Mitochondria are the power plants of the cell, responsible for producing the energy store molecule ATP that powers cellular operations. Hundreds of these organelles can be found in every cell, the distant descendants of symbiotic bacteria long ago integrated into core cellular mechanisms. They contain their own small remnant genome, and when worn or damaged, they are broken down and recycled by cellular maintenance mechanisms. Mitochondria reproduce by fission like bacteria, but also fuse together at times, and promiscuously swap component parts among one another. Cells can also transfer mitochondria between them. This makes it something of a challenge to track the consequences of mitochondrial damage in aging.
Mitochondrial DNA is more vulnerable and less capable of repair than the nuclear genome deeper inside cells. Some forms of random damage can knock out mitochondrial genes necessary for the most efficient form of energy production. Mitochondria with this particular problem are inefficient, but also somehow more likely to replicate than their peers: they either evade maintenance processes, or perhaps replicate more rapidly. A cell can be quickly taken over by broken mitochondria running inefficient, harmful forms of energy production. The cell becomes dysfunctional and exports damaging, oxidative molecules into the surrounding tissue. The growth in this sort of problem cell is thought to be one of the root causes of aging.
Definitively proving that to be the case is challenging, short of building the necessary technology to repair or prevent mitochondrial DNA damage, such as the allotopic expression methodology advocated by the SENS Research Foundation. There are various forms of mitochondrial mutator mice with artificially high levels of particular types of mitochondrial DNA damage, and these have been used to both make and counter the argument that only deletion mutations are important in aging. Applying that understanding to normally aging mice is a whole other line of work, however. Investigations in normally aging mice have to date been contradictory and inconclusive; it doesn't help that mitochondria are also subject to a range of other, unrelated changes in behavior and activity with age.
So what to make of the current state of research in this part of the field? The two papers I point out here might be taken as the basis for considering that short-lived species simply don't experience this cause of aging to any significant degree. They do not undergo meaningful amounts of stochastic mitochondrial DNA damage. That might go some way towards explaining why earlier investigations have so far not led to the desired destination.
Disruption of mitochondrial metabolism and loss of mitochondrial DNA (mtDNA) integrity are widely considered as evolutionarily conserved mechanisms of aging. Human aging is associated with loss in skeletal muscle mass and function (Sarcopenia), contributing significantly to morbidity and mortality. Muscle aging is associated with loss of mtDNA integrity. In humans, clonally expanded mtDNA deletions colocalize with sites of fiber breakage and atrophy in skeletal muscle. mtDNA deletions may therefore play an important, possibly causal role in sarcopenia.
The nematode Caenorhabditis elegans also exhibits age-dependent decline in mitochondrial function and a form of sarcopenia. However, it is unclear if mtDNA deletions play a role in C. elegans aging. Here, we report identification of 266 novel mtDNA deletions in aging nematodes. Analysis of the mtDNA mutation spectrum and quantification of mutation burden indicates that (a) mtDNA deletions in nematode are extremely rare, (b) there is no significant age-dependent increase in mtDNA deletions, and (c) there is little evidence for clonal expansion driving mtDNA deletion dynamics. Thus, mtDNA deletions are unlikely to drive the age-dependent functional decline commonly observed in C. elegans.
Computational modeling of mtDNA dynamics in C. elegans indicates that the lifespan of short-lived animals such as C. elegans is likely too short to allow for significant clonal expansion of mtDNA deletions. Together, these findings suggest that clonal expansion of mtDNA deletions is likely a private mechanism of aging predominantly relevant in long-lived animals such as humans and rhesus monkey and possibly in rodents.
The accumulation of acquired mitochondrial genome (mtDNA) mutations with aging in somatic cells has been implicated in mitochondrial dysfunction and linked to age-onset diseases in humans. Here, we asked if somatic mtDNA mutations are also associated with aging in the mouse. MtDNA integrity in multiple organs and tissues in young and old (2-34 months) wild type mice was investigated by whole genome sequencing.
Remarkably, no acquired somatic mutations were detected in tested tissues. However, we identified several non-synonymous germline mtDNA variants whose heteroplasmy levels (ratio of normal to mutant mtDNA) increased significantly with aging suggesting clonal expansion of inherited mtDNA mutations. Polg mutator mice, a model for premature aging, exhibited both germline and somatic mtDNA mutations whose numbers and heteroplasmy levels increased significantly with age implicating involvement in premature aging. Our results suggest that, in contrast to humans, acquired somatic mtDNA mutations do not accompany the aging process in wild type mice.