Impact of Vitamin D on Skin Aging, and Age-Related Dermatological Conditions

Abstract

Human skin is a physical and biochemical barrier that protects the internal body from the external environment. Throughout a person’s life, the skin undergoes both intrinsic and extrinsic aging, leading to microscopic and macroscopic changes in its morphology. In addition, the repair processes slow with aging, making the older population more susceptible to skin diseases. Intrinsic factors associated with advanced age gradually degrade the dermal collagen matrix, resulting in fine wrinkles and reduced elasticity; this is accelerated in post-menopausal women due to estrogen deficiency. In contrast, extrinsic factors associated with advanced age, primarily caused by exposure to ultraviolet (UV) radiation, lead to coarse wrinkles, solar elastosis, hyperkeratosis, irregular pigmentation, and skin cancers. UVB radiation, while contributing to skin photo-aging, also induces the cutaneous synthesis of vitamin D. Vitamin D, in turn, protects the skin from oxidative stress, inflammation, and DNA damage, thereby delaying both chronological and photo-aging. Moreover, research has demonstrated an association between lower vitamin D levels and a higher prevalence of certain cutaneous diseases. This review explores and summarizes the critical role of vitamin D in skin aging and age-related skin diseases. The data presented highlight the importance of maintaining vitamin D adequacy throughout life.

Graphical abstract

Keywords

vitamin D / skin aging / age-related skin diseases

1. Introduction

The skin, the largest organ in the human body, acts as a physical barrier that safeguards internal structures from external threats. The skin comprises three layers: the epidermis, dermis, and hypodermis, with each layer exhibiting distinct anatomical features. The outermost layer, the epidermis, protects the skin from external damage and maintains hydration. It primarily consists of keratinocytes originating from the basal layer and moving upward toward the surface (Fig. 1).

As keratinocytes ascend, they become highly keratinized, mature, change shape, and join the stratum corneum, the dead surface layer of the skin [1, 2, 3]. The epidermis also includes melanocytes, Langerhans cells, and Merkel cells. Melanocytes produce melanin, a pigment that gives the skin its color. Antigen-presenting dendritic Langerhans cells act as the skin’s first line of defense, and Merkel cells in the stratum basale function as mechanoreceptors for light touch [4]. The layer directly below the epidermis, the dermis, is comprised of fibroblasts, vasculature, nerve fibers, sensory receptors, and extracellular matrix (ECM). The ECM is composed of two major components: collagen and elastic fibers. Collagen is the major structural component that provides both structure and tensile strength. Elastic fibers maintain tissue elasticity and resilience to restrain stretching [5] and are composed of elastin and microfibrils. The deepest layer, the hypodermis, is located under the dermis and composed of loose connective tissue with larger blood vessels, subcutaneous fat, and areolar connective tissues that provide insulation, thermoregulation, and cushioning to the skin [6].

As the body’s outermost layer, the skin is continuously subjected to external stressors such as solar radiation. Ultraviolet (UV) radiation from the sun can be categorized into three types based on wavelength: UVA (320–400 nm), UVB (280–320 nm), and UVC (100–280 nm) [7, 8, 9, 10]. The impact of UVC is minimal since the ozone layer completely absorbs it. However, the ozone layer only absorbs some UVA and UVB rays. This incomplete absorption allows a portion of UVB and UVA rays to reach the skin and penetrate the epidermis. Prolonged exposure to UVB can cause erythema and DNA damage in both keratinocytes and melanocytes, as well as stimulate proteolytic enzyme production. UVA is 10–100 times more abundant near the Earth’s surface than UVB and penetrates deeper, affecting both epidermal and dermal components (Fig. 2) [10, 11].

UVB radiation converts 7-dehydrocholesterol (7-DHC) into pre-vitamin D, which gets photo-converted to vitamin D₃ in the subcutaneous tissue (see Fig. 2). The cutaneous generation of vitamin D varies based on several factors, such as the amount of skin area exposed, intensity of sunlight, zenith angle of the sun, duration of exposure, skin type & thickness, and the application of sun-blocking chemicals [12]. Due to enhanced UVB absorption by melanin, individuals with dark skin have a lower capacity to generate vitamin D than those with lighter skin [13].

Vitamin D (calciferol) is a secosteroid molecule produced in the skin upon UVB exposure (Fig. 2). Following sufficient UVB exposure, 7-DHC is converted to pre-vitamin D₃ in the epidermal basal and spinous cell layers. This pre-vitamin D₃ gets converted to vitamin D₃ (cholecalciferol) by thermal isomerization. The photosynthesized vitamin D₃ and vitamin D₂ (ergocalciferol) absorbed from the diet are fat-soluble compounds. They bind to the vitamin D binding protein (DBP) and are transported to the liver and other tissues via circulation [14]. In the hepatocytes, vitamin D₂ and D₃ are hydroxylated by the 25-hydroxylase enzyme (transcribed from CYP2R1), generating 25-hydroxycalciferol [25(OH)D], also known as calcifediol or calcidiol [15, 16]. Calcidiol is the predominant vitamin D metabolite in the bloodstream and the most accurate indicator of vitamin D nutritional status.

