Skin Aging, Metabolism, and Related Products

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1		Weidong Xie	--	3782	2024-01-18 07:49:28	\|
2	Reference format revised.	Lindsay Dong	Meta information modification	3782	2024-01-19 03:32:07	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms242115930

Skin aging affects the metabolism of three major substances, which are glucose, protein, and lipids, and the metabolism of the three major substances in the skin also affects the process of skin aging. Some drugs or compounds can regulate the metabolic disorders mentioned above to exert anti-aging effects. Currently, there are a variety of products, but most of them focus on improving skin collagen levels. Skin aging is closely related to metabolism, and they interact with each other. Regulating specific metabolic disorders in the skin is an important anti-aging strategy.

skin aging glucose metabolism protein metabolism lipid metabolism

1. Introduction

The skin is considered the most extensive organ system in mammals ^[1]; making up 10% of body weight, the skin needs to rely on material and energy metabolism to maintain structural and functional integrity. In recent years, with the improvement in people’s living standards and the increase in the aging population, people, especially women, have begun to pay attention to the topics of skin aging and anti-aging ^[2]^[3]. Changes in the skin barrier occur during skin aging ^[4]. Aging skin exhibits wrinkles, uneven skin tone ^[5]^[6], a loss of elasticity, and thinning ^[7]. There are many factors that affect skin aging. Generally speaking, skin aging problems naturally occur with age, and skin aging is also influenced by both internal (genetics and diseases) and external factors (ultraviolet radiation, air pollution, smoking, alcohol consumption, etc.), leading to accelerated aging ^[8]^[9]^[10].

The skin’s structural complexity involves a diverse assembly of specialized cell types, including keratinocytes, fibroblasts, melanocytes, and immune cells, which are all strategically organized to execute their unique roles within the skin’s intricate framework ^[11]. For instance, keratinocytes, the predominant cell type in the epidermis, form a protective barrier against environmental factors and pathogens ^[12]. Fibroblasts, residing in the dermal layer, play crucial roles in synthesizing extracellular matrix components, particularly collagen and elastin, which are responsible for skin elasticity and firmness ^[13]. Melanocytes are responsible for skin pigmentation, and immune cells act as sentinels, defending the skin against infections and injuries ^[14].

Unveiling the intricate process of aging and its impact on the skin demands a multifaceted approach. Beyond the external factors shaping skin aging, a profound understanding of the skin’s internal architecture is pivotal. Currently, various types of skin cells, such as keratinocytes, fibroblasts, and melanocytes, are well identified and, as described above, play significant roles in the structure and function of the skin ^[15]. With the passage of time, changes in the cellular and structural elements in the skin manifest as aging characters, e.g., wrinkles, reduced elasticity, and pigmentation fluctuations. Comprehending the complexities of skin aging hinges on a grasp of the skin’s biological procession. Intertwined within this narrative lies the symbiotic relationship between skin biology and metabolism, a key element in unraveling the mystery of skin aging.

Metabolism, in general, refers to a series of organized chemical reactions that occur within an organism to sustain life. These metabolic processes enable organisms to grow, reproduce, maintain their structures, and respond to the external environment. Metabolism is categorized into material metabolism and energy metabolism, with material metabolism primarily encompassing three major metabolites: glucose metabolism, protein metabolism, and lipid metabolism. Metabolism plays a vital role in maintaining physiological functions and influences the occurrence and development of diseases within the body ^[16].

2. The Impact of Skin Aging on Metabolism

2.1. Skin Metabolism

2.1.1. Glucose Metabolism

Glucose metabolism refers to a series of complex chemical reactions that occur in the body between glucose and glycogen. The main forms of glucose that are present in the body are glucose and glycogen. Glucose metabolism includes catabolism and anabolism ^[17]. Glycolysis metabolism refers to the breakdown of glucose into small substances, which undergo a series of decomposition in the organism, releasing a large amount of energy and forming large carbon shelves such as lipids, proteins, and nucleic acids. Glycosynthesis metabolism is the process by which organisms convert certain non-glucose small molecules into monosaccharides and polysaccharides, which requires energy.

