Running Lean and Mean: Drastic diet foils free radicals without slowing metabolism (Calorie restriction; Reactive oxygen species)
Authors: Leslie Mitch 
Published: August 2003

Driving less reduces pollution. But using a fuel-efficient car abates toxic output without restricting mobility. A new study suggests that slashing food consumption--which makes worms, rodents, and other lab denizens live longer--might extend life in a similar manner: by tuning up the cell's energy-producing machinery rather than by stemming energy output.

No one knows why dramatically reducing food intake--a regimen called calorie restriction--extends life or whether it works in humans. Many scientists suspect that skimpy meals suppress manufacture of reactive oxygen species (ROS), DNA-hammering molecules spawned by metabolism that might drive aging (see
"The Two Faces of Oxygen"
). However, few studies have tried to prove that connection. One of the first came last year, when López-Torres and colleagues showed that heart cells from calorie-restricted rats generated less hydrogen peroxide, a kind of ROS, than did cells from normal animals.

Investigating further, the same team raised rats on a normal diet for a year, then chopped the rations for one group by 40%--a typical life-extending regime. After another year, the researchers killed both sets of animals, removed their livers, and isolated mitochondria, the energy-producing organelles where most ROS materialize. The team measured the amount of hydrogen peroxide and the degree of DNA damage in the mitochondria. Mitochondria from the calorie-restricted animals made nearly 50% less hydrogen peroxide and showed only half the DNA damage evident in organelles from well-fed animals. According to the researchers, the findings show that calorie restriction benefits the liver, a hardworking hub of metabolism.
Additional results challenge scientists who argue that calorie restriction works by decreasing metabolic rate. López-Torres and colleagues measured oxygen use with an oxygen-sensitive electrode. They found that mitochondria of the calorie-restricted rodents consumed the same amount of oxygen as those of controls, indicating that metabolic rate remained constant. Their results support an alternative explanation for how calorie restriction works: It extends life by boosting metabolic efficiency. Mitochondria harvest energy by passing electrons along a chain of proteins, but sometimes those electrons escape the chain and instead spark the formation of ROS. In the hungry animals, the mitochondria produced less hydrogen peroxide for each electron pumped into the chain, hinting that calorie restriction doesn't curb energy production but instead makes mitochondria burn cleaner.
"It's an encouraging paper," says Bruce Kristal, a biochemist at Cornell University's Weill Medical College in White Plains, New York. To generalize the findings, he says, the researchers need to obtain the same results in other animals and other strains of rats. The next step is to work out how the mitochondria adapt to fewer calories, says David Nicholls, a mitochondrial biologist at the Buck Institute for Age Research in Novato, California. Looking for changes in the amounts of particular proteins inside the mitochondria might reveal how calorie restriction chokes off the production of ROS, he says. That might help scientists figure out ways to reduce toxic emissions without sacrificing pep.
--Mitch Leslie; suggested by Holly Van Remmen and Arlan Richardson

M. López-Torres, R. Gredilla, A. Sanz, G. Barja, Influence of aging and long-term caloric restriction on oxygen radical generation and oxidative DNA damage in rat liver mitochondria.
Free Radic. Biol. Med.
32
, 882-889 (2002).
[Abstract]
[Full Text]