Molecular insights of human skin epidermal and dermal aging

Abstract

Human skin is the most widespread and abundant type of tissue in the human body. With the passage of time, most of our organs, including a substantial part of the skin, tend to undergo a gradual thinning or decrease in size. As we age, there is a gradual and progressive reduction in the thickness of both the epidermis and dermis layers of our skin. This is primarily attributed to the decline of epidermal stem cells and the loss of dermal collagen, which is the most abundant protein in the human body. Age-related alterations of the epidermis and dermis impair skin structure/function and create a tissue microenvironment that promotes age-related skin diseases, such as impaired skin barrier, delayed wound healing, and skin cancer development. This review will examine the current body of literature pertaining to our knowledge of skin epidermal and dermal aging.

1. Introduction

Aging is characterized by the gradual accumulation of damage over time, which disrupts the functioning of cells, tissues, and organs, ultimately leading to the onset of disease and mortality. The process of aging is intricate and influenced by a variety of factors, including genetic predisposition, epigenetic factors, and environmental influences.

The skin, being the largest and heaviest organ in the human body, serves as a primary barrier against various environmental hazards, including solar ultraviolet (UV) radiation, physical and chemical trauma, pathogenic infections, and water loss. Skin is a complex and versatile organ with two primary layers: the epidermis and the dermis. The epidermis is mainly composed of keratinocytes that differentiate to produce keratins, forming the stratum corneum, the skin’s outermost protective layer. In contrast, the dermis is a fibrous structure, predominantly rich in collagen, elastin, fibronectin, and proteoglycans [1]. These ECM proteins make up most of the dermis, providing the skin with tensile strength and mechanical properties as they interact closely with the epidermis and subcutaneous fat [2]. Dermal fibroblasts synthesize, organize, and maintain the collagen-rich ECM in human skin.

The aging of the skin is a highly visible and prominent sign of aging that holds a central position in our social and visual interactions. As a result, the appearance of our skin can significantly affect our quality of life, both emotionally and psychologically. As with all other organs, the human skin undergoes a natural aging process as time passes [3,4]. Apart from the natural aging process, the human skin is subjected to constant environmental stress and damage, particularly from sources like solar UV radiation, which sets it apart from other organs [4]. There are two types of skin aging that can be classified according to their underlying causes: intrinsic or chronological aging, which happens naturally as time passes, and extrinsic aging, also known as photoaging, which results from exposure to external factors such as UV radiation [4,5]. Both types of aging accumulate over time, with photoaging affecting the skin on top of the changes caused by chronological aging. The face, neck, forearms, and lower legs are the areas where the signs of aging are most visible, as a result of a combination of chronological aging and photoaging [6]. Skin diseases related to aging are also most found in these regions.

The morphology of human skin undergoes significant changes because of the aging process, as evidenced by histological and ultrastructural studies. These changes are mainly characterized by a reduction in the thickness of both the epidermis and dermis [3,4]. Extensive evidence confirms that the age-related thinning of the epidermis has a considerable impact on skin function. It notably hampers the skin’s ability to act as a protective barrier against environmental aggressors and to prevent moisture loss. In addition to the epidermis, the aged skin dermis became thin largely due to the loss of collagen, the major structural protein in the skin. Age-related alterations of the epidermis and dermis are directly related to skin pathologies, such as increased fragility [4,7], impaired vasculature support [8], poor wound healing [9,10], and promotion of cancer development [11-13]. Hence, skin aging encompasses more than just a cosmetic concern, as it greatly contributes to age-related skin issues.