Glucose is the main fuel for skin energy production. A total of 70% of glucose in the human epidermis is converted into lactic acid through anaerobic glycolysis ^[18]. Lactic acid can be directly secreted into the body to exert antibacterial effects, while also entering the bloodstream to participate in gluconeogenesis. Only 2% of glucose participates in complete aerobic glucose metabolism through the tricarboxylic acid cycle. The pentose phosphate metabolism pathway of glucose is common in the skin and plays an important role in the growth and repair of skin tissue cells. Glycogen is synthesized from glucose monomers and plays an energy storage role in the skin. When glucose is lacking in energy, the distribution of fuel is redistributed, and the skin’s energy source shifts to other fuels such as glycogen or lipids ^[19].

2.1.2. Protein Metabolism

Protein metabolism refers to the biochemical processes of proteins and amino acids, including synthetic metabolism and catabolism. During the process of protein catabolism, amino acids can be produced through protease degradation ^[20].

The metabolism of skin proteins is an indispensable and important process for maintaining skin function ^[21], and the integrity of skin tissue largely depends on its protein matrix. The primary function of collagen is to maintain skin homeostasis, and it can appropriately regulate the structure of the skin matrix, which is a crucial role in skin homeostasis ^[22].

Glutamine has been proven to be the amino acid with the highest content in plasma and muscle ^[19]. Glutamine can serve as a donor for energy and nitrogen sources required for purine/pyrimidine formation, participating in mitochondrial metabolism and cell growth regulation ^[12]. During hunger stress, glucose utilization is hindered, and protein is degraded into glutamine or becomes an important energy source for skin tissue ^[19]. During wound healing, epidermal cells divide and grow, and glutamine is an important growth factor. Glutamine can be degraded by glutaminase to produce glutamate, which can be converted into α- Ketoglutaric acid participates in the tricarboxylic acid cycle as a replenishment substrate ^[17].

2.1.3. Lipid Metabolism

Lipids are important components of all cell types and play various biological functions, including energy storage, cell membrane construction, cell transduction, protection, and mitochondrial regulation ^[23]^[24]. Fatty acids can be considered as energy fuels in situations where energy is required. The oxidation of fatty acids has been shown to produce acetyl CoA and NADH. Fatty acids not only have important significance in lipid metabolism but also play a very important role in protecting the skin’s epidermal structure ^[18].

Lipids such as fatty acids are important energy sources for skin tissue cells after glucose. When hungry, skin tissue can utilize fatty acids as a source of energy. In addition, lipids play important roles in supporting the basic structure of skin cells and preventing skin water loss ^[25]^[26]. An important characteristic of lipid metabolism in aging skin is a decrease in protective lipid synthesis and secretion. In aging skin, there is a notable slowdown in lipid synthesis and metabolism, resulting in reduced lipids that serve as protective barriers for the skin. This phenomenon contributes to skin thinning and heightens the propensity for an accelerated aging process ^[27].

3. The Impact of Metabolism on Skin Aging

3.1. The Effect of Glucose Metabolism on Skin Aging

In skin cells, glucose metabolism disorders can have significant impacts on skin aging. On the one hand, the excessive metabolism of glucose in the mitochondria can produce excessive reactive oxygen species (ROS), which can stimulate the body’s stress system and cause skin damage. On the other hand, when glucose metabolism slows down, due to glucose accumulation, proteins and glucose form a cross-link in the body through non-enzymatic glycosylation reactions, producing advanced glycation end products (AGEs) ^[28], damaging the skin ^[29], and accelerating skin aging ^[30].

