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Oxygen to live — Oxygen to age
by Will Sansom

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Why do we age? Many scientists point the finger at a certain type of oxygen molecules called free radicals. While oxygen is absolutely required for life, some types of oxygen molecules produced by cells can actually damage cells. Not content to live in peace with other molecules, they roam like bulls in china closets, damaging everything in their path. These molecular pinballs cause the death of many cells, doing hidden harm to the heart, brain, skin and all other parts of the body.

"Over time, they may accelerate aging and contribute to many diseases that occur during aging," said Brian A. Herman, Ph.D., professor and chairman of cellular and structural biology at the Health Science Center.

Dr. Herman is principal investigator on a new five-year, $5.8 million program project grant from the National Institute on Aging (NIA). The NIA funding enables UTHSC researchers to study complementary aspects of the aging puzzle, including free radical damage to cell energy centers called mitochondria.

Mitochondrial energy metabolism generates some free radicals, Dr. Herman said. These molecules damage the DNA, or genetic material, found in the mitochondria. Proteins, the products of gene expression, are in turn damaged. Over time, this chain of events is believed to result in aging, he said.

Dr. Herman said the free radical collisions may damage cells enough to contribute to "apoptosis," a term scientists coined to describe the seemingly intentional, or programmed, death of cells as animals age.

His laboratory has found that enzymes called caspases are critical for cell death. "We found that the activation of two caspases increases in certain organs in mice as they age," Dr. Herman said. "These caspases are in mitochondria and are activated by free radicals. To test our hypothesis, which is that activation of these caspases by free radicals contributes to aging, we are engineering mice that lack the genes to express these caspases, with the idea that this should retard the aging process in these animals."

A number of companies are trying to develop drugs that inhibit apoptosis in stroke, cancer, rheumatoid arthritis, heart disease, Alzheimer’s disease and other diseases, he said. Apoptosis is thought to be important in all these diseases that occur as we age.

Christi A. Walter, Ph.D., professor of cellular and structural biology and a project leader, is studying whether free radical damage to mitochondrial DNA may impair mitochondrial function and lead to apoptosis. Her team measures damage through a variety of molecular and chemical techniques. "The principle is that DNA damage will impede mitochondrial processes necessary for energy production and may lead to cell death," she said.

Arlan G. Richardson, Ph.D., professor of physiology, director of the Aging Research & Education Center and V.A. career scientist, is another project leader. Dr. Richardson is testing whether the effect of free radicals on aging occurs because of damage to proteins and mitochondrial membranes. He is using transgenic mice that overexpress a protein called Mn-superoxide dismutase. "We hypothesize that these mice, which have enhanced antioxidant defense systems, will be able to more efficiently neutralize free radicals and the mitochondria will sustain less damage, resulting in slower aging," Dr. Richardson said.

Calcium is an important messenger molecule in cells. James D. Lechleiter, Ph.D., associate professor of cellular and structural biology and another project leader, is studying how the mitochondria regulate calcium signaling — and vice versa — during aging. Calcium enhances cell survival by signaling mitochondria to make energy, but if the signal is prolonged or too high, the result can be cell death. "We’re trying to understand how the calcium signaling connection is affected by or contributes to aging," Dr. Lechleiter said.

The Health Science Center has one of the nation’s premier programs in aging research. UTHSC is second only to Harvard/Massachusetts General Hospital nationwide in the amount of federal funding for aging studies. Dozens of Health Science Center faculty are asking fundamental questions about aging as part of four ongoing multimillion-dollar program project grants from the National Institute on Aging.

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