Antioxidants, reactive oxygen and nitrogen species, gene induction and mitochondrial function

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

“…Based on extensive in vivo and in vitro studies, it now appears that senescence is associated with increased oxidant generation, a decline in the robustness of cellular defenses and repair, and an accumulation of the end products of the oxidative damage [331,336,[339][340][341][342][343][344][345][346][347][348][349][350][351][352][353][354]. In general, the three main classes of biological macromolecules (lipids, nucleic acids and proteins) are susceptible to free radical attack and suffer oxidative damage in vivo [331,336,[339][340][341][342][343][344][345][346][347][348][349][350][351][352][353][354].…”

“…In general, the three main classes of biological macromolecules (lipids, nucleic acids and proteins) are susceptible to free radical attack and suffer oxidative damage in vivo [331,336,[339][340][341][342][343][344][345][346][347][348][349][350][351][352][353][354]. Because cellular membranes house the production of these radicals, membrane lipid peroxidation is now regarded as the major process that produces ROS damage during aging [354,355].…”

“…The risk of lipid peroxidation is especially high for steroidogenic cells, which use molecular oxygen for steroid biosynthesis [356,357] in addition to a more standard cell function [353][354][355]358]. Cytochrome P450 enzymes of the steroidogenic pathway use molecular oxygen to hydroxylate substrates.…”

“…As a result, steroidogenic cells, like other mammalian cells, are well equipped with antioxidant systems to combat free radicals [370][371][372][373][374][375]. These antioxidant systems are comprised of 1) low molecular weight agents such as vitamin E (atocopherol), vitamin C (ascorbic acid), reduced glutathione (GSH), carotenoids, flavonoids, uric acid, bilirubin, and lipoic acid; 2) iron and copper sequestering proteins such as transferrin, lactoferrin, hemopexin, albumin, and ceruloplasmin; 3) antioxidant enzymes such as superoxide dismutase (Cu,Zn-SOD, Mn-SOD), glutathione peroxidases (e.g., cytosolic glutathione peroxidase [cGPX], phospholipid hydroperoxidase glutathione peroxidase [PHGPX], plasma glutathione peroxidase [pGPX]), catalase, heme oxygenase, and thioredoxin reductase (TR); and 4) accessory antioxidant proteins such as thioredoxins, glutaredoxins, and peroxyredoxins [331,[350][351][352][353][376][377][378][379][380][381].…”

“…These are linked, with time, to a dramatic reduction in the normally protective antioxidant defense system, thus, leading to excessive oxidative stress, and, we believe, ultimately to the decline of steroid production in the aging animals, i.e., the increase in lipid peroxidation in steroidogenic tissues may be the underlying cause of the age-related decrease in corticosterone/testosterone synthesis. It is unclear why steroidogenic cells do not respond to this oxidant balance by simply modulating the expression of antioxidant enzymes [372,374], oxidant-sensitive transcription factors, AP-1 and NF-B [353,358,[382][383][384][385] and other stress inducible cytoprotective genes invoking cellular protective mechanisms [386]. We speculate that up-regulation does not occur in the aging animals because the continuous oxidant burden likely overwhelms the cells, leading to the failure of cellular transcriptional/translational machinery and, thus, the function of various proteins involved in the transport of cholesterol to the mitochondrial sites of P450scc.…”