ABSTRACT
Numerous studies have been carried out in an attempt to elucidate the biochemical and molecular mechanisms of the aging process. The basic biochemical process underlying the aging process was first introduced in 1956 with the free radical theory of aging (1). This theory states that oxidative damage to DNA and other cellular components is the main driving force behind aging. More recent versions of this theory predict that mitochondria are a major source of reactive oxygen species (ROS) that cause oxidative damage. The idea that genetically damaged mitochondria accumulate with time and are causally responsible for the aging phenotype via a disturbed energy production and excessive ROS production is at the core of the so-called mitochondrial theory of aging (2). In 1989, Monnier proposed the Maillard theory of aging, stating that the fundamental aging process might be mediated by the Maillard reaction (the nonenzymatic reaction between reducing sugars and proteins, also known as the glycation process) (3). The free radical-glycation/Maillard reaction theory of aging brings those two views together. It suggests that free radicals (ROS) and reactive carbonyl species (RCS) from Maillard reactions may represent interactive elements of a more complex biochemical pathway. The age-related deterioration then results from the cumulative damage induced by ROS, by RCS, and by their interactions (4). Glycation of mitochondrial proteins results in the excessive formation of intracellular superoxide (5). It was recently shown that senescent human fibroblasts are characterized by a partial uncoupling of the respiratory chain, resulting in increased proton leakage and enhanced electron transport activity (6). Sto¨ckl et al. (7) even suggested a cause-effect relationship between impaired mitochondrial coupling and premature senescence. Others have proposed a key role for high-level ROS-generating enzymes of the NOX family NADPH oxidases in causing age-related diseases (8,9). Oxidative damage to DNA has been found to be an important determinant of life span at least in lower organisms such as Drosophila melanogaster. Studies in higher organisms argue for a role of oxidative stress in age-related disease, especially cancer; however, the data remain inconclusive on whether oxidative stress determines life span (10). The general consensus appears to be that the aging process is multifactorial and that it results from an accumulation of damage with an underlying glycoxidative mechanism. Our interpretation of the glycoxidative model of aging is presented schematically in Figure 1.
