Anti-ROTS and cutis
Significance and meaning of ROTS
As studies are progressing, it is increasingly acknowledged that ROTS (Reactive Oxygen Toxic Species) or more commonly known as free radicals, are somehow involved in the development of many diseases and dysfunctions of body metabolism. Let us therefore schematically consider the mechanisms through which they are acting. It should be stressed that superoxides (O2-) and hydroxyl radicals (OH) are the most noxious and hence most involved free radicals. Iron and copper play a clear-cut pro-radical role, whereas the present position of zinc is more articulated. ROTS are chemically reactive molecules which our body has constantly to deal with. Some of these molecules are necessary for given metabolic processes, in which case our body produces enzymes to keep them under control and prevent them from doing harm. Superoxide-dismutase (SOD) and glutathione-peroxidase are some of the substances that control the ROTS produced in our body. Without these enzymes we would soon die and all living and breathing creatures need these enzymes for their survival. High energy radiations kill by generating ROTS in living organisms. The most important ROTS sources in our body, which cause ageing, may be found in the products of non correct lipid oxidation, a sudden drop in hydrogen peroxide and those produced by normal metabolism (Pearson, Shaw). The specific aspect of skin ageing may be due to changes caused by ROTS, the pattern of which is becoming ever more similar to the ageing pattern. ROTS function induces lesions in specific organelles, such as the bio-membrane and the endoplasmic reticulum which ensure metabolic turnover and structural protein synthesis. ROTS are the common denominator of the effects which metal oxidation (e.g. iron and copper) chlorophyll photosensitization, porphyrin and hyperbarism have on fats. In particular they are generated by poly-unsaturated fats (*-linolenic acid is thirty times more active than linoleic acid and almost ten times more than oleic acid), lecithins with polyunsaturates in position 2.
ROTS' Intervention Mechanisms
ROTS may be mediators in peroxide formation through non cyclic or cyclic (hydroperoxide and cycloperoxides) autocatalytic mechanisms as well as in the formation of secondary compounds and polymers. Hydroperoxides are the most abundant and polymorphous conversion compounds induced by ROTS; they are chromogen, fluorescent and form at a temperature of about 180°C not only as a result of malonyldialdehyde. The latter does not only depends on lipo-oxygenase circuits and does not represent all compounds that are found in lipofuscin at pH 3.8 reacting with the thiobarbituric acid test. The presence of covalent bonds is proved by the magnetic properties of the unpaired electron; they are paramagnetic i.e. they attract inside a magnetic field (electron resonance or electron spin resonance method). Fatty acid molecules (especially if unsaturated) are thus transformed due to metals (iron etc.), heat or irradiation (e.g. by losing an H+). The resulting compounds cause lesions because the cells get in touch with an alteration mechanism of metallothioneine and of the cell membrane which in the skin causes the typical desquamation through collapsing of the moisture barrier regulating the epidermal maturation cycle. The pathogenic equivalent of the covalent bond is the difficult formation of lipoproteins, especially in the liver but also in the skin, due to the altered permeability of membrane lipids, thus jeopardizing the barrier properties (causing desquamation and weeping eczema). Chelating compounds that will neutralize metals and prevent ROTS may be used as antidotes. The result of lipoperoxidation is a group of compounds ending up in the formation of aldehydes and ketones. The malonyl-aldehyde essay is the most currently used global index for lipoperoxidation as leader of the reagents reacting with tiobarbituric acid (which has a specific UV absorption index). Aldehydes also react with some amine groups (periodic acid- Schiff stain) and SH groups. Pathogenic equivalents are fatty infiltrations of the cells (especially liver steatosis); the formation of lipofuscin in the cutis is deemed a sign of ageing; converging in cancerization.
Consequences of lipoperoxidation on the skin
Lipoperoxide formation on the skin (and more generally on all cells especially in the liver) leads to adipose degeneration caused by vanishing of polyunsaturated fatty acids (linoleic, series n-6; a-linolenic, series n-3) that are indispensable to protect the cell structure from ageing and degeneration processes. Physiologic antioxidants, e.g. Vitamin E and C are particularly effectual as antidotes provided they are taken per os but not by topical application. The third phase is called "terminal" because the radical cascade is interrupted by combination or between two free radicals or between two peroxide radicals or between one free and peroxide radical leading to fat polymerization. On the long run, they all lead to the formation of cyclic compounds (whether polymers, dimers and monomers), having the combined effect of causing necrobiosis (cell death and/or mutagen alteration of the genetic patrimony) and oncogenic (tumoral) effects. Ulcerative and probably also cancerogenic lesions may appear on the skin together with a lower natural antioxidant level (Vit.E).
The altered dynamics of desaturating enzymes is another specific mechanism of ageing. Its most interesting effect is the inhibition of delta 5-desaturase, an adaptive enzyme, with its elongation factor forming the so-called C20-chain acids also called eicosanoids derived from the three series of alimentary and tissutal unsaturated fatty acids i.e.:
- oleic acid (n-9), ETA (eicosatrienoic acid) or Holman's triene;
- linoleic acid (n-6) which - through arachidonic acid (C20-4 delta 5-8-11-14) will form prostaglandin and thromboxane by cyclo-oxygenation and leukotrienes by lipo-oxygenation;
- linolenic acid (n-3) having similar effects, especially as far as eicosapentaenoic acid is concerned which inhibits cyclo-oxygenase. (prostaglandin synthetase). Problems related to triene n-9 are very interesting since it appears in the tissues whenever there is a shortage of AGE or as a co-factor, for example of ageing.