2. Molecular basis of human skin aging

The natural process of intrinsic skin aging is triggered by various factors such as genomic instability, cellular senescence, and telomere shortening, leading to a deterioration in skin function and appearance. Conversely, extrinsic aging is caused by external factors like UV radiation, pollution, tobacco smoke, and alcohol consumption, which expedite the aging process and result in premature skin aging. During the aging process, the skin undergoes a series of transformations, often characterized by a thinning and flattening of the epidermis, along with damage to the dermis caused by the fragmentation of collagen fibrils. The dysregulation of ECM turnover, especially the degradation of collagen fibers by matrix metalloproteinases (MMPs) and other proteases, is one of the crucial molecular events that characterize skin aging [3]. Collagen is the main structural protein in the skin, and its loss or fragmentation leads to a decrease in skin elasticity, firmness, and resilience, as well as the appearance of wrinkles and fine lines. Both intrinsic and extrinsic aging are associated with a decline in collagen synthesis and an increase in collagen degradation, although the mechanisms may differ. Skin aging can be categorized into two distinct types, namely epidermal aging and dermal aging, based on the structural changes that occur within the skin (Fig. 1).

Fig. 1.

Molecular insights of human skin epidermal and dermal aging. Human skin, like all other organs, undergoes remarkable morphologic changes with aging as a consequence of the passage of time. Meantime, human skin, unlike other organs, continuously experiences harmful stress and damage from environmental sources such as solar UV radiation and micro-organisms. Among a series of structural modifications, thinning of the epidermis and dermis is the most prominent feature of aged human skin. Epidermal aging: COL17A1 is mainly expressed in the uppermost projections of the ret ridge regions (deep yellow lines), which provide a specialized environment for the growth of skin stem cells. However, this gene is broken down by various enzymes, including MMPs, in response to environmental damage like UV exposure and as a part of the natural aging process. When the COL17A1 expression decreases in the stem cell niches, it causes a weaker attachment of stem cells to the underlying basement membrane, leading to the loss of stem cells and resulting in the flattening of the raised ridges and thinning of the skin, which are commonly seen in aged skin. Dermal aging: Human skin dermis also undergoes a natural aging process because of the passage of time and environmental insults. Aberrant dermal collagen homeostasis, which is caused by impaired dermal fibroblast function, is primarily responsible for human skin dermal aging. Dermal fibroblast functions in aged skin are significantly impaired in collagen homeostasis because of impaired TGF-β signaling, the major regulator of collagen production, and increased production of multiple MMPs, which results in collagen fibril fragmentation, the characteristic feature of the aging dermis. Furthermore, reduced YAP/TAZ activity in aged dermal fibroblasts plays a role in disrupting collagen homeostasis by fostering an inflammatory dermal microenvironment, triggering MMP-1 induction, and impairing TGF-β/Smad signaling. Changes occurring in the dermis with age negatively impact the structural integrity and mechanical characteristics of the skin, creating a microenvironment within the tissue that plays a significant role in the decline of skin function and the development of age-related skin diseases.

2.1. Epidermal aging

While dermal aging has been more extensively studied, the importance of the epidermis in maintaining skin health and defending against environmental stressors cannot be overstated. Composed mainly of keratinocytes that produce keratin, the epidermis plays a critical role in the maintenance of skin homeostasis, and it protects our body from water loss and physical, chemical, and infectious insults. The stratum corneum, which is the outermost layer of the skin, serves as a barrier between the external environment and the underlying epidermal and dermal layers. The ability of the stratum corneum to recover from damage caused by external factors, such as exposure to sun, pollution, or harsh chemicals, is diminished in aged skin compared to younger skin [14]. This may be due to changes in the composition of the stratum corneum, such as a reduction in the levels of natural moisturizing factors, as well as changes in the underlying structure [15]. These age-related alterations in the stratum corneum can contribute to skin dryness, roughness, and a weakened barrier function, which can lead to an increased susceptibility to environmental insults and skin damage.

