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Oxidative Stress and the Aging Brain: From Theory to Prevention.


In: Riddle DR, editor.


Brain Aging: Models, Methods, and Mechanisms. Boca Raton (FL): CRC Press/Taylor & Francis; 2007. Chapter 15.
Frontiers in Neuroscience.


Aging is characterized by a progressive decline in the efficiency of physiological function and by the increased susceptibility to disease and death. Currently, one of the most plausible and acceptable explanations for the mechanistic basis of aging is the “free radical theory of aging.” This theory postulates that aging and its related diseases are the consequence of free radical-induced damage to cellular macromolecules and the inability to counterbalance these changes by endogenous anti-oxidant defenses. The origin of this explanation has a foundation in the “rate of living theory” [1], according to which the lifespan of an individual depends on its rate of energy utilization (metabolic rate) and on a genetically determined amount of energy consumed during adult life. Pearl [1] proposed that the longevity of an organism is inversely correlated to its mass-specific metabolic rate: increasing an organism’s metabolic rate will decrease longevity, whereas factors that decrease the metabolic rate will increase longevity. The correlation between metabolic rate and longevity has been questioned due to the exception posed by birds, which have a high metabolic rate yet live much longer than mammals [2]. However, despite their high rate of oxygen consumption, it has been shown that birds have a low rate of free radical production in brain and in other tissues; their mitochondria produce up to 10-fold fewer reactive oxygen species (ROS) in vitro [3, 4]. This observation suggests that the mitochondrial rate of free radical production may be more important than the metabolic rate in terms of longevity. Indeed, the mitochondrial rate of free radical production seems to have a much stronger correlation with maximum longevity. Harman [5] originally proposed the “free-radical theory” of aging in the mid-1950s. He suggested that free radicals produced during aerobic respiration have deleterious effects on cell components and connective tissues, causing cumulative damage over time that ultimately results in aging and death. He initially speculated that free radicals were most likely produced through reactions involving molecular oxygen catalyzed in the cells by the oxidative enzymes and enhanced by trace metals such as iron, cobalt, and manganese. The skepticism first spread around this theory was weakened by the discovery in 1969 of the enzyme superoxide dismutase (SOD) [6]. The existence of an intracellular enzyme whose sole function is to remove superoxide anions (O2−•) has provided strong biological evidence that free radicals are involved in the aging process. In 1972, Harman expanded his original studies to include the involvement of mitochondria in the physiological processes of aging [7]. Harman proposed that mitochondria generate a significant amount of cellular energy and, through consumption of most of the intracellular oxygen, set the limit on the lifespan. Approximately 90% of cellular oxygen is consumed within the mitochondria, mainly in the inner membrane, where oxidative phosphorylation occurs. Since the early 1970s, several studies have emerged to give support to this theory, and the free radical theory of aging has been expanded to the mitochondrial free radical theory of aging. The premise of the mitochondrial free radical theory of aging is that mitochondria are both producers and targets of reactive oxidative species. According to the theory, oxidative stress attacks mitochondria, leading to increased oxidative damage. As a consequence, damaged mitochondria progressively become less efficient, losing their functional integrity and releasing more oxygen molecules, increasing oxidative damage to the mitochondria, and culminating in an accumulation of dysfunctional mitochondria with age. Although the deleterious effects of free radicals in the aging process have been demonstrated, ROS also are important in maintaining homeostasis. Recent studies have shown that ROS act as an additional class of small molecules that function as cellular messengers. For example, oxidants (nitrous oxide [NO]) act as signaling molecules to promote long-term potentiation (LTP) [8]. Moreover, it has been shown that stimulation of growth factors induces the production of free radicals that are subsequently involved in regulating the proliferative response [9]. The human organism is equipped with very efficient antioxidative defense mechanisms that, among others, include antioxidative enzymes such as SOD, catalase, glutathione peroxidase, and glutathione reductase [10]. When the production of ROS is prolonged, the endogenous reserves of antioxidants become insufficient, leading to cell damage. Similarly, the production of ROS below physiological levels induces a decreased proliferative response.

Copyright © 2007, Taylor & Francis Group, LLC.

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