Mitochondrial damage is important in aging, and many of the means shown to modestly slow aging in various species involve increased cellular maintenance activities directed towards mitochondria. One of these is mitophagy, a specialized form of autophagy that recycles damaged mitochondria. There is plenty of evidence to suggest that more efficient mitophagy is good for long-term health. There is also plenty of evidence for increased autophagy of all sorts to be one of the more important mediating mechanisms in many of the interventions shown to slow aging in laboratory species, including the long-studied and simple approaches of calorie restriction and exercise. In this paper, the authors review what is known of the effects of exercise on mitophagy and mitochondrial function in older individuals. We all know the rough boundaries of the benefits that can be produced by exercise; the open question for researchers is the degree to which various specific mechanisms contribute to those benefits.
The maintenance of mitochondrial structural integrity, biogenesis, and function is essential to cells, since mitochondrial dysfunction can induce disturbances in energy metabolism, increase reactive oxygen species (ROS) production and, consequently, trigger mechanisms of apoptotic cell death. Moreover, during the last decades, multiple lines of evidence in model organisms and humans have demonstrated that impaired mitochondrial function can contribute to the aging process, as well as age-associated diseases. In fact, it has been shown that decreased mitochondrial performance is a hallmark of aging possibly due to the central role of mitochondria in metabolism and cellular function. Thus, the potential toxicity of mitochondrial ROS (mtROS), originating from the mitochondrial respiratory chain, led to the formulation of the oxidative stress theory of aging, which suggested that the accumulation of oxidative damage to macromolecules is an important point in the aging process.
Mitochondrial DNA has two characteristics that make it a key target of mtROS: on the one hand, its proximity to the respiratory chain and, on the other, the lack of protective histones. Damaged mitochondrial DNA alters the respiratory chain, increasing the free radical generation and triggering a vicious cycle. These changes result in organic dysfunction and aging phenotype. Recently, however, in contrast to the original theory favoring oxidative damage as a cause for mtDNA mutations and corresponding declines in mitochondrial function, there are strong data arguing that most mammalian mtDNA mutations originate as replication errors made by the mitochondrial DNA polymerase.
Since mitochondria are involved in both adaptive metabolism and survival in response to cellular stress, it is necessary to maintain good mitochondrial functioning through a tight mitochondrial quality control. Recently, mitophagy has gained importance because the damage accumulated in the mitochondria may result in a large number of cell consequences. This process of dysfunctional mitochondria removal occurs by two major pathways, damage-induced mitophagy and developmental-induced mitophagy. Mitophagy not only clears dysfunctional mitochondria but also participates in adaptive response to nutrient deprivation, hypoxia, or developmental signals, promoting a reduction in the overall mitochondrial mass.
Physical exercise has been proposed as a nondrug treatment against different diseases for people of all ages. In addition, it is suggested that regular exercise could promote an increase in mitophagy capacity and produce effects on the mitochondrial life cycle. Theoretically, physical exercise could also have effects on the major signaling pathways that are involved in the quality and quantity control of mitochondria during the aging process, such as mitophagy. Mitochondria produce ROS that can act as signaling molecules, inducing a survival response or causing damage to cellular components. However, contraction of the skeletal muscle during physical exercise can activate a mitochondrial response that improves the quality of mitochondria in different ways: (1) increasing biogenesis; (2) enhancing the expression and action of the proteins involved in mitochondrial dynamics; (3) raising mitochondrial turnover by the action of mitophagy proteins; and (4) increasing the quality control of mitochondria through the degradation of damaged or dysfunctional mitochondria.
Although the studies analyzed do not exhibit a general consensus, it seems that aging impairs mitochondrial biogenesis and dynamics and decreases the mitophagic capacity of the organism. Several interventions, such as any type of physical exercise, are able to affect the activity and turnover of mitochondria by increasing biogenesis. In addition to the changes detected in the biogenesis, aerobic exercise or combined long-term training also seem to produce increases in several markers of mitochondrial dynamics and mitophagy.