Researchers here produce models to argue that the role of accumulating mitochondrial mutations in aging can only play out significantly in long-lived species. If this in fact turns out to the be the case it would be a hindrance to efforts to develop mitochondrial repair technologies as a rejuvenation therapy, as they would have little effect in laboratory mice. That would make it harder to drum up the enthusiasm to proceed further towards clinical applications.
The fastest way to find out whether the models presented in this paper actually reflect reality is to develop a working implementation of mitochondrial DNA (mtDNA) repair, but like many areas of research that are potentially applicable to extending healthy life there is comparatively little funding for this sort of work. With much greater funding, an actual implementation is only a few years away.
The mitochondrial theory of ageing is one of the main contenders to explain the biochemical basis of the ageing process. An important line of support comes from the observation that mtDNA deletions accumulate over the life course in post-mitotic cells of many species. A single mutant expands clonally and finally replaces the wild-type population of a whole cell.
One proposal to explain the driving force behind this accumulation states that the reduced size leads to a shorter replication time, which provides a selection advantage. However, this idea has been questioned on the grounds that the mitochondrial half-life is much longer than the replication time, so that the latter cannot be a rate limiting step. To clarify this question, we modelled this process mathematically and performed extensive deterministic and stochastic computer simulations to study the effects of replication time, mitochondrial half-life and deletion size.
Our study shows that the shorter size does in principle provide a selection advantage, which can lead to an accumulation of the deletion mutant. However, this selection advantage diminishes the shorter is the replication time of wt mtDNA in relation to its half-life. Using generally accepted literature values, the resulting time frame for the accumulation of mutant mtDNAs is only compatible with the ageing process in very long lived species like humans, but could not reasonably explain ageing in short lived species like mice and rats.
There are proposals for other mechanisms to explain how damaged mitochondria can overtake cells and replace the undamaged type: for example, through greater resistance to being cleared out by quality control mechanisms such as mitophagy.