The research here notes an aspect of mitochondrial biochemistry that declines with age in a way that appears unaffected by fitness and exercise. One of the challenges inherent in investigating the mechanisms of aging in muscle tissue is determining the difference between decline due to disuse (secondary aging) versus decline due to intrinsic processes of damage accumulation (primary aging). We live in a world in which being older tends to mean being wealthier, with greater access to transportation and calories. Near all older adults fail to maintain a good program of exercise and diet, and the difference between those who make the effort to remain fit and slim and those who do not is sizable. That much is demonstrated by the significant gains in cardiovascular health and muscle strength that can be achieved in the elderly through structured exercise programs. So it is interesting to see research results in which the data makes it very clear that a specific measure of aging in muscle tissue is independent of exercise.
Aging is a complex process associated with skeletal muscle and strength loss as well as insulin resistance. The cellular mechanisms causing muscular and/or metabolic dysfunction with aging remain poorly understood. However, one proposed mechanism of action driving the aging process is an increase in mitochondrial-derived reactive oxygen species (ROS). Specifically, increased ROS emission has been associated with motor unit loss and abnormal morphology, muscle fiber atrophy, insulin resistance, inflammation, and apoptosis. Conversely, transgenic and pharmacological approaches that attenuate mitochondrial ROS have been shown to preserve insulin sensitivity, mitochondrial content, and muscle mass in diverse models while also prolonging lifespan. Altogether, these data implicate mitochondrial ROS as a fundamental mechanism of action influencing the aging phenotype.
Although these elegant rodent models provide compelling evidence to link mitochondrial ROS with age-associated pathologies, the data in humans remain ambiguous. Contradictory findings suggest that either mitochondria are not responsible for the increased oxidative stress with aging or, alternatively, contemporary in vitro assessment of mitochondrial ROS emission does not accurately reflect in vivo responses. ADP transport is a highly regulated process that is attenuated with rodent models of insulin resistance and improved following high-intensity exercise. Moreover, there is indirect evidence to suggest that the protein required for ADP transport into mitochondria, adenine nucleotide translocase (ANT), is impaired with aging in housefly and rat skeletal muscle. Therefore, previous assessments of mitochondrial ROS emission in the absence of ADP may not adequately reflect the in vivo environment, and as a result current data from human skeletal muscle may underestimate the importance of mitochondrial ROS in the aging process.
In the present study we re-evaluated mitochondrial bioenergetics by establishing a protocol in permeabilized muscle fibers to simultaneously examine mitochondrial respiration and hydrogen peroxide (H2O2) emission in the presence of various substrates and ADP concentrations. Using this in vitro protocol, we assessed age-related mitochondrial defects by comparing healthy young males to healthy older males. We also examined whether potential age-related defects in mitochondrial bioenergetics could be improved over 12 weeks of resistance exercise training. We provide compelling evidence that although the capacity for mitochondrial ROS emission is not increased with aging, mitochondrial ADP sensitivity is impaired, such that mitochondrial ROS, and the fraction of electron leak to ROS, are increased in the presence of virtually all ADP concentrations examined. In addition, although resistance-type exercise training improved several aspects of muscle health in older individuals, the fraction of electron leak to ROS, mitochondrial H2O2 emission rates in the presence of ADP, and muscle oxidative stress were unaltered, suggesting an increase in mitochondrial ROS accompanies the aging process.
Altogether, the assessment of mitochondrial bioenergetics in the presence of sub-saturating ADP concentrations has revealed that there are age-associated impairments in mitochondrial bioenergetics, which are not fully recovered with prolonged resistance-type exercise training. The mechanism for the attenuation in ADP sensitivity remains unknown, but oxidative damage has been proposed as a likely explanation. Regardless of this knowledge gap, the present data imply that an increase in mitochondrial ROS is associated with the primary aging process. Moreover, despite the inability of resistance training to rectify age-related mitochondrial ROS emission, older individuals experienced favorable changes in muscle mass, strength, and fat mass, reinforcing the importance of a physically active lifestyle throughout the lifespan.