The DBP-bound vitamin D and 25(OH)D re-enter the circulation and are transported to proximal renal tubular cells in the kidney and peripheral target cells [16]. In the kidney, 25(OH)D undergoes additional hydroxylation by the enzyme 1\alpha-hydroxylase (transcribed from CYP27B1), resulting in the formation of the most active secosteroid, 1,25(OH)₂D (calcitriol). In addition to hepatocytes, peripheral target cells have both CYP2R1 and CYP27B1 genes. Therefore, peripheral cells contain the enzyme 25-hydroxylase, promoting the endogenous synthesis of calcitriol [13, 17, 18, 19]. The intracellular synthesis depends on the sufficient diffusion of vitamin D and 25(OH)D from the bloodstream into target cells [13, 20]. Cell membranes of the target cells can also endocytose DBP-bound D₃ and 25(OH)D. Still, this endocytosis occurs to a lesser extent than the quantities entering via diffusion from circulation [21]. The cholecalciferol (D3) synthesized in the skin indirectly regulates its own catabolic enzyme, 24-hydroxylase (transcribed from CYP24A1), through a negative feedback mechanism [22, 23, 24]. This catabolizes excess vitamin D into the inactive form, 24(OH)D [25], preventing high levels of vitamin D from entering the circulation and causing adverse effects.

Vitamin D Signaling and Target Genes in the Skin

The skin is the only organ capable of producing vitamin D, converting it to biologically active 1,25(OH)₂D, and responding to it in a cell-specific manner [23, 26]. The metabolite 1,25(OH)₂D is the high-affinity ligand of the transcription factor calcitriol receptor (used to known as vitamin D receptor, VDR). VDR regulates the expression of hundreds of target genes by binding to the vitamin D response elements on the chromosome [13, 14, 27, 28]. Under the direct influence of vitamin D, these target genes perform various skeletal and extraskeletal functions. A review by Carlberg C. [29] comprehensively covers the general overview of vitamin D signaling and VDR target genes.

In the skin, keratinocytes are the cells that respond to 1,25(OH)₂D. VDR is most active in keratinocytes during cellular differentiation and proliferation [23], with the highest levels of VDR and CYP27B1 expression found in the stratum basale (basal layer) of the skin [30, 31]. Epidermal stem cells within the stratum basale produce transient amplifying cells, which begin the differentiation process as they ascend into the stratum spinosum. Once in the stratum spinosum, 1,25(OH)₂D promotes the production of involucrin, keratin 1, and transglutaminase, which helps maintain proper barrier function [23].

The cells in the stratum granulosum contain profilaggrin, which is cleaved proteolytically to release filaggrin. In response to 1,25(OH)₂D, cells in the stratum granulosum produce filaggrin and loricrin proteins, which together form the cornified envelope [23, 32]. Proteins play a crucial role in maintaining the integrity and function of the skin barrier [33].

The activation of genes by VDR and 1,25(OH)₂D in the skin depends on the level of cellular differentiation. Coregulators such as the Mediator complex (MED, previously known as DRIP) and Steroid Receptor Coactivator (SRC) complex (SRC2 and SRC3) modulate the transcriptional activity of VDR in a cell-specific manner [34]. In undifferentiated cells, MED directly interacts with VDR to inhibit its activity. In differentiated cell layers within the stratum granulosum, the coactivators SRC2 and SRC3 enhance VDR activity [35]. Calcium also influences the effects of 1,25(OH)₂D and VDR indirectly by acting through the multifunctional protein \beta-catenin and the calcium-sensing receptor (CaSR) [23, 36]. The close proximity of VDR and \beta-catenin response elements in many genes suggests a dual regulation. As an example of this duality, VDR and 1,25(OH)₂D₃ have been shown to repress the oncogenic actions of \beta-catenin, thus protecting against skin cancer [37]. Recent evidence also indicates that VDR regulates the highly conserved Grainyhead-like (GRHL) family genes. These genes code for transcription factors necessary for the maintenance and development of different types of epithelia [28]. Understanding the regulatory pathways and molecular mechanisms by which vitamin D influences the skin remains incomplete, highlighting the need for further research.

2. Skin Aging—Structural, Physiochemical, and Functional Changes

The skin undergoes genetic, molecular, cellular, and organ-specific changes throughout a human’s lifetime [3, 38]. Intrinsic aging refers to the natural chronological changes that affect the entire human body over time. Extrinsic aging is defined as additional body changes exacerbated by environmental factors such as UV exposure and smoking. Fine wrinkles, thinning of the epidermis, reduced subcutaneous fat, and laxity are characteristic features of intrinsic skin aging.

In contrast, extrinsic aging involves additional changes exacerbated by environmental factors such as UV exposure and smoking [3, 8, 39, 40, 41]. As individuals age, intrinsic and extrinsic factors contribute to permanent skin modifications, resulting in thinner, dry, unevenly pigmented, and wrinkled skin with a sagging appearance [42, 43]. Fig. 3 (Ref. [44]) illustrates the characteristic features of young and aged skin.

All layers of human skin undergo structural, physiological, and functional changes with age. The main structural changes in the epidermis include a reduction in thickness and changes in composition. The thinning of the epidermis is more noticeable in exposed regions of the body, with an overall reduction rate of 5–7% per decade. Decreases in dermal collagen and elastin, along with the reduction of subcutaneous fat in the hypodermis, are the major contributors to the overall thinning of the skin [45, 46]. With aging, the number of cells and epidermal turnover rate decrease, causing cells and tissues to undergo characteristic changes (Fig. 3).

