Mice live longer and show signs of delayed aging when they express the antioxidant enzyme catalase in their mitochondria, according to a report appearing today in Science online. The results of the study, by Peter Rabinovitch and his colleagues at the University of Washington in Seattle, support the theory that oxidative damage to cells contributes to aging and eventually death in higher animals. Their results also show that mitochondria, now under intense scrutiny for their role in age-related neurodegenerative disorders, are an important source of toxic reactive oxygen species (ROS) in normal cells. ROS are produced as a byproduct of the pathway that generates energy in the mitochondria, the cell’s power plant. During respiration, electrons escape the mitochondria and react with free oxygen to produce highly toxic negative ions. If left alone, the ions inflict irreversible damage to proteins, lipids, and DNA. Cells can defend themselves with detoxifying enzymes like catalase and superoxide dismutase that break down ROS. The balance between production of ROS and their destruction by antioxidant enzymes determines the rate at which oxidative alterations accumulate, and may set an upper limit on how long we can live. Increasing oxidative damage is also hypothesized to trigger aging-related Alzheimer disease and other neurodegenerative disorders (see live discussion of the “mitochondrial cascade hypothesis” of AD).
To determine whether ROS, and in particular hydrogen peroxide (H2O2), do in fact limit lifespan in mammals, first author Samuel Schriner worked with colleagues from the University of California, Irvine, and University of Texas at San Antonio to create transgenic mice overexpressing human catalase in their mitochondria. Catalase, found mainly in peroxisomes, rapidly converts toxic H2O2 into water and oxygen. In two independent lines of mice, the mitochondrial catalase (MCAT) expressers showed about a 20 percent, or a 5-month, increase in median and maximal lifespan compared to wild-type littermates. The ability of catalase to increase longevity was most apparent when the enzyme was targeted to mitochondria: Mice that expressed the enzyme in peroxisomes (PCAT) had a slightly longer median lifespan, but no increase in maximal life. Nuclear catalase expression had no effect on either parameter.
MCAT mice appeared to age more slowly than their control littermates by several measures. While histological comparisons showed little difference between WT and MCAT lines in young mice (9-11 mo), aged transgenic mice (20-25 mo) had significantly less arteriosclerosis and cardiomyopathy than their wild-type siblings. One strain showed a delay in cataract formation in mid-life. Biochemical studies showed that slower aging in the MCAT mice was associated with a lower level of oxidative stress and DNA damage. H2O2 production by cardiac mitochondria from MCAT mice was decreased 25 percent, and mitochondria containing catalase were protected from the toxic effects of H2O2. Age-related increases in oxidative damage to total DNA, and fragmentation of mitochondrial DNA were also slowed in skeletal muscle of MCAT mice.
Despite the indication that MCAT mice were at least partially spared the ravages of time in terms of oxidative damage, catalase is not quite a fountain of youth. Its effects on lifespan, while significant, are much smaller than those observed with caloric restriction or in some genetic models of aging. The question of whether mitochondrial catalase might be additive or synergistic with other life-lengthening treatments was not addressed. The researchers did show that peroxisomal catalase expression together with superoxide dismutase overexpression increased median lifespan more than either alone, but maximum time of survival was not affected. They speculate that because MCAT mice survive longer than PCAT mice, the combination of MCAT and superoxide dismutase may show even more benefit.
Like the aging brain, AD and Parkinson disease brains show signs of oxidative stress, and mitochondrial dysfunction has been reported in both diseases. In models of AD, ROS appear to enhance Aβ deposition (see ARF related news story), and Aβ itself can be toxic to mitochondria (see ARF related news story), causing an increase in ROS. One of the two MCAT transgenic lines displayed increased catalase expression in the brain, and these animals will no doubt come in handy to further explore the links between the accumulated oxidative insults of normal aging and sporadic AD or other age-related neurodegenerative disease.—Pat McCaffrey
- Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf N, Van Remmen H, Wallace DC, Rabinovitch PS. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science. 2005 Jun 24;308(5730):1909-11. PubMed.