Sci. Aging Knowl. Environ., 17 December 2003
Catalase and Mouse
Enzyme-enhanced rodents scurry longer
Key Words: Aconitase cDNA chick -actin promoter
SCOTTSDALE, ARIZONA--Judging by their consumption of vitamin E supplements and antioxidant-packed foods such as blueberries, Americans have swallowed the idea that reactive oxygen species drive aging. Researchers aren't so sure, but new work gives the notion a boost. Mice that produce extra amounts of an enzyme that squelches oxidants survive longer, according to research presented here on 11 December at the Phoenix Conference on Longevity Health Sciences. The study is one of the few to address the role of antioxidant enzymes in mammalian aging by increasing rather than slashing their output.
The "oxidant hypothesis" that reactive oxygen species (ROS) gnaw DNA, proteins, and other molecules and trim life span is 50 years old (see "The Two Faces of Oxygen"). Mitochondria, the cell's power plants, discharge most of these noxious byproducts of metabolism. Studies of flies, worms, and mice suggest that weakening antioxidant defenses shortens life, but researchers want to know whether fortifying these defenses will stretch longevity. Pathologist George Martin of the University of Washington, Seattle, and colleagues decided to test whether mice that are overendowed with an ROS-battling compound called catalase live longer.
The scientists hitched the gene for catalase to genetic switches that would allow them to ramp up output of the enzyme. After equipping the DNA snippets with a molecular ZIP code that guides them to either the nucleus or the mitochondria, the group injected them into early mouse embryos. After the rodents grew up, the team compared mice carrying extra catalase in their mitochondria to unaltered animals from the same litter. The enzyme-enhanced rodents were about half as likely to develop cataracts and only one-tenth as likely to suffer from subendocardial fibrosis, an accumulation of scar tissue seen in many older people with heart failure. The catalase-enhanced mice also outlived their littermates by about 18%. When the researchers plotted the survival of altered and control rodents over time, the curves had similar shapes, but catalase-enhanced rodents lasted longer before they started to die off, suggesting that the extra enzyme was forestalling aging. "It looks like we're delaying the beginning of the decline in survival," Martin says. By contrast, mice that made extra catalase in the nucleus squeaked out only a tiny increase in life span. To strengthen the oxidant hypothesis, researchers should enhance antioxidants in multiple strains of mice, Martin says. In this study, the additional catalase could be remedying a defect peculiar to the strain, he notes.
Mitochondria don't normally make catalase. But the study shows that adding the enzyme to them can delay the onset of aging, says Thomas Kensler, a molecular toxicologist at Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. How to use the result to fight human deterioration is the tough question, he adds: "The challenge will be to find a way to get the right antioxidant in the right place at the right time." For now, it looks like blueberry growers can count on ripening profits.
December 17, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150