Looking Ahead to Mitochondrial DNA Replacement Therapies

If you wend your way back through the Fight Aging! archives, you'll find a lot of material on mitochondria, mitochondrial DNA, and how accumulated damage to mitochondrial DNA contributes greatly to aging. The short version is this:

Mitochondria are the cell's power plants, important in the operation of metabolism, central to the mechanisms by which metabolism determines life span, and implicated as the culprit in many age-related diseases. As described in the mitochondrial free radical theory of aging, a small number of mitochondrial genes are known to be crucial to its operation as the cell's power plant. Damage to those genes is unfortunately a natural consequence of the operation of a mitochondrion, and leads to a Rube Goldberg sequence of events in which is a healthy cell is turned into a damaged cell that spews forth damaging biochemicals into your body. As these errant cells accumulate, their actions collectively give rise to many of the unwelcome forms of change and damage that come with age: systems failing, organs shutting down, and important biochemical processes running awry because their component molecules are corrupted.

But you should certainly read one of the longer versions, as that will provide a better introduction to the mitochondrial free radical theory of aging. You should also look into some of the early stage work presently taking place to either replace damaged mitochondrial DNA throughout the body, replace just the few relevant damaged genes, or make all such damage irrelevant and harmless. We can hope that these lines of research will gain the funding and support needed to produce therapies capable of reversing mitochondrial damage and its contribution to degenerative aging. Knowledge is power.

I noticed a paper today that might be taken as evidence that working to repair mitochondrial DNA is an idea slowly gaining popularity in the scientific community. These researchers note that a range of natural repair mechanism exist (but are clearly overwhelmed by damage over a human life span), and that improving upon these mechanisms is only a matter of time:

Mitochondrial DNA (mtDNA) directs key metabolic functions in eukaryotic cells. While a number of mtDNA mutations are known causes of human diseases and age-related dysfunctions, some mtDNA haplotypes are associated with extreme longevity. Despite the mutagenic mitochondrial environment naturally enhancing somatic mtDNA mutation rates, mtDNA remains grossly stable along generations of plant and animal species including man. This relative stability can be accounted for by the purging of deleterious mutations by natural selection operating on growing cells, tissues, organisms and populations


In the adult multicellular organism, however, mtDNA mutations accumulate in slowly dividing cells, and, to a much higher degree, in postmitotic cells and tissues. [The following processes:]

1) Dynamic mitochondrial fusion and fission, by redistributing polymorphic mtDNA molecules;

2) mitophagy, by clearing defective mitochondria and mutated mtDNA;

3) compensatory mutations and mtDNA repair

can compensate for the accumulation of mtDNA mutations only to a certain extent, thereby creating a dysfunctional threshold. Here we hypothesize that this threshold is naturally up-regulated by both vertical and horizontal transfers of mtDNA from stem cells or cell types which retain the capacity of purging deleterious mtDNA through cell division and natural selection in the adult organism. When these natural cell and tissue mtDNA reserves are exhausted, artificial mtDNA therapy may provide for additional threshold up-regulation.

Replacement of mtDNA has been already successfully accomplished in early stage embryos and stem cells in a number of species including primates. It is thus simply a matter of refinement of technique that somatic mtDNA therapy, i.e., therapy of pathological conditions based on the transfer of mtDNA to somatic eukaryotic cells and tissues, becomes a medical reality.

You'll notice the reference to mitophagy there. This is one aspect of autophagy, or recycling of cellular components - here the interest is in that recycling process when it operates to tear down damaged mitochondria before they can cause harm. Recall that it is plausible that much of the benefit to health and longevity derived from increased autophagy, such as occurs in calorie restriction, administration of calorie restriction mimetic drugs, and in most of the life-extending genetic manipulations examined to date, is due to cells more aggressively clearing out mitochondrial damage.

ResearchBlogging.orgDani MA, & Dani SU (2010). Improving upon nature's somatic mitochondrial DNA therapies. Medical hypotheses PMID: 20116178


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