Genetic manipulation cuts nerve damage, boosts life span

Feb 15 2005

A novel genetic manipulation significantly extends the life spans of flies by reducing the amount of wear and tear suffered by nerve cells in adults, according to new work published in Cell Metabolism. The findings support the idea that therapies designed to protect the adult nervous system by curbing the production of damaging free radicals might effectively increase longevity in other animals, including humans, the researchers said.

"We've identified a new point of intervention for extending life span by adjusting the amount of oxidative damage to nerve cells," said Stephen Helfand of the University of Connecticut Health Center in Farmington. Oxidative damage by free radicals is thought to be one of the primary forces driving the process of aging and determining life span, he added.

Free radicals, or reactive oxygen species (ROS), are a normal byproduct of energy production in the membrane bound cellular powerhouses known as mitochondria. Mitochondria produce chemical energy by setting up a gradient of hydrogen atoms, or protons, across their inner membranes. In the process, free radicals are generated.

Once the proton gradient is sufficiently established, protons begin to flow back across the membrane through a special enzyme that harnesses the energy released in the form of ATP molecules. However, so-called mitochondrial uncoupling proteins (UCPs) allow some of the protons to leak into the matrix, thus disrupting the electrochemical gradient and partially "uncoupling" proton flow from ATP synthesis. Mitochondrial uncoupling, in turn, lowers the membrane potential, decreases ATP production, and increases metabolic rate, among other functions that vary among tissues.

To explore the effect of mitochondrial uncoupling on the production of free radicals and aging, Helfand's group inserted human UCP2 into flies such that the gene could be turned on specifically in the mitochondria of nerve cells during adult life. Expression of hUCP2 in adult neurons extended life span on average 28 percent in female flies and 11 percent in males as compared to genetically identical flies not expressing hUCP2, they report.

That life span extension traced back to an increase in mitochrondrial uncoupling in the neuron-rich flies' heads, which led to a decline in ROS production and oxidative damage and an increased resistance to oxidative stress. What's more, the researchers found, the benefits to longevity came without a cost to the flies in terms of reproduction or physical activity levels.

"Our findings highlight the plasticity of mitochondria and suggest the intriguing possibility that genetic or pharmaceutical interventions altering mitochondrial respiration in adults could have significant positive effects on healthy life span" in other animals, the researchers wrote.