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  5. Chibirova T.T., Merdenova L.A. Main pathophysiological mechanisms of external and internal skin aging

Chibirova T.T., Merdenova L.A. Main pathophysiological mechanisms of external and internal skin aging

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Publication date: 01.12.2021
DOI: 10.51871/2588-0500_2021_05_04_23
UDC 612.79

MAIN PATHOPHYSIOLOGICAL MECHANISMS OF EXTERNAL AND INTERNAL SKIN AGING

T.T. Chibirova, L.A. Merdenova

Institute of Biomedical Investigations – the branch of Vladikavkaz Scientific Centre of Russian Academy of Sciences, Vladikavkaz, Russia

Key words: skin aging, dermis aging, dermis atrophy, collagen, estrogens, androgens, oxidative stress.

Annotation. Aging of the skin is a multifactorial process that affects all its layers, is characterized by such signs as wrinkles, loss of elasticity, flabbiness and uneven relief and is accompanied by phenotypic changes in skin cells, structural and functional changes in the components of the extracellular matrix (collagen and elastin). This is a natural and irreversible process that can occur both in its physiological and in an accelerated pathological form. The article analyzes manuscripts reflecting the influence of external and internal factors on the pathophysiological mechanisms of skin aging. The PubMed database was analyzed for the following key words: skin aging, dermis aging, dermal atrophy, collagen, estrogens, androgens, oxidative stress. It has been shown that the leading role among the "external" factors of skin aging belongs to ultraviolet radiation, which causes oxidative stress in skin cells, reduces the adaptive resource of the organism's antioxidant system, which leads to alteration and disruption of repair mechanisms. Among the factors of "internal" aging, the main role belongs to endocrine system imbalance. Understanding these mechanisms and developing geroprotective methods of influencing important pathogenetic mechanisms of the chain of age-related changes will slow down the aging process of the skin, which largely determines the psychoemotional state of a person.

Introduction. Aging is a dynamic physiological process, which is characterized by progressing age changes in metabolism and physicochemical properties of cells, leading to disruption in self-regulation, regeneration and structural changes in functional tissues and organs [1-2]. Skin aging is a multifactorial process that involves all skin layers and underlying tissues. Cell renewal in the epidermis decreases, keratinocytes proliferation slows down. Dermoepidermal interactions weaken, the derma atrophy with a decrease in a number of cells, vessels and change in the extracellular matrix (ECM) (disarrangement, fragmentation and reduction of collagen fibers) occur [3]. Ratio of the I and II type collagen increases, which is substantially related to a loss of the I type collagen [4]. According to the data given by S. Shuster and M. Black, total collagen content per unit of the skin area surface decreases by 1% each year. The subcutaneous tissue also begins to atrophy (due to mechanisms of aging, lypolisis and visceral redistribution) that leads to occurrence of wrinkles, flabbiness and uneven pigmentary coating [5-6].  

Age changes occur under the influence of a whole number of internal and external factors and are an important reason of many invasive or non-invasive procedures, aimed towards improving esthetic features of the skin. Understanding skin changes that are due to aging is relevant for developing methods of slowing down the process and can contribute to appropriate cosmetic and functional results for patients [1-10].

The aim of this study was to analyze scientific works published in the PubMed database from years 2011 to 2021, dedicated to research on skin aging mechanisms under the influence of exogenous and endogenous factors.  

Results and discussion. Researchers described two main mechanisms of skin aging: internal and external (fig.). There is also a possibility of a “random” factor – cell damage due to mutations when implementing metabolic processes because of free radicals production. External factors of aging include sun exposure, air pollution by metal pollutants, nicotine addiction, alcohol abuse, poor nutrition etc. Internal reasons include structural changes that occur in the skin as a natural consequence of biological changes in the course of time and cause time sequence of histological, physiological and biochemical modifications. Internal reasons of aging are defined by inheritance, intensity of metabolic processes and the level of functioning of the nervous, endocrine and immune systems [11].

