Every cell contains hundreds of mitochondria, the distant descendants of ancient symbiotic bacteria. They have evolved to become cellular components, tightly integrated into many vital functions, but still replicate like bacteria, and still contain a small remnant circular genome, known as mitochondrial DNA. Of the varied tasks undertaken by mitochondria, the most important is the generation of the chemical energy store molecule ATP, used to power cellular operations. This is a necessarily energetic operation and produces oxidative molecules as a byproduct, capable of reacting with and damaging the proteins that make up cellular machinery. This sort of reaction happens constantly and is repaired constantly, as a cell is a fluid bag of countless proteins and other molecules bumping into one another. Too much is harmful, however.
Mitochondrial DNA encodes a few vital proteins, necessary for the correct function of mitochondria, particularly when it comes to the mechanisms of ATP generation. Unfortunately mitochondrial DNA is right next door to the machinery that produces ATP and reactive molecules, it replicates far more frequently than the DNA of the cell nucleus, thus generating errors at a greater rate, and in addition has inferior protective and repair mechanisms in comparison to nuclear DNA. Mutations accumulate over time, in a random way.
The core of the mitochondrial theory of aging is that this mutational damage contributes to aging. The mechanism of production of ATP is disrupted, moves to much less efficient modes, and generates excessive reactive byproducts. Cells appear in which mutant mitochondrial have taken over, being more resistant to cellular quality control systems, or being able to replicate more efficiently. These cells cause harm to surrounding tissues, exporting large numbers of reactive oxidative molecules, resulting in oxidatively damaged lipids travelling far and wide in the body via the bloodstream, contributing to the progression of degenerative aging. As the open access paper here notes, however, there is an ongoing debate in the research community over which forms of mutation are more important, and how they occur. The evidence is contradictory, and each new attempt to produce mice in which certain forms of mitochondrial mutation are prevalent muddies the waters further. The paper is an example of the continued scholarly discussion on this topic.
The SENS rejuvenation research approach to mitochondrial DNA damage is to copy the thirteen vital mitochondrial genes into the cell nucleus, suitably altered so that the proteins will be shipped back to mitochondria. The advantage of this approach is that it doesn't matter how the mutations happen - the approach will fix the problem regardless of its source. No matter how ragged mitochondrial DNA might become, the proteins needed for correct function will still be available. It bypasses the need to fully understand the roots of the problem, a task that is proving to be challenging, slow, and expensive. To date, the SENS program - at the Methuselah Foundation and later the SENS Research Foundation - has funded the work that led to Gensight Biologics and their focus on copying the ND4 gene into the cell nucleus, and then demonstrated a similar proof of concept for ATP6 and ATP8.
The central principles of the mitochondrial theory of aging are that (i) mitochondrially produced reactive oxygen species (ROS) can damage mitochondrial DNA (mtDNA), and (ii) ROS-induced lesions in mtDNA can lead to somatic mutations that accumulate, affect the integrity of respiratory chain, and cause mitochondria-dependent aging. More recent data seem to indicate that mtDNA might be more resistant to oxidative damage than previously thought. Instead, many have suggested that the origin of somatic mtDNA mutations is associated with the fidelity of the mtDNA polymerase γ (POLG). Additionally, there seems to be little experimental support for the vicious cycle theory, which attempts to explain the age-dependent accumulation of mutations by proposing a mutation-dependent increase of mitochondrial ROS production that, in turn, would result in elevated oxidative mtDNA damage.
Rather, the age-dependent increase in the somatic mutation load of mtDNA reported by many groups can be explained sufficiently by the replicative segregation of mitochondrial mutations. This theory has been supported by evidence that individual cells of aged persons accumulate high levels of only one specific mutation. Additionally, the effect of mtDNA mutations on mitochondrial ROS production has been reported to be strongly mutation dependent. Only certain mutations that affect the activity of Complex I and Complex V have been convincingly shown to increase mitochondrial ROS production, while random mtDNA point mutations do not seem to be associated with elevated oxidative stress.
One of the most important issues relating to the mitochondrial theory of aging is the very low frequency of somatic mutations detected in the mtDNA in tissue samples from older individuals. Obviously, the mitochondrial genome is present in multiple copies (approximately 10 copies per mitochondrium), and it is a well-established fact that intact mtDNA can complement for mutated genomes. Therefore, it is difficult to imagine how minor changes in the mitochondrial genome could lead to functional effects on the cellular level. Only a mosaic distribution of mutated genomes, resulting from preferential accumulation of mutants in certain cells, can explain the occurrence of such functional effects in these cells. To cause a functional effect within a cell, a pathogenic point mutation must typically exceed 85-90% heteroplasmy, while deletions appear to cause functional effects at heteroplasmy levels above only 60%.
This threshold concept has been validated in tissue samples from numerous patients with mitochondrial diseases harboring pathogenic point mutations or mtDNA deletions, which contain a mosaic of cells with defects in oxidative phosphorylation (OxPhos) that are usually detectable by testing for missing cytochrome c oxidase (COX). Similar mosaics of cells that do not have COX have been reported in postmitotic tissues, such as skeletal muscle, heart muscle, or the brain. However, the number of cells lacking COX in these cases is much lower than that reported in cases of mitochondrial diseases.
First attempts have been made to clarify the potential physiological impact of low amounts of cells lacking COX on intact tissues. In research studying such effects on mouse hearts, compelling evidence has been provided that if the frequency of deletions in a small number of individual heart cells exceeds the above-mentioned threshold, then arrhythmia - a typical symptom of age-related heart disease - may develop. Similarly, it is easy to imagine that individual neurons with impairment of OxPhos, which have been detected in many central nervous system disorders and in the aging brain, can affect the function of complex neuronal networks. However, this hypothesis remains to be investigated and further substantiated.