Novel antioxidants may slow brain's aging.

Many of the degenerative changes that can accompany aging-from atherosclerosis and muscle tremors to memory loss and cancer-have been linked to the cumula-tive effects of free radicals in the body. These highly reactive molecular fragments can alter proteins, including the enzymes responsible for tissue repair. Moreover, such damage can accelerate with age.

Last year, researchers in Texas showed that the vulnerability of brain proteins to free radicals determines where and how quickly many age-related neurodegenerative changes occur (SN: 5/18/96, p. 311). Now, other researchers have shown that nitrones-novel antioxidants designed to trap free radicals- can prevent the protein damage that seems to underlie such brain impairment.

The new findings "are really supportive of the concept that [free] radicals are involved in aging," says Earl R. Stadtman of the National Heart, Lung, and Blood Institute in Bethesda, Md. Together with a host of related studies, he says, these data suggest the possibility of developing a drug "to reverse some of the age-related changes" that can debilitate the elderly.

Until leaving to form Centaur Pharmaceuticals in Sunnyvale, Calif., last year, pharmacologist John M. Carney was part of a research team at the University of Kentucky in Lexington that worked with two strains of specially bred mice. One strain ages at a faster than normal pace and can serve as a model for memory and learning impairments in the elderly. A longer-lived, genetically related strain shows normal resistance to the oxidative changes underlying those impairments.

The Kentucky team injected a nitrone known as PBN into 10-month-old mice of both strains daily for 2 weeks. After the last injection, the researchers compared the brains of these animals to those of untreated mice. In the quickly aging strain, PBN protected brain proteins from the free-radical-induced oxidation that would otherwise have occurred. However, PBN had no apparent effect on the normally aging strain, the team reports in the Jan. 21 Proceedings of the National Academy of Sciences.

This is significant, Carney says, because it suggests that PBN is "selectively controlling only those pathological [free radical] modifications that give rise to dysfunction or disease."

Indeed, the body normally harnesses free radicals not only to eliminate invaders and unwanted tissues but also to synthesize many important compounds, including hormones. The PBN treatment did not appear to depress these healthy, free-radical-based processes, he explains.

The new study also shows for the first time that PBN's protection extends to the proteins that make up a cell's cytoskeleton, or framework. These struc- tural proteins "are fundamentally important," he says, to controlling a cell's shape. Other proteins that were protected contribute to a cell's ability to communicate with other brain cells.

Stadtman notes that at least one study has found that PBN can extend the life of mice. In another, old rodents treated with PBN suddenly performed maze tests as well as young animals. Carney reports that test-tube experiments show that PBN treatment "can prevent [Alzheimer's disease] plaque formation" and will probably improve the removal of this plaque.

Though PBN appears safe in animals, Carney says it has the drawback of sedat- ing them. However, he notes, at Centaur "we've already made something better" and have just launched safety trials with that related chemical in 30 people. Are nitrones the proverbial Fountain of Youth? "Maybe they won't really extend life," Stadtman says, but that's not so bad if they improve the quality of life in old age. "They ought to be able to do that," he adds.