Of Mice and Mitochondria

I was going to post some thoughts on the recently reported hard proof for mitochondrial theories of aging, but Randall Parker has already done an excellent job of that at FuturePundit. I quote a fair amount below, but you should read the whole thing:

Mice genetically engineered to have a defective mechanism for repairing only the DNA found in mitochondria age more rapidly and have less than half the life expectancy of normal mice.

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Mitochondria are organelles that exist inside all eukaryotic cells (most complex life forms including humans have eukaryotic cells) and function to break down sugars to produce energy. Mitochonida have their own DNA for a small subset of their proteins. The Swedish team introduced a mutation to break a repair mechanism for the DNA in mitochondria in order to study how important accumulation of damage to mitochondrial DNA is to the overall rate of aging. The results suggest that damage accumulation to mitochondrial DNA is as important as some scientists have argued for years.

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Why does the accumulation of mitochondrial DNA damage accelerate aging? One obvious possibility is that the DNA damage knocks out genes needed for energy production and hence cells begin to malfunction due to a lack of energy. But another quite plausible possibility is that the mutations knock out steps in sugar metabolism in a way that leads to the generation of lots of free radicals. In this model (suggested by Aubrey de Grey - more about him below) the cells that have defective mitochondria become toxic free radical generators for all the cells around them. In essence, a fairly small number of cells become mini-toxic waste sites. Someone call in the Environmental Protection Agency. This sort of thing should be forbidden by tough pollution law enforcement.

He goes on to discuss Aubrey de Grey's proposals to alter cells to make mitochondrial damage less unhealthy:

Aubrey has repeatedly argued for funding of experimental work to move genes into the nucleus of a mouse cell to then be used to clone and raise mice that have all their mitochondrial genes in their nuclei. The effect might be the opposite of the experiment reported above. Rather than shortening life the mice might live much longer. Such a result would lend further support for the argument that mitochondrial DNA gene therapy should be developed as a rejuvenation technique.

I imagine that this would a logical next step for researchers to look into. I also imagine that Aubrey de Grey is spending a lot of time on the phone right now...

Comments

My understanding is that the DNA that remains in the mitochondria is the DNA from which are produced proteins that can't easily be transported through the mitochondrial membrane into a mitochondrion. If one were to put the DNA into the cellular nucleus, one would also have to devise new means for the proteins produced from the DNA to be transported across the mitochondrial membrane. I'm sorry that I can't offer a source for this point; I'm relying on memory.

Posted by: Doug at May 28th, 2004 8:02 PM

Doug, your memory is quite correct. The idea of putting the mtDNA into the nucleus was first explored about 20 years ago, and though there were some promising early results progress has since been slow for exactly the reason you mention. The tricks needed for a solution are not as drastic as you suggest, though: we don't have to improve the import machinery (or design a new one). Instead, we can in principle identify changes to the 13 relevant genes that make their encoded proteins a bit easier to import, while not impairing their function once they get there. A promising way to do that is to look at other species that have succeeded in transferring to the nucleus some genes that are still in the mtDNA in humans. Plenty of progress has been made in this area in the past couple of years, so I'm very optimistic that all we need now is the resources to try a bunch of promising-looking changes until we find ones that work. Each of the 13 genes can be worked on independently in cell culture.

There's more about this at my website:

http://www.gen.cam.ac.uk/sens/mtmut.htm

and in my publications at AdGpubs.htm .

Posted by: Aubrey de Grey at May 29th, 2004 1:07 PM

More relevant is finding that there were farm animals from a particular region in Australia that were enjoying long life. One of the theories is the water they drink contains particular concentrations of Magnesium Bicarbonate which buffers against acidosis in the cell. For more information, google for "unique water".

Posted by: Chui at December 5th, 2004 10:11 PM

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