Enhanced Mitochondrial Catalase has Different Effects in Young and Old Mice

Mitochondria are important in aging, and this appears to be related to the generation of oxidative molecules that takes place as a side-effect of the creation of chemical energy stores. A fair number of the ways to modestly slow aging in short-lived species change the operation of mitochondria so as to also change the output of oxidants. These reactive molecules can disrupt cellular machinery, but also act as signals, so it is still far from clear as to which are the most important secondary consequences in the various contexts of interest. In the longer term, it is plausible that these oxidants are causing DNA damage in the mitochondria themselves, something that has the potential to spiral out of control to lead to dysfunctional mitochondria, a dysfunctional cell, and damage that can spread out into surrounding tissues. One potential way to suppress the output of oxidative molecules is genetic engineering to increase levels of natural antioxidant compounds localized to the mitochondria, and one of the earliest attempts to do this targeted mitochondrial catalase in laboratory mice. This has produced varied outcomes, however, ranging from little effect to slowed aging. The paper noted here might go some way towards explaining why research groups have seen mixed results from this approach, as the age of the mice used in these studies appears to be a crucial factor:

Reactive oxygen species (ROS) are associated with the progression of a broad spectrum of pathologies including aging. Mechanistically, this has largely been attributed to oxidative modification of cellular macromolecules, including lipids and proteins. While ROS have been widely regarded as a major component of aging since the 'free radical theory of aging' was proposed in the 1950s, there is an increasing appreciation that ROS also serve important physiological signaling roles. It is therefore important to closely examine both negative and positive consequences of therapeutic interventions that target ROS. Given that oxidative modifications can impair the activity of macromolecules, and the well-documented correlation between oxidative damage and aging reported in almost all models studied, it has been tempting to conclude that this is a likely mechanism for aging. However, there are many observations at odds with this theory of aging. Clinical trials of dietary antioxidants have thus far shown little to no efficacy. Some have shown adverse outcomes. In mice, deletion of many antioxidant enzymes has little effect on lifespan and, importantly, overexpression of several antioxidants including superoxide dismutase and peroxisomal catalase has failed to extend lifespan.

Our group has previously shown that mice overexpressing mitochondrial-targeted catalase (mCAT), but not nuclear or peroxisomal catalase, have an approximately 20% increased median and maximal lifespan, suggesting that reducing ROS specifically in the mitochondria is key to achieving a beneficial effect on aging. mCAT has been shown to reduce oxidative modification of DNA and proteins and delays the progression of multiple pathologies. We have also demonstrated that mCAT is protective against cardiac aging. However, it has been increasingly recognized that ROS has beneficial roles in signaling, hormesis, stress response, and immunity. We therefore hypothesized that mCAT might be beneficial only when ROS approaches pathological levels in older age and might not be advantageous at a younger age when basal ROS is low. We analyzed abundance and turnover of the global proteome in hearts and livers of young (4 month) and old (20 month) mCAT and wild-type (WT) mice. In old hearts and livers of WT mice, protein half-lives were reduced compared to young, while in mCAT mice the reverse was observed; the longest half-lives were seen in old mCAT mice and the shortest in young mCAT. Protein abundance of old mCAT hearts recapitulated a more youthful proteomic expression profile. However, young mCAT mice partially phenocopied the older wild-type proteome. Age strongly interacts with mCAT, consistent with antagonistic pleiotropy in the reverse of the typical direction. These findings underscore the contrasting roles of ROS in young vs. old mice and indicate the need for better understanding of the interaction between dose and age in assessing the efficacy of therapeutic interventions in aging, including mitochondrial antioxidants.

Link: http://onlinelibrary.wiley.com/doi/10.1111/acel.12472/full