Sci. Aging Knowl. Environ., 16 February 2005
Short Circuit, Long Life
Sloppy wiring in mitochondria extends fly longevity
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2005/7/nf14
Dimming the lights can extend a bulb's life. Similarly, a protein that turns down the current running through cellular power plants prolongs fly survival, new results reveal. The protein works by squelching the production of noxious oxidants.
Cells need energy, but when their mitochondria turn food into fuel, the organelles churn out reactive oxygen species (ROS), malevolent compounds that can mar other molecules and that might hasten aging (see "The Two Faces of Oxygen"). Tweaking mitochondria to minimize ROS production might delay an organism's demise, and some researchers think that molecules called uncoupling proteins (UCPs) can perform the feat.
Mitochondria burn sugars and fats to create an imbalance of protons across their membranes--a process known as respiration. The protons flow back across the membrane through protein turbines, providing the energy to craft ATP. UCPs lighten the ROS load by creating membrane leaks that lessen the proton gradient before ATP forms, "uncoupling" respiration from ATP synthesis. By doing so, they speed respiration and diminish ROS formation by the metabolic machinery (see "Bouncer at the Energy Bar" and Nicholls Perspective). Some studies suggest that augmenting UCPs can protect organisms. For instance, mice that make extra UCPs resist stroke damage (see "Plugging a Deadly Leak"). In addition, mice with inefficient metabolism tend to live longer than normal, and they carry extra UCPs (see "Slipshod Survival").
To investigate whether boosting UCPs extends life, Fridell and colleagues introduced the gene for a particular human UCP--UCP2--into fruit fly neurons; they could turn it on by feeding flies the drug RU-486. When the scientists cranked on the gene in adult flies, females lived almost 30% longer and males lived about 11% longer than they did without UCP2. They also boasted 40% less of the oxidant hydrogen peroxide and carried 32% less of a particular oxidized lipid.
Next, the team analyzed isolated mitochondria from the insects. By measuring respiration rates under various conditions, they determined that mitochondria from animals with UCP2 produced energy less efficiently than did organelles from controls, an indicator of uncoupling. Adding a molecule that shackles UCP2 improved efficiency, suggesting that UCP2, rather than general membrane leakage, triggered the uncoupling. Boosting UCP2 in muscle also altered metabolism but did not extend life span, indicating that mitochondria activity in neurons influences longevity of the entire organism, at least in flies.
The work is the first demonstration that boosting UCP activity extends life span, says biochemist Martin Brand of the Medical Research Council in Cambridge, U.K. He praises the researchers for showing that UCP triggers uncoupling. Leaks can sprout in membranes for a variety of reasons, an artifact that has tainted previous experiments on UCP, he says. Mitochondrial biologist David Nicholls of the Buck Institute for Age Research in Novato, California, says that in order to maximize the benefits of UCP, researchers must decipher how cells control UCP. Too much of the protein at the wrong time could deplete neurons of needed energy, he says. Further work should shine a brighter light on UCP's role in life span.
February 16, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150