CAUSES OF SKIN AGING
Maurizio Ceccarelli M.D., Sc.D., Cl.Path.S.
Aging represents the decline of function and integrity of cells, tissues and organs, this leads to an increased risk of disease, disability and ultimately death. The skin, like all the tissues of our body, is subject to damage that causes it to age. On the skin, to the detriment of time that characterize all the fabrics, the damages due to the action of UV rays are added, being this fabric exposed to the external environment and to the light.
The causes of the chronoaging are numerous and, on the etiopathogenetic level, they are referred to different biological processes that, however, in the end, lead back to the same type of damage. We can have an aging following the glycation of cellular proteins, defined by the name of glycaging. We can have an aging that follows the inflammatory processes that damage the biological structures, defined by the name inflammaging. We can have an aging resulting in a transient reduction of tissue oxygenation, followed by reoxygenation. We can have an aging following the percentage increase of oxygen free radicals, normally produced in the mitochondria. And finally, for the skin, we have aging due to the damage activated by the ultraviolet rays of light.
In glycaging we have an excess of sugars (glucides) that bind, in a non-enzymatic way, to the amino acids of proteins, structural and functional, inactivating them. These glycated proteins are then metabolized and the end products of this metabolization activate, at the cellular level, the release of ROS (oxygen free radicals) and inflammatory cytokines.
In particular, we have the initial formation of the Schiff Bases (imine) still reversible. These are followed by the formation of the irreversible Amadori Products, and, finally, of the Advanced Glication Products, called AGE.
AGEs, by binding at the cellular level on the specific RAGE receptor, induce the activation of NADPH Oxidase which increases cellular oxidative stress with the release of free radicals. Moreover, through the up-regulation of Nuclear Factor kB (NF-kB), they promote the expression of pro-inflammatory cytokines,
It follows that the glycaging caused by the non-enzymatic binding of sugars to proteins, in addition to determining the loss of biological function of the latter, induces release of ROS (oxidative damage) and release of cytokines (inflammatory damage).
The inflammatory processes, defined by the term Inflammaging, damage all biological structures. Inflammatory damage induces activation of M1 macrophages with release of inflammatory cytokines with a chemotactic action on leukocytes. Activated leukocytes release ROS and induce tissue damage. The M1 phase-activated macrophage also produces tyrosine hydroxylase with production of norepinephrine. The action of catecholamines on the microcirculation induces vasoconstriction with circulatory alteration and subsequent damage.
Physiologically the pro-inflammatory processes are regulated by anti-inflammatory processes. This is to avoid excessive biological damage resulting from the inflammatory reaction. As we age the immune system undergoes a gradual deterioration defined with the term Immunosenescence. In Immunosenescence there is a fall in innate immunity due to a reduction, at the macrophage level, of the Toll-Like Receptors. TLRs recognize molecules commonly expressed by bacteria or viruses such as lipopolysaccharide. After binding to the respective microbe molecule, transcriptional factors are activated that copy the genes that encode inflammatory cytokines. All this causes a shift of the Infammaging adjustment scale in favor of pro-inflammatory responses. This situation is then aggravated by the decrease in DHEA (anti-inflammatory hormone) characteristic of aging.
In the previously described state of immunosenescence, the onset of immune responses (innate or adaptive) towards pathogens settled in our body (such as cytomegalovirus and herpes virus) induce a chronic inflammatory response and the consequent inflammaging. The main actor in this answer is the macrophage. This derives from the circulating monocytes which, recalled by the chemotactic stimulus of the interferon gamma in the infected area, differentiate into the M1 form and release inflammatory cytokines and ROS.
In particular, NK (innate immunity) lymphocytes attack the virus-infected cell and release interferon gamma. This, in turn, induces the recall of monocytes and the formation of M1 macrophages.
In fact, we can distinguish two different types of macrophages. Those pro-inflammatory, called M1, which once activated synthesize inflammatory cytokines (IL1 and TNF), lysosomal enzymes and ROS. And the anti-inflammatory ones, called M2, which release cytokines that regulate the inflammatory response (IL10) and stimulate the reparative process (Collagenogenesis). From all this, it is clear the need to block the activity of the macrophage M1 in infammaging and transform it into a macrophage M2 to avoid the release of ROS and inflammatory cytokines that produce oxidative and inflammatory damage.