According to data given by Barja G. (2004), one of aging mechanisms is the free radicals production that increases with age, when at the same time capacity of endogenous defense mechanisms that oppose them decrease, which leads to a progressing damage of cellular structures and, consequently, to repair reduction.  During the chronological process of aging, free radicals appear naturally as a result of normal metabolism. In case of “external” aging, they are produced by exogenous factors, such as ultraviolet (UV) radiation, smoking and alcohol consumption.

 

Fig. External and internal factors influencing pathophysiological mechanisms of skin aging

Note: MC – microcirculation, ROS – reactive oxygen species

Derma aging starts by an increased activity of matrix metalloproteinases and disturbance in transferring signals of the transforming growth factor β, caused by reactive oxygen species that occur during aging. Decrease in a number of collagen hinders mechanical interaction between fibroblasts and the ECM. Consequently, it leads to a worse function of fibroblasts and further reduction in a number of skin collagen. Other ECM components, including elastic fibers, glycosaminoglycans (GAG) and proteoglycans (PRG), also change during aging, which consequently leads to a decrease in a number of functional components. Changes in GAG and PRG levels are quite versatile. The data from scientific literature gives contradictory results of their participation in the aging process. Decrease in levels of the derma’s functional components factor into an occurrence of clinical signs of aging, such as wrinkles and loss of elasticity [12].

UV radiation. Generation of reactive oxygen species (ROS) under the influence of UV is the main natural mechanism of premature aging [13]. UV can cause occurrence of ROS, influencing cellular components directly or using mechanisms of photosensitivity: catalase activation and increase in NO-synthase (NOS) synthesis on the one hand, on the other hand – reduced expression of the protein kinase C (PKC). UV is able to modify ROS and other chromophores, which leads to an increase in the ROS level. In case of imbalance, related to an exceedence of ROS production over antioxidant protection mechanisms of the organism, oxidative stress occurs. Oxidative stress causes cell alteration (e.g. lipid peroxidation and DNA fragmentation) apoptosis and cell necrosis. A degree of increasing ROS level varies depending on the intracellular oxidation state that has a genetic component. Thus, UV-induced ROS production is implemented [14].

ROS also induces skin inflammation, activating signal transduction of the NF-κB. NF-κB is a key nuclear transcription factor that plays a regulatory role when implementing inherent and acquired immunity, inflammatory response and tumor progression. It is responsible for expression of different inflammatory cytokines in the skin. Preventing a cascade of NF-κB signals is an important goal for suppressing occurrence of wrinkles, induced by UV.

The state of evolutionary defense mechanism – antioxidant system (AOS), presented by a combination of biochemical substances that contribute to a protection from endogenous and exogenous oxidative stress by eliminating free radicals, is of great significance. This combination includes antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) and non-enzymatic antioxidant molecules (vitamin E, vitamin C, glutathione and ubiquinone). UV suppresses the AOS, since when exposed to UV, a number of ROS increases and oxidative stress grows [15].

A number of experimental works demonstrated mechanisms of protecting the skin cells with non-enzymatic molecules (Lephart E., 2009; Martini, 2004). In fibroblasts of the skin, the antioxidant effect of magnesium lithospermate B (MLB) is due to direct ROS elimination and inhibition effect on the NF-κB-dependent inflammation genes. MLB inhibits expression and activity of NF-κB and AP-1-dependent matrix metalloproteinases (MMP) by regulating ROS production and MARK pathways. Therefore, by reversing reduction of pro-collagen in the skin, related to age and UV exposure, MLB can have a potential role in fighting wrinkles and aging through inhibition of activity of NF-κB and AP-1-dependent MMP. Moreover, mycosporine-like amino acids (MAA), isolated from Porphyratenera, inhibit the transcription factor NF-κB and decrease expression of MMP-1, MMP-3 and TNF-ɑ through NF-κB and the MARK pathway. MAA suppressed MMP expression, induced by UV, blocking the MARK pathway, and thus reducing regulation of MMP activity in case of skin photoaging, caused by UV radiation [16].

