Mitochondria, the power plants of the cell, carry their own DNA, encoding a few proteins essential to mitochondrial operation. Mutational damage to these genes can result in broken mitochondria that take over cells and cause the export of oxidizing molecules, contributing to the progression of aging. Not all mitochondrial DNA damage is the same, however: point mutations versus deletion mutations, for example. Researchers have struggled to produce consistent data in mice and nematodes with increased levels of mitochondrial DNA damage of various sorts. Some mice engineered to have greater mutation rates in mitochondrial DNA exhibit accelerated aging, while others do not, with little sign of a coherent explanation as to why beyond the sentiment that short-lived species are not useful models in this case.
The work here in nematodes, using radiation to produce mitochondrial DNA damage, should probably taken as more in the same vein. The researchers find no correlation between damage levels and life span, and this may well be because they are not introducing the right sort of mutational damage that occurs over the course of aging in longer-lived species. It is thought that deletion mutations, or other equally drastic damage, is necessary, for example. But nematodes do not accumulate such damage over the course of their very short lives. They may just be a very poor model for any consideration of the mitochondrial contribution to the aging process.
The mitochondrial free radical theory of aging (mFRTA) proposes that accumulation of oxidative damage to macromolecules in mitochondria is a causative mechanism for aging. Accumulation of mitochondrial DNA (mtDNA) damage may be of particular interest in this context. While there is evidence for age-dependent accumulation of mtDNA damage, there have been only a limited number of investigations into mtDNA damage as a determinant of longevity. This lack of quantitative data regarding mtDNA damage is predominantly due to a lack of reliable assays to measure mtDNA damage.
Here, we report adaptation of a quantitative real-time polymerase chain reaction (qRT-PCR) assay for the detection of sequence-specific mtDNA damage in C. elegans and apply this method to investigate the role of mtDNA damage in the aging of nematodes. We compare damage levels in old and young animals and also between wild-type animals and long-lived mutant strains or strains with modifications in reactive oxygen species detoxification or production rates. We confirm an age-dependent increase in mtDNA damage levels in C. elegans but found that there is no simple relationship between mtDNA damage and lifespan.
In order to more directly test the relevance of mtDNA damage in the context of lifespan determination, we introduce damage to mtDNA directly by exposing young C. elegans to UV- or γ-radiation. Sufficiently high levels of UV-radiation cause extensive mtDNA damage and this indeed shortened C. elegans lifespan. However, we found that lower levels of this stressor still significantly increase mtDNA damage but without causing significant detriments and that some levels even resulted in lifespan extension and healthspan improvements.
This is consistent with the concept of hormesis; that exposure to mild stress, through evoking adaptive responses and strengthening stress defense mechanisms can lead to lifespan extension. However, it is worth noting that in our experiments, even under conditions where UV damage results in hormetic benefits, damage remained detectably elevated, even on the day following exposure. The lack of evidence for a tight relationship between mtDNA damage burden and lifespan in C. elegans is consistent with our recent finding that, most likely due to the short lifespan of nematodes, mtDNA deletion do not accumulate with age in C. elegans.