Mitochondrial DNA, inherited from the mother, has a handful of varieties - known as haplogroups - in each species. Mitochondrial damage and function plays an important role in determining the natural progression of aging, and there is plenty of evidence to show that some haplogroups are a little better or a little worse than others when it comes to the mechanisms of aging, damage, and function. Here, researchers have produced a particularly clear example of this point in mice, in which the improved health observed likely results from hormesis, in that a small amount of damage is being generated within cells by increased oxidative molecule production in mitochondria, that results in greater cellular repair activities, and the result is a net benefit.
Mice bred such that their nuclear and mitochondrial DNAs derive from different strains tend to grow old in better health than mice whose mitochondrial and nuclear DNAs are ancestrally matched. These apparent health benefits occur despite signs of oxidative stress in the mismatched animals. Mitochondria, the energy-producing power stations of cells, have their own small genomes. And, compared with the human nuclear genome, these mitochondrial genomes are highly variable. But with the exception of known disease-causing mitochondrial DNA (mtDNA) mutations, he noted, "we always considered this variability just not relevant." The idea was that if the variants did somehow alter metabolic physiology, they would likely have been lost during evolution. But growing evidence suggests that normal non-pathogenic mtDNA variations could have more subtle effects on physiology than first thought. Such variations have been suggested to reflect mitochondrial and metabolic adaptations to different climates, for example. And in cells, mitochondria from different strains of mice have indeed been shown to exhibit different metabolic outputs.
Because mitochondria are only inherited maternally, the team crossbred female mice of the strain NZB/OlaHsd with male mice of the strain C57BL/6. For 20 generations, the researchers mated the resulting female offspring with C57BL/6 males, essentially diluting the nuclear DNA from the NZB/OlaHsd strain until it was practically non-existent. The resulting "conplastic" mice thus had mtDNA from NZB/OlaHsd, but nuclear DNA from C57BL/6. Compared with mice whose nuclear and mtDNA was of C57BL/6 origin, the conplastic animals had a longer median life span (although maximal life span was similar). They also showed better preservation of their ovaries in advanced age, fewer tumors at death, and maintained more steady cholesterol levels with age. In short the conplastic animals had better health spans. "We were surprised that the foreign DNA made the animals look healthier and age healthier."
And there were more surprises. The healthier disposition of the conplastic animals was - counterintuitively - associated with increased levels of potentially damaging reactive oxygen species (ROS), at least in young animals. "What they are seeing in the mismatched cases is basically an increase in oxidative stress. And that appears to be having generally a beneficial effect on health." One possible explanation is that because the mitochondrial enzyme complexes contain subunits encoded by both nuclear and mitochondrial genes, when the two genomes are mismatched these complexes may not function quite as efficiently, which would result in a mild stress response. And, "a mild stress response, as long as it's not too much, might be good for your overall health."