Some age-related cellular changes in the epidermis include shorter and fatter keratinocytes, enlarged corneocytes, and reduced melanocytes, leading to uneven pigmentation. The number of Langerhans cells also declines with age, reducing antigen-trapping capability and hence impairing cutaneous immunity [47, 48]. Finally, subcellular changes due to aging also occur. For example, the dermo-epidermal junction, which provides strength, resistance, and nutrition to the skin, flattens with advanced age, increasing the skin’s vulnerability to damage from shear forces. The reduced nutrient and oxygen supply poses a risk for dermo-epidermal separation, contributing to wrinkles [45, 49].

Collagen, elastin, and hyaluronic acid, the main extracellular components of the dermis, all deplete in the aging skin (see Table 1, Ref. [40, 42, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68]). Dermal fibroblasts synthesize collagen, which strengthens and provides elasticity to the skin, and occurs in multiple forms. Type I collagen predominates in the skin’s connective tissue, followed by smaller amounts of type III [69]. Disorganized and fragmented collagen fibrils are a characteristic feature of the aged dermis. Collagen fiber bundles become stiffer and more rigid with age, creating rougher surfaces [50].

Elastic fibers, a highly durable macromolecular component of the ECM, provide elasticity to the skin and other tissues, but become fragmented and thinned with age, leading to reduced tissue elasticity [70, 71]. Oxidative damage, enzymatic degradation, calcification, carbamylation, aspartic acid racemization, formation of advanced glycation end products, and mechanical fatigue intrinsically lead to functional impairment of elastic fibers [71, 72, 73, 74]. Meanwhile UV-induced extrinsic aging fragments functional elastin and collagen, deposits non-functional elastotic material, and causes the accumulation of damaged elastin. All these effects contribute to solar elastosis [72, 75]. Table 1 further illustrates the changes associated with the structure of aged skin.

3. Molecular Mechanisms of Skin Aging

3.1 Oxidative Stress

Oxidative stress contributes to both intrinsic and extrinsic aging processes. The skin is constantly challenged with intrinsically generated reactive oxygen species (ROS) through normal biological processes. ROS are independent molecules with at least one oxygen (radical) atom and one or more unpaired electrons. They include molecules such as hydroxyl radical (\cdotOH), superoxide anion radical (O₂^–), hydrogen peroxide (H₂O₂), peroxynitrite (ONOO^–), nitric oxide (NO), and singlet oxygen (¹O₂), that are highly reactive and capable of forming free radicals [76, 77].

External insults such as UV radiation, volatile and non-volatile chemical pollutants, and smoking cigarettes further increase ROS production beyond the levels generated by intrinsic factors. The skin undergoes oxidative stress when the level of reactive species surpasses the neutralizing capability of its endogenous antioxidant defense systems. The excess ROS can induce DNA mutations, damage proteins, lipids, and carbohydrates, regulate inflammatory cytokines, and trigger cell apoptosis [76, 78, 79]. ROS also affects other biological responses and signaling pathways related to aging. These pathways include mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-\kappaB), phosphoinositide-3-kinase/AKT (PI3K/Akt), and Kelch-like ECH-Associating protein 1-nuclear factor erythroid 2-related factor 2-antioxidant response element (Keap1-Nrf2-ARE) [80, 81, 82].

Skin cells contain multiple antioxidant substances and enzymes, which have protective functions to negate oxidative stresses. Compared to the dermis, antioxidant enzymes such as superoxide dismutases, peroxidases, glutathione reductases, and catalases display elevated activity in the epidermis. Antioxidant substances like alpha-tocopherol (vitamin E), ubiquinol-10, glutathione, uric acid, and ascorbic acid are also significantly higher in the epidermis. Other enzymatic antioxidants such as thioredoxin reductase, methionine sulfoxide reductase, heme oxygenase-1, and peroxiredoxins have also been observed in the epidermis and dermis [83, 84, 85, 86]. Given the enhanced exposure of the superficial layers of the skin to external insults, elevated levels of antioxidants in the epidermis are expected [87].

3.2 DNA Damage

Intrinsic and extrinsic factors that cause DNA damage accelerate skin aging [88]. During chronological aging, skin cells produce more ROS, which oxidatively damage bases and lead to single-strand breaks and basic sites (apurinic/apyrimidinic site) in DNA [89]. Prolonged exposure of skin cells to ROS may influence the shortening of telomeres, further promoting cellular senescence [90]. Age-related reduction in DNA repair in the skin may also lead to the accumulation of damaged DNA in cells [91].

UV radiation predominantly causes the formation of cyclobutane-pyrimidine dimers (CPD) and 6-4 pyrimidine-pyrimidone (6-4PP) photoproducts in DNA [92, 93]. Additionally, UV radiation causes less common photoproducts such as Dewar valence isomers [94], purine photoproducts [93], and single and double-strand breaks in the phosphate backbone of DNA [95]. These DNA damages may disturb essential cellular functions, causing cell cycle arrest, apoptosis, or uncontrolled growth, leading to malignancy [92].

