Decrease in antioxidant defences
Age-related decreases in antioxidant defences are the second factor thought to leave tissues vulnerable to damage by ROS. As such, the expression and activity of the major antioxidant enzymes, glutathione peroxidise, glutathione reductase, superoxide dismutase (SOD) and catalase have been investigated in depth. For example, one group assayed these enzymes in both the epidermis and dermis of young and old hairless mice (Lopez-Torres et al, 1994). Catalase, SOD and glutathione reductase were shown to have similar activity levels in young and old rats with glutathione peroxidise activity decreasing in old mice. It was concluded that skin ageing is not accelerated with age due to a general decrease in the antioxidant capacity of the tissue. A similar result was observed with the measurement of glutathione levels in human plasma from age-related macular degeneration (ARMD) patients, non-ARMD diabetic patients, aged non-ARMD and non-diabetic individuals and young individual without ARMD and diabetes (Samiec et al, 1997). No difference in glutathione levels was observed in aged or ARMD individuals but a decrease in glutathione was found to be associated with diabetes. Another study specifically concentrated on expression and activity of two SOD isozymes (Mn SOD and CuZn SOD) in three different skeletal muscle fiber types of young and old rats (Hollander et al, 2000). This study found that despite a decrease in mRNA expression in ageing muscle, an increase in enzyme activity was observed. Therefore, it was suggested that mRNA levels is not a determinant of SOD production, but due to post-transcriptional and/or post-translational mechanisms. Increases in enzyme activity have also been reported in a study which sought to characterise age-related changes in glutathione peroxidise, SOD and catalase in the rat aorta of young middle aged and old animals (Demaree et al, 1999). Glutathione peroxidise activity was found to increase with age, whereas SOD decreased in middle age before gradually increasing in old rats. Catalase activity was found to decrease significantly between young and old rats.
These increases in antioxidant enzymes with age may be an attempt to combat increasing attacks from elevated levels of ROS. If cellular damage is occurring despite the presence of antioxidant enzymes, it may be because these enzymes are not 100% efficient resulting in a gradual accumulation of damage. Over-expression of antioxidant enzymes have been shown to extend lifespan. For example, the over-expression of catalase in transgenic mice extended lifespan on average by 5 months (Schriner et al, 2005). These mice also showed a delay in cardiac pathology, cataract development and a reduction in oxidative damage and mitochondrial deletions. Over-expression of catalase and SOD has also been shown to impede the development of atherosclerosis in ApoE-/- mice (Yang et al, 2004).
Interestingly, a number of groups which generated mice lacking a particular antioxidant enzyme, found that these mice generally develop normally with no affect on lifespan. Mice lacking catalase were found to develop normally and showed no difference in hyperoxia-induced lung damage or increase susceptibility to oxidative stress in the lenses compared with wild type mice (Ho et al, 2004). Similarly, mice lacking glutathione peroxidise showed no difference with control mice in regard to longevity, vitality, weight, lens biochemistry or morphology (Spector et al, 2001). The absence of extracellular SOD in mice also showed no effect on lifespan, but these mice were more sensitive to hyperoxia than control mice (Carlsson et al, 1995 and Sentman et al, 2006). There are three possible explanations for why there appears to be no difference in lifespan of antioxidant enzyme lacking mice:
1) One antioxidant enzyme counteracts for the loss of another.
2) Repair mechanisms are sufficient to cope with any excess damage resulting from loss of an antioxidant enzyme.
3) Oxidative damage is not responsible for an ageing phenotype.