Mitochondrial theory of aging
Aging occurs at every level of biological organisation. The physiological capacities of organisms increase during maturation and then linearly decay with age.
This process leads to a decrease in resistance and an increase in cell fragility that, over time, manifests itself as age-associated diseases. The slow and progressive accumulation of oxygen and nitrogen free radicals (ROS/RNS) that are naturally produced throughout life is now thought to be one of the main causes of aging. Free radicals, both those generated in mitochondria, as well as those derived from the cytosol, inexorably damage cells, slowly decreasing mitochondrial function. This causes the electron transport chain (ETC) and oxidative phosphorylation to become inefficient, decreasing the production of ATP. Therefore, mitochondria become more vulnerable to attack by ROS/RNS, further decreasing their efficiency. Thus, a vicious circle is closed which ends in apoptosis or programmed cell death. This is the basis of the mitochondrial theory of aging.
In the vast majority of degenerative pathologies associated with aging, the increased production of reactive species is associated with the perpetuation of a chronic inflammatory process. In contrast, ionising radiation—such as ultraviolet radiation (UVR)—is a clear example of a ROS inducer which is responsible for oxidative damage and immune damage of peripheral tissues such as skin. Thus, exposing ‘nude’ rats to UVR produces an increase in ROS and causes the Langerhans cells to disappear in the epidermis. In skin, this has been correlated with some erythrocytic and epidermal parameters used to measure oxidative stress, especially glutathione disulfide (GSSG), glutathione peroxidase (GPx) and glutathione reductase (GRd), and catalase (CAT). Therefore, the aging process involves increased ROS production and a progressive loss of Langerhans cells.
Recent data indicate that, in addition to ROS, nitric oxide (NO), a component of nitrogen free radicals, significantly affects respiration, and is a direct cause of mitochondrial failure. NO and oxygen compete for the same binding site on complex IV of the ETC. As the concentration of NO increases inside mitochondria, complexes I, II, and III are inhibited, which severely damages the ETC, increasing the production of ROS/RNS and resulting in the release of cytochrome c into the cytosol in order to initiate the processes of apoptosis. In addition, peroxynitrites formed by the reaction of NO with superoxide anions, irreversibly inhibit several mitochondrial enzymes such as aconitase, reduced nicotinamide adenine dinucleotide (NADH), succinate dehydrogenase, and superoxide dismutase (SOD). If this mitochondrial damage is not simultaneously repaired, the cellular failure can become irreversible because of complete ETC failure.
Some of the NO that reaches mitochondria is derived from several different NOS isoenzymes, especially nNOS, eNOS, and iNOS, with the latter producing the massive quantities of NO responsible for most of the nitrosative damage caused in many inflammatory processes, including aging itself. In addition, we now also know that another iNOS isoform, mitochondrial (i‑mtNOS) is found in this organelle and increases degenerative-inflammatory processes. i‑mtNOS is very important because it can produce, in situ, a lot of the NO that negatively affects mitochondrial respiration.
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