3.3 Protein p53

The tumor suppressor protein p53 functions as a transcriptional regulator modulating the expression of numerous genes that control cell death, senescence, cell cycle arrest, aging, DNA repair, carcinogenesis, and oxidative stress [96, 97]. p53 gets activated upon UVB-induced DNA damage and promotes G1 arrest in the cell cycle, providing time to recover from the DNA damage. Under weak to moderate oxidative stress, p53 protects the cell by stimulating antioxidant genes [98]. Irreversibly damaged cells will be eliminated by p53 through the triggering of apoptosis [99]. With these functions, p53 is critical in preventing skin cancers and recovering from skin photo damage. However, long-term skin exposure to UV radiation can cause mutations in the p53 gene. Mutated p53 has been observed in 50% of skin cancers, emphasizing the impact of these mutations [100, 101].

3.4 Inflammation

Persistent low-level systemic inflammation is a main contributor to the aging process. ‘Inflamm-aging’ describes the age-related activation of a persistent pro-inflammatory state via immune system dysregulation, which results in immuno-senescence [102]. Furthermore, inflammation plays a pivotal role in the degradation of ECM components, including elastin, collagen, and dermal hyaluronic acid, thus promoting the formation of wrinkles. Degraded collagen acts as a potent chemoattractant for immune cells, leading to increased inflammation [103].

UVR-induced DNA and ECM damage triggers cellular stress and activates inflammatory responses in the skin. Cellular senescence from photoaged skin has been detected in keratinocytes, fibroblasts, melanocytes, and subcutaneous preadipocytes. Cells undergoing senescence arrest their proliferation and secrete both anti-and pro-inflammatory mediators [104]. These mediators include interleukins (IL-1, IL-3, IL-6, IL-8, IL-33), platelet-derived growth factor (PDGF), various colony-stimulating factors (GM-CSF, M-CSF, G-CSF), high-mobility group box 1 (HMGB1) protein, and transforming growth factor \alpha and \beta (TGF-\alpha, TGF-\beta) [105, 106]. Finally, UV irradiation enhances the transcription of NF-\kappaB, a pivotal mediator of inflammatory response [105, 107]. Inflammation plays a major role in the intrinsic aging process as well. Inflammatory mediators like IL-1\beta, IL-6, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-\alpha (TNF-\alpha), were found at elevated levels in various human tissues during chronological aging [108, 109].

3.5 Changes in Collagen and Elastin

Fragmented dermal collagen is a characteristic feature of aged skin. The low level of collagen production from aged fibroblasts and the age-related increase in collagen-degrading matrix metalloproteinases (MMPs) are the key contributors to the changes in collagen [50, 69, 110, 111, 112].

The MMPs constitute a group of zinc-dependent endopeptidases secreted by multiple cells, including keratinocytes and fibroblasts, and are responsible for breaking down nearly all components of the ECM. Based on the substrate specificity, the MMPs are divided into collagenases, gelatinases, stromelysins, and membrane-type MMPs [113, 114]. The collagenases (MMPs 1, 8, 13, and 18) degrade interstitial collagen I, II, and III; Gelatinase A (MMP-2) degrades type I and IV gelatin, whereas gelatinase B (MMP-9) degrades type IV collagens [113]. The activity of tissue inhibitor metalloproteinase-1 (TIMP-1), which inhibits many members of the MMPs, declines with advancing age [115], contributing to collagen fragmentation.

Finally, fragmentation of dermal collagen can occur due to internal factors stimulated by external and internal stresses. For example, during UV-induced photo-aging, ROS production and activation of cell surface receptors trigger the activation of MAP-kinase (mitogen-activated protein kinase) p38, JNK (c-Jun amino-terminal kinase), and ERK (extracellular signal-regulated kinase), which in turn recruit transcription factors like c-Fos and c-Jun. This cascade leads to the expression of the transcription factor AP-1 (activator protein-1) and induces the expression of collagen-degrading MMPs 1, 3, and 9 in fibroblasts and keratinocytes [116]. The observation of two elastolytic MMPs, matrilysin (MMP-7) and human macrophage metalloelastase (MMP-12), around elastotic material suggests the possible involvement of MMPs in the remodeling of elastotic areas in photodamaged skin [117].

3.6 Other Mechanisms Associated with Skin Aging

Age-associated changes have been detected in epidermal proteins such as keratin 10, involucrin, pre-albumin, Hsp 27, and Rho B, which are involved in human keratinocytes’ differentiation and proliferation. These proteins are abundant in the epidermis of young individuals, but their expression diminishes with age and often becomes undetectable in older individuals [41]. Other mechanisms, such as epigenetic modifications [118] and the formation of advanced glycation end products [119], also significantly contribute to the skin’s aging process.

4. Vitamin D’s Protective Effect During Skin Aging

Vitamin D has exhibited protective roles, preventing intrinsic and extrinsic skin aging. These include inducing collagen production, regulating oxidative stress and inflammation, reversing the damage caused by UV radiation, increasing epidermal barrier function, and contributing to wound healing [77, 120].