3.2. The Impact of Protein Metabolism on Skin Aging

Protein serves as a noticeable marker in both healthy skin and aging skin, with a particular emphasis on collagen. Collagen assumes a pivotal role in the examination of skin structural support and the aging process, making it a direct indicator of skin aging. A decline in collagen levels can significantly impact skin quality, contributing to the manifestation of age-related skin characteristics ^[31].

Glutamine is very instrumental in cell growth, detoxification, and barrier building in the skin ^[12]. Studies have shown that the homeostasis of glutamine in skin cells plays an important role in metabolism, and the antioxidant capacity and defense against external stimuli in skin cells largely come from glutathione (GSH), which is derived from glutamine ^[32]. To some extent, the more glutamine available, the easier it is for the skin to remain youthful ^[33].

3.3. The Effect of Lipid Metabolism on Skin Aging

The lipid profile of the skin is the foundation for maintaining a protective barrier to the external environment ^[34]. A decrease in skin lipid synthesis can lead to the loss of skin moisture and promote the occurrence of skin aging. Ultraviolet radiation may affect the skin’s lipid homeostasis ^[35], causing lipid peroxidation and the formation of brown pigments, leading to the occurrence and development of skin aging. The metabolic product of lipids, fatty acids, can affect matrix metalloproteinases (MMPs), which affect the amount of collagen produced and directly affect the degree and state of skin aging. Therefore, skin lipid metabolism is also very complex, and its metabolic disorders can also play very important roles in skin aging.

4. Metabolism and Aging in Specific Skin Cells

4.1. Keratinocytes

Keratinocytes constitute the primary component of the skin’s outermost layer—which is crucial for skin protection—and lipid metabolism, which is essential for maintaining the skin’s barrier function. This barrier acts as a protective shield, preventing moisture loss and the infiltration of external substances. Furthermore, protein metabolism within keratinocytes involves the synthesis of keratin, which forms the structural foundation of the epidermal layer. This structural support is instrumental in preventing moisture loss and the intrusion of external elements, thereby bolstering skin health and appearance ^[36].

Several mechanisms come into play in the context of glucose metabolism within aging keratinocytes. With age, these cells may experience alterations in glucose uptake and utilization. Reduced glucose uptake can impact energy production and oxidative stress management ^[37]. The cells might also face changes in the expression of critical enzymes that are involved in glycolysis and the citric acid cycle, potentially leading to diminished energy production ^[38].

4.2. Fibroblasts

Fibroblasts, which are situated deep within the skin’s dermal layer, assume a pivotal role in skin health by actively synthesizing essential proteins, mainly collagen and elastin ^[39]. These structural proteins provide the skin with the necessary framework and elasticity. In youthful skin, fibroblasts exhibit robust metabolic activity, characterized by the prolific synthesis of collagen and a high degree of cellular regeneration ^[17]. This dynamic activity maintains the skin’s structural integrity and suppleness, contributing to its youthful vitality. However, age brings about changes in the metabolic functions of fibroblasts.

Fibroblasts are integral to sugar metabolism within the skin. Their ability to maintain stable sugar metabolism is essential for preventing the formation of advanced glycation end products (AGEs) ^[28]. AGEs are compounds that are formed when proteins, including collagen and elastin, become glycated due to the exposure to excess sugar. The accumulation of AGEs can lead to the cross-linking of proteins and the loss of skin elasticity, contributing to visible signs of aging such as wrinkles and sagging ^[40]. Therefore, the age-related changes in the metabolic activities of fibroblasts can have direct impacts on the formation of AGEs and subsequently affect the skin’s aging process.

4.3. Melanocytes

Melanocytes, residing in the basal layer of the epidermis, are the custodians of skin pigmentation, chiefly through the intricate process of melanin biosynthesis ^[41]. Melanin imparts color to the skin and is pivotal in shielding the skin against the detrimental effects of ultraviolet (UV) radiation ^[42]. The metabolism of melanocytes plays a pivotal role in skin aging, as it encompasses a complex interplay of glucose, lipid, and protein metabolism. This metabolic orchestra is instrumental in regulating not only the production of melanin but also the overall health of the skin.

