Is Less Enough?
Authors: Davenport R. John 
Published: August 2003

COLD SPRING HARBOR, NEW YORK
--A rusty bike might screech around the turns, but it gets you where you want to go. Similarly, mice with half-doses of a protective enzyme suffer more oxidative damage and cancer than normal but live as long as animals with a complete defense system do, according to work presented here 6 October 2002 at the Cold Spring Harbor Laboratory's Molecular Genetics of Aging meeting.

Molecules called reactive oxygen species (ROS), formed as a byproduct of metabolism, glom onto proteins, DNA, and lipids and generally disrupt cellular activities (see
"The Two Faces of Oxygen"
). ROS appear to promote aging, but exactly how much they contribute isn't clear. To probe that question, scientists have impaired the cellular defenses against ROS and measured the effect on life-span. The results can be fatal: Mice that lack both copies of the
Sod2
gene--which produces MnSOD, an enzyme that defuses ROS in the mitochondria--die almost immediately after birth. But animals with one good copy of the gene develop normally.

Physiologist Arlan Richardson and colleagues at the University of Texas Health Science Center in San Antonio wondered whether the MnSOD-deficient mice accumulate excess oxidative damage and age rapidly. The team extracted DNA from the animals and measured the amount of a chemical change inflicted by ROS. Oxidative damage in animals with full and half-loads of MnSOD increased with age, but the absolute amounts were higher in mice with less of the enzyme. Adolescent mutants, for example, suffered as much DNA damage as did normal littermates four times their age. The molecular marring appeared to spur cancer: Animals with a half-dose of MnSOD developed tumors twice as often as normal.

The group expected that the buildup of DNA damage and the associated increase in cancer would reduce life-span, but animals with only one copy of the
SOD2
gene died at the same rate as did animals with two copies. Both groups of rodents also showed similar amounts of skin and eye damage, and their immune cells divided equally well in petri dishes when goaded with growth-spurring chemicals. Together, the results suggest that increasing the oxidative load on an organism does not necessarily speed aging, says Richardson.

"It's a surprising result, given the oxidative theory," says molecular geneticist Leonard Guarente of the Massachusetts Institute of Technology in Cambridge. "At least in these mice, oxidative stress doesn't limit life-span." Other researchers say that the work doesn't threaten the theory. "One experiment in one genetic background isn't going to make 1000 studies irrelevant," says Simon Melov, a biochemist at the Buck Institute for Age Research in Novato, California. "Oxidative damage might be more important in some contexts than in others." Mice commonly die of cancer, which can arise from mutations caused by ROS, but geneticist Doug Wallace of the University of California, Irvine, notes that the genetic line used in the study might be particularly susceptible to a lethal condition that kills before cancer does. Sorting out the details could help researchers discern when oxidative damage shortens a body's lifetime and when it just creates a rough ride.

--R. John Davenport

A. Richardson, Using transgenic and knockout mice to study the role of oxidative stress in aging. Cold Spring Harbor Laboratory, Molecular Genetics of Aging, 2 to 6 October 2002, Cold Spring Harbor, New York.
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