Recent research has investigated the protective role of vitamin D against chronological and photo-aging of the skin. A study conducted by Chaiprasongsuk et al. [121] reported the potential of 1,25(OH)₂D, cytochrome P450 11A1 (CYP11A1)-derived D₃-hydroxyderivatives [20(OH)D₃, 1,20(OH)₂D₃, 20,23(OH)₂D₃, 1,20,23(OH)₃D₃], lumisterol, and its hydroxy-derivatives [20(OH)L₃, 22(OH)L₃, 20,22(OH)₂L₃, and 24(OH)L₃] to protect human epidermal keratinocytes against UVB-induced damage. Supplementation of any of the previously mentioned compounds at a concentration of 100 nM significantly reduced oxidant formation in human epidermal keratinocytes treated with 50 mJ/cm² of UVB radiation [121]. In the treated keratinocytes, p53 phosphorylation at Ser-15 and nuclear localization of p53 were increased. The treatments also increased the expression of Nrf2-regulated antioxidant genes [121].

4.1 Reversal of DNA Damage

VDR plays a critical role in protecting the skin from UV-induced DNA damage. The impaired ability of VDR-null mice to remove 6-4 PP and CPDs and their susceptibility to UV-induced epidermal tumors suggests an association between VDR and DNA repair [38, 122]. In keratinocytes, VDR promotes nucleotide excision repair (NER) by facilitating the timely dissociation of Xeroderma Pigmentosum Complementation Group C (XPC) from the site of damaged DNA. This allows the timely assembly of downstream NER proteins and the pre-incision complex, thereby promoting DNA repair [123]. When keratinocytes are exposed to UV, vitamin D derivatives employ a variety of mechanisms to enhance DNA repair. These mechanisms include reduced reactive oxygen species, increased DNA repair and p53 expression, and higher energy allocation [124].

4.2 Regulation of p53 Signaling

Vitamin D regulates genome-wide p53 signaling, protecting the cells against photo-aging and skin cancers [101]. When treated with 1,25(OH)₂D, UV-irradiated skin cells produce increased levels of nuclear p53 (p 0.01) compared to untreated cells. p53 upregulation facilitates skin pigmentation, thereby protecting against DNA damage and photo-aging. Treatment with 1,25(OH)₂D also reduced the number of sunburn cells (p 0.01), production of nitric oxide (p 0.05), and thymidine dimers (p 0.001) in the treatment group compared to the control [101, 125].

Apart from directly controlling gene expression, vitamin D exerts its regulatory effect by controlling the regulators of p53. One such example is the murine double minute (Mdm2) gene, a negative regulator of p53. Evidence suggests that 1,25(OH)₂D and VDR receptors regulate Mdm2 gene expression in a p53-dependent manner [126]. However, future research investigating the indirect control of vitamin D on p53 regulators is required to solidify the novel regulatory pathways controlled by vitamin D in humans.

4.3 Vitamin D and Antioxidant Enzymes

The enzymes superoxide dismutase (SOD) and catalase are key players in the cutaneous enzymatic antioxidant defense system. Studies show that SODs protect type I and type IV collagen from oxidative damage by interacting through the matrix-binding domain or heparin [127, 128]. The results of a longitudinal study comparing extracellular (EC)-SOD‒overexpressed transgenic and wild-type mice indicate that the expression of cutaneous EC-SOD gradually declines with advancing age. EC-SOD promotes collagen production in aged mice by activating adenosine monophosphate-activated protein kinase and nuclear factor erythroid-2 related factor 2 (Nrf2)/heme oxygenase-1 pathways, thus reducing skin aging [128]. Untari et al. [129] observed decreased SOD activity in vitamin D deficiency, suggesting a correlation between vitamin D levels and SOD activity.

Further, supplementation of vitamin D has increased the expression of the antioxidant defense enzymes SOD and glutathione peroxidase (GPX) in various human organ systems [130, 131]. However, vitamin D’s role in regulating these enzymes’ expression in human keratinocytes remains largely unknown, leaving an avenue for future research.

1,25(OH)₂D-treated keratinocytes displayed a significant reduction (p 0.05) in free radical nitric oxide (\cdotNO) [125]. This reactive nitrogen species is created from the nitric oxide synthase (iNOS) enzyme in the skin, which is induced in a UV radiation-dependent manner. When combined with superoxide, the radical \cdotNO generates a cytotoxic oxidant, peroxynitrite (ONOO^–), causing DNA damage and oxidative stress [132].

4.4 Vitamin D and Matrix Metalloproteinases (MMPs)

MMPs degrade collagen, thus challenging the integrity of the skin. Recent research has provided evidence for the protective role of calcipotriol against MMPs. The dose-dependent suppression of mRNA and proteins in the MMP-9 and MMP-13 families by calcipotriol has been shown in a human squamous cell carcinoma (SCC) cell line [133]. Similar experiments using other cell lines have provided evidence of vitamin D’s protective role against MMPs. Stimulation of human lung fibroblast (HFL-1) cells with interleukin-1\beta (IL-1\beta) promotes MMP-9 production and mRNA expression, while trypsin converts MMP-2 and MMP-9 into active forms. The expression of MMP-9 mRNA and activation of MMP-2 and MMP-9 are significantly reduced by 1,25(OH)₂D (100 nM) and 25(OH)D (100 nM). IL-1\beta suppresses the mRNA expression of TIMP-1 and TIMP-2, but vitamin D, including 25(OH)D and 1,25(OH)₂D, can notably counteract this inhibition caused by IL-1\beta. As a result, there is a reduction in the activity of MMPs. IL-1\beta inhibits the mRNA expression of TIMP-1 and TIMP-2, but vitamin D, 25(OH)D, and 1,25(OH)₂D can significantly reverse the IL-1\beta mediated inhibition of TIMP-1 and TIMP-2 leading to less active MMPs [134].

