Fibroblast Growth Factors: A Controlling Mechanism Of Skin Aging

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Keywords

Anti-aging·Fibroblast growth factor·Cell signaling

Abstract

Cutaneous aging is a complex and continuous biological process characterized by cellular and molecular alterations, with progressive reduction of the body's capacity to maintain the homeostasis, senescence, and/or apoptosis of the dermal cells. Fibroblast growth factors (FGF) have elicited studies to evaluate their role in the repair and remodeling of the dermis during the skin anti-aging process since they arereg-regulatory proteins that mediate important signaling pathways and act on cell regeneration and repair processes. FGF acts primarily through binding to tyrosine kinase receptors through the autophosphorylation of their residues, promoting the phosphorylation of serine, threonine, and tyrosine residues of specific target proteins such as Raf-1, MAPK/Erk kinase, and extracellular signal-regulated kinase-1, which are part of the cascade of MAP kinases (mitogen-activated protein kinase). cistanche life extension Then, FGF initiates signaling cascades inside the cell, where each kinase activates the following by phosphorylation, resulting in alterations of cellular functions. In addition, the FGF has a relevant role in anti-aging therapy because it is related to collagen and elastin synthesis activation responsible for skin resistance and elasticity, characteristics that are diminished with skin aging. Thus, the present

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Introduction

Skin is the largest organ of the human body, protecting it against external aggressions, such as microorganisms, chemicals, and physical agents, including sun rays. Skin also plays a role in thermal regulation, water retention, and cell regeneration. This protective barrier is formed by dermal and epidermal cells, including specialized glands for the secretion of sebum and sweat, which form a special layer as a real protective mantle[1,2]. Despite these protective features, skin is permeable and absorbs substances that can either benefit or impair its function, such as those involved in skin aging.

Aging is a complex and continuous biological process characterized by cellular and molecular changes, with progressive reduction of the body's capacity to keep homeostasis and an increase in senescence and/or apoptosis. This process varies between individuals and from organ to organ, cistanche nz and skin exhibit the effects of the passage of time most evidently[3].In addition, the use of ultra-violet radiation, excessive alcohol consumption, tobacco abuse, environmental pollution, and other factors can influence and accelerate this physiological process, causing premature skin aging [4].

Cistanche has an anti-aging function

In this context, finding mechanisms that restore the juvenile aspect of the skin is a research field of interest for the scientific community. Therefore, the cosmetic industry acts in this process, constantly seeking new compounds to prevent and attenuate skin aging [5-7].

Growth factors have become an important therapeutic option to avoid aging, because they are responsible for cell differentiation and maturation, being directly correlated with the minimization of the topic of aesthetic changes resulting from age advancement [5,6]. Growth factor proteins are naturally secreted by cells and interact directly or are sequestered by the surrounding extracellular matrix for presentation to cell surface receptors. Events such as cell migration, survival, adhesion, proliferation, growth, cistanche penis size, and differentiation are triggered by the binding of the specific growth factor receptor, which stimulates cell signal transduction pathways. These growth factor-stimulated cellular responses in greater proportions are involved in organ development, angiogenesis, and wound healing [8].

The introduction of growth factors in certain damaged sites in the body seeking to stimulate regeneration is clinically related to regenerative medicine, where researchers intend to replace or repair damaged cells, tissues, and organs to effectively restore normal function. The effects of growth factors can be verified clinically, for example, in bone grafting and wound healing in oral, maxillofacial, orthopedic, and cardiac surgery, in addition to the promising results presented regarding the reduction of hair loss. Recently, the interest in growth factors applied in dermatology and plastic surgery has increased, both in fat grafting and skin rejuvenation [9-11].

Among the existing growth factors, we highlight the fibroblast growth factor(FGF), which induces the synthesis of type I collagen and therefore presents a relevant role in the process of skin aging control. In the search for new anti-aging compounds, one of the strategies used for skin revitalization and wrinkle treatment is the stimulation of collagen formation. Collagen is the protein responsible for the structure, elasticity, and firmness of the skin and it is produced by cells called fibroblasts [12-14]. Considering the clinical need to seek new therapeutic options for aging, FGFs have led to studies to evaluate their role in the repair and remodeling of the dermis in the skin anti-aging process. Thus, the present review article aims to clarify the cell signaling pathways involved with the action of FGFs on skin aging.

