Oxidative damage elicited by imbalance of free radical scavenging enzymes is associated with large-scale mtDNA deletions in aging human skin

Mitochondrial DNA (mtDNA) mutations and impaired respiratory function have been demonstrated in various tissues of aged individuals. We hypothesized t hat age-dependent increase of ROS and free radicals production in mitochond ria is associated with the accumulation of large-scale mtDNA deletions. In this study, we first confirmed that the proportion of mtDNA with the 4977 b p deletion in human skin tissues increases with age. We then investigated t he 8-hydroxy-2'-deoxyguanosine (8-OH-dG) content in skin tissues and lipid peroxides content of the skin fibroblasts from subjects of different ages. The results showed an age-dependent increase of 8-OH-dG level in the total DNA of skin tissues of the subjects above the age of 60 years. The specific content of malondialdehyde, an end product of lipid peroxidation, was also found to increase with age. On the other hand, we examined the enzyme acti vities of Cu,Zn-superoxide dismutase (Cu,Zn-SOD), Mn-superoxide dismutase ( Mn-SOD), catalase, and glutathione peroxidase (GPx) in the skin fibroblasts . The activities of Cu,Zn-SOD, catalase and glutathione peroxidase were fou nd to decrease with age. However, the activity of Mn-SOD was increased with age before 60 years but was decreased thereafter. Moreover, the activity r atios of Mn-SOD/catalase and Mn-SOD/GPx exhibited the same pattern of chang e with age. This indicates that free radical scavenging enzymes can effecti vely dispose of ROS and free radicals before 60 years of age. However, elev ated oxidative stress caused by an imbalance between the production and rem oval of ROS and free radicals occurred in skin fibroblasts after 60 years o f age. Taken together, we suggest that the functional decline of free radic al scavenging enzymes and the elevation of oxidative stress may play an imp ortant role in eliciting oxidative damage and mutation of mtDNA during the human aging process. (C) 1999 Elsevier Science B.V. All rights reserved.