Li et al. [135] investigated the possible impact of vitamin D on articular cartilage degradation by MMPs using the rat vitamin D deficiency model and rat articular chondrocyte cells. Rat articular cartilage under vitamin D deficiency displayed elevated MMP-9 and MMP-13 expression and treating with 1,25(OH)₂D reversed this effect. Supplementation with TNF-\alpha or phorbol-12-myristate-13-acetate (PMA) further induces the production of MMP-9 and MMP-13 in the articular chondrocytes, and this effect is subsequently reversed by treatment with 1,25(OH)₂D in vitro [135].

5. Vitamin D Against Inflammation

Recent research has investigated the protective role of vitamin D against autoimmune diseases. A randomized controlled trial involving 25,871 patients with autoimmune diseases observed that vitamin D supplementation over five years could reduce the risk of autoimmune diseases by 22% [136].

Calcitriol helps counteract the inflammatory responses caused by UV damage. It reduces the levels of suppressive inflammatory cytokines such as TNF, IL-1, IFN-gamma, and IL-2\alpha, while increasing anti-inflammatory cytokines IL-4 and IL-10 derived from Th2 and Tregs, respectively [137, 138]. Vitamin D also downregulates the differentiation of pro-inflammatory T helper-1 (Th1) and Th17 lymphocytes [139]. In contrast, a reduction in vitamin D₃ is associated with aging and may contribute to the increased inflammation and occurrence of diseases in the aged skin [140]. The impact of vitamin D against intrinsic and extrinsic skin aging and age-associated skin diseases is illustrated in Fig. 4.

6. Age-Associated Skin Diseases

With advancing age, the likelihood of developing skin conditions tends to increase. One study estimated that 50% of otherwise healthy older adults experience cutaneous diseases at some part of their adult life [141]. Cutaneous disorders can be painful, uncomfortable, and disfiguring, causing considerable physical and emotional distress in older people. They can negatively affect the appearance of already-aged skin, harming self-confidence and promoting self-isolation and social withdrawal. Skin diseases can also interfere with daily activities, decreasing the quality of life in aged populations [142]. The progressive immunosenescence contributes to the increased severity of infections associated with aging. The most common immunosenescence-associated diseases in geriatric populations are listed in Table 2 (Ref. [143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165]).

6.1 Vitamin D Protects Against Skin Diseases in the Elderly

The World Health Organization estimates that over 2 billion people worldwide suffer from deficiencies in essential vitamins and minerals [166]. Geriatric patients exhibit a higher prevalence of skin diseases and are generally low in serum vitamin D levels [167]. Recent studies have reported that vitamin D may play a role in protecting the skin against various diseases [168, 169, 170, 171].

6.2 Vitamin D Enhances Innate and Adaptive Immunity

Infections are common in aged skin; vitamin D regulates innate and adaptive immunity, protecting the skin from infections. Calcitriol is essential for adequately functioning immuno-modulating cells, such as T and B lymphocytes, monocytes, macrophages, and dendritic cells [172]. It directly stimulates the production of antimicrobial peptides, such as cathelicidin and \beta-defensin 2, and other proteins to control microbial infections [173]. The effect of vitamin D on immunity has been critically evaluated in the review by Wimalawansa SJ [138].

6.3 Fungal Infections

A continuous layer of microbes inhabits human skin. These microbes reside in the epidermis, dermis, and skin-associated glands and follicles, forming a diverse community known as the ‘normal skin microbiota’. Natural skin microbiome consists predominantly of bacterial species belonging to Actinobacteria, Firmicutes, Proteobacteria, and Bacteroidetes, and fungi belonging to Ascomycota and Basidiomycota [174]. Comparative studies have suggested age-related changes in the diversity and abundance of the skin microbiome and shown that any alterations to the native microbiota influence disease risk [175].

Cutaneous fungal infections are prominent among the aged populations. Factors including keratinocyte retention due to slower cell turnover, poor barrier function, and immunosenescence increase these infections [176]. Dermatophytosis, cutaneous candidiasis, and onychomycosis of the toenails are common fungal diseases affecting older people. Although direct studies investigating the role of vitamin D in combating fungal skin infections are lacking, there is a substantial amount of evidence proving the antifungal potential of vitamin D, as discussed below.

Vitamin D exhibits direct antifungal activity against the invasive fungus Cryptococcus neoformans. This fungus causes acute and chronic infections, including cryptococcal meningitis in humans. The broth microdilution assay indicates that vitamin D₃ inhibits the fungus at a minimum inhibitory concentration (MIC 90) of 0.4 mg/mL. Vitamin D-induced intracellular ROS accumulation, altered cell membrane permeability, and compromised cell wall integrity in C. neoformans are the proposed mechanisms of fungal inhibition. Further, vitamin D reduces fungal cell adhesion and hydrophobicity while inhibiting biofilm formation in different C. neoformans developmental stages. The in vivo studies involving G. mellonella larval infection model demonstrated significantly reduced fungal burden in the vitamin D-treated group with enhanced survival of G. mellonella larvae [177].

