Intervention cuts nerve damage, boosts life span

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Medical News Today 16 Feb 2005

Intervention cuts nerve damage, boosts life span

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 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.

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Yih-Woei C. Fridell, Adolfo Sánchez-Blanco, A. Silvia, and L.

Helfand: " Targeted expression of the human uncoupling protein 2 (hUCP2) to adult

neurons extends life span in the fly "

The researchers include Yih-Woei C. Fridell, Adolfo Sánchez-Blanco, A.

Silvia, and L. Helfand of the School of Medicine at the University of

Connecticut Health Center. This work was supported by grants from the NIA,

American Federation for Aging Research/Pfizer Research Award, Glenn/AFAR

scholarship on Research, and the Donaghue Foundation and the Ellison Medical

Foundation. S.L.H. is an Ellison Medical Research Foundation Senior Scholar and

a member of the Scientific Advisory Board of Elixir Pharmaceuticals, Inc.

Publishing in Cell Metabolism, Volume 1, Number 2, February 2005, pages 145-152.

http://www.cellmetabolism.org