The open access paper I'll point out today should be taken as an opinion piece rather than something more rigorous, I think. The authors link together a few findings from past years in order to make an argument about some of the specifics of mitochondrial function and its importance in aging. It is interesting, albeit a touch overwritten, when considered in the bigger picture. It is certainly the consensus in the scientific community that mitochondria are important in aging, a consensus based on many lines of research and a large amount of evidence accumulated over decades. Atop that consensus, however, there is still considerable room to debate the precise details and mechanisms involved in the influence of mitochondria upon aging. I suspect that this will continue to be the case until someone builds a working rejuvenation therapy based on one or another mitochondrial theory of aging. Biology is complex enough that at the present stage of technological development it is easier to prove a point through intervention than through investigation.
Mitochondria are the power plants of the cell, though they also have many other duties; nothing is ever simple in cellular biochemistry. They evolved from symbiotic bacteria, a replicating herd of them in every cell, and their primary task is to generate chemical energy store molecules to power cellular operations. This makes their correct function especially important in more energy-hungry tissues such as the brain, and thus declines in mitochondrial function frequently appear as a topic in research into most neurodegenerative conditions. Declines in mitochondrial activity across the board may be due to regulatory reactions to rising levels of cell and tissue damage, but the full picture of this process is still hazy with regards to how the known pieces of the puzzle fit together. Beyond this, there is the view of mitochondrial damage in which certain rarely occurring forms of dysfunction can produce mitochondria that take over their host cell and make it malfunction in ways that promote aging, exporting a flood of reactive molecules into surrounding tissues.
Researchers can also compare mitochondrial biochemistry between species with different life spans, and have found strong correlations between life span and mitochondrial activity and structure. Species in which mitochondria have a more resilient composition, made up of molecules more resistant to oxidative damage, tend to live longer. There is even a fair amount of evidence to suggest that differences in mitochondrial function are important in natural variations in longevity between individuals of the same species. Thus there is a great deal of evidence that, when considered as a whole, should encourage greater efforts to repair mitochondrial function in the old, to reverse observed declines, to fix damaged mitochondria. There is every reason to think that this might be one of the forms of therapy needed to produce rejuvenation.
A wealth of biomedical data supports a key role of impaired mitochondrial bioenergetics functionally linked to marked dysregulation of diverse cellular processes as a unifying causative factor in the etiology and persistence of major pathological conditions afflicting human populations. It appears that the contextual bases of normal aging, genetically determined lifespan, and mortality are intrinsically linked to the total number of tissue- and organ-specific multicellular complexes competing for relatively limited energy sources during temporal stages of growth and development. It follows that the stereotypically defined lifespans of diverse species of higher animals reflect the existential "price" to pay for the exquisite cellular diversity required for integrated regulation of complex organ function. Variations in longevity within individual members across species of higher animals may then be effectively sorted according to age-dependent losses of single-cell metabolic integrity functionally linked to impaired mitochondrial bioenergetics within compromised complex organ systems.
Recent studies have focused on the functional role of mitochondrial heteroplasmy, defined as a dynamically determined co-expression of wild-type (WT)-inherited polymorphisms and somatic mutations in varying ratios within individual mitochondrial DNA (mtDNA) genomes. Based on the empirically determined number of mitochondria with differing mtDNA copy numbers distributed in tissue-specific cell types, the total concentration of mtDNA molecules exceeds the number of nuclear DNA molecules by two to five orders of magnitude. It is also apparent that high levels of heteroplasmic mtDNA genomes within the intra-mitochondrial compartment in individual human cell types is required for normative mitochondrial bioenergetics that is markedly compromised in human disease states.
A potential window of opportunity for practical achievement of aging reversal and extended longevity in human populations is alluded to in a study that has highlighted the importance of functional mitochondria in the maintenance of differentiation and reprogramming of induced pluripotent stem cells (iPSCs). A transition from somatic mitochondrial oxidative metabolism to glycolytic metabolism, highly reminiscent of cancer cells, was observed to be required for successful reprogramming of iPSCs. Importantly, somatic mitochondria and associated oxidative bioenergetics were extensively remodeled with the induction of an iPSC-like phenotype. Preservation of tissue-selective patterns of mtDNA heteroplasmy within a viable reserve of iPSCs would appear to represent a key molecular target for practical augmentation of anti-aging therapies and lifespan extension.
State-dependent transfer of functional mitochondria from healthy to metabolically compromised cell types has been extensively documented. Interestingly, within developing and/or reparative cellular systems, intercellular trafficking of optimally functional mitochondria is achieved using tunneling nanotubes or cellular derived vesicles in an elaborate transfer system. Thus, technological transplantation of functionally viable mitochondria comes with the anticipation of the significant restoration of normative cellular function functionally linked to the preservation of cell-specific mosaic patterns of heteroplasmic mtDNA expression. From a translational perspective, restoration of genetically determined patterns of mitochondrial heteroplasmy has the potential to restore and maintain mitochondrial dynamics in multiple organ systems. Long-term restoration and preservation of tissue- and organ-specific patterns of mitochondrial heteroplasmy and mtDNA copy number represent practical goals for bioengineering strategies designed to overcome age-related limitations in meeting physiological energy demands.
Cell-specific patterning of mtDNA heteroplasmy encompassing thousands of mitochondrial genomes within a single cell may be viewed as a reservoir required to effect minute changes in energy requirements critically linked to physiological demands. Normative cellular expression of mtDNA heteroplasmy may effectively represent a sophisticated molecular coping strategy with critical biological importance to cellular/organismic survival and health, and mechanistic relevance to lifespan extension and longevity. Within this context, chronic dysregulation of mitochondrial function leading to the initiation and persistence of diverse pathophysiological states may be attributed to a temporal loss of ongoing restorative processes that appear to be inherently dependent on normal mitochondrial heteroplasmy. We surmise that the extent of short- and long-term cellular and mitochondrial damage may be effectively ameliorated by the selective targeting and reversal of debilitating somatic mutations in mtDNA. Restoration of relatively slow, age-related, perturbations of normative mitochondrial heteroplasmy is then proposed to promote enhanced quality of life via prolonged maintenance of essential cellular signaling pathways that have been widely associated with age-related metabolic rundown.