Oxidative stress in brain aging: Implications for therapeutics of neurodegenerative diseases
Introduction
Brain aging has become an area of intense research and a subject of much speculation fueled largely from the widely recognized fact that age is the biggest risk factor in most neurodegenerative diseases. It is widely held that oxidative stress increases in brain during aging. In this report we present a fresh examination of this concept based upon a selective and careful review of the recent literature. This review has primarily focused on the most rigorous data obtained from human studies. Trends from these studies have then been compared, in some cases, with some of the best experimental animal studies to help evaluate the general validity of the observations. We have especially focused on those reports where rigorous techniques and protocols have examined parameters useful in evaluating if the basic science supports the concept that oxidative stress increases with brain age.
In conducting a fresh examination of this field, we have kept foremost in mind these basic questions: (a) does oxidative stress (and oxidative damage) increase as brain aging occurs; (b) what parameters can be used to unambiguously answer the questions posed; (c) what are the underlying processes involved causing the oxidative stress changes observed with age; and (d) are there approaches and/or therapeutic possibilities that may act fundamentally to alter and/or inhibit the age-mediated changes in oxidative stress that influence the development of neurodegenerative diseases? This review provides a critical perspective on these questions.
Section snippets
Basic concepts of oxidative stress in brain
We and others have previously reviewed the field of oxidative stress in brain [23], [24], [25]. Our original overall rationale to examine oxidative stress in aging brain focused on the following premise: (a) brain has a high content of easily peroxidizable unsaturated fatty acids (especially high in 20:4 and 22:6 fatty acids); (b) brain requires very high amounts of oxygen per unit weight (about 20% of the total amount used in humans); (c) brain has a high content of both Fe and ascorbate
Importance of age in neurodegenerative diseases
Two recent studies provide some of the best data illustrating very clearly the importance of age on the incidence of stroke [112] and on cognitive impairment (CI) as well as development of Alzheimer’s disease (AD) [79]. Fig. 2 presents a summary of the stroke data and clearly shows the effect of age on the incidence of stroke in men and women. Earlier we showed that increasing age was extremely important on the severity of outcome of experimental stroke in gerbils [28] and until now a careful
Does microvascular changes occur in aging brain?
In the case of the significant increase of stroke with age, it is reasonable to expect that age-dependent changes in the brain vasculature may be one primary factor. Brain microvasculature represents a very large surface area, i.e., we have estimated 400 ft.2 for a human brain based on neuronanatomical estimates of the total length of the microvasculature from which the surface area was calculated. Microvasculature alteration with age and its contribution to neurodegenerative diseases is most
Does oxidized protein increase in aging brain?
Accumulation of oxidized proteins in many tissues is widely considered a hallmark of aging [105]. There is a paucity of careful studies of oxidized protein in brain. Nevertheless, most of the studies done in this area conclude that the amount of oxidized protein does increase with age. Perhaps the best study conducted thus far in humans was done by Smith et al. [103]. In this study, the amount of protein oxidation was measured by a general 2,4-dinitrophenylhydrazine assay of protein carbonyl
Do lipid peroxidation products increase in aging brain?
Peroxidation of biological lipids yields a large number of compounds. The most widely studied and apparently the most important from a biomedical perspective are the active aldehydes and the isoprostanes. Non-enzymatic peroxidation of arachidonic acid causes the formation of specific peroxidation products referred to as F2-isoprostanes [94]. Measurement of the level of these compounds has recently become considered one of the best methods to index in vivo oxidative damage to lipids. In the
Does oxidative damage to DNA increase in brain aging?
In general, oxidative damage to DNA occurs at all times leading to many oxidation-damaged bases and strand breaks. Utilizing mass spectroscopy and other analytical methods, about 100 different oxidative damaged bases have been found. Many repair enzyme systems have evolved to remove and replace the damaged nucleosides and repair the broken strands. One of the most widely studied base lesions is 8-OHdG. This oxidized base is mutagenic and at least three different proteins are involved in its
Do neuroinflammatory processes occur in aging brain?
The hallmark of inflammatory processes, in general, is enhanced production of ROS. Therefore, it is rationale to associate enhanced oxidative stress with neuroinflammatory processes. The association of enhanced ROS with neuroinflammatory processes has been reviewed recently [16]. Numerous reports have emphasized a clear association of enhanced neuroinflammatory processes with neurodegenerative diseases [22], [52], [85], [120], [121]. The question remains, however, does normal aging brain have
Novel therapeutics for neurodegenerative diseases
Basic research into the mechanistic basis of oxidative stress in aging brain has provided many new leads and approaches for the possible treatment of neurodegenerative diseases. This is a very intensely studied area and the subject area is much too large except for only briefly summarizing it here. Probably the two major categories of therapeutic approaches that have arisen directly from the subject areas we have discussed include Vitamin E supplementation and anti-neuroinflammatory drugs. Two
Acknowledgements
This research was made possible by monies from the Merrick Chair for Aging Research and in part by the National Institutes of Health (NS35747, PO1-AG05119 and 5P50-AG05144), the Oklahoma Center for the Advancement of Science and Technology (OCAST H67-097), and the Abercrombie Foundation.
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