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Stavros C. Manolagas, De-fense! De-fense! De-fense: Scavenging H2O2 While Making Cholesterol, Endocrinology, Volume 149, Issue 7, 1 July 2008, Pages 3264–3266, https://doi.org/10.1210/en.2008-0402
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It has been long appreciated that abnormal glucose, lipid, and bone metabolism, as well as atherosclerosis and neuronal degeneration, are common accompaniments of old age—often present as co-morbidities in the same individual. However, it is only recently that shared molecular pathogenetic mechanisms related to aging per se have been implicated in the development of these conditions. This forward stride is largely due to significant advances in our understanding of the biology of aging, genetic discoveries in animal models and humans, the demonstration of a similar function of the same genes in different organs, and better grasp of integrative physiology and pathophysiology.
To date the most durable and widely accepted mechanistic explanation of aging is oxidative stress. According to this theory, cellular stress caused by reactive oxygen species (ROS) is a major determinant of aging and life span (1). Approximately 90% of ROS arise in the mitochondria as byproducts of aerobic metabolism—the process that is fueled by nutrients such as glucose and is responsible for the formation of ATP. ROS are generated by the escape of somewhere between 0.1 and 2% of electrons passing through the electron transport chain. Escaped electrons are added to molecular oxygen to generate superoxide (O2·−), hydrogen peroxide (H2O2), and the hydroxyl radical (OH·−). A series of important discoveries highlighted in recent review articles (2–4) indicate that H2O2 is a critical signal for the replicative capacity of regenerative cells, as well as for apoptosis, for changes in gene expression leading to aging and aging-related diseases. Compared with (O2·−) and (OH·−), H2O2 has the highest oxidative activity, the highest stability, and the highest intracellular molar concentration. Importantly, proapoptotic signals including ROS release the adapter protein p66shc from an inhibitory complex in the inner mitochondria membrane. Active p66shc serves as a redox enzyme that catalyzes reduction of O2 to H2O2 through electron transfer from cytochrome c. H2O2 in turn causes opening of the mitochondrial permeability transition pore, swelling, and apoptosis.
