A number of studies have demonstrated that mitochondrial integrity declines as a function of age.
Age-dependent increases in the level of damaged DNA have been commonly assessed through biomarkers such as the formation of 8-ox-2-deoxoguanosine (oxo8dG) in post mitotic tissue such as brain.
The levels of oxo8dG are significantly higher in mitochondrial compared to nuclear DNA.
Reasons for these differences are thought to include the proximity of mitochondrial DNA to the source of oxidants and the lack of any protective histone covering.
This postulated and observed increased sensitivity of mitochondrial DNA to oxidative damage has led to the concept of the "vicious cycle" in which an initial ROS-induced impairment of mitochondria leads to increased oxidant production that, in turn, leads to further mitochondrial damage.
Experimental evidence both for and against the vicious cycle exists.
For instance, many studies have demonstrated that old mitochondria appear morphologically altered and functionally produce more oxidants and less ATP.
Nonetheless, other investigators have recently criticized the methodology employed in some of these studies.
Therefore, whether or not there is a significant impairment of electron transport activity as mitochondria age remains somewhat of an open question.
Recent genomic studies, however, suggest that, transcriptionally, components of the electron transport chain are indeed affected by aging.
In one interesting study, the authors compared micro array data between two organisms (C. Elegans and Drosophila) as they aged in an effort to obtain a consensus aging transcriptosome.
In both species, there was a small but approximate 2-fold decrease in a large set of genes involved in ATP synthesis and mitochondrial respiration although these studies would seem to support the vicious cycle concept, two caveats are worth mentioning.
First these authors were studying nuclear-encoded, not mitochondria-encoded, transcripts.
Second, the exact timing of the down regulation for these transcripts occurred when the animal was at the early adult stage.
This transcriptional change therefore appears to occur before the usually observed decline in mitochondrial function and presumably also before one would expect the cumulative effects of oxidants to begin having their peak effects.
Since the formation of ROS species is a function of ambient oxygen concentration the cellular and organismal response to high oxygen concentrations may represent an insightful stress to explore the mechanisms of aging.
Here again, transcriptional profiling may provide a glimpse of underlying mechanism.
For instance, comparison of the gene expression patterns of Drosophila undergoing normal aging and those flies exposed to acute hyperoxia revealed significant concordance.
In another recent study, the biological resistance to hyperoxia was used as a genetic screen to obtain Drosophila mutants that are either overly sensitive or resistant to this stress.
A careful analysis of the morphological changes that mitochondria underwent after high oxygen exposure demonstrated that individual mitochondria develop a previously unknown “swirl” phenomenon.
This altered morphology presumably occurs due to a rapid reorganization of mitochondrial cristae in response to oxidative stress.
Interestingly, mitochondria from older files have significantly more swirls than younger files, and mutants selected for increased swirl formation have a significantly shorter life span.
The cellular response to high oxygen also supports a role for intracellular oxidants as at least one important determinant of the life span of mammalian cells in culture.
Cellular senescence is an interesting biological phenomenon whereby non-immortalized cells, after a discrete number of passages, undergo a permanent withdrawal from the cell cycle.
The senescent state is accompanied by consistent morphological and biochemical changes, suggesting it may be programmed in much the same way as differentiation or apoptosis.
Significant questions persist as to whether the molecular mechanisms underlying cellular senescence are relevant to overall organismal aging.
With that said, it has been recognized for some time that lowering the ambient oxygen concentration can significantly extend the life span of primary cells in culture.
Similar prolongation of cellular life span can be achieved by augmenting antioxidant levels.
For instance, increasing the level of superoxide dismutase extends the life span of primary fibroblasts as well as decreasing the rate of telomere shortening.
Conversely, knockdown of SOD using RNAi was demonstrated to induce senescence.
Interestingly, reducing SOD by RNAi resulted in the induction of p53, and this induction was required for senescence.
Cellular induction of p53 can result in either apoptosis or senescence, and there is some evidence that the decision for what cell fate pathway is chosen may depend on the intracellular level of ROS.
In a similar fashion, expression of an activated form of Ras proteins can induce senescence in some primary fibroblasts.
This Ras-induced senescence is also accompanied by p53 induction as well as a rise in ROS levels.
Again, either antioxidant augmentation or lowering the level of ambient oxygen rescued Ras-expressing cells from entering senescence.
Recently, Seladin-1, a gene previously implicated in cholesterol metabolism, was implicated as an important redox-sensitive intermediary between Ras and p53.