Mice engineered to generate a high level of deletion mutations in mitochondrial DNA exhibit accelerated aging. As in most cases of accelerated aging, we can debate whether or not it is correct to call it accelerated aging. The important point is whether or not the type of cellular damage involved provides a significant contribution to the normal aging process, which in this case it does. The normal lower levels of mitochondrial DNA damage are implicated as a cause of aging and age-related disease. Then the question becomes whether or not it is acceptable to continue to call it aging given a vastly greater presence of just one of the types of age-related damage, or is it now some other form of pathology?
Putting this to one side, here researchers show that SkQ1, a mitochondrially targeted antioxidant shown to modestly slow aging in laboratory species, helps to ameliorate the harm done by high levels of mitochondrial deletion mutations. To my eyes, at least, it would have been unexpected to find another outcome, given what is known of the mechanisms involved here. This class of targeted antioxidant compounds come with a good deal of evidence backing their impact on mitochondrial metabolism; to the degree that deletions occur due to oxidative damage, and to the degree that they in turn cause greater levels of oxidative damage throughout the cell through disarrayed mitochondrial function, the presence of antioxidants in the mitochondria should reduce the harmful outcomes. This class of compound is currently being developed as a treatment for inflammatory eye conditions, as this is one of the areas in which the benefits are both reliable and large, and the regulatory path to market is comparatively smooth.
As a cause for the decreasing health status that accompanies aging, mitochondrial deterioration has been repeatedly suggested. Particularly, it has been discussed that an accumulation of errors in mitochondrial DNA (mtDNA) replication would lead to mitochondrial dysfunction, including increased production of reactive oxygen species (ROS) that may both further deteriorate the mitochondria and affect the function of the rest of the cell. However, the significance of ROS for the aging process has been doubted, particularly based on observations in the mtDNA mutator mice. These mice accumulate errors in their mtDNA and demonstrate subsequent alterations in their respiratory chain composition. They also demonstrate an early occurrence of characteristics normally associated with aging, and they die at a young age. However, there has been no convincing evidence that oxidative damage causes these problems.
Experimentally, an alternative avenue to examine the possible involvement of ROS in the development of aging characteristics would be to examine the ability of mitochondrially targeted antioxidants to ameliorate the health problems associated with experimentally induced aging. In this paper, we find that the mitochondrially targeted antioxidant 10-(6'-plastoquinonyl)decyltri-phenylphosphonium cation (SkQ1) substantially counteracts the acquisition of aging characteristics in the mtDNA mutator mice. We also find that parameters for oxidative damage not earlier examined (cardiolipin depletion and accumulation of hydroxynonenal protein adducts) are diminished by SkQ1 treatment. These data clearly indicate that ROS production and oxidative damage are substantial factors in the development of aging characteristics in the mtDNA mutator mice.
As the presently reluctance to associate mitochondrial dysfunction with aging through ROS and oxidative damage are largely based on the notion that these phenomena were apparently not involved in aging in mtDNA mutator mice, and as our present data indicate the opposite to be the case, our observations may also be of significance for discussions of the nature of aging and the possibility to ameliorate the aging process therapeutically.