Sci. Aging Knowl. Environ., 12 May 2004
Mice that produce energy inefficiently live longer than those that don't
Sloppiness has unexpected virtues. Mice with slovenly metabolism live longer than their neat-freak cousins, new research shows. The finding supports the idea that reactive oxygen species (ROS), troublemaking molecules that attack cells, shorten life span.
One of the oldest theories of aging addresses why smaller animals, such as mice, die younger than do larger animals, such as humans. The rate-of-living hypothesis proposes that petite creatures, which generally have speedy metabolisms, burn through their time quicker. But the many exceptions--bats outlive dogs, for example--imperiled the idea's acceptance. Further work has revealed that the hypothesis doesn't hold up even within some species: Small dogs live longer than large dogs do. Some scientists argue that the best test would be to alter an individual animal's metabolism and determine the effect on life span, an impossible experiment.
Zoologist John Speakman of the University of Aberdeen, U.K., and colleagues decided to do the next best thing. They assessed metabolic differences and longevity in a mouse species whose members are about the same size and weight. Unlike inbred lab mice, these rodents are genetically diverse, providing variety in metabolic rates and life span. The scientists determined energy expenditure by subtracting the weight of byproducts excreted from the weight of food eaten. As a rate-of-living skeptic, Speakman expected to find no difference between the longest- and the shortest-lived animals. But he did--and in the opposite direction from the hypothesis's predictions. The top 25% of energy consumers lived 36% longer than did the bottom 25%.
Energy use might influence life span through ROS. The accumulation of ROS-induced damage over time causes aging, many researchers argue (see "The Two Faces of Oxygen"). Mitochondria make ROS while converting food into cellular fuel. This process creates a reservoir of protons, which later run through molecular turbines to generate fuel. Mitochondria make fewer ROS per food nibble when the proton reservoir isn't full. This situation arises when, for example, proteins called uncoupling proteins (UCPs) let protons leak from mitochondria (see "Bouncer at the Energy Bar"). To investigate whether proton leaks alter life span, the researchers measured seepage from skeletal muscle mitochondria in the longest- and shortest-lived mice. Tests on 6-month-old mice showed that mitochondria from animals destined to endure leaked more protons than did those from rodents that would die younger. Additional tests revealed that the difference in mitochondrial efficiency stemmed from activation of a particular UCP in long-lived mice.
The results support the idea that slowing ROS accumulation prevents an early demise, says biogerontologist Arlan Richardson of the University of Texas Health Science Center in San Antonio. Biochemist Bruce Kristal of Cornell University's Weill Medical College in New York City says that the notion that extra UCP activity might lead to a life-extending reduction in ROS is reasonable, based on the data, and "potentially very exciting." But he cautions that UCPs affect mitochondrial function in other ways, so demonstrating that reduced ROS production prolongs life will be difficult. Presumably, slackers won't be the ones working out those details.
May 12, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150