Sci. Aging Knowl. Environ., 31 October 2001
Gumming Up the Works: Animals that lack oxidative damage cleanser die young
Key Words: antioxidant MsrA (methionine sulfoxide reductase) life-span longevity hyperoxic
Abstract: For decades, researchers have explored whether accumulated oxidative gunk on molecules hastens an organism's decline (see "The Two Faces of Oxygen"). New results have now bolstered this idea: Absence of an enzyme that scrapes scum off proteins cuts life short. Previous work has shown that high levels of antioxidants prolong the lives of worms and fruit flies, and mice that lack the antioxidant enzyme manganese superoxide dismutase sicken and die when they are a few weeks old. But the current work demonstrates for the first time that an incomplete oxidative repair system curtails life-span in a mature mammal. Because the mice seem to develop normally into adulthood, they might prove useful for understanding the effects of oxidative damage later in life.
In bacteria and yeast, methionine sulfoxide reductase (MsrA) strips off the sulfoxides that accumulate on the amino acid methionine as a result of processes that convert food into energy. Deprive the single-celled critters of MsrA, and their survival rate plunges. Moskovitz and colleagues wondered whether mammals also require the enzyme to live normal lengths of time. To investigate, they engineered mice that lack MsrA. They exposed 4.5-month-old mutants and normal controls to an oxygen-rich environment; this treatment kills the mice by condensing a lifetime of oxygen exposure into several days. During that time, the MsrA-deficient mice accumulate excess amounts of oxidative damage in the proteins of their kidneys, livers, brains, and lungs. Furthermore, animals that lack the enzyme survive in the high-oxygen environment for approximately 10% less time than do normal mice; under regular oxygen conditions, the life-span difference inflates to 40% between animals missing the MsrA gene and those that retain at least one copy of it. All of the animals eat comparable quantities and weigh the same when they die, a result that rules out the possibility that lower food intake causes longer life in the normal mice.
These data are consistent with the idea that oxidative damage contributes to normal aging, but other explanations exist. In mammals, MsrA might play a vital role unrelated to its antioxidant properties. Moreover, a mutation that truncates life-span doesn't necessarily speed the rate of aging; it might simply weaken the animal and, for example, render it more susceptible to a fatal infection. Extending mouse life-span by overproducing MsrA would more strongly implicate this enzyme in the aging process. An earlier paper by the same group hints at this possibility: T cells of the human immune system better withstand one type of oxidant--hydrogen peroxide--when they overproduce MsrA. Perhaps future experiments will show that mice with extra power to scrub their proteins clean can squeak into unusually ripe old ages.
See Bulletin Board for a conversation about this topic.
J. Moskovitz, S. Bar-Noy, W. M. Williams, J. Requena, B. S. Berlett, E. R. Stadtman, Methionine sulfoxide reductase (MsrA) is a regulator of antioxidant defense and lifespan in mammals. Proc. Natl. Acad. Sci. U.S.A., 16 October 2001 [e-pub ahead of print]. [Abstract] [Full Text]
Citation: K. Miller, Gumming Up the Works: Animals that lack oxidative damage cleanser die young. Science's SAGE KE (31 October 2001), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2001/5/nw16
Science of Aging Knowledge Environment. ISSN 1539-6150