raised the public's awareness of gerontology, and also challenged those of us involved in the study of aging."

Prior to Weindruch's lecture, Drs. Karen McCullough and Craig Caldwell, both of NIA's Laboratory of Biological Chemistry, received Nathan Shock Trainee awards. McCullough was recognized for her talk, "GADD153 sensitizes cells to ER stress by down-regulating bc12 and perturbing the cellular redox state." Caldwell was recognized for his poster, "SAGE analysis of the influence of VHL on gene expression." Each received a $500 travel award and a plaque. The research competition, held yearly, is sponsored by the Nathan W. and Margaret T. Shock Aging Research Foundation. Dr. Nathan W. Shock, who died in 1989, was the first NIA scientific director and is considered by some to be the father of gerontology.

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