Although epidermal aging is well recognized, the underlying mechanism of epidermal aging remains largely elusive. The epidermis becomes atrophic, cellular turnover slows, and barrier function declines. The characteristic feature of the aged human skin epidermis is thin and flat. The basal layer of the epidermis in youthful skin is not flat but undulates, known as rete ridges (as shown in the left panel of Fig. 1). Rete ridges are extensions of the epidermis that protrude into the underlying dermal ECM. They are a characteristic feature of healthy, young skin and are essential for maintaining the skin’s structural integrity and mechanical stability, contributing to various skin functions [16]. Interfollicular epidermal (IFE) stem cell niches often reside in the uppermost projections of rete ridges [17]. The epidermis is a highly active tissue that undergoes a continuous renewal process through the generation of fresh keratinocytes. Nevertheless, as the skin ages, a decline in the population of stem cells can cause a decline in the production of keratinocytes. This can result in the flattening of rete ridges and thinning of the epidermis, both of which are hallmarks of aged skin (as illustrated in the right portion of Fig. 1)[18,19]. When the rete ridges flatten, there is a potential reduction in the surface area available for exchange between the epidermis and dermis. This can make the epidermis more susceptible to shearing forces, ultimately leading to increased fragility. Consequently, the decrease in thickness of the epidermis and the flattening of the rete ridges may play a substantial role in heightening the vulnerability of older individuals to skin damage and compromised barrier function. The basal keratinocytes, including the stem cells of the interfollicular epidermis, connect to the underlying dermal stroma via a specialized basement membrane zone, which acts as a complex interface between the epidermis and the dermis. Collagen 17A1 (COL17A1) is a transmembrane structural component of the basement membrane. COL17A1 is expressed in the uppermost projections of the rete ridges region, in which IFE stem cell niches reside. COL17A1 plays an important role in the maintenance of IFE stem cells [20-23]. In recent reports, it has been demonstrated that COL17A1 is significantly reduced in chronologically aged, photoaged, and acute UV-irradiated human skin in vivo [23,24]. The reduced expression of COL17A1 in the region specific to rete ridges may weaken the adhesion of stem cells to their niches, resulting in their elimination from the skin surface due to the process of terminal epidermal differentiation [20]. As a result, the deficiency of COL17A1 results in reduced rates of keratinocyte renewal and thinner epidermal layers, which is the primary morphological feature of aging epidermis. As such, reduced expression of COL17A1 in epidermal stem cell niches (uppermost ret ridge region) could impose a significant impact on epidermal aging. Age-related loss of COL17A1 would be also expected to weaken IFE stem cell’s epidermal adhesion to the dermis and protective mechanical function between the epidermis and dermis. Therefore, age-related loss of COL17A1 may also contribute to skin conditions in the elderly through less resistance to shearing force and more vulnerable to environmental injury.

Aging of the hair refers to the natural changes that occur in hair as a person gets older. These changes can manifest in various ways and may include gray hair, deceased hair growth rate, hair loss, changes in hair dryness and texture. It has been postulated that the maintenance of hair-follicle stem cells (HFSCs) is also dependent on the integrity of COL17A1 [21,25]. Gray hair is one of the most noticeable signs of aging, characterized by a loss of pigment, which results in the hair appearing colorless or white. This loss of pigment is due to a decrease in the number and activity of melanocytes, the cells responsible for producing the pigment melanin that gives hair its color. Melanocyte stem cells (McSCs) are thought to play an important role in maintaining the population of melanocytes, and recent research has suggested that age-related loss of McSCs may contribute to the graying of hair [25]. Studies conducted on mouse models of skin aging have indicated that the decrease in COL17A1 expression is responsible for the decline in the number of HFSCs and McSCs associated with aging [21,25]. Furthermore, as evidenced by Xie et al. [23], the recent research highlights that the diminished size of the HFSC physical niche is linked to age-related hair loss through the Piezo1-calcium-TNF-α signaling pathway [26]. Piezo1 is particularly important in sensing mechanical forces and plays a crucial role in various physiological processes. As such, age-related loss of HFSCs is likely influenced by alterations in the microenvironment surrounding HFSCs, including changes in mechanosensory signals and molecular signaling pathways. Overall, age-related loss of skin stem cells can have significant impacts on hair and skin health and contributes to the visible signs of aging such as gray hair and thinning hair.

