Antioxidant enzyme activities are not broadly correlated with longevity in 14 endotherm species

Department of Biological Sciences, Brock University, 500 Glenridge Ave., St. Catharines, ON, Canada L2S 3A1.
Age (Impact Factor: 3.45). 06/2010; 32(2):255-70. DOI: 10.1007/s11357-010-9131-2
Source: PubMed


The free radical theory of ageing posits that accrual of oxidative damage underlies the increased cellular, tissue and organ dysfunction and failure associated with advanced age. In support of this theory, cellular resistance to oxidative stress is highly correlated with life span, suggesting that prevention or repair of oxidative damage might indeed be essential for longevity. To test the hypothesis that the prevention of oxidative damage underlies longevity, we measured the activities of the five major intracellular antioxidant enzymes in brain, heart and liver tissue of 14 mammalian and avian species with maximum life spans (MLSPs) ranging from 3 years to over 100 years. Our data set included Snell dwarf mice in which life span is increased by approximately 50% compared to their normal littermates. We found that CuZn superoxide dismutase, the major cytosolic superoxide dismutase, showed no correlation with MLSP in any of the three organs. Similarly, neither glutathione peroxidase nor glutathione reductase activities correlated with MLSP. MnSOD, the sole mitochondrial superoxide dismutase in mammals and birds, was positively correlated with MLSP only for brain tissue. This same trend was observed for catalase. For all correlational data, effects of body mass and phylogenetic relatedness were removed using residual analysis and Felsenstein's phylogenetically independent contrasts. Our results are not consistent with a causal role for intracellular antioxidant enzymes in longevity, similar to recent reports from studies utilising genetic modifications of mice (Pérez et al., Biochim Biophys Acta 1790:1005-1014, 2009). However, our results indicate a specific augmentation of reactive oxygen species neutralising activities in brain associated with longevity.

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    • "Regarding the unusually low levels of cytoplasmic protein oxidation in the human cortex, these proteins might profit more than membrane proteins from enhanced enzymatic antioxidant defenses, which tend to be considerably more active in the larger brains of longer-lived animals (Page et al., 2010). For example, catalase and manganese superoxide dismutase have been found to be more than 3-fold more active in cow or deer brain than in mouse or rat brain (Page et al., 2010). Most likely, a related effect also accounts for the low level of lipid peroxidation observed in human tissues. "
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    ABSTRACT: Oxidative stress is thought to be one of the main mediators of neuronal damage in human neurodegenerative disease. Still, the dissection of causal relationships has turned out to be remarkably difficult. Here, we have analyzed global protein oxidation in terms of carbonylation of membrane proteins and cytoplasmic proteins in three different mammalian species: aged human cortex and cerebellum from patients with or without Alzheimer’s disease, mouse cortex and cerebellum from young and old animals, and adult rat hippocampus and cortex subjected or not subjected to cerebral ischemia. Most tissues showed relatively similar levels of protein oxidation. However, human cortex was affected by severe membrane protein oxidation, while exhibiting lower than average cytoplasmic protein oxidation. In contrast, ex vivo autooxidation of murine cortical tissue primarily induced aqueous protein oxidation, while in vivo biological aging or cerebral ischemia had no major effect on brain protein oxidation. The unusually high levels of membrane protein oxidation in the human cortex were also not predicted by lipid peroxidation, as the levels of isoprostane immunoreactivity in human samples were considerably lower than in rodent tissues. Our results indicate that the aged human cortex is under steady pressure from specific and potentially detrimental membrane protein oxidation. The pronounced difference between humans, mice and rats regarding the primary site of cortical oxidation might have contributed to the unresolved difficulties in translating into therapies the wealth of data describing successful antioxidant neuroprotection in rodents.
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    • "Similar measurements of two other antioxidant enzymes, glutaredoxin and thioredoxin reductase, also failed to reveal significant positive correlations with lifespan in any of these three tissues. Thus, of 21 tested associations , only two showed the hypothesized positive correlations (Page et al. 2010; Salway et al. 2011). Measurements made in whole-tissue homogenates, as above, provide little insight into subcellular compartment-specific ROS neutralization. "
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    ABSTRACT: In animal mitochondria, the four electron reduction of molecular oxygen to produce water at respiratory complex IV is the terminal step in substrate oxidation. However, respiratory complexes I, II, and III can participate in the single electron reduction of oxygen to produce the radical species superoxide. This progenitor reactive oxygen species (ROS) participates in a number of reactions that generate other ROS. These molecules may react with, and damage, intracellular macromolecules, leading to cellular dysfunction. Mitochondrial ROS production is often considered from this perspective of macromolecular damage and is central to the “oxidative damage theory of aging”, which suggests the accumulation of oxidative damage in animal cells underlies the aging phenotype and limits lifespan. In this review, we discuss some experimental results accumulated over the past decade that are inconsistent with this theory. A limitation of the theory is that it presupposes mitochondrial ROS are inherently harmful. However, it is increasingly apparent that some basic cellular functions are physiologically regulated by normal levels of mitochondrial ROS. For example, cell growth and division, the apoptotic pathway, and mitochondrial fusion–fission dynamics all appear to be redox-regulated by mitochondrial ROS and perhaps the matrix manganese superoxide dismutase (MnSOD). Therefore, it is less clear how the balance between ROS regulation of normal cellular activities and ROS-mediated macromolecular damage is maintained and how this relates to aging and longevity in animals.
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    • "In contrast, catalase activities are not different and glutathione peroxidase activities are an order of magnitude lower in the naked mole rat liver. Page et al. [46] measured all five of the antioxidant enzymes listed above in brain, heart and liver tissues of 14 species of endotherm vertebrates. Of 15 tested correlations (five enzymes x three tissues), only two were positive and statistically significant. "
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    ABSTRACT: Since its inception more than four decades ago, the Mitochondrial Free Radical Theory of Aging (MFRTA) has served as a touchstone for research into the biology of aging. The MFRTA suggests that oxidative damage to cellular macromolecules caused by reactive oxygen species (ROS) originating from mitochondria accumulates in cells over an animal's lifespan and eventually leads to the dysfunction and failure that characterizes aging. A central prediction of the theory is that the ability to ameliorate or slow this process should be associated with a slowed rate of aging and thus increased lifespan. A vast pool of data bearing on this idea has now been published. ROS production, ROS neutralization and macromolecule repair have all been extensively studied in the context of longevity. We review experimental evidence from comparisons between naturally long- or short-lived animal species, from calorie restricted animals, and from genetically modified animals and weigh the strength of results supporting the MFRTA. Viewed as a whole, the data accumulated from these studies have too often failed to support the theory. Excellent, well controlled studies from the past decade in particular have isolated ROS as an experimental variable and have shown no relationship between its production or neutralization and aging or longevity. Instead, a role for mitochondrial ROS as intracellular messengers involved in the regulation of some basic cellular processes, such as proliferation, differentiation and death, has emerged. If mitochondrial ROS are involved in the aging process, it seems very likely it will be via highly specific and regulated cellular processes and not through indiscriminate oxidative damage to macromolecules.
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