Oxygen reaches our tissues linked to hemoglobin (oxyhemoglobin). In the pericellular district, the high temperature, the low partial pressure of oxygen and the acidosis resulting from the high partial pressure of carbon dioxide, displaces the Bohr Equilibrium in favor of the release of oxygen from hemoglobin by regulating the oxidative metabolism mobile phone.
The reduction of blood perfusion to tissues induces acute hypoxia. The hypoxic state (often caused by the release of catecholamines by M1 macrophages) must be rapidly resolved to avoid tissue necrosis (infarction). The return of oxygen generates a transient hyperoxia with release from oxygen free radicals, which induce oxidative damage.
Metabolic oxidative aging
The formation of energy at the cellular level occurs by synthesis of the ATP at the level of the intracellular mitochondria. The reduced dehydrogenases (NADH and FADH) produced during the metabolic degradation of food, enter the enzymatic chain of Electron Transport present on mitochondrial crests. This transport of electrons is combined with a transport of protons which, by activating the ATPase enzyme, forms the high energy ATP molecule.
The Electron Transport Chain provides for a progressive passage of these into different enzymes until it reaches the Cytochromoxidase, which transfers them to oxygen. This last step involves the movement of only one electron at a time. In other words, the oxygen is initially charged with an electron becoming Radical and must wait for the second electron to stabilize and bind to two hydrogen atoms to form water. The Oxygen Radical (ROS) can free itself, without waiting for the second electron, and interact with other molecules, oxidizing them. Physiologically a small amount of ROS is released which, foreseen in the evolutionary process, is blocked by the antioxidants present in the cell.
Incongruous nutrition or physical activity, producing excess ATP, activates this enzyme system by increasing the rate of ROS release resulting in oxidative damage.
The sun, while allowing animal life through the production of oxygen derived from chlorophyll photosynthesis, induces in our skin significant damage due to UV rays.
It determines damage to the skin, both early (actinic erythema, dyskeratosis, delayed pigmentation, epidermal hyperplasia) and late skin (roughness, elastosis, senile lentigo, telangiectasia, actinic keratosis, guttate hypomelanosis) up to the possibility of inducing the formation of a skin cancer.
The solar rays are divided on the basis of the wavelength in: infrared rays, (702-1500 nm); visible rays, (400-700 nm); ultraviolet rays, (295-400 nm); X-rays and cosmic rays. The shorter the wavelength and the greater the ability to penetrate the skin and the ability to give biological damage. UVC rays, such as those of shorter length, X-rays and cosmic rays, are normally stopped by the ozone layer.
Exposure to UVB rays leads to the release of oxygen free radicals (ROS) which leads to inflammatory damage through the release, at keratinocyte level, of plasminogen. This turns into plasmin which activates cellular phospholipase with release of arachidonic acid and formation, through the cascade of ecosanoids, of inflammatory prostaglandins. UVA2 rays induce the formation of thymine dimers at the DNA level inducing genetic mutations; UVA1 rays increase UVB damage by releasing free radicals and activating proteinases. All this causes cell damage and degradation of the components of the dermal matrix.
From the above we can highlight that UV rays induce: fibroblastic damage, due to lipoperoxidation of biological membranes, with loss or reduction of the function of these cells; epidermal hypertrophy, due to overproduction of EGF, stimulated by damage and reduction of the inhibitory function of calones; skin pigmentation, due to activation of melanogenesis, and anarchic passage of melanosomes in the corneocytes and in the matrix; degradation of the dermal matrix, by activation of metalloproteinases, with consequent solar elastosis; variation of metabolic exchanges, due to gelation of the matrix resulting from its acidification due to inflammation.
From the above it appears that the skin is subject to numerous types of aging that can be mainly traced to ROS damage and inflammatory cytokine damage.
The process of preventing the causes that induce the described biological damages is obviously fundamental, but, also necessary, the treatment of blockade of ROS and inflammatory cytokines.
We reduce the harmful effect of ROS by systematically and locally introducing antioxidants. Remembering, however, the need for regulation of their concentration. In fact, antioxidants perform low-dose cellular protection, while they become pro-oxidants at high concentrations.
We reduce the release of inflammatory cytokines by systemically and locally introducing sulfo-adenosil-methionine (SAM). SAM plays a powerful methylating action on inflammatory genes by binding a methyl group to the operon of these genes. It follows the impossibility of attack of RNA-polymerase, necessary to read the gene and its silencing, with reduction of the synthesis of specific inflammatory proteins.
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