The Nonenzymatic Antioxidant Systems In Aging Skin

The free radical theory of aging established the role of oxidative stress as one of the main causes of aging and skin aging. Reactive oxygen species (ROS) – produced as byproduct of oxidative energy metabolism and induced by external factors – are known to damage protein, DNA, cellular membrane and are known to be the intracellular signal to activate the signal transduction pathways, leading to the activation of transcription factors NF-kB and AP-1 which regulate various genes involved in skin aging. Body has an internal natural antioxidant system to prevent and protect skin cells and extracellular matrix from ROS damage. Endogenous antioxidant system is composed of a network of enzymatic antioxidants or antioxidant enzymes such as glutathione peroxidase, superoxide dismutase, and catalase, and nonenzymatic low-molecular-weight antioxidants such as vitamin E isoforms, vitamin C, Coenzyme 10, glutathione (GSH), Alpha Lipoid Acid, NADPH, thioredoxin. Antioxidant enzymes system of the skin not only removes detrimental ROS and free radicals, some of the redox antioxidant enzyme system such as gluthathion reductase also capable of regenerating active antioxidant (reduced form) from antioxidant radicals (inactive oxidized form). Once an antioxidant removes ROS, itself become oxidized. In living systems, however, antioxidants can be regenerated, often with the help of other antioxidants. For example, glutathione can regenerate a number of other antioxidants such as vitamin C and vitamin E

Vitamin C is the most abundant antioxidant in both the dermis and epidermis. Epidermis contain more vitamin C than that of dermis. Vitamin C concentrations in both layers are approximately equal to that of glutathione. L-ascorbic acid is the active form of vitamin C and is water soluble as the major aqueous phase antioxidant. The body can not synthesize vitamin C. Vitamin C in the skin is normally transported from the bloodstream. Transport proteins specific for ascorbic acid are found on cells in all layers of the skin. Keratinocytes is more efficient in vitamin C transport, possibly due to the limited vascularization of the epidermis. When plasma vitamin C levels are saturated, skin vitamin C concentrations can no longer increase. Aging, however, causes a decline in vitamin C content in both the epidermis and dermis. Excessive exposures to UV light may also lower vitamin C content, primarily in the epidermis. Besides having antioxidant properties, Vitamin C also stimulate the collagen synthesis and is one of the major exogenous topical ingredient in skin care products. Vitamin C is a cofactor for enzymes involved in several collagen synthesis reactions.

Vitamin E is the most abundant endogenous antioxidant of the lipid phase cellular membranes with alpha-tocopherol being the most biologically active form. Vitamin E act as a peroxyl radical scavenger and terminates lipid peroxide radicals (LOOs) chain propagation on cell surface or cellular lipid/membrane. Lipid peroxyl radicals are the oxidation product resulting from the ROS damage.The antioxidant activities of alpha-tocopherol are heavily relied on the regeneration of reduced form by other antioxidants such as glutathione, vitamin C and Coenzyme 10. Glutathione and vitamin C are the major cofactors for Vitamin E antioxidant activity. UV irradiation has been shown to deplete this effective antioxidant.

Coenzyme 10 also known as ubiquinone is present in most cells, primarily in the mitochondria. It is a component of the electron transport chain and participates in cellular respiration, generating energy in the form of ATP. There are three redox states of coenzyme Q10: fully oxidized (ubiquinone), semiquinone (ubisemiquinone), and fully reduced (ubiquinol). The capacity of this molecule to exist in a completely oxidized form and a completely reduced form enables it to perform its functions in the electron transport chain and as an antioxidant. CoQ10 prevents lipid peroxidation by removing lipid peroxyl radicals (LOO), perferryl radical and oxygen radical. CoQ efficiently prevents the oxidation of DNA bases, particularly mitochondrial DNA by neutralizing hydroxyl radicals. In addition, it also regenerates other antioxidants such as vitamin E. The reduced form of CoQ effectively regenerates active vitamin E from the a-tocopheroxyl radical (the oxidized form of Vitamin E). Besides having antioxidant properties, Vitamin E also has anti-inflammatory effect through interfering the eicosanoid pathway.