Vitamin D₃ also exhibits antifungal activity against several Candida species, including Candida albicans (ATCC 10261), C. krusei (ATCC 6258), C. tropicalis (ATCC 750), C. glabrata (ATCC 90030), C. dubliniensis (CBS 8501), and C. parapsilosis (ATCC 4344) with MIC ranging from 1–128 µg/mL. Further, it showed a significant reduction in Candida biofilm formation of up to 88% at 60 µg/mL with an IC₅₀ value of 7.5 µg/mL [178]. According to a study by Lei et al. [179], vitamin D₃ exhibited anti-Candida activity against standard and clinically isolated Candida species, with 90% growth inhibition achieved at a concentration of 0.4 mg/mL. The initiation, development, and maturation processes of biofilms in Candida albicans were also significantly affected. Reverse transcription-quantitative PCR analysis of vitamin D₃ exposed C. albicans ATCC MYA-2876 cells proved the involvement of vitamin D₃ in carbon metabolism, biogenesis of ribosomes, and biosynthesis of enzymes. A recent in vivo study conducted in IAC mouse models demonstrated that the fungal burden in the liver and kidney was reduced from day 3 to 14 with daily intraperitoneal treatment of high dose vitamin D₃ (24,000 IU) [179].

A randomized, placebo-controlled clinical trial involving 416 pediatric patients between 12 months and five years has also provided evidence for the reduction of Candida infections upon supplementation of 300 IU/Day vitamin D in a yogurt drink. The prevalence of Candidaemia and Candiduria was significantly reduced in the vitamin D-treated group compared to the placebo group [180]. Finally, several studies have reported the role of vitamin D in enhancing host pulmonary resistance to the fungal pathogen Aspergillus fumigatus since vitamin D regulates the autophagy and Treg cells involved in A. fumigatus infection [181, 182, 183, 184].

6.4 Urticaria and Pruritus

Dry skin (xerosis) and pruritus are common dermatological conditions affecting most elderly people. It is speculated that pruritus affects virtually all individuals by the time they reach eighty years of age [185]. Chronic urticaria is another common allergic skin condition that causes itchy wheals lasting six weeks or more [186]. Multiple studies have examined the importance of serum vitamin D levels and the effects of vitamin D supplementation on these diseases [187, 188, 189].

In a retrospective case series, 57 patients with low vitamin D levels [25(OH)D 32 ng/mL] and pruritus, rash, and urticaria/angioedema were treated with 50,000 IU weekly doses of vitamin D for 8 to 12 weeks, followed by daily supplementation [168]. In the vitamin D treatment group, 70% (40/57) of patients achieved complete resolution of symptoms in a mean time of 4.2 weeks. The patient group who responded to vitamin D treatment had significantly lower mean 25(OH)D levels than the non-responsive treated group (mean 25(OH)D of 16.8 ng/mL vs. 20.9 ng/mL, p = 0.02, unpaired t-test). Symptom recurrence was observed in the patients who acquired vitamin D insufficiency in the following months [168].

A randomized case-control study involving 192 patients with chronic urticaria (CU) observed that vitamin D deficiency [25(OH)D 20 ng/mL] or insufficiency (30 ng/mL) was present in 91.3% of CU patients. Vitamin D₃ supplementation combined with antihistamines and systemic corticosteroids for six weeks significantly improved CU patients’ 5-dimension itch and visual activity scores [190]. Li et al.’s meta-analysis [191] concluded that the urticarial population had reduced serum 25(OH)D levels by 9.35 ng/mL compared with healthy individuals. Highly significant improvements in the urticarial severity score were detected in vitamin D-supplemented studies [191]. Pooled results from randomized controlled trials observed a significant reduction in severity by –3.63 using a dosage of about 4000 IU daily for 12 weeks. The results from repeated measure trials observed a reduction of clinical urticarial score by –1.54 with a daily supplementation of 7000–20,000 IU vitamin D for 6–12 weeks [191].

6.5 Atopic Dermatitis

Atopic dermatitis (AD) is an inflammatory, pruritic skin disease commonly occurring among pediatric and elderly (>65 years old) populations. The presentations and associated clinical signs differ depending on the age, duration, and complications of eczema [175]. Dry skin (xerosis) and pruritus are significant clinical symptoms present universally among AD patients.

Recent research has demonstrated a link between low serum vitamin D levels and atopic dermatitis. In a meta-analysis of eleven studies, a mean difference of –14 nmol/L 25(OH)D (95% CI –25 to –2) was observed in the AD patient group compared to healthy controls [192]. Another study showed that 84.3% of Bangladeshi children and young adults living in London with eczema had deficient or insufficient 25(OH)D levels. The research revealed a correlation between 25(OH)D deficiency and worse eczema severity among the study population [193].

Multiple studies have identified vitamin D supplementation as a promising treatment for AD. A meta-analysis of three trials identified that the supplementation of vitamin D significantly lowered scores on the scoring atopic dermatitis (SCORAD) by 11 points (95% CI –13 to –9, p 0.00001). The result surpassed the minimal clinically significant difference of 9 points. The selected studies for this analysis maintained 1500–1600 IU/daily as the mean weighted dose. Better outcomes were achieved in trials lasting at least three months [192]. Several other studies involving pediatric, mixed, and adult populations have observed significant improvements in the clinical outcomes of AD patients with vitamin D supplementation [194, 195, 196, 197, 198, 199, 200, 201]. However, in a randomized, placebo-controlled trial with 101 pediatric patients, weekly vitamin D supplementation did not affect the severity of AD or type 2 immunity biomarkers compared to placebo [202].

