Innovita Research Foundation

I.R.F. / Aging news / General / 03061201

Skin Aging
Posted on: June 12, 2003

How skin is composed

Skin serves as a protective barrier between internal organs and the environment. Skin is a complex organ with multiple cell types and structures. Skin is divided into three regions: epidermis, dermis, and subcutaneous tissue. The epidermis is the cell-rich superficial layer composed mainly of keratinocytes, which are the most numerous cells in the skin, pigment producing melanocytes, and antigen presenting Langerhans cells. A basement membrane separates the epidermis from the dermis, which is composed primarily of extracellular matrix proteins, produced by resident fibroblasts. The vascular supply to the skin resides in the dermis. The subcutaneous tissue consists of fat cells that underline the connective tissue framework.

Type I collagen is the most abundant protein in skin connective tissue, which also contains other types of collagen (III, V, VII), elastin, proteoglycans, fibronectin, and other extracellular matrix proteins. Newly synthesized type I procollagen is secreted into the dermal extracellular space where it undergoes enzymatic-processing, arranging itself into a triple helix configuration. The triple helix complexes associate with other extracellular matrix proteins such as leucine-rich small proteoglycans, to form regularly arranged fibrillar structures. This process, called fibrillogenesis, results in formation of collagen bundles that are responsible for the strength and resiliency of the skin.

UV light induces skin aging

Skin aging is influenced by several factors, including genetics, environmental exposure (ultraviolet (UV) irradiation, xenobiotics, mechanical stress), hormonal changes, and metabolic processes (generation of reactive chemical compounds such as activated oxygen species, sugars, and aldehydes). Taken together, these factors lead to cumulative alterations of skin structure, function, and appearance. The influence of the environment, especially solar UV irradiation, is of considerable importance for skin aging. Skin aging due to UV exposure (photoaging) is superimposed on chronological skin aging. Historically, photoaging and chronological skin aging have been considered to be distinct entities. Although the typical appearance of photoaged and chronologically aged human skin can be readily distinguished, recent evidence indicates that chronologically aged and UV-irradiated skin share important molecular features including altered signal transduction pathways that promote matrix-metalloproteinase (MMP) expression, decreased procollagen synthesis, and connective tissue damage. This concordance of molecular mechanisms suggests that UV irradiation accelerates many key aspects of the chronological aging process in human skin. Based on this relationship between UV irradiation and chronological aging, acute UV irradiation of human skin may serve as a useful model to study molecular mechanism of skin chronological aging.

Morphology of chronologically and UV-irradiated aged human skin

Chronologically aged skin appears thin, smooth, dry, unblemished, with some loss of elasticity. Comparison of skin surface makings between young and aged sun-protected skin reveals a modest age-related loss of architectural regularity. At the histological level, chronologically aged skin shows general atrophy of the extracellular matrix reflected by decreased number of fibroblasts, and reduced levels of collagen and elastin. The organization of collagen fibrils and elastin fibers is also impaired. This impairment is thought to result from both decreased protein synthesis that particularly affects types I and III collagens in the dermis and increased breakdown of extracellular matrix proteins.

Visual comparison of chronologically sun-exposed (typically exterior surfaces of face, forearms, and hands) and sun-protected skin (typically back, trunk, and buttock) readily reveals that aged-associated alterations in the appearance of human skin derives primarily from sun exposure. Photoaged skin appears wrinkled, lax, coarse, with uneven pigmentation, and brown spots. Histological and ultrastructural studies have revealed that photodamaged skin is associated with increased epidermal thickness, and alterations of connective tissue organization. The hallmark of photoaged skin is accumulation of amorphous elastin-containing material that resides beneath the epidermal dermal junction. Impairment of the fibrillar organization of collagen and elastin is typically more severe in photoaged skin, compared to sun-protected chronologically aged skin. The severity of photoaging is proportional to accumulated sun exposure and inversely related to degree of skin pigmentation. Individuals with fair skin are more susceptible to solar UV-induced skin damage than darker-skinned individuals.

Figure 1. Role of oxidative stress in aging and UV response: UV irradiation and aging both lead to increased ROS production, which alters gene and protein structure and function. This results in dysregulation of intracellular and extracellular homeostasis that can modify cellular behavior and cell-matrix interactions as well, thus leading to an impaired function of the skin.

UV irradiation generates reactive oxygen species

Oxidative stress is thought to play a central role in initiating and driving the signaling events that lead to cellular response following UV irradiation. UV irradiation of skin increases hydrogen peroxides and other reactive oxygen species (ROS), and decreases anti-oxidant enzymes. These features are also observed in chronologically aged human skin. In both cases, increased ROS production alters gene and protein structure and function, leading to skin damage (Fig. 1).

UV light induces signal cascades leading to skin damage

One of the earliest detectable responses of human skin cells to UV irradiation is activation of multiple cytokine and growth factor cell surface receptors, including epidermal growth factor receptor (EGF-R), tumor necrosis factor (TNF)-α receptor, platelet activating factor (PAF) receptor, insulin receptor, interleukin (IL)-1 receptor, and platelet derived growth factor (PDGF) receptor.

