Long live the mammals: antioxidant redirection extends mouse life span.

Cranking up the amount of antioxidants naturally produced in the body and directing those molecules to where they're needed can dramatically slow the aging process, according to a new study in mice. The finding adds credence to the controversial idea that antioxidants can extend life in people and other mammals.

Negatively charged molecular fragments generated by normal metabolism can damage cells and organs. Antioxidant molecules produced by cells or present in the diet can chemically neutralize those fragments, called free radicals, and stem the damage. One popular theory of aging dictates that with time, free radicals eventually overwhelm this natural defense, leading to various age-related declines.

Numerous studies in simple organisms, such as yeast, worms, and flies, have supported this theory by showing that enhancing production of natural antioxidants can extend life. However, evidence that antioxidants can slow the aging process in mammals has been less convincing.

To investigate whether increased concentrations of natural antioxidants give mammals longer lives, Peter S. Rabinovitch of the University of Washington in Seattle and his colleagues genetically engineered mice to overexpress a gene responsible for making the antioxidant called catalase.

The catalase that a cell makes normally goes directly into organelles known as peroxisomes. Rabinovitch's team designed its genetic manipulation so that in some of the mice, the extra catalase went into its normal location. However, the team altered some of the mice so that the extra catalase went into the cell nucleus. A third group of engineered mice directed the enzyme into mitochondria, the cell's energy-producing organelles. Mitochondria produce most of an organism's free radicals as a side effect of converting food into energy.

Rabinovitch and his colleagues saw no difference in life span between normal animals and those engineered to keep the extra catalase in the nucleus. Mice engineered to direct catalase to its usual place, in peroxisomes, showed only a modest increase in life span. However, animals that guided catalase to mitochondria lived significantly longer than normal mice, adding about 5 months to their normal 3-year life spans.

When the researchers dissected some of the mice, they found early signs of age-associated disease, such as cataracts and heart disease, at later ages in the long-lived, engineered mice than in the others. The team reports its findings in an upcoming Science.

The results are exciting not only because the engineered mice lived longer but also because they stayed healthy later in life than mice normally do, says Toren Finkel, a researcher who studies aging at the National Heart, Lung, and Blood Institute in Bethesda, Md.

"Lots of people believe that diseases of aging, such as cancer, atherosclerosis, and neurodegenerative diseases, are related to free radical biology," he says. "As Rabinovitch's team showed here, if you can neutralize free radicals, you not only live longer but you might free yourself of age-related health problems."

Rabinovitch says that the new findings may eventually lead to drugs that achieve the same result, but he stresses that the jury is still out on whether dietary antioxidants could have a similar life-extending effect.