The precise mechanism responsible for the reduction in COL17A1 expression in aging human skin remains unclear. In mouse model of skin aging, COL17A1 is specifically broken down by proteolysis, which is carried out by various proteases, including MMPs [21]. It is well-known that elevated multiple MMPs are common features in naturally aged and photoaged as well as UV-irradiated human skin [4,27]. GM6001, a potent and broad-spectrum MMPs inhibitor, prevents UV-induced COL17A1 downregulation in both keratinocytes and mouse skin [24]. MMPs also diminish other basement membrane proteins in photoaged skin [28]. These findings suggest that the upregulation of MMPs, which occurs as a result of aging, could potentially contribute to the age-related decline in COL17A1 expression by promoting its proteolytic degradation.

2.2. Dermal aging

Most of the skin’s volume is occupied by the dermis, which provides crucial mechanical stability and physical resilience. The dermis is composed mainly of tightly packed bundles of collagen fibrils, which together create a complex three-dimensional ECM. This collagenous ECM is produced by dermal fibroblasts, which reside within and around the collagen bundles. During aging, both the collagen bundles and fibroblasts undergo harmful changes. These alterations include fragmentation/disorganization of collagen fibrils, reduced collagen production, and establishment of an inflammatory dermal microenvironment (inflammaging) [3,29]. These age-related changes in dermal microenvironment are directly related to skin pathologies, such as increased fragility [4], impaired vasculature support [8], poor wound healing [9,10], and promotion of cancer development [11-13]. It is becoming more evident that aberrant ECM homeostasis is a hallmark of age-related disorders. Age-related alterations of collagen that impair tissue architecture could cause an aberrant tissue microenvironment, which in turn may deleteriously influence the risk of developing age-related diseases in other tissues and organs. Indeed, a growing body of evidence suggests that an abnormal tissue microenvironment resulting from aging contributes significantly to the pathophysiology of various diseases, such as cancer, fibrosis, and non-healing wounds. [30-32].

MMPs are a group of zinc-dependent proteinases that can specifically break down collagen and other ECM proteins. There are currently over 20 known members of the human MMP gene family, each with their own unique structural characteristics and substrate specificities [33,34]. MMPs play critical roles in both physiological and pathological processes that involve breakdown and remodeling of the ECM, such as ECM restructuring during wound healing, angiogenesis, and the development and invasion of cancer [33,35,36]. In human skin, MMP-1 (also known as collagenase 1) is principally derived from dermal fibroblasts. MMP-1 is the major protease capable of initiating the cleavage of native collagen fibrils [37]. MMP-1 levels are typically low in healthy, young skin, but the levels significantly increase with age, causing increased fragmentation and disorganization of collagen fibrils in the dermis [7]. The levels of MMP-1 also show a significant increases following acute UV exposure and in photoaged human skin in vivo [3]. Elevated levels of MMP-1 initiate collagen fibrils fragmentation, resulting in irreversible damage to the structural and mechanical properties of the dermal ECM. Consequently, the skin becomes more susceptible to injury, such as bruising, and the functional interplay between dermal cells and the ECM can also be adversely affected. The gradual buildup of MMP-1-induced collagen fibril fragmentation is a primary cause of the distinct features associated with aging in the human dermis, referred to as dermal aging. Recently, our laboratory generated mouse models of dermal aging by selective expression of human MMP-1 in dermal fibroblasts driven by the fibroblast-specific collagen1A2 (Col1a2) promoter and upstream enhancer [12]. Human MMP-1 transgenic mice displayed many of the hallmarks of aged human skin dermis, characterized by dermal collagen fibrils fragmentation and disorganization; reduced dermal thickness and dermal collagen fibril density; increased expression of multiple endogenous MMPs, and age-related proinflammatory mediators Il-1β, IL-6, and IL-8. Importantly, human MMP-1 transgenic mice exhibit an enhanced preponderance of keratinocyte cancer in mouse model of skin carcinogenesis, cutaneous two-stage chemical carcinogenesis. These data demonstrate that age-related alteration of the dermal microenvironment is necessary for the development of keratinocyte cancer, which partially explains the prevalence of skin cancer in the elderly.