Glutathione (GSH), most abundant tissue thiol, is a tripeptide antioxidant. Thiol groups of cysteine are reducing agents that can neutralize ROS and other free radicals after which itself is oxidized, forming glutathione disulfide (GSSG). The active/reduced Glutathione is regenerated from its oxidized form – glutathione disulfide (GSSG) – by glutathione reductase. In healthy cells and tissue, more than 90% glutathione is in the reduced form (GSH) and less than 10% exists in the disulfide form (GSSG). An increased GSSG-to-GSH ratio is considered indicative of oxidative stress. Glutathione acts synergistically with the other endogenous antioxidants to scavenge free radicals and is vital in maintaining and regenerating the ascorbates of vitamin C and the tocopherols of vitamin E in their reduced form. Glutathione works with the enzyme glutathione peroxidase to break down hydrogen peroxide and lipid hydroperoxides. Redox status is an parameter for assessing the in vivo prooxidant environment. Several indicators of in vivo redox status (oxidative stress) are available, including the ratios of GSH to GSSG, NADPH to NAPD+, and NADH to NAD+, as well as ratio of reduced and oxidized thioredoxin. Among these redox pairs, the GSH-to-GSSG ratio is one of most abundant redox indicator. The effect of aging on the glutathione redox system has been studied. A progressively decrease of GSH-GSSH ratio (increased oxidative stress) has been observed.

Alpha lipoic acid (ALA) is an endogenous dithiol antioxidant that is both hydrophilic and hydrophobic, making it an antioxidant to combat free radicals in aqueous and lipid phase of cell. Endogenous ALA is essential cofactors of several mitochondria enzyme complex for the aerobic metabolism, similar in function to many of the vitamins B . Alpha lipoic acid (ALA) has an essential role in mitochondrial dehydrogenase reactions. Its reduced form, Dihydrolipoic acid (DHLA), neutralize reactive oxygen species such as superoxide radicals, hydroxyl radicals, oxygen radical, hypochlorous acid. Two cytosolic enzymes, glutathione reductase (GR) and thioredoxin reductase (Trx1), and two mitochondrial enzymes, lipoamide dehydrogenase and thioredoxin reductase (Trx2), reduce ALA to DHLA. In addition to its antioxidant activities, Dihydrolipoic acid (DHLA), may exert prooxidant actions through reduction of iron. It may also exert antioxidant effects in biological systems through transitional metal chelation. Dihydrolipoic acid has been shown to have antioxidant but also pro-oxidant properties in systems in which hydroxyl radical was generated. Alpha lipoic acid also regenerates active forms of other antioxidants such as vitamin C and glutathione. ALA increases intracellular glutathione and coenzyme 10 levels.

A comprehensive in vivo study of the changes in major antioxidant enzymes and antioxidant molecules during intrinsic aging and photoaging processes in the epidermis and dermis of skin suggest that the components of the antioxidant defense system in human skin are probably regulated in a complex manner during the intrinsic aging and photoaging processes. The data showed that the activities of superoxide dismutase and glutathione peroxidase are not changed while the activity of catalase was significantly increased in the epidermis of photoaged (163%) and naturally aged (118%) skin, but it was significantly lower in the dermis of photoaged (67%) and naturally aged (55%) skin. The activity of glutathione reductase was significantly higher (121%) in naturally aged epidermis. The concentration of alpha-tocopherol was significantly lower in the epidermis of photoaged (56%) and aged (61%) skin, but this was not found to be the case in the dermis. Ascorbic acid levels were lower in both epidermis (69% and 61%) and dermis (63% and 70%) of photoaged and naturally aged skin. Glutathione concentrations were also lower.

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