Mitochondria are the power plants of the cell, a host of organelles evolved from symbiotic bacteria. They each carry a small amount of DNA, and this accumulates damage with age. Some sorts of damage can spread rapidly within a cell's mitochondria, causing all of them to become dysfunctional. The cell itself also malfunctions as a result, exporting damaging reactive molecules into surrounding tissues. A small but significant portion of all the cells in the body suffer this fate by the time old age rolls around, and their presence contributes to degenerative aging.
Any comprehensive rejuvenation toolkit developed in the near future must include some way to deal with this issue. One possibility is a form of gene therapy for all cells in the body, delivering fixed and fully functional mitochondrial DNA, coupled with removal of the damaged strains to prevent them from spreading once more. The use of TALENs is showing some promise here, but at this point the research community is focused on inherited mitochondrial diseases rather than aging:
Mutations in mitochondrial DNA (mtDNA) can be specifically targeted and removed by transcription activator-like effector nucleases (TALENs) in murine oocytes, single-celled mouse embryos, and fused human-mouse hybrid cells, providing proof of principle for a method that could one day be used to treat certain hereditary mitochondrial disorders in people.
Between 1,000 and 100,000 mitochondria power each human cell. Often, mitochondria in the same cell have different genomes, or haplotypes, a condition known as heteroplasmy. Certain haplotypes include mutations that impact mitochondrial function and cause disease, particularly in energy-hungry organs such as the brain and heart. Because mitochondria segregate randomly as cells divide, it is impossible to determine early in embryonic development how a mix of wild-type and mutated mitochondria inherited from the mother will affect an organism.
To rid mitochondria of these harmful mutations, researchers have used restriction enzymes as well as zinc-finger nucleases (ZFNs) and TALENs, which can be designed to recognize any DNA sequence, to cut and eliminate mutated mitochondrial genomes from heteroplasmic cells. "Because the cell likes keeping the number of mtDNA molecules constant, after elimination of the faulty ones, the wild-type copy will repopulate the cell."
Now, an international team has used mitochondria-targeting restriction enzymes and TALENs in the mammalian germline and early-stage mouse embryos for the first time. Injecting mRNAs encoding each enzyme into mouse cells with two different wild-type mtDNA haplotypes selectively removed the targeted genome variant, and the edited embryos grew into normal mice. The team did not observe any off-target effects. To determine whether the enzymes could be used to edit human mtDNA, the researchers fused mouse oocytes with fibroblast cells from patients with one of two mitochondrial disorders - Leber's hereditary optic neuropathy or neurogenic muscle weakness, ataxia, and retinitis pigmentosa. Unlike in the mouse experiment, mutant mtDNA was still detectable, albeit at lower levels, after TALEN mRNA injection. Mutated mtDNA usually only causes disease if more than 60 percent to 75 percent of a cell's mitochondria harbor the error, so "the reduction that we observed was more than enough for the phenotype to disappear."