Oxidative Stress and the Aging Brain: From Theory to Prevention

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 (O