Endocrine system imbalance. One of the main reasons of “internal” aging is a change in hormone status, menopause in particular, which is accompanied with estrogen (E) deficiency. Estrogens significantly modify skin physiology, influencing keratinocytes, fibroblasts, melanocytes, hair follicles and sebaceous glands, improve angiogenesis, wound healing and immune responses. It was proven in early studies of Ashcroft D.M., LiWanPo A., Griffiths C.E. (1997) that E hold and recover skin humidity by means of stimulating sebaceous matter secretion by regulating expression of receptors of insulin-like growth factors and increase of their production in fibroblasts, which, in its own turn, induces lipogenesis in sebocytes and leads to keeping humidity.

Estrogen is a main signal molecule in a woman’s organism. Its production is regulated by the expression of the aromatase gene (CYP19A1) from the ovaries and peripheral tissues area. Chemical signals of estrogen are transferred through classic nuclear hormone estrogen receptors (ER) alpha and beta, as well as the fast-acting G-bound membrane estrogen receptor. The estrogen level reaches its peak in the middle and late 20s in women. It decreases by 50% by the age of 50 [17-18]. After menopause, a decrease of 17β-estradiol occurs in the ovaries, which leads to a rapid worsening of health and skin well-being: loss of collagen, elastin, fibroblasts function, decrease of vascularization, increase of MMP activity, reduced work of the AOS. All of it lead to cellular and extracellular degradation, dryness, wrinkles, atrophy, disturbed wound healing, reduced barrier function and antioxidant ability, physically – reduces attractiveness and mental health [19].

Skin and its dermal appendages are substantially subject to influence of androgens (A) that modulate epidermis and derma thickness. Age reduction of circulating androgens changes not only morphology, but also key functions of the skin, such as homeostasis of the epidermal barrier, wound healing, growth and differentiation of hair.

Androgens are divided into two categories: adrenal adaptogenes (androstenedione, 11β-hydroxyandrostenedione, dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA) and gonadal androgens (testosterone)). Direct biological activity of adrenal adaptogenes on the skin is minimal. They function as precursors for peripheral transformation into active androgenic hormones, i.e. testosterone and 5α-dihydrotestosterone (5α-DHT).

In men with normal genital function, transformation of androstenedione into testosterone by  the adrenal glands is less than 5% from the level of this hormone’s production, which is why its physiological effect is small. The adrenal glands in women contribute substantially to general production of adaptogenes by means of peripheral transformation of androstenedione. In follicular phase of the menstrual cycle, precursors of the adrenal glands amount to two thirds of testosterone production and a half of 5α-DHT production. At the middle of the cycle, contribution of the ovaries increases, and the share of adrenal precursors is only 40% of testosterone production.

Effects of testosterone and 5α-DHT are mediated through connection with one-nucleus androgen receptor (AR). Most skin cells express AR, such as epidermal and follicular keratinocytes, sebocytes, sweat glands cells, dermal papilla cells, dermal fibroblasts, endothelial cells and genital melanocytes. 

DHEA is related to a process of skin aging through regulation of production and degradation of the extracellular matrix. DHEA deficiency reduces pro-collagen synthesis, contributes to collagen degradation through reducing MMP and collagenase synthesis, increase of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) and stromelisin-1 in fibroblasts [20].

Conclusion. Therefore, considering data from modern literature, dedicated to skin aging mechanisms, we can conclude that the leading role among “external” factors of skin aging belongs to UV radiation, which sets into action oxidative stress in skin cells and reduces adaptive resources of antioxidant protection of the organism that leads to alteration and disturbance in repair mechanisms. Among factors of “internal” aging, main role belongs to endocrine system imbalance. Understanding these mechanisms and developing geroprotective methods of influencing important pathogenetic mechanisms of the chain of age-related changes will slow down the aging process of the skin, which largely determines the psychoemotional state of a person.

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Information about the authors: Tamara Tamerlanova Chibirova – Junior Researcher of the Institute of Biomedical Investigations – the branch of Vladikavkaz Scientific Centre of  Russian Academy of Sciences, Vladikavkaz, e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.; Larisa Akhsarbekovna Merdenova – Junior Researcher of the Institute of Biomedical Investigations – the branch of Vladikavkaz Scientific Centre of  Russian Academy of Sciences, Vladikavkaz, e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it..

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