ROTS cause pigment accumulation, gradually smothering brain cells and also brown ageing spots which normally appear on the skin of elderly people.
How to prevent the damage caused by ROTS
Many of these disturbances may be prevented by integrating the diet with nourishing elements that will protect against ROTS. Many of these nutrients have even increased the life span of test animals. These anti-ROTS nutrients (also called antioxidants) include Vitamin A, C, E, B1, B5 and B6, the aminoacids cysteine, triaminoacid glutathione (a compound containing cysteine), phenolic aminoacids and catecholamines such as tyrosine and L-Dopa, catecholaminic compounds as found in bananas and potatoes, phenol-based substances (com-pounds like BHT) that are found in grapes and other fruit, minerals like zinc and selenium, bioflavonoids and synthetic antioxidants such as BHT and BHA (Pearson, Shaw). Changes caused by ROTS include cumulative oxidation effects which are undesirable for collagen (a constituent of the connective tissue accounting for approx. 30% of all body proteins); for elastin (a protein providing, for instance, elasticity to the artery walls and completely useless if applied to the skin) and for genetic material (DNA and RNA, useless on the skin). ROTS also cause rupture of heavy carbohydrate molecules accounting for mucus production (used, for instance, to lubricate our joints) through an oxidative degradation process.
Other effects: build-up of pigments such as lipofuscin and waxy matter, typically found in ageing organisms, by oxidative polymerization involving lipids (especial-ly unsaturated fats) and proteins, peroxidation of the lipid membrane and narrowing or closing of tiny arteries and capillaries caused by toxic peroxidation products which are present in the serum, formation of substances irritating the vessel walls and suppression of PGI2 prostacyclin synthesis, a natural hormone helping to prevent the formation of normal blood clots. ROTS are intermediate products in many important metabolism reactions. Therefore all organisms using oxygen for breathing have to develop defense reactions against ROTS: catalase and peroxidase enzymes demolish hydrogen peroxide and other peroxides, superoxide dismutase (SOD) controls free superoxide radicals whereas glutathione-peroxidase also controls peroxides. Antioxidants like Vitamin C, E and zinc and selenium minerals help to keep ROTS under control. For instance, each molecule of the well known glutathione peroxidase enzyme needs four selenium atoms to be effective, administered of course per os.
ROTS repressors
ROTS generate other ROTS. The compounds that may facilitate interruption of the reaction chain are called ROTS repressors or clearers. Antioxidants like Vitamin A, E and C, sulphated cysteine aminoacid, glutathione triaminoacid which contains cysteine, phenolic and catecholic aminoacids such as tyrosine and L-Dopa, selenium and synthetic antioxidants like BHT BHA and ethoxykine are all effective repressors. Trioxene percutaneously administered is a specific ROTS repressor. It may be generally affirmed that the ageing process is mainly due to the progressive decrease of the antioxidant rate in blood and tissue. As a matter of fact, zinc is a known cofactor of skin ageing and is generally involved in the complex relation between linoleic and arachidonic acid in the biomembrane of the epidermal cells and in the prostaglandine-genesis cascade.
The zinc problem
On this subject it was observed that zinc activates PGEI synthesis (a linoleic acid derived anti-aggregant); phospholipase A2 which releases arachidonic acid, delta-9-desaturase (which forms oleic acid when saturated fatty acids tend to prevail), cyclo-xygenase which synthetizes PGE2 (an aggregant) from arachidonic acid.
Zinc deficiency induces pathognomonic skin lesions while excessive zinc may have arachidonic dependent, trophopathogenic effects, with release of generically significant phlogotic compounds.
Because of its antiradical properties and its correlation with essential fatty acids (linoleic, arachidonic and gamma-linolenic acids), zinc has therefore the following effects:
- it controls the immune system; its positive effects on the helper-inducers lymphocyte sub-population has been proved (Chandra)
- it stimulates young collagen synthesis
- it modulates the hair maturation cycle; activates the enzymes related to prostaglandin synthesis, especially arachidonic-dependent PGE2; it inhibits delta-9 desaturase thus preventing excessive desaturation of oleic acid;
- it is synergic with the antiradicals selenium and magnesium and antagonistic with the proradicals iron and copper;
- when deficient, it has seborrheic effects on the skin but has immunosuppressant and parakeratosis effects when in excess.
A very interesting cue is given for the antiradical mechanism of zinc, which is at least partly ascribed to its role as a (non enzymic) catalyst on the formation of condensation compounds (Mayllard's reaction) between oligosaccharides and aminoacids (especially when sulphated) in the skin. This has recently led to the implementation of Oligoidyne-Zn, Vevy codex 18.2960 (which is an aminoacid zinc salt and not an inorganic one), which represents, together with Oligoidyne-Se, Vevy codex 18.2961 (a aminoacid selenium salt) and Trioxenes, the most advanced preventive treatment for ROTS-induced skian ageing.