Researchers digging deeper into the mechanisms by which exercise produces benefits have found that it improves the resistance of blood vessels to oxidative stress. With age the presence of oxidizing molecules and oxidative modification of proteins, preventing correct function, increases for reasons that include damage to mitochondria, the power plants of the cell. Oxidative damage to molecular machinery is somewhere in the middle of the chain of cause and effect that starts with fundamental forms of damage to cells and tissues and spirals down into age-related diseases. Near all of this oxidation is repaired very quickly, the damaged molecules dismantled and recycled, but in most contexts more of it over the long term is worse than less of it.
Cardiovascular diseases (CVD) are the leading cause of death in developed societies. The risk of CVD increases progressively with advancing age, such that greater than 90% of deaths from CVD occur in people over the age of 55. Although the mechanisms underlying the age-related increase in CVD risk have not been fully elucidated, strong evidence indicates that the development of arterial dysfunction is a key factor. An important manifestation of arterial dysfunction is vascular endothelial dysfunction, characterized by a decline in endothelium-dependent dilation (EDD).
A major mechanism underlying the development of age-related endothelial dysfunction is oxidative stress, characterized by excessive production of reactive oxygen species (ROS) relative to endogenous antioxidant defense capacity. Oxidative stress can disrupt many aspects of arterial function, including reducing the bioavailability of the vasodilatory and vasoprotective molecule nitric oxide (NO), resulting in impaired EDD. A key source of arterial oxidative stress is excessive production of mitochondrial reactive oxygen species (mtROS). Whereas healthy mitochondria are critical mediators of arterial homeostasis and produce physiological levels of mtROS vital for cell signaling, declines in mitochondrial health are characterized by excessive mtROS production. We have recently shown that excess arterial mtROS production is a major contributor to tonic arterial oxidative stress-mediated suppression of EDD with primary aging in mice. Emerging evidence suggests that, in addition to baseline deficits in vascular function, aging may also be accompanied by reduced arterial resilience, i.e., the ability to withstand stress. Because human aging occurs in the presence of numerous stressors, it is important to understand how aging alters arterial resilience and to identify potential interventions that may improve the ability of arteries to withstand these challenges.
Mitochondria are critical components of the cellular stress response and interact with and regulate other stress response mediators, including antioxidant enzymes and heat shock proteins (Hsp). Thus, mitochondrial dysregulation has the potential to impact major upstream mechanisms, such as oxidative stress, that mediate vascular function. However, it is unknown whether age-related declines in arterial mitochondrial health contribute to decreased resilience in the presence of acute stressors. Aerobic exercise is a powerful intervention that improves baseline endothelial function in the setting of aging. It is well known that aerobic exercise improves mitochondrial biogenesis and homeostasis in non-vascular tissues, and recent work suggests that exercise can also improve markers of arterial mitochondrial content and health in healthy animals, but the effects of aerobic exercise on arterial mitochondria with primary aging are unclear. We tested the hypothesis that aging would be associated with impaired arterial resilience to acute stress and reduced arterial mitochondrial health in mice, and that voluntary aerobic exercise initiated in late-life (10 weeks of voluntary wheel running) would increase resilience and improve mitochondrial health in aging arteries.
In line with a recent study in our laboratory, we observed that age-related vascular endothelial dysfunction is accompanied by elevated arterial mitochondrial superoxide production. Importantly, we show here that voluntary aerobic exercise normalized mitochondrial superoxide production in arteries of old mice, suggesting that exercise-induced reductions in arterial mitochondrial oxidative stress may contribute to improvements in vascular endothelial function. Our findings further extend previous work by demonstrating that, in addition to restoring baseline vascular endothelial function, voluntary aerobic exercise improves arterial resilience to acute stressors in old mice. Consistent with our previous report, we observed that acute treatment with rotenone, a mitochondrial Complex I inhibitor that can also induce mitochondrial superoxide production, impairs carotid artery endothelial function in old mice to a greater degree than arteries from young mice, indicating that aging arteries are more vulnerable to a mitochondria-specific challenge. In the present study, we show that voluntary aerobic exercise completely restores the ability of aged arteries to withstand this acute mitochondrial stress.