Today I'll point out a fairly readable review paper that walks through the high points of what is known of the mitochondrial contribution to degenerative aging and the common, well-studied age-related diseases that cause the greatest amounts of suffering and death. Every cell has a few hundred mitochondria swarming inside it, evolved descendants of ancient symbiotic bacteria that are now fully integrated components of the cell. They are highly active components: they replicate and fuse, pass molecular machinery between one another, are destroyed by cellular quality control mechanisms when they become damaged, and can even transfer between cells, all conducted at a rapid pace. Most of their DNA has moved into the cell nucleus, but a small number of genes remain to form the circular mitochondrial DNA. Mitochondria are primarily responsible for generating chemical energy stores, providing the power for cellular operations, but they also participate in many other fundamental cellular processes in one way or another.
There are two ways we might think of mitochondria in the context of aging. The first is the SENS view of the mitochondrial contribution to aging. The mitochondrial DNA becomes damaged, either through replication or because building energy store molecules is a process that generates potentially damaging, reactive molecules as a side-effect. Sometimes that damage cuts out an important part of the energy generation machinery, creating a mitochondrion that both runs hot, producing many more harmful molecules, but is also more competitive than its peers when it comes to replication within the cell. Perhaps it can evade quality control, perhaps it replicates more rapidly; whatever the cause, whenever this rare form of damage occurs, the descendants of the damaged mitochondrion very quickly take over the entire population within that cell.
The result is a pathological cell that churns out harmful reactive molecules in large amounts into the surrounding tissue. This can, for example, cause atherosclerosis through oxidative damage of lipids that end up in the bloodstream. There the damaged molecules irritate blood vessel walls, resulting in the lesions that will become atherosclerotic plaques and eventually rupture. This could be avoided via any reliably means of sabotaging this chain of events. The proposed SENS Research Foundation approach is to use gene therapy to copy mitochondrial DNA into the cell nucleus to provide a backup supply of protein machinery; if carried out, then it won't matter how ragged the mitochondrial DNA becomes. The mitochondria will still function correctly, and cells will remain unharmed.
The second way to think of mitochondrial in aging is given far more attention in the scientific mainstream. It is a sort of general malaise found in all cells in aged tissue, in which mitochondrial dynamics are altered, the size of mitochondria changes, and their ability to generate energy stores falters. The processes of cellular quality control responsible for destroying problematic mitochondria start to fail as well. This is well studied by researchers who specialize in neurodegenerative diseases, as the brain requires a great deal of energy to function, and lack of that energy is a real problem. Why does this happen? That remains a question; which of the forms of damage that drive aging lead to this reaction, and what exactly is the chain of cause and effect? Researchers are making some inroads in tinkering with this mitochondrial malaise, speeding it up and slowing it down somewhat, but the roots remain obscure.
Mitochondrial dysfunction is linked to various aspects of aging including impaired oxidative phosphorylation (OXPHOS) activity, increased oxidative damage, decline in mitochondrial quality control, reduced activity of metabolic enzymes, as well as changes in mitochondrial morphology, dynamics, and biogenesis. Mitochondrial dysfunction is also implicated in numerous age-related pathologies including neurodegenerative and cardiovascular disorders, diabetes, obesity, and cancer.
The role of mitochondria in aging was first proposed more than 40 years ago in the free radical theory of aging, suggesting that accumulation of cellular damage with increasing age results from reactive oxygen species (ROS) and mitochondria are one of the most important sources and targets of ROS that could function as an 'aging clock'. Since then, a growing body of evidence has shown that mitochondrial dysfunction contributes to aging in multiple model organisms and that several factors cause increased mitochondrial dysfunction with chronological age including accumulation of somatic mtDNA mutations, enhanced oxidative damage, decreased abundance and quality of mitochondria, as well as dysregulation of mitochondrial dynamics.
Mitochondria are unique as they harbor their own genome (mtDNA). Point mutations and deletions are the two most frequent types of mutations that arise in mtDNA genome with age mainly due to spontaneous errors during mtDNA replication or damage repair. A wealth of supportive evidence demonstrates that mitochondrial dysfunction occurs with age due to accumulation of mtDNA mutations; however, the causative role of mtDNA mutations in aging remains controversial. Various mtDNA point mutations have been shown to significantly increase with age in the human brain, heart, skeletal muscles and liver tissues. Increased frequency of mtDNA deletions/insertions have also been reported with increasing age in both animal models and humans. The strongest evidence to date that favors a causative role of mtDNA mutations in aging comes from the study of mtDNA mutator mice that exhibit significant accumulation of mtDNA mutations as well as a premature or accelerated aging phenotype.
Mitochondria are highly dynamic structures as they continuously undergo fission and fusion processes that shape their morphology and regulate mitochondrial size, number and function. Mitochondrial dynamics is essential for mitochondrial viability and response to changes in cellular bioenergetic status. Mitochondrial fission is vital for mitotic segregation of mitochondria to daughter cells, distribution of mitochondria to subcellular locations, and mitophagy. Unopposed fission leads to mitochondrial fragmentation, loss of OXPHOS function, mtDNA depletion and ROS production, which are associated with metabolic dysfunction or disease. Mitochondrial fusion is essential for maintaining mitochondrial membrane potential, ATP production, and maximal respiratory capacity. Unopposed fusion generates a network of hyperfused mitochondria associated with increased ATP production, reduced ROS generation and which exhibit an ability to counteract metabolic insults, protect against autophagy as well as apoptosis.
In the past decade, several studies have shown that mitochondrial dynamics plays a crucial role in the regulation of mitochondrial function and metabolism. Studies suggest that dysregulation of mitochondrial dynamics could contribute to aging and age-related pathologies. However, there are several outstanding questions that yet remain to be addressed regarding the link between mitochondrial dynamics and aging. For example, which factors cause altered expression of mitochondrial fission and fusion proteins during aging, and are these factors genetic or affected by environmental stimuli? Is altered mitochondrial dynamics a major cause of mitochondrial dysfunction in aged cells or tissues? Can proteins involved in mitochondrial dynamics serve as promising candidates for promoting healthy aging and/or alleviating various age-related pathologies? Future experimental studies that are designed to address these questions would help to better understand the role of mitochondrial dynamics in aging and age-related pathologies.