Asecond focus of aging in the CNS is oxidative stress and the mitochondrion. Reactive oxygen species (ROS) are oxidants that, if unrestricted, can cause oxidative damage to the mitochondria, cellular proteins, lipids, and nucleic acids. ROS are the normal byproducts of cellular metabolism in the mitochondrion. Free radicals are chemical species with a single unpaired electron, which is highly reactive. The majority of free radicals that damage biological systems are oxygen radicals and other ROS, which are byproducts formed in the cells of aerobic organisms. The generation of mitochondrial ROS is a consequence of oxidative phosphorylation, a process that occurs in the inner mitochondrial membrane and one that involves the oxidation of NADH to produce energy. Under normal circumstances our natural antioxidant defense systems detoxify the superoxide anion by the mitochondrial manganese (Mn) superoxide dismutase
(MnSOD) to yield hydrogen peroxide (H2O2), and the H2O2 is then converted to H2O by catalase. H2O2 in the presence of reduced transition metals can also be converted to hydroxyl radical.
In the aging brain as well as in the case of several neurodegenerative diseases, there is a decline in the normal antioxidant defense mechanisms that increase the vulnerability of the brain to the deleterious effects of oxidative damage.18 The antioxidant enzymes superoxide dismutase (SOD), catalase, glutathione peroxidase, and glutathione reductase, for example, display reduced activities in the brain of patients with Alzheimer's disease.19 It is believed that free radicals of mitochondrial origin are one of the primary causes of mitochondrial DNA (mtDNA) damage. Several studies have found increased levels of 8- hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, in mtDNA in the aged brain.20 Other studies have shown that the age-related increase in oxidative damage to mtDNA is greater than the oxidative damage that occurs to nuclear DNA in rodents.21,22 For instance, oxidative DNA damage has been detected in human brain mtDNA and in rat liver at levels more than 10 times higher than in nuclear DNA from the same tissue.20,23-25
Aging is also accompanied by changes in membrane fatty acid composition, including a decrease in the levels of polyunsaturated fatty acids (PUFAs) and an increase in monosaturated fatty acids. PUFAs, such as arachidonic acid (AA), are abundant in the aging brain and are highly susceptible to free radical attack. A correlation between the concentration of AA and LTP has been shown,8,26 suggesting that oxidative depletion of AA levels may relate to a cognitive deficit in rats. For example, levels of AA are decreased in the hippocampus of aged rats with impaired ability to sustain LTP. Oxidative damage to lipids can also occur indirectly through the production of highly reactive aldehydes. Peroxidation of AA forms malondialde-hyde (MDA), which induces DNA damage by reacting with amino acids in protein to form adducts that disrupt DNA base-pairing. Increased levels of MDA have been found in the aged canine brain.27 In the aged human brain, MDA has been found to be increased in inferior temporal cortex and in cytoplasm of neurons and astrocytes,28 as well as in the hippocampus and cerebellum of aged rodents.29 Peroxidation of linoleic acid forms 4-hydroxy-2-nonenal (HNE). HNE is more stable than free radicals and it is able to migrate to sites that are distant from its formation, resulting in greater damage. The most damaging effect of HNE is its ability to form covalent adducts with histidine, lysine, and cysteine residues in proteins enabling a modification in their activity.30 It has been shown that the HNE-modified proteins, along with neur-ofibrillary tangles, are present in the senile plaques in aged dogs.31 Increased levels of HNE have also been found in Alzheimer's and Parkinson's disease.32 This finding gave support to the hypothesis that lipid peroxidation contributes to the deterioration of CNS function. Most of the studies conducted to assess the role of protein oxidation in aging brains conclude that there is an increase of oxidized proteins. An increase in the oxidation of mitochondrial proteins with age has been demonstrated by measuring the levels of protein carbonyl groups in the human cerebral cortex along with age.33 Carbonyl formation can occur through a variety of mechanisms including direct oxidation of amino acid side chains and oxidation-induced peptide cleavage. Increasing evidence suggests that protein oxidation may be responsible for the gradual decline in physiological functioning that accompanies aging. Elevated protein carbonyls have been shown to be present in the hippocampus of aged rats with memory impairment.34 Increased protein carbonyl levels were found in the frontal and occipital cortex of aged humans.33'35 and rats.36 Measuring protein 3-nitrotyrosine (3-NT) levels is another way to assess the oxidative modification of proteins. Increased 3-NT levels have been identified in the hippocampus and the cerebral cortex of aged animals as well as in the CSF of aged human and in the white matter of aging monkeys.37-39 3-NT immunoreactivity has been observed in the cerebellum in the Purkinje cell layer, the molecular layer, and in the cerebellar nuclei of aged rats.40 However, contradictory findings of decreased protein 3-NT levels of brain homogenate were reported in aged Wistar rats. Recently, proteomics studies enabled the identification of specific proteins that undergo oxidative stress in Alzheimer's disease (AD) patients.41,42
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