Sci. Aging Knowl. Environ., 5 November 2003
JNK-ing Cellular Poisons
Embryo-shaping genetic pathway stanches oxidation
Key Words: real-time PCR serial analysis of gene expression hemipterous transcription factor
Adults who are under pressure at work or harried by bill collectors don't usually need their childhood pacifiers or stuffed animals to cope. But organisms do seem to revisit their youth when they need to battle stress caused by metabolic byproducts, according to a new study. The work suggests that fruit flies reuse a molecular pathway that's crucial during embryonic development to orchestrate the adult's defenses against cell-wounding reactive oxygen species (ROS).
Mutations that disrupt insulin-related signaling hike stress resistance and prolong life in a range of creatures (see "Stay Mellow, Stay Young" and "Growing Old Together"). Researchers suspect that another pathway, known as JNK, might exert similar protective effects. One of JNK's jobs involves molding the developing embryo. In fruit flies, for example, it helps the newly formed skin zip closed to sheathe the body. The pathway presides over 172 genes with a variety of functions, and some studies suggest that adult organisms deploy it in response to stress. For example, ultraviolet radiation and oxidants rouse JNK. However, scientists were unsure whether JNK is protective or incites damage: In the culture dish, prodding JNK sometimes boosts resistance to ROS but can also drive cells to commit suicide. Geneticist Heinrich Jasper of the University of Rochester Medical Center in New York and colleagues wanted to find out whether JNK shields living animals from ROS.
To answer the question, Jasper and colleagues studied fly lines in which JNK activity was higher or lower than normal. When flies that carry a feeble version of a JNK-activating gene slurped paraquat, a compound that instigates ROS production, about 50% of them perished, versus about 40% of controls. The researchers also fed paraquat to flies that had a weakened version of a gene that normally stymies the pathway. Fewer than 10% of those insects died, suggesting that the pathway does confer protection from ROS. To gauge JNK's effects on longevity, the team measured the survival of two lines of flies with a lazy JNK-suppressing gene. They outlived controls by more than 30%. The researchers also found that animals with overactive JNK sported up to 45% fewer proteins scarred by oxidation than did controls. "The work shows for the first time in an intact organism that this pathway responds to stress and protects the animal," Jasper says.
"I'm convinced that JNK is having a beneficial effect on oxidative resistance," says molecular biologist John Tower of the University of Southern California in Los Angeles. But whether it stretches life span remains uncertain, he cautions. Tower notes that the control group in the longevity studies was inbred but that the experimental groups resulted from matings between genetically distinct lines. It's impossible to tell if the extended life span of the experimental animals stems from heightened JNK activity or from increased genetic diversity, he says. Molecular biologist Roger Davis of University of Massachusetts Medical School in Worcester wonders whether JNK meshes with known life-extending pathways, such as insulin-like circuits. Probing such questions might reveal whether a key to getting through early life is also instrumental for surviving the stresses of adulthood.
--Mitch Leslie; suggested by Nick Bishop and Arjumand Ghazi
November 5, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150