Activation of cell surface cytokine and growth factor receptors results in recruitment in cytoplasm of adaptor proteins that mediate downstream signaling. Assembly of these signaling complexes results in activation of small GTP-binding protein family members which are key upstream regulators of the certain MAP kinases. The action of certain GTP-binding protein results in an increased formation of superoxide anion. This increased production of ROS likely participates in amplification of the signal leading to the activation of the downstream enzyme complexes, exactly MAP kinase. ROS are necessary participants in multiple MAP kinase pathways.

Increased intracellular ceramide content may also contribute to activation of the MAP kinase pathways by UV irradiation. UV-induced ceramide generation seems to be dependent on increased ROS production, since ceramide and ROS levels rise in parallel, and UV-induced ceramide production is inhibited by the free radical scavenger Vitamin E.

Now the UV-induced signal cascades enter the nucleus. MAP kinase activation results in induction of transcription factor AP-1 that is a major effector of the MAP kinase pathways. AP-1 regulates expression of many genes involved in the regulation of cellular growth and differentiation. Transcription of several MMP (matrix-metalloproteinase) family members is strongly regulated by AP-1. Several MMPs are upregulated by AP-1. These include MMP-1 (interstitial collagenase or collagenase 1) which initiates degradation of types I and III fibrillar collagens, MMP-9 (gelatinase B), which further degrades collagen fragments generated by collagenases, and MMP-3 (stromelysin 1), which degrades type IV collagen of the basement membrane and activates proMMP-1.

MMP induction is, in part, responsible for UV-induced damage to skin connective tissue. Together, MMP-1, MMP-3, and MMP-9 have the capacity to completely degrade mature fibrillar collagen in skin. Consistent with this, increased collagen breakdown has been demonstrated within 24 h after UV irradiation in human skin in vivo. Thus, UV irradiation of human skin causes extracellular matrix degradation via induction of transcription factor AP-1, and subsequent increased MMP production.

In addition to causing collagen breakdown, UV irradiation impairs new type I collagen synthesis. UV irradiation has been shown to decrease collagen production and impair organization of collagen fibrils in skin in vivo. In addition, increased breakdown of extracellular matrix proteins is also observed in UV-irradiated fibroblasts in vitro and in human skin in vivo. Down-regulation of type I collagen is mediated in part by UV-induced AP-1, which negatively regulates transcription of both genes that encode for type I procollagen (COL1A1 and COL1A2).

UV-induced down-regulation of collagen synthesis also occurs via paracrine mechanisms involving TGF-β and other cytokines. TGF-β is a major profibrotic cytokine, which regulates multiple cellular functions including differentiation, proliferation, and induction of synthesis of extracellular matrix proteins. The biological effects of TGF-β are diverse and strongly dependent on its expression pattern and cell type. In human skin, TGF-β inhibits growth of epidermal keratinocytes and stimulates growth of dermal fibroblasts. Moreover, TGF-β induces synthesis and secretion of the major extracellular matrix proteins collagen and elastin. TGF-β also inhibits expression of certain specific enzymes involved in the breakdown of collagen, including MMP-1 and MMP-3.

Many of the molecular alterations observed following UV irradiation occur in sun-protected chronologically aged human skin in vivo

A major feature of aged skin is reduced types I and III procollagen synthesis. This reduction results in skin thinning and increased fragility. Both types I and III procollagen mRNA and protein expression are reduced in aged skin.

In addition to impaired collagen synthesis, increased production of several MMP family members, including MMP-1, MMP-2 (gelatinase A), MMP-3, and MMP-9 occurs in chronologically aged skin. With the exception of MMP-2, these MMPs are regulated by AP-1 and induced by UV irradiation. Interestingly, AP-1 expression is increased in aged human skin in vivo and aged skin fibroblasts in vitro.

Oxidative stress is thought to be of primary importance in driving the aging process. The free radical theory of aging, first proposed several decades ago, envisions that the molecular basis of aging derives from accumulation, over a lifetime, of oxidative damage to cells resulting from excess ROS, which are produced as a consequence of aerobic metabolism. Although skin possesses extremely efficient anti-oxidant activities, it has been demonstrated that during aging, ROS levels rise and anti-oxidant defenses decline. ROS are necessary participants in multiple MAP kinase pathways. MAPK activation results in induction of AP-1, which in turn, upregulates expression of MMPs. This scenario provides a plausible mechanism for the observed increased collagen degradation in aged human skin.

In spite of existing differences, many critical molecular features of aged and UV-irradiated human skin bear striking similarities. It could be stated that these similarities reflect the central role that oxidative stress plays in UV irradiation-induced responses and aging in human skin. Viewed in this light, it is not surprising that UV irradiation and aging evoke similar molecular responses, since both are responding to oxidative stress. Nor is it surprising that the consequences of UV irradiation and aging have similar damaging impact on skin connective tissue.

Source: Laure Rittié, Gary J. Fisher; UV-light-induced signal cascades and skin aging; Ageing Research Reviews 1 (2002) 705-720.
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