The free radical theory of aging: A critical review

Although the free radical theory of aging was proposed several decades ago the involvement of radicals in the aging process remains obscure. Considerable progress has been made in detecting oxygen free radicals in biological environments and such radicals are now known to be generated during a variety of metabolic processes. The failure to achieve substantial lifespan extensions with antioxidants casts doubt on the validity of the theory as originally formulated. Further doubts about the theory arise from studies with cultured cell aging models, which fail to exhibit an expected sensitivity to the oxygen concentration in their growth environments. Only one nutritional manipulation, caloric restriction, is known to exert substantial life-extending effects; however its relationship to free radicals has not been resolved. Thus, present knowledge does not argue for a predominant role of free radicals in aging. However, compelling evidence exists for the involvement of free radicals in life-shortening diseases, including autoimmunity, cancer, atherosclerosis, and Parkinson's disease. Further studies of the effects of normally-occurring free radicals are warranted; quantitative data on damage associated with these species may reveal that previous analyses failed to identify critical cellular targets.