The regulation of glucose metabolism in melanocytes is of utmost importance. Glucose serves as the primary energy source for melanin production ^[43]. Within melanocytes, the tyrosinase enzyme catalyzes the conversion of tyrosine into melanin precursors. This enzymatic process is highly sensitive to glucose levels, and any imbalances can lead to irregularities in melanin production, contributing to variations in skin pigmentation ^[44].

5. Membrane or Cytoskeleton Proteins in Skin Metabolism and Aging

5.1. Connexins and Intercellular Communication

Connexins, a class of channel proteins situated on the cell membrane, play pivotal roles in coordinating and balancing three fundamental metabolic processes: glucose metabolism, protein metabolism, and lipid metabolism.

In glucose metabolism, connexins are crucial for absorbing, transporting, and utilizing intracellular glucose to meet the cell’s energy requirements ^[45]. By forming intercellular channel connections, connexins enable cells to share metabolic products, including glucose and other sugar molecules. This communication aids in coordinating glucose metabolism and ensures that cells can adapt to changes in energy demands ^[46]. The dynamic nature of gap junctions allows for cells to rapidly adjust the number of gap junction channels at the plasma membrane in response to external or internal signals. Emerging evidence suggests that ubiquitination plays a critical role in regulating connexin turnover and endocytic processes, affecting the functional statuses of gap junctions.

In lipid metabolism, connexins are involved in synthesizing, breaking down, and transporting lipid molecules, meeting the cell’s energy and structural needs ^[46]. Connexins enable cells to share lipid molecules, including lipoproteins and fatty acids, through intercellular channel connections. This sharing helps to maintain the integrity and functionality of cell membranes and ensures that cells have access to necessary lipid resources. Impaired connexin function can lead to disruptions in lipid metabolism, potentially involving issues like high cholesterol or other lipid-related diseases ^[45].

5.2. Desmin and Cytoskeletal Integrity

Desmin is a crucial component of the cell’s internal structure, and it is indispensable in maintaining skin cells’ morphology and structural integrity. These roles are critical in understanding the cellular basis of skin aging.

Desmin’s influence on glucose metabolism stems from its role in maintaining the cell structure. A well-organized cell structure is crucial for efficient glucose transport, particularly in insulin-responsive tissues like muscles ^[47]. Disrupted desmin function can lead to structural disarray, affecting the distribution of glucose transporters like GLUT4 and impairing insulin signaling and glucose transport ^[48].

In terms of protein metabolism, desmin’s function is closely tied to the maintenance of structural integrity. Healthy protein turnover is vital for repairing and maintaining the cytoskeletal framework ^[49]. Altered desmin can disrupt this balance, leading to protein synthesis and degradation imbalances ^[50].

In lipid metabolism, desmin’s role is linked to the structural integrity of skin cells. Impaired desmin can compromise lipid metabolism, impacting the synthesis and transport of lipids that are essential for skin health. This disruption can affect lipid synthesis and storage within skin cells, potentially leading to skin-related issues, including impaired skin barrier function ^[51].

5.3. Occludins and Barrier Function

Occludins, as crucial players in forming intercellular tight junctions, are integral to maintaining the skin’s barrier function as a protective barrier against water loss and the intrusion of external agents ^[52]. This function becomes particularly significant in skin aging, making the skin more susceptible to environmental stressors like UV radiation, pollution, and pathogens. These stressors accelerate aging by compromising collagen integrity and inducing oxidative stress. The skin’s resilience against these aggressors heavily relies on the integrity of occludins and the tight junctions that they support. Disrupted tight junctions can increase skin permeability, rendering it more vulnerable to damage ^[53].

In the realm of metabolism, the connection between occludins and sugar, protein, and lipid metabolism is evident. Elevated blood glucose levels can adversely affect occludins’ integrity and tight junctions. High glucose levels can trigger the formation of advanced glycation end products (AGEs), potentially interfering with occludin function ^[54].

