THE FREE RADICAL THEORY OF AGING
The free radical theory of aging, proposed by Harman in 1956,1 is one of the most widely accepted theories to explain the cause of aging.2 Free radicals, also known as reactive oxygen species (ROS), are compounds formed when oxygen molecules combine with other molecules yielding an odd number of electrons. An oxygen molecule with paired electrons is stable; however, oxygen with an unpaired electron is “reactive” because it seeks and seizes electrons from vital components leaving them damaged.3 DNA, cytoskeletal elements, cellular proteins, and cellular membranes may all be adversely affected by activated oxygen species.4 ROS have not only been implicated in the overall aging process,5 but are believed to be involved cutaneously in causing photoaging, carcinogenesis, and inflammation. It is known that ultraviolet (UV)-induced damage to the skin is in part mediated by reactive oxygen intermediates.6 If antioxidants can absorb some of the resulting free radicals, they may be able to mitigate UV-induced damage to the skin. Free radicals may also lead to inflammation, which is believed to play a role in skin aging.6 Lipid peroxidation, another sequela of free radical production, causes harm to cell membranes and can lead to skin aging, atherosclerosis, and other signs of aging. Free radicals are also thought to contribute to the development of skin cancer. There are multiple studies in the literature describing the role of free radicals and skin cancer. The exact mechanisms for all of the detrimental effects of free radicals have not been completely elucidated, however.
Free radicals also play an important role in intrinsic and extrinsic skin aging. They are formed naturally through normal human metabolism, but can be produced as a result of exogenous factors, such as UV exposure, air pollution, smoking, radiation, alcohol use, exercise, inflammation, and exposure to certain drugs or heavy metals such as iron. In fact, UV radiation, stress, cigarette smoke, pollution, drugs, and diet can be sources of ROS such as superoxide, hydroxyl anion, hydrogen peroxide (H2O2), and singlet oxygen. Recent data suggest that free radicals can induce a number of transcription factors, such as activator protein-1 (AP-1) and nuclear factor-κB (NF-κB).7 Further, ROS increase the expression of matrix metalloproteinases (MMPs), specifically collagenase, which has the ability to degrade skin collagen.8,9 Collagenase formation occurs as a result of the activation of transcription factors c-Jun and c-Fos, which combine to produce the AP-1 that, in turn, prompts the activity of the MMPs.10 Additionally, the mitogen-activated protein kinase (MAPK) pathway is also a target of oxidative stress11 (see Chapter 6).
The body has developed defense mechanisms, known as antioxidants, which protect against the ravages of free radicals by reducing and neutralizing them. Antioxidative enzymes that naturally-occur in the skin include superoxide dismutase, catalase, and glutathione peroxidase (GPX); the nonenzymatic endogenous antioxidative molecules are ...