Mitochondrial Mutations in Mammalian Aging: An Over-Hasty About-Turn?

Interestingness: 7

By Aubrey DNJ De Grey, in Rejuvenation Research, Northern Autumn 2004, 7(3): 171-174. doi:10.1089/rej.2004.7.171.

A short piece of commentary trying to raise the profile of, I think, this paper:  "Construction of transgenic mice with tissue-specific acceleration of mitochondrial DNA mutagenesis", by Zhang D et al (http://www.ncbi.nlm.nih.gov/pubmed/11031098), but mainly about lowering the importance of "Premature ageing in mice expressing defective mitochondrial DNA polymerase" by Trifunovic A et al (http://www.ncbi.nlm.nih.gov/pubmed/15164064 ) . I haven't read the former, and I've only read the latter just now (separate post).

Zhang's paper is  about mice with a mutant mtDNA polymerase which produced more errors, but is only activated in the heart, and only after birth.  Trifunovic's paper is a similar concept but they made it active in all tissue. Also, while in Trifunovic's experiment they modified the built-in version of the mtDNA polymerase, I am not sure if that is what was done in Zhang's version, or if they just added a second copy.

The results of the modifications are that in Zhang's, the mice get cardiomyopathy, while Trifunovic's mice get fucked up all over and die at around the year mark.

de Grey's objection to the importance of Trifunovic's paper is that the effects seem to hit mainly tissue undergoing rapid replication (the spleen, the skin, testes and blood), and that the heart issues were a compensation mechanism for the anaemia.  His claim is that this failure of rapidly replicating tissue cannot cause a shortening of lifespan since the failing cells can just be replaced by the replication of the still-good cells, unless the cells are failing faster than they can be replaced, which is what he thinks is happening during the experiment.

It would be good if he'd have addressed specifically the coincidence that in both cases the mice suffered from enlarged hearts, but according to him due to separate causes (ie is it a coincidence?).  I don't know the timing of the cardiomyopathy in the Zhang experiment though, so it might have come around much later and there might not be anything to address.