Imbalances in protein metabolism can directly affect skin proteins, including occludins. With age, accelerated protein degradation, potentially involving occludins, can disrupt tight junctions and make the skin more vulnerable to external aggressors ^[55]. Maintaining a balance between protein synthesis and degradation is critical to preserve occludin function and the integrity of the skin’s barrier ^[56]. In lipid metabolism, imbalances can alter the skin’s lipid composition, which is crucial for the skin barrier. Changes in the lipid composition can interfere with the function of tight junction proteins like occludins, ultimately affecting the skin barrier’s integrity. Maintaining the health of the lipid layer is essential to ensure that occludins can uphold tight junctions and preserve the skin’s barrier function ^[57].

6. Anti-Aging Strategies Based on Metabolic Regulation

6.1. Inhibiting Skin Glycation

AGEs play an important role in skin glycation damage. Reducing the formation of AGEs can resist skin aging ^[58]. Aminoguanidine (AG) prevents protein modification through advanced Maillard reactions and is a glycosylation inhibitor.

6.2. Increasing Skin Protein Levels

Skin proteins, e.g., collagen and membrane or other cytoskeleton proteins (such as connexins, desmins, and occludins), play important roles in skin structure and aging. However, most tactics are focused on how to increase collagen levels. Below are some tactics on how to increase skin collagen.

6.2.1. Inhibiting Collagen Degradation

Skin aging is intricately linked to collagen degradation, resulting in diminished skin elasticity and the formation of unsightly wrinkles. These processes are often orchestrated by the upregulation of matrix metalloproteinases (MMPs). Consequently, a variety of approaches have been developed to counteract collagen degradation, primarily through the inhibition of MMP activity.

Resveratrol, a natural compound, exhibits the capability to reduce MMP expression and thwart collagen degradation by inhibiting pathways mediated by reactive oxygen species (ROS), such as MAPK and COX-2. This action provides photoprotective effects against skin aging induced by UVB radiation ^[59].

Eighteen β- Glycyrrhetinic acid derivatives can resist skin aging caused by UVB in doses of 10 and 25 μ M, possess good antioxidant activities ^[60], resist apoptosis, prevent collagen degradation, and significantly restore UVB-induced damage ^[61]

AYAPE (Ala-Tyr-Ala-Pro-Glu) is a pentapeptide isolated from Isochrysis zhanjiangensis. The biological activity of AYAPE against skin aging was assessed using UVB-induced HaCat cells. Studies on UVB-induced HaCat cells have found that AYAPE has the potential to inhibit the production of MMP-1, indicating its role in inhibiting collagen degradation in skin cells, a compound that effectively slows skin aging ^[62].

6.2.2. Promoting Collagen Synthesis

Ascorbic acid (AA), an essential nutrient, is known for its remarkable ability to reduce oxidative stress and stimulate collagen expression. AA plays a significant role in mitigating the effects of skin aging by promoting collagen synthesis ^[63].

Chondroitin phosphate (CS) has been identified as an agent that not only boosts the proliferation of keratinocytes and fibroblasts but also triggers the migration and synthesis of extracellular matrix (ECM) components in fibroblasts. Its influence on collagen synthesis is channeled through the activation of the extracellular signal-regulated kinase pathway, leading to the expression of type I procollagen. This counteracts collagen loss and effectively resists skin aging ^[64].

The assessment of extracellular matrix components such as collagen, elastin, and glycosaminoglycan has proven to be instrumental in understanding the dynamics of skin aging. Components like L-fucose and chondroitin sulfate have demonstrated their capacity to protect the skin. They provide essential building blocks for glycosaminoglycans (GAGs), thereby enhancing the production of collagen and elastin in the extracellular matrix.