Transforming growth factor-β (TGF-β) is involved in various aspects of ECM homeostasis, including the regulation of collagen synthesis, deposition, and degradation, which are essential for maintaining the structural integrity of tissues and organs [3]. A large body of evidence indicates a primary role of TGF-β/Smad signaling in ECM synthesis. The TGF-β/Smad pathway is involved not only in enhancing ECM gene expression but also in inhibiting ECM degradation. As such, the TGF-β/Smad pathway is recognized as a primary regulator of ECM homeostasis. The dysregulation of TGF-β signaling is a significant contributor to the development of conditions linked to ECM proteins. When TGF-β signaling is upregulated, it can lead to the abnormal buildup of ECM proteins in affected tissues. This phenomenon is observed in systemic sclerosis, a chronic connective tissue disorder characterized by skin and internal organ fibrosis [38]. In contrast, down-regulation of TGF-β signaling negatively regulates collagen homeostasis and has a significant impact on human skin dermal aging [3]. Laser capture microdissection coupled with quantitative real-time RT-PCR indicates that the TβRII mRNA level is reduced by 59 % in aged (80 +years), compared to young (20–30 years) skin dermis. Interestingly, reactive oxygen species (ROS), which are considered to play a pivotal role in the biology of aging, substantially reduce TβRII, but not TβRI, gene expression [39]. The mRNA levels of TβRII also show a significant decrease following acute UV exposure and in photoaged human skin in vivo [40]. As described above, TGF-β initiates its cellular actions by binding its cell surface receptor complex. Reduced expression of TβRII causes decreased binding of TGF-β to the surface of dermal fibroblasts, and reduced TβRII signal transduction. Preventing loss of TβRII by over-expression restores TGF-b activation of Smad3, and therefore protects against ROS inhibition of type I procollagen gene expression. The decrease in TβRII expression is a significant factor in the age-related decrease in dermal collagen production that results in skin thinning in aged individuals. The TGF-β/Smad pathway is essential for regulating both the synthesis and degradation of the ECM, which is crucial for maintaining tissue and organ function and structural integrity. The dysregulation of TGF-β/Smad signaling can contribute to various pathological conditions, including fibrosis, cancer, and autoimmune diseases, which are characterized by abnormal ECM synthesis and degradation.

The mechanical properties of the tissue, such as stiffness, elasticity, and forces, play a crucial role in regulating various cellular processes, including cell adhesion, migration, proliferation, and differentiation. Aging is accompanied by changes in the composition and structure of the ECM, resulting in changes in the mechanical properties of connective tissues in older individuals [41]. In recent research, several studies have shown that the mechanical property of the dermal ECM plays a causal role in skin aging. Notably, the loss of YAP/TAZ resulting from an age-related alteration of dermal ECM mechano-microenvironment induces cGAS-STING activation, leading to cellular senescence and skin aging [42]. In aged human skin dermal fibroblasts in vivo, the expression of YAP/TAZ is indeed decreased [43]. This reduced expression of YAP/TAZ leads to the induction of MMP-1 and inhibition of TGF-β signaling [43,44]. These findings imply that the decline in YAP/TAZ activity is a contributing factor to the dermal aging (Fig. 1). Additionally, age-related stiffened microenvironment drives the atrophy of skin vasculature that enhances the differentiation of epidermal stem cells in aging skin [45]. Indeed, Shao et al. reported that photoaged skin dermis displayed increased stiffness and hardness, attributed to collagen fragmentation and cross-linking [46]. These results imply that age-related changes in the dermal mechano-microenvironment play a significant role in skin aging.

