Cardiac mitochondrial bioenergetics, oxidative stress, and aging

Abstract

Mitochondria have been a central focus of several theories of aging as a result of their critical role in bioenergetics, oxidant production, and regulation of cell death. A decline in cardiac mitochondrial function coupled with the accumulation of oxidative damage to macromolecules may be causal to the decline in cardiac performance with age. In contrast, regular physical activity and lifelong caloric restriction can prevent oxidative stress, delay the onset of morbidity, increase life span, and reduce the risk of developing several pathological conditions. The health benefits of life long exercise and caloric restriction may be, at least partially, due to a reduction in the chronic amount of mitochondrial oxidant production. In addition, the available data suggest that chronic exercise may serve to enhance antioxidant enzyme activities, and augment certain repair/removal pathways, thereby reducing the amount of oxidative tissue damage. However, the characterization of age-related changes to cardiac mitochondria has been complicated by the fact that two distinct populations of mitochondria exist in the myocardium: subsarcolemmal mitochondria and interfibrillar mitochondria. Several studies now suggest the importance of studying both mitochondrial populations when attempting to elucidate the contribution of mitochondrial dysfunction to myocardial aging. The role that mitochondrial dysfunction and oxidative stress play in contributing to cardiac aging will be discussed along with the use of lifelong exercise and calorie restriction as countermeasures to aging.

Metabolic Syndrome, Aging and Involvement of Oxidative Stress

“…Accumulation of these mtDNA alterations may lead to impairment of the respiratory chain complexes, leading to a vicious cycle with an increase in mitochondrial ROS production and a subsequent accumulation of more mitochondrial DNA mutations. This chain reaction has been proposed to be involved in the increased oxidative damage during aging that induces to the progressive decline in cellular and tissue function as a result of insufficient supply of energy and/or increased susceptibility to apoptosis [36][37][38]. Agerelated increase in oxidative damage to DNA, lipids, and proteins has been well documented [39][40], as well as evidence supporting increased mtDNA deletions and mitochondrial dysfunction with aging [41][42][43][44][45][46].…”

Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity

“…6 In contrast, excessive ROS generation is detrimental, negatively affecting the function and integrity of not only the mitochondria, but also of proteins, lipids and other organelles in the cytoplasm and potentially leading to impaired cellular homeostasis and organ functioning. 7,8 Importantly, mitochondrial DNA is particularly susceptible to such oxidative damage, primarily due to its close proximity to the site of ROS production, the lack of protective rapamycin have been demonstrated in animal models of ischemia/reperfusion as well as in cardiac hypertrophy. 23,24 In addition, rapamycin also protects against neurodegeneration by mediating the removal of aggregated proteins through autophagy induction.…”

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

“…Although, numerous aging theories have been proposed to explain mechanisms of aging [330], no theory has been more lasting in this regard than that known as the "free radical theory of aging," in which damage by free radicals (reactive oxygen species [ROS]) is deemed critical in determination of life span [331][332][333]. This theory proposed in 1956 by the Denham Harman [334] states that free radicals, especially ROS formed as by-products of normal metabolic processes, cause oxidative damage to macromolecules, whose accumulation causes cellular dysfunction, and this ultimately determines the lifespan of an organism [335,336].…”

“…Later with the realization that mitochondria are at the same time major sources and targets of ROS, the theory was renamed as the "mitochondrial theory of aging" [331,332,335,337,339]. According to this theory of aging, ROS produced as by-products of the mitochondrial oxidative respiratory chain damage mitochondrial macromolecules, especially mitochondrial DNA (mtDNA).…”