Today I'll point out a commentary on recent research in which a method of degrading mitochondrial function was shown to produce aspects of accelerated aging in mice. The commentary is somewhat more approachable than the paper it comments on. The challenge here is the same as in any form of research in which something vital is broken in animal biochemistry, and wherein the result looks a lot like a faster pace of aging. These forms of artificial breakage are almost never relevant to the understanding of normal aging; they create an entirely different state of metabolism and decline.
It is true that normal aging is a process of damage accumulation and reactions to that damage. But it is a specific mix of damage of specific types. That damage has the downstream consequence of loss of cell and tissue function, which in turn leads to the visible, well-known symptoms of aging and age-related disease. Near any form of significant damage and breakage in biochemistry will also lead to loss of cell and tissue function, however, even if it doesn't normally occur in the wild. Very high levels of unrepaired nuclear DNA damage, far greater than exist in normal animals, produce conditions that look a lot like accelerated aging. Consider Hutchinson-Gilford progeria syndrome as a natural example. But this doesn't tell us much about normal aging despite the fact that lower levels of nuclear DNA damage are a feature of normal aging.
In the research referenced in the commentary here, mitochondrial DNA is removed from cells, leaving them with an abnormally low count of genome copies in the mitochondrial population. The result looks a lot like accelerated aging. Mitochondria are the power plants of the cell, responsible for producing the chemical energy store molecules used to power all cellular processes. Progressive loss of function in mitochondria is implicated in aging and many age-related diseases, but just as in the case of raised levels of nuclear DNA damage, it isn't at all clear that artificial breakage of mitochondria tells us anything useful about the mitochondrial contribution to normal aging. It definitely tells us what happens when you break things, but any other insights are tenuous and highly dependent on the details.
Ageing is characterized by a decline in mitochondrial function, including a reduction in TCA cycle enzymes, a decrease in the respiratory capacity, and an increase in reactive oxygen species (ROS) production, in both animal models and humans. These alterations can lead to DNA mutations, cell death, inflammation, and a reduction in stem cell function, contributing to tissue degeneration. The increase in mitochondrial DNA mutations observed in aged mitochondria from both mouse models and humans is the proposed driving force.
Mitochondrial DNA (mtDNA) is replicated by a dedicated mitochondrial DNA polymerase (DNA pol γ), whose proofreading activity has been ablated to generate a mouse model, i.e., the so-called "mitochondrial mutator mouse", able to introduce random mutations in mtDNA. This model displays a strong ageing phenotype, including hair loss, graying, and kyphosis, along with reduced mitochondrial respiratory complex activity and increased oxidative stress.
Researchers have recently described a novel transgenic mouse with an inducible depletion of mtDNA, i.e., the mtDNA-depleter mouse. This model carries an aspartate to alanine conversion at position 1135 of POLG1 that behaves as a dominant negative for DNA pol γ, whose expression is under the control of a Tet-responsive promoter. Doxycycline administration leads to the induction of mutant DNA pol γ that blocks mtDNA replication. As mtDNA is removed by mitophagy for recycling, the activation of the transgene leads to a reduction of more than 60% in the total mtDNA content after 2 months. As mtDNA codes the core subunits of mitochondrial respiratory complexes, a significant impairment was observed in their activity.
At the macroscopic level, the mtDNA-depleter mouse shows expected accelerated ageing, including weight loss and kyphosis, but ageing of the skin was particularly severe and characterized by hair loss, wrinkles, and pigmentation, while at the histological level, this mouse displayed hyperplastic and hyperkeratotic epidermis, degeneration of hair follicles and extensive inflammatory infiltrates. Although the model requires extensive additional characterization, histological sections of other tested tissues (considered to have a high demand for mitochondrial activity), including the liver, brain and myocardium, do not display major alterations.
How mtDNA depletion affects ageing is a rather interesting question. The extended inflammatory infiltrates suggest that mitochondria could produce ROS as ROS can act as signaling molecules for inflammasome activation; unfortunately, the author did not report measurements of oxidative stress, but cells depleted of mtDNA are usually characterized by diminished oxygen consumption and ROS production, suggesting that oxidative stress should not mediate the ageing phenotype observed here. However, the following two major consequences were observed in a cell model of mtDNA depletion using the same strategy as that used in the depleter mouse: (1) a significant rearrangement of histone acetylation due to indirect alterations in the citrate levels, and (2) a reduction in cell proliferation due to a reduction in the membrane potential and destabilization of Hif1a. While the type of epigenetic rearrangement that occurs during ageing is unclear, Hif1a depletion has been shown to lead to an accelerated aged skin phenotype in mice.
Another extremely interesting point in this study is the recovery of the phenotype. Halting doxycycline exposure led to a surprising and almost complete recovery of the mtDNA content and skin phenotype after one month. The recovery of the mtDNA content is expected since the original mtDNA was not completely exhausted. The recovery of the skin phenotype is more intriguing. The mutator mouse model provided important insight into how mitochondria can induce an ageing phenotype by affecting haematopoietic and neural stem cell self-renewal capacities. We speculate that mtDNA depletion affects epidermal stem cell function, leading to skin ageing. Although it has long been thought that stem cells do not rely on mitochondrial function (at least for ATP production), additional observations in adult stem cells from other tissues suggest that mitochondria can be fundamental for stem cell self-renewal. However, progenitor cells, which have an established dependency on mitochondrial respiration in many models, could be more sensitive to mtDNA depletion and therefore responsible for the rapid recovery.