Today's open access review discusses oxidative signaling and damage in aging muscles. All considerations of oxidative molecules in aging are complex, but then nothing in biology is simple. Decades ago, the research community proposed that aging was caused by oxidative damage, but the data that led to that theory of aging was only a small part of the overall story. The original theory has since fallen to the wayside. Yes, there is oxidative damage in old tissues, cell components disrupted by reacting with oxidizing molecules. But cells also use oxidative molecules as signals, and respond to rising levels of oxidation with greater repair efforts. A number of the ways to slow aging in short-lived laboratory species work because they cause a modest increase in the production of oxidative molecules by mitochondria, and any greater level of damage to cellular mechanisms is outweighed by increased activity of cellular maintenance processes.
Mitochondria are the primary source of oxidative molecules, but the process may be fairly indirect, even given the loss of mitochondrial quality and function that is characteristic of aging. In the SENS view of mitochondrial dysfunction, a small fraction of cells become overtaken by broken mitochondria and, as a consequence, export significant volumes of oxidative molecules into surrounding tissue. It is a multi-step process that only begins with mitochondrial damage. Further, consider that levels of oxidative molecules in circulation go hand in hand with inflammation. The immune system declines with age, falling into a state of ineffective chronic inflammatory activity. This may also be an important source of age-related oxidative stress. It is usually challenging to pick apart the degree to which specific mechanisms contribute to aging, as it is hard to alter any one mechanism in complete isolation.
The skeletal muscle is the largest organ in the body comprising ~40% of its mass. It plays fundamental roles in movement, posture, and energy metabolism. The loss of skeletal muscle mass and function with age can have a major impact on quality of life and results in increased dependence and frailty. Age-related decline of skeletal muscle function (sarcopenia) results in strength loss. This loss stems from two major sources, reductions in muscle mass (i.e., quantity) and decrease in its intrinsic capacity for producing force (i.e., quality). Both can be the consequence of several factors, including oxidative stress that is the result of the accumulation of reactive oxygen and nitrogen species (ROS/RNS). The free-radical theory of aging was established more than 60 years ago and has become one of the most studied theories to have been proposed. It is now accepted that this theory and its various spin-offs cannot alone explain the aging process. Nevertheless, huge amounts of data indicate that ROS-mediated aging phenotypes and age-related disorders exist
During physiological homeostasis the overall oxidative balance is maintained by the production of ROS/RNS from several sources and their removal by antioxidant systems, including endogenous or exogenous antioxidant molecules. At physiological concentrations ROS/RNS play essential roles in a variety of signaling pathways. There is an optimal level of ROS/RNS to sustain both cellular homeostasis and adaptive responses, and both too low and too high levels of ROS/RNS are detrimental to cell functions. The skeletal muscle consumes large quantities of oxygen and can generate great amounts of ROS and also reactive nitrogen species. Mitochondria are one of the most important sources of ROS in the skeletal muscle.
The origin of the increased ROS production and oxidative damage is mitochondrial dysfunction with aging, caused by age-related mitochondrial DNA mutations, deletions, and damage>, as well as the impaired ability of muscle cells to remove dysfunctional mitochondria. Oxidative phosphorylation impairment can lead to decreased ATP production and further generation of ROS. Interestingly, aging is associated not only with an increase in oxidative damage but also with an upregulation of antioxidant enzymes in the skeletal muscle. Furthermore, the iron content of the mitochondria in the skeletal muscle increases with aging, amplifying the oxidative damage with the generation of ROS. Increased ROS production, mitochondrial DNA damage, and mitochondrial dysfunction was observed in aged muscles.
The skeletal muscle is highly plastic and shows several adaptations towards mechanical and metabolic stress. Oxidative stressors, like ROS, have long been taken into account as harmful species with negative effects in the skeletal muscle. Proteins are frequently affected by oxidation; thus, elevated ROS levels can cause reversible or irreversible posttranslational modification of cysteine, selenocysteine, histidine, and methionine. Oxidative posttranslational modifications of proteins are characteristic in the aged muscle, such as carbonylation which alters protein function. The oxidative capacity of muscles is strongly associated with health and overall well-being. Enhanced oxidative capacity in the skeletal muscle protects against several pathological phenomena (insulin resistance, metabolic dysregulation, muscle loss with aging, and increased energetic deficits in myopathies). These protective effects are largely associated with enhanced mitochondrial function and elevated numbers of mitochondria, which can protect against cellular stress.