Regular readers will be at least passingly familiar with the commercial development of mitochondrially targeted antioxidant compounds that has taken place over the past decade. This initially attracted attention in this community because the evidence suggests that these molecules can modestly slow the progression of aging, though unfortunately not to the same degree as interventions like calorie restriction, which to my eyes at least means that serious life extension efforts are better directed elsewhere. The furthest advanced of these mitochondrially targeted antioxidants is the SkQ series of plastinquinones, currently being developed as a treatment for a few different conditions by Mitotech. It turned out that the effects on inflammatory eye conditions were considerably larger than the effects on aging, so that is the direction presently taken. Another of the compounds under development by a different set of researchers is SS-31; you'll find an introduction in the Fight Aging! archives. In the paper noted below, SS-31 is used to demonstrate that reducing oxidative stress in muscle cells doesn't slow the age-related loss of muscle mass and strength known as sarcopenia. This is a nice piece of work that might help focus future research efforts in more productive directions.
Given that straightforward antioxidants of the sort purchased in a supplement store either do nothing for health and aging or actually somewhat harm long term health, why would be expect antioxidants targeted to the mitochondria within the cell to be a different proposition? It helps to start by noting that the roles of oxidative molecules and antioxidants in the cell are manifold and complicated. Oxidative molecules cause damage by reacting with important protein machinery, but they are also used as signals. Too much is bad, and too little is bad. Exactly where there is too much or too little is also of great importance. Globally suppressing oxidative signaling via high levels of ingested antioxidants has negative effects like blocking the benefits of exercise, which depend upon that signaling. Mitochondria are central to all discussions of oxidative signaling, as they generate oxidative molecules as a result of their primary role as power plants, supplying energy store molecules to power the cell. Many of the genetic alterations and other interventions that modestly slow aging in laboratory species change mitochondrial function, either increasing or reducing the flux of oxidative molecules.
There are several likely ways in which altered mitochondrial output of oxidative molecules can affect long term health, that alteration achieved either by changing the rate at which such molecules are created, or by applying targeted antioxidants that soak them up immediately. Firstly there is hormesis: a slightly higher than usual output and the resulting damage can trigger greater and lasting repair and maintenance activities in the cell, leading to a net benefit. Or, alternatively, a lower level of output of oxidative molecules might just lead directly to less damage. Further, there are many other aspects of cellular metabolism that might run in ways better suited to a slower pace of aging if mitochondria generate either more or less oxidative molecules; that is poorly mapped and highly dependent on species, tissue, and circumstances. Lastly there is the important matter of mitochondrial DNA damage in aging. Mitochondrial dysfunction appears to be an important contribution to aging, and it is likely driven by mutational damage to DNA in the mitochondria caused by their own generation of oxidants. This DNA damage can produce mitochondria that are both dysfunctional and resistant to quality control. They quickly overtake a cell, and over the course of a lifetime ever more cells fall into this state. Their behavior contributes to degenerative aging in a range of ways, starting with the export of much larger amounts of oxidizing molecules into the surrounding tissues.
Thus rising levels of oxidative stress are considered important in many aspects of the progression of aging, but it is far from the only type of change, damage, and dysfunction taking place. So it shouldn't be a complete surprise to find that some conditions are not affected in the slightest by adjusting mitochondrial oxidant output, even when the indications suggested that outcome to be plausible enough to try. Metabolism is a ferociously complex business, incompletely understood, which is why bypassing its alteration in favor of identifying and fixing fundamental forms of damage should be a much more efficient approach to the treatment of aging and age-related conditions. We have a metabolism that works well when young, even it isn't fully understood, and researchers have a list of the fundamental, first cause differences between young and old tissues, so the goal should be to revert those differences and maintain the working system, rather than try to adjust it.
Skeletal muscle is a major site of metabolic activity and is the most abundant tissue in the human body. Age-related muscle atrophy (sarcopenia) and weakness, characterized both by loss of lean muscle mass and reduced skeletal muscle function, is a major contributor to frailty and loss of independence in older people. Studies of humans indicate that by the age of 70, there is a ~25-30% reduction in the cross sectional area (CSA) of skeletal muscle and a decline in muscle strength by ~30-40%. Age-dependent loss of muscle mass and function has a complex aetiology and the primary biochemical and molecular mechanisms underlying this process have not been fully determined.
Oxidative stress has been suggested to be a key factor contributing to the initiation and progression of the muscle atrophy that occurs during aging. Consistent with a role of oxidative stress as a contributor to sarcopenia, studies have shown that genetic manipulations of redox regulatory systems can alter the aging process in muscle. Skeletal muscle decline with advancing age has been linked to an altered oxidative status of redox-responsive proteins and a number of studies have indicated a positive correlation between tissue concentration of oxidized macromolecules and life span including an increase in DNA damage, accumulation of oxidized proteins and increased levels of lipid peroxidation with age. In support of these findings recent quantitative proteomic approaches have further provided evidence that muscle aging is associated with a reduction in redox-sensitive proteins involved in the generation of precursor metabolites and energy metabolism, implying age-related redox changes as an underlying cause of age-related muscle atrophy.
Skeletal muscle produces reactive oxygen and nitrogen species (RONS) from a variety of subcellular sites and there is evidence that isolated skeletal muscle mitochondria exhibit an age-related increase in hydrogen peroxide (H2O2) production. Furthermore, muscle aging is associated with reduced mitochondrial oxidative-phosphorylation, reduced mitochondrial DNA (mtDNA) content, accumulation of mutated mtDNA, impaired mitophagy and increased mitochondrial permeability transition pore sensitivity, which are all proposed to contribute to the sarcopenic phenotype. Although cumulative oxidative stress has been proposed to induce age-associated reductions in mitochondrial function, this remains a controversial topic.
We and others have recently reported that pharmacological application of the mitochondria-targeted SS31 tetrapeptide can attenuate mitochondrial superoxide production in intact mitochondria of skeletal muscle fibers. This pharmacological approach complements genetic approaches, including those using targeted overexpression of the human catalase gene to mouse mitochondria. Such pharamacological agents may have substantial translational implications for the use and/or development of mitochondria-targeted antioxidants for treatment of human mitochondrial myopathies as well as mitochondrial reactive oxygen species (mtROS) mediated muscular dysfunctions. The purpose of the present study was to determine the effect of the mitochondria-targeted SS31 peptide on redox homeostasis in muscles of old mice, including mtROS and oxidative damage, mitochondrial content and mitophagy and on age-related muscle atrophy and weakness. Through this approach we aimed to determine the role of modified mitochondrial redox homeostasis on age-related loss of muscle mass and function.
Our findings demonstrated that a reduction in mtROS in response to SS31 treatment prevented age-related mitochondrial oxidative damage and improved mitophagic potential, but further demonstrated that changes in mitochondrial redox environment towards a more reduced state failed to rescue the sarcopenic phenotype associated with muscle fiber atrophy and loss of muscle mass and strength. This work has therefore identified that the age-related changes in mitochondrial redox potential play a key role in the loss of mitochondrial organelle integrity that occurs with aging, but are not involved in the processes of age-related muscle fiber atrophy.