Considerations about the Skin and the Cutaneous Aging Process

The skin undergoes constant changes, with a high capacity for repair and renovation. It is constituted of three main layers: epidermis, dermis, and hypodermis. The epidermis is the outermost layer of the skin. It stands out in the barrier function, essentially determined by one of its integral parts, the stratum corneum, where the melanocytes and keratinocytes are located. Keratinocytes synthesize keratin, the main protein structure of the epidermis, as well as cytokines that act as chemical mediators that activate cel-lunar processes. Thus, it is the epidermis that determines the depth of migration of the active substances through the skin, playing a major role as an obstacle to penetration, which will be the limiting step of this process[15,16].

The dermis is the layer of skin that possesses the widest variety of cell types such as nerves, blood vessels, and lymph, surrounded by connective tissue formed by fibroblasts, collagen, and reticular and elastic fibers. The hypodermis is the innermost and deepest layer that connects the skin to deeper structures such as muscles and bones. It is composed of an adipose mantle which acts as thermal insulation and nutritive reservoir, protecting the body from trauma and allowing the mobility of the skin with respect to adjacent structures [17].

Physiologically, aging is associated with loss of fibrous tissue, a slower rate of cell turnover, and reduction of the vascular and glandular network. In addition, the barrier function that maintains cellular hydration is also im-paired. Depending on genetics and environmental factors, the normal physiological functions of the skin may decrease by 50% until midlife [1].

Aging is a natural process that happens in all human beings and can be divided into two types: intrinsic and extrinsic aging. Intrinsic aging occurs with the passage of time, determined genetically, with slow tissue deterioration, hormonal status, and metabolic reactions, such as oxidative stress. In this case, skin atrophy and fine wrinkles occur because they mainly affect dermal elastic fibers, causing reticular dermatosis [6,18].

Extrinsic aging is caused by external factors, such as chronic sun exposure or cigarette smoke [19]. The latter increases the intrinsic deterioration of the skin, cistanche powder which is related to an age-related progressive decline in the anti-oxidant capacity associated with increased production of reactive oxygen species from oxidative metabolism in skin cells [20].

Multiple biochemical pathways are modulated by overloading of these stressors, which may result in the suppression of the receptor of transforming growth factor β-I, increased expression of matrix metalloproteinases [21], increased inflammation through the nuclear kappa factor, as well as direct damage to the structural proteins of the skin that UV radiation can cause [22]. There is evidence that these processes of aging, intrinsic and extrinsic, have biological, biochemical, and molecular mechanisms that partially overlap.

Intrinsic aging affects the skin in a manner similar to other organs, because the telomeres continually lose part of their sequences, limiting their cellular replicative capacity. However, the main aging-related skin changes occur in the matrix and in fibroblast pattern expression, cistanche salsa extract which remains in the stationary phase in the dermis for a long period of time, proliferating when there is stimulation, without shortening of telomeres[3].

Factors derived from fibroblasts are essential for the normal growth and differentiation of keratinocytes, which are affected by telomere loss. Therefore, the skin that underwent extrinsic aging and the one that underwent intrinsic aging present different characteristics. However, reduced life expectancy, decreased growth factor response, increased proteolytic activity, and disruption of extracellular matrix synthesis are typical changes observed in both [23]. Such processes act independent from and simultaneous with biologically distinct factors that affect the structure of the skin.

During the aging process, the proliferative and metabolic activity of fibroblasts decreases, and their functions are impaired, leading to a reduction of the synthesis of structural substances such as collagen, elastin, hyaluronic acid, and chondroitin. In addition, decreased levels of growth factors, reduced amount of collagen, abnormal accumulation of elastin, and reduction in the epidermal and dermal thickness, manifest clinically as xerosis, wrinkles, sagging, blemishes, tonus loss, and all signs of skin aging were observed during the aging process [24,25]. Thus, fibroblasts have an important role in preventing the formation of signs of skin aging due to the production of these basic structural substances. Collagen and elastin fibers provide, respectively, firmness and elasticity to the skin. Additionally, mucopolysaccharides, hyaluronic acid, and chondroitin provide skin hydration [13,15,18].

This article is extracted from Skin Pharmacol Physiol 2019;32:275-28 Received: October 2, 2018, Accepted after revision: May 24, 2019 DO:10.1159/000501145 Published online: July 26, 2019