Imbalance of oxygen activation and energy metabolism as a consequence or mediator of aging.

Ever increasing numbers of aging theories suggest that free radicals are only one factor among others that may initiate stochastic disorders finally terminating life. It is therefore compelling not only to demonstrate the existence of increasing steady-state concentrations of free 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 influence and challenge oxygen homeostasis of cell respiration. Among these factors are environmental pollutants, therapeutics, and transient hypoxia. Although the nature of these "hits" is different, mitochondrial respiration was found to respond in a similar manner to each of them. The major derangement was an univalent electron leak to oxygen giving rise to the establishment of oxidative stress. Associated with this transformation, oxidative phosphorylation was impaired with the resultant reduction of cellular ATP. Mitochondria from senescent rats exhibited similar alterations of all cell parameters found when adult animals were exposed to "environmental stress" or transient ischemia. Age-related stimulation of mitochondrial oxygen radical generation is therefore suggested to result from accumulation of minihits during life. Based on our data, together with those from other laboratories, it is possible to assess the ranking order of oxygen radicals in the development of stochastic events associated with (or causing) aging.