Hopefully by now most folk here know that mitochondria are the power plants of our cells, toiling in their thousands inside each cell to turn food into ATP, a chemical used as fuel by other cellular processes. Mitochondria contain their own DNA, separate from the DNA in the cell nucleus, a legacy of their symbiotic nature. If some crucial portions of that DNA are damaged, then a mitochondrion will become dysfunctional - and a Rube Goldberg process unfolds from this point, causing age-related degeneration as damage to mitochondrial DNA spirals outwards into increasing forms of disarray and damage in and around your cells.

Unfortunately, mitochondrial DNA is comparatively unprotected, and sits right next to the mitochondrial food-processing machinery that produces all sorts of reactive, damage-inducing molecules as a matter of course. In theory a cell's repair and recycling mechanisms should destroy damaged mitochondria before things get out of hand, but in practice it doesn't work that way enough of the time. Hence damage accumulates over the years, and we witness the results of that damage as some fraction of the degenerations of aging.

What I've outlined in the paragraphs above is the mitochondrial free radical theory of aging. You can read more of the details back in the Fight Aging! archives.

Damage to DNA is also known as mutation - any change in the molecular structure that throws a spanner in the works. But there are numerous different forms of mutational damage, ranging from tiny point mutations to terrible double strand breaks or linear deletions in which whole regions are snipped out of DNA.

A little while back, one group of researchers was arguing against the mitochondrial free radical theory of aging on the basis of mice loaded up with point mutations in their mitochondrial DNA:

The data, which contradict a prominent theory that mitochondrial mutations drive the aging process, show that mice with mitochondrial mutations 500 times higher than normal levels do not show signs of premature aging.

The response to this from other researchers was much along the lines of "well of course it's not point mutations - the real culprit is large deletions in mitochondrial DNA that happen to knock out one of the dozen or so crucial genes used to build the mitochondrial machinery."

I noticed a paper today that muddies the waters further - you'll see a lot of that in any active field of research. The researchers claim that point mutations are in fact sufficient to cause issues, but not in a direct fashion. The affected mitochondrial machinery is the respiratory chain or electron transport chain, a mechanism that cycles various molecules and electrons through a process that generates ATP:

The mtDNA mutator mice have high levels of point mutations and linear deletions of mtDNA causing a progressive respiratory chain dysfunction and a premature aging phenotype. We have now performed molecular analyses to determine the mechanism whereby these mtDNA mutations impair respiratory chain function. We report that mitochondrial protein synthesis is unimpaired in mtDNA mutator mice consistent with the observed minor alterations of steady-state levels of mitochondrial transcripts. These findings refute recent claims that circular mtDNA molecules with large deletions are driving the premature aging phenotype. We further show that the stability of several respiratory chain complexes is severely impaired despite normal synthesis of the corresponding mtDNA-encoded subunits.

To translate: point mutations don't interfere with the production of proteins needed to build the respiratory chain, but they can make this machinery unstable and inefficient. This can lead to much the same end result as losing a vital gene completely to a more serious mutation, and here it leads to premature aging in mice engineered for point mutations.

That one group of researchers has point-mutation-bearing mice that age normally and another group has point-mutation-bearing mice that age faster indicates that there's more to this story, however. Something is unknown, always the case when solid research appears to be contradictory, and more research is needed to get to the bottom of the mechanisms here. But note that we could sidestep all of these issues with a technology that repairs or replaces mitochondrial DNA globally throughout the body - such as protofection, demonstrated back in 2005. If we replace all mitochondrial DNA with fresh new mitochondrial DNA, then it doesn't matter why or how its prior state was causing issues because we just fixed the problem.

This is as good an example as any to show that we don't need complete understanding of human biochemistry in order to make important inroads into repairing the damage of aging. More understanding helps, but we have enough knowledge now to move ahead with significant and important rejuvenation technologies - were there a large research community and the will and funding to forge ahead. But here, as in so many nascent fields of biotechnology with great potential, we are left lacking. There is no large research community focused on replacing mitochondrial DNA, and to the best of my knowledge only a few small groups are presently working on this sort of technology.

If you wish to understand why this is the case, you might look at the regulatory environment. The FDA will not approve treatments for aging, and - in conjunction with a pharmaceutical industry happy to squash disruptive upstart companies - ensures that commercial development of new medical technology is made so ridiculously expensive that no great interest is attached to minority diseases. Mitochondrial diseases beyond aging don't affect enough people to make it financially viable for a large development industry to form under the present constraints. This is generally true of highly regulated industries: experimentation is discouraged, and anything other than the broadest application is made unprofitable.

In the years ahead, with the costs of biotechnology falling ever faster, we'll have to take matters into our own hands if we want to see any real progress.

Edgar, D., Shabalina, I., Camara, Y., Wredenberg, A., Calvaruso, M., Nijtmans, L., Nedergaard, J., Cannon, B., Larsson, N., & Trifunovic, A. (2009). Random Point Mutations with Major Effects on Protein-Coding Genes Are the Driving Force behind Premature Aging in mtDNA Mutator Mice Cell Metabolism, 10 (2), 131-138 DOI: 10.1016/j.cmet.2009.06.010