Current thoughts on the role of mitochondria and free radicals in the biology of aging.

Abstract

THE charge of this discussion group was to assess what we know about the role of mitochondrial oxidative stress in aging and to determine potential directions for future research in this area. The Free Radical or Oxidative Stress Theory of Aging posed by Harman (1) just more than 50 years ago has been one of the leading and most studied theories in aging research. The basis of this theory is that free radical species generated by normal cellular processes translate to gradual and cumulative damage over the life span of an organism and contribute to age-related declines in physiological function and an increase in age-related pathologies. Despite the attractive and logical nature of this tenet, the existing evidence in support of the role of oxidative stress in aging remains essentially correlative. In addition, some recent studies using transgenic and knockout mouse models have provided data that do not support the theory as originally stated. For example, mice deficient in manganese superoxide dismutase (MnSOD) show increased oxidative damage to DNA, increased pathology, and yet no reduction in life span (2). Likewise, a number of other mouse models with increased or reduced levels of key antioxidant enzymes do not show changes in life span (3-5; Y. Zhang et al., in preparation). Part of the reason for the lack of conclusive evidence in support of this theory is that experimental approaches to date have not provided clear proof or tests of the principles underlying the theory. Below, we discuss some potential problems that may have contributed to the lack of conclusive evidence in this area to date, and we suggest strategies to more definitely investigate the role of oxidative stress in aging.