3. Future directions

Skin aging is inevitable and a complex biological process of changes that occur in the skin over time as a person gets older. Although our comprehension of the molecular mechanisms involved in skin aging is advancing, there are still significant gaps in our fundamental understanding. By continuing to investigate the underlying mechanisms of skin aging and developing new interventions to slow down the process, we may be able to help people maintain healthy, youthful-looking skin as they age.

Recently, a broad range of aging hallmarks has been proposed [47]. There are a few potential directions for future research in the field of human skin aging underlying mechanisms: 1) Investigating the role of the microbiome: Recent research has shown that the microbiome plays an important role in skin health [48], suggesting that changes in the microbiome may contribute to skin aging. Future studies could explore how changes in the skin microbiome with age impact on skin aging, such as understanding how age-related changes in the skin microbiome influences local metabolic processes and skin health.; 2) Studying the epigenetics of skin aging: Epigenetic changes can impact gene expression and play a role in aging [49]. Future studies could explore how epigenetic changes contribute to skin aging and how they can be targeted to potentially slow down the aging process; 3) Investigating the role of senescent cells in skin aging: Senescent cells are cells that have stopped dividing but remain active, and they have been implicated in the aging process. Future research could investigate how senescent cells accumulate in the skin over time and how interventions that target senescent cells (such as senolytics) may impact skin aging; 4) Investigating the role of DNA damage in skin aging: Accumulated DNA damage over time, such as damage caused by exposure to UV radiation from the sun, can lead to changes in gene expression and cellular function, which can contribute to skin aging; 5) Investigating how reactive oxygen species (ROS) influence mitochondrial dysfunction: Metabolism generates ROS as byproducts. As we age, the body’s ability to neutralize free radicals with antioxidants may decrease, leading to increased oxidative damage to the skin and accelerated aging. Gaining insights into the effects of ROS on mitochondrial dynamics, bioenergetics, and cellular signaling is of paramount importance in skin aging research. 6) Investigating the role of inflammation in skin aging: Recent research has shown that aged skin shows signs of chronic inflammation and that increased IL-17 signaling plays an important role in skin epidermal aging [50]. Chronic low-grade inflammation (inflamm-aging) in the skin can contribute to aging by promoting tissue damage and dysfunction; and 7) Examining the effects of lifestyle factors on skin aging: lifestyle factors such as diet, exercise, and sun exposure can all impact skin health and aging. Future studies could explore how these factors interact to impact skin aging and how interventions targeting lifestyle factors may slow down the aging process.

Biography

Dr. Quan is a Research Professor at the Department of Dermatology, University of Michigan Medical School, Ann Arbor. He earned his Ph.D from Akita University School of Medicine in Japan in 1992, and his MD degree from Norman Bethune University Medical Science in Changchun, China in 1983. Following that, Dr. Quan underwent postdoctoral training in the Department of Dermatology at Wayne State University and the University of Michigan in 1997. The primary focus of Dr. Quan’s research laboratory is to investigate the molecular mechanisms underlying skin aging and age-related diseases. Their work encompasses three main areas: matrix biology, cell-matrix interaction, and the tumor microenvironment and its relation to skin cancer. Presently, their research is concentrated on understanding how the age-associated dermal microenvironment (AADM) affects skin structure and function, and how it contributes to the development of age-related skin diseases such as poor wound healing and skin cancer. A key aspect of their research involves using mouse models to study dermal aging, skin cancer, and scar formation. Furthermore, Dr. Quan’s laboratory explores the regulation and degradation of collagen, with a specific focus on TGF-ß/Smad signaling, MMPs (matrix metalloproteinases), and Yap/Taz proteins. Through their investigations, Dr. Quan and his team have published numerous peer-reviewed papers and books, with Dr. Quan also serving as an editor. Additionally, they have been successful in securing multiple NIH RO1 grants under Dr. Quan’s leadership as the principal investigator.