Human adipose-derived stem cells (ADSCs) are used to treat skin aging by isolating exosomes from ADSC culture medium. ADSC-derived exosomes (ADSC Exos) can alleviate the aging of human dermal fibroblasts (HDF), and ADSC Exos can increase the expression level of type I collagen and reduce reactive oxygen species (ROS) and the positive rate of β- Galactosidase (SA-β-Gal).

Collagen peptides derived from poultry and chicken bones, often containing molecules with a molecular weight below 3000 Da, have shown profound effects on aging skin. These peptides contribute to the reduction in skin oxidation levels, the inhibition of AP-1 expression, and the activation of the TGF-β/Smad signaling pathway, all of which culminate in enhanced collagen synthesis. The experimental results attest to the anti-aging potential of these collagen peptides ^[65].

6.2.3. Simultaneously Inhibiting Collagen Degradation and Promoting Collagen Synthesis

The intricate balance between collagen degradation and synthesis significantly influences the skin’s collagen levels, and certain tactics aim to simultaneously inhibit degradation and promote synthesis. This dual approach offers valuable insights into combating skin aging with a focus on collagen maintenance.

Tendon enzyme C (TNC), a constituent of the extracellular matrix (ECM), holds a pivotal role in various tissues, including the skin. TNC, particularly its TNC-L and TNC-S variants, orchestrates an upregulation of type I collagen expression while concurrently downregulating MMP-1 expression in fibroblasts. Furthermore, TNC induces an increase in TGF-β mRNA levels, which, in turn, activates the TGF-β signaling pathway. This cascade of events culminates in an elevated expression of type I collagen, contributing to ECM integrity and the prevention of skin aging ^[66].

The production of proteins within the ECM stands as a fundamental component in preserving normal skin structure and delaying skin aging. Copper, which is recognized for its role as a catalyst, is known to stimulate the synthesis of ECM proteins.

Collagen and elastin are prominent constituents of skin evaluation, with both playing crucial roles in maintaining skin health. Collagen peptides and elastin peptides have garnered widespread use for their anti-inflammatory effects. Employing a combination of these two compounds can effectively address skin aging induced by factors like D-galactose and ultraviolet radiation. The mechanism underlying this therapeutic effect involves the upregulation of hyaluronic acid and hydroxyproline expression, along with the inhibition of MMPs and IL-1α. This combined approach enhances skin health by supporting the extracellular matrix and mitigating skin aging ^[67].

6.3. Regulating Skin Lipid Metabolism

The regulation of lipid metabolism disorders in the skin is also an important strategy. A study examining the effects of facial and neck skin lipids on women aged 50–69 years showed that retinol can reduce surface lipids and increase skin regeneration ability. This demonstrates that retinol possesses the ability to alleviate the symptoms of skin aging ^[68]. By improving the lipid metabolism, the vitality of subcutaneous adipocytes is boosted, demonstrating that lipid metabolism regulation can impact skin aging ^[69]. Improving the gene transcription of cholesterol and fatty acid synthase is important for the integrity of the skin permeability barrier and can improve skin aging ^[70].

6.4. Regulating Mitochondrial Energy Metabolism in the Skin

The regulation of mitochondrial energy metabolism within the skin emerges as a pivotal strategy in the battle against skin aging. The metabolic shifts related to substances such as glucose, proteins, and lipids, whether there is reduced efficiency or an accelerated metabolism, significantly impact skin aging. The excessive generation of ROS through mitochondrial energy metabolism can lead to oxidative stress, a prominent factor in skin aging. Therefore, interventions promoting mitochondrial health and energy regulation promise to mitigate skin aging effects. Compounds like metformin, nicotinamide, and vitamin D exhibit the potential to enhance mitochondrial function, reducing oxidative stress and delaying skin aging. Proper calorie restriction can also inhibit mitochondrial ROS production, contributing to skin rejuvenation. Understanding the profound connection between mitochondrial energy metabolism and skin aging may generate novel strategies and interventions, offering hope for more effective anti-aging solutions.

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Xin He

Xinyu Gao

Weidong Xie

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