IMBALANCE OF OXYGEN ACTIVATION AND ENERGY-METABOLISM AS A CONSEQUENCEOR MEDIATOR OF AGING

Over increasing numbers of aging theories suggest that free radicals a re only one factor among others that may initiate stochastic disorders finally terminating life. It is therefore compelling not only to demo nstrate the existence of increasing steady-state concentrations of fre e oxygen radicals during senescence, but it is essential to show that they act in concert with other postulated triggering factors of aging. We have recently shown that various factors may have a life-long infl uence and challenge oxygen homeostasis of cell respiration. Among thes e factors are environmental pollutants, therapeutics, and transient hy poxia. Although the nature of these ''hits'' is different mitochondria l respiration was found to respond in a similar manner to each of them . The major derangement was an univalent electron leak to oxygen givin g rise to the establishment of oxidative stress. Associated with this transformation, oxidative phosphorylation was impaired with the result ant reduction of cellular ATP. Mitochondria from senescent rats exhibi ted similar alterations of all cell parameters found when adult animal s were exposed to ''environmental stress'' or transient ischemia. Age- related stimulation of mitochondrial oxygen radical generation is ther efore suggested to result from accumulation of minihits during life. B ased on our data, together with those from other laboratories, it is p ossible to assess the ranking order of oxygen radicals in the developm ent of stochastic events associated with (or causing ?) aging. (C) 199 7 Elsevier Science Inc.