Accumulating Mitochondrial DNA Damage: More Harm or Less Repair?

The mitochondrial free radical theory of aging tells us that accumulating damage to the DNA inside the mitochondria in our cells is a prominent cause of age-related degeneration. Mitochondria are powerplants, thousands to a cell swarming to turn food into the fuel chemical ATP, and their DNA, separate from the DNA in the cell's nucleus, is the blueprint for their assembly and operation. You'll find a simplified layman's explanation of the mitochondrial free radical theory of aging back in the Fight Aging! archives - there are a lot of steps and processes run awry between damaged mitochondrial DNA and the large-scale damage of aging.

Damaged mitochondria proliferate in some cells and, like damaged factories, pollute those cell with excess reactive oxygen species (ROS) and free radicals produced as metabolic byproducts. Each damaged cell then tries to maintain itself by exporting more reactive oxygen species and free radicals from its cell membrane structures, spreading the damaging pollution far and wide in the body.

We humans are self-repairing systems to some degree, as are the cells we are made up of. When considering an accumulation of damage in a self-repairing system, it isn't as simple as "dents and errors add up over time." Is the rate of damage changing? Is the damage causing a feedback loop that makes it more likely for more of the same damage to occur? Is the accumulation of damage actually a result of failing repair systems (i.e. ongoing damage is perfectly normal, expected, and repaired in a young individual, but some other aspect of aging causes the damage repair machinery to decline in effectiveness over the years)?

Here's a recent paper theorizing on the repair failure scenario:

The free radical theory of ageing states that ROS play a key role in age-related decrease in mitochondrial function via the damage of mitochondrial DNA (mtDNA), proteins and lipids. In the [fungus] Podospora anserina ageing is, as in other eukaryotes, associated with mtDNA instability and mitochondrial dysfunction.

Part of the mtDNA instabilities may arise due to accumulation of ROS induced mtDNA lesions, which, as previously suggested for mammals, may be caused by an age-related decrease in base excision repair (BER). ... We report for the first time the presence of BER activities in P. anserina mitochondrial extracts. ... the increased mtDNA instability with age may be caused by decreased ability to repair mtDNA damage and hence contribute to ageing.

Debating the exact method by which damage is happening may seem esoteric, but it does affect our expectations as to what sort of therapy would be most effective in rolling back the effects of mitochondrial DNA damage. For example, if the problem is largely a failing repair system, then a complete replacement of damaged mitochondrial DNA throughout the body - such as via protofection, demonstrated in mice four years ago - won't buy us as much time as we'd like. That new mitochondrial DNA is getting dumped into an environment that won't repairing it well, so it won't last as long.

In this "failing self-repair" scenario, the SENS approach of moving specific crucial mitochondrial genes into the cell nucleus is much better. Do it once, and never have to worry about the problem again: it doesn't matter how ratty the mitochondrial DNA is getting because there's a backup in place that continues to provide the right blueprints. This is very illustrative of the philosophy behind the Strategies for Engineered Negligible Senescence (SENS): pick an approach that is as little affected as possible by present uncertainties in scientific knowledge. You'll notice that it matters little how and why mitochondrial DNA damage is happening, the nucleus backup strategy still fixes the problem for the long term.

ResearchBlogging.orgSoerensen, M., Gredilla, R., Müller-Ohldach, M., Werner, A., Bohr, V., Osiewacz, H., & Stevnsner, T. (2009). A potential impact of DNA repair on ageing and lifespan in the ageing model organism Podospora anserina: Decrease in mitochondrial DNA repair activity during ageing Mechanisms of Ageing and Development DOI: 10.1016/j.mad.2009.05.003

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