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Signs of aging in the fruit fly
Drosophila study identifies changes in gene expression linked to age, stress
Edward R. Winstead

Life is short, especially for the fruit fly. Most fruit flies live less than two months, making the insect a favorite among scientists who study aging. Two years ago, researchers extended the life span of some flies by manipulating a single gene. Now that the Drosophila genome is sequenced, researchers are taking a genomic approach to identifying genes that play a role in longevity and biological processes related to aging.

To view Drosophila data, visit the Jan Lab website.

Researchers at the University of California, San Francisco, monitored the expression of more than 4,500 Drosophila genes over the course of a fly's lifetime under both normal and stressful conditions. To investigate the role of oxygen radicals in aging, the researchers exposed flies to paraquat, a chemical generator of free radicals. These molecules are byproducts of oxygen reactions, and they have been linked to DNA damage and changes associated with aging.

Since the 1950s, proponents of the free-radical theory of aging have argued that, over time, the accumulation of these highly reactive molecules can damage cells. Cells have tools for eliminating free radicals, but their effectiveness may lessen with age. According to some models, aging involves a breakdown in the balance between the generation and removal of toxic molecules.

The Drosophila study, led by Yuh Nung Jan, a Howard Hughes Medical Investigator at UCSF, found support for the free-radical theory of aging. Most of the changes in gene expression, however, were not associated with free radicals.

"The findings suggest that free radicals are important in aging, but they are not the only genetic factor in determining life span," says Sige Zou, of UCSF. He adds that life span is likely to be influenced by many genetic factors, some of which have nothing to do with free radicals. Of course, the aging process is also influenced by environmental factors. Zou points out that changes in room temperature can have dramatic effects on the life span of fruit flies in the laboratory.

The researchers identified 127 fly genes whose expression levels were regulated up or down with age. The activity of about one-third of these genes was influenced by changes in exposure to free radicals.

Writing in Proceedings of the National Academy of Sciences, the researchers note that similar genome-wide approach studies have examined changes associated with aging in the mouse. A comparison of fly and mouse data found no genes that are regulated in the same direction in aging in both species. But the surveys did not include the entire genomes, and the analysis revealed some themes.

In each species, for example, genes in energy metabolism were expressed at lower levels with age, although different sets of genes were involved. "Taken together," the researchers conclude, "these results suggest that these two species alter their cellular processes in a similar way during aging, but do so through the regulation of distinct genes."

Microarray technology, which is used to monitor the expression of thousands of genes simultaneously, does not reveal anything about the function of a gene, only whether its expression changes under certain circumstances. The data, however, give researchers potential markers for aging and a starting point for examining what are likely to be very complex biological processes.

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Zou, S. et al. Genome-wide study of aging and oxidative stress response in Drosophila melanogaster. Proc Natl Acad Sci U S A 97, 13726-13731 (December 5, 2000).

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