6.6 Seborrheic Keratosis (SK)

Seborrheic keratosis is a common slow-growing, noncancerous skin growth, usually appearing in sun-exposed areas of the elderly population [169, 203]. SK is typically removed via surgery and other methods, including liquid nitrogen freezing and laser therapy. Various gene mutation studies and the utilization of topical vitamin D analogs such as Calcitriol evidence an association between vitamin D deficiency and SK [203, 204].

In a clinical study carried out by Mitsuhashi et al. [170], when 116 SK patients were treated with topical vitamin D₃ ointments (tacalcitol 2 µg/g, calcipotriol 50 µg/g or maxa-calcitol 25 µg/g) for 3- to 12-months, 35 (30.2%) patients showed 100% or more than 80% decrease in the tumor volume, while 54 (46.6%) patients achieved a volume reduction between 40–80%. A Serbian study treating 12 patients with facial solitary seborrheic keratosis using 0.005% calcipotriol ointment for 3–8 months resulted in a complete regression of the lesions [169].

Finally, 30 adult SK patients (mean 52.7 \pm 14.04 years) were instructed to apply calcipotriol 50 µg/g twice daily for 12 weeks, after which more than 80% reduction in the diameter of the tumor was observed in 76.7% of lesions [205]. However, Herron et al. [206] failed to observe significant clinical improvements in SK when using 0.005% calcipotriene for four months. Given these mixed findings, additional clinical studies are needed to determine the potential benefits of vitamin D for SK.

6.7 Rosacea

Rosacea is an age-related chronic inflammatory skin condition mainly affecting facial skin, characterized by transient or persistent redness (erythema), telangiectasia, swelling, and lesions, including papules and pustules [207, 208]. Several studies reported an association between low vitamin D levels and the occurrence of rosacea. A study conducted by Park et al. [209] observed significantly reduced average serum 25(OH)D levels in rosacea patients than healthy controls (12.18 \pm 5.65 vs. 17.41 \pm 6.75 ng/mL, p = 0.001). A cross-sectional population-based cohort study utilizing UK-based 370,209 individuals supported an inverse correlation between the risk of rosacea and serum 25(OH)D level. The findings of this study reported a 23% reduction in the risk of rosacea with each increment in standard deviation in the serum 25(OH)D levels [210]. Contrary to these findings Akdogan et al. [211] observed higher vitamin D levels in the rosacea patients compared to healthy controls (12.9 \pm 6.8 ng/mL vs. 10.5 \pm 3.7 ng/mL, p 0.001). Supporting the Akdogan et al. [211], a study conducted by Ekiz et al. [207] involving 44 rosacea patients also witnessed higher serum vitamin D levels in rosacea patients (21.4 \pm 9.9 vs. 17.1 \pm 7.9 ng/mL). No recent attempts have been reported on supplementation of vitamin D as a treatment for rosacea. Further studies with well-controlled randomized controlled trials (RCTs) are necessary to evaluate the impact of vitamin D on rosacea [212].

6.8 Vitiligo

Vitiligo is an autoimmune condition characterized by skin-depigmented white patches due to epidermal melanocyte damage [213, 214]. Although the onset of vitiligo is most common in childhood or young adults, late-onset has also been reported in adults [215]. Cytokines play a crucial role in the development and progression of this disease. Reduced vitamin D levels may significantly contribute to the development of vitiligo by influencing Th1- and Th17-related immune responses [216]. Many studies with controversial results have investigated the association between vitamin D deficiency and vitiligo [217, 218, 219, 220, 221]. In a population-based study, no significant difference was observed when serum vitamin D levels were compared in patients with vitiligo and healthy controls [217]. Similarly, a significant difference was not detected between the patients and controls in studies conducted in Jordan [218] and Turkey [219]. Contrary to that, a case-control study identified significantly lower vitamin D levels in 100 Indian vitiligo patients (16.170 \pm 8.629 ng/mL) compared to healthy controls (25.49 \pm 1.02 ng/mL) (p = 0.0001) [220]. A meta-analysis conducted by Varikasuvu et al. [221] included 31 studies and further observed a decreased circulatory vitamin D level (standardized mean difference = –1.03; p 0.0001) in vitiligo patients. A study involving Caucasian adult patients with vitiligo reported vitamin D deficiency (\le20 ng/mL) (p = 0.036) or insufficiency (21–29 ng/mL) (p = 0.041) associated with active vitiligo, whereas the stability of the disease and re-pigmentation were associated with vitamin D sufficiency (30–100 ng/mL) (p = 0.043) [222].

The efficacy of vitamin D supplementation as an option for enhancing the success of laser-based treatments has been investigated in treating vitiligo. Intramuscular cholecalciferol injection could enhance the therapeutic effects of the excimer laser in vitiligo patients with low vitamin D levels (20 ng/mL) [223]. In a meta-analysis, Liu et al. [224] concluded that supplementation of either tacalcitol or calcipotriol could enhance the efficacy of the narrowband ultraviolet B treatment compared to phototherapy alone.

6.9 Skin Cancers

Recent studies using in vitro cell lines, tissues, and animal systems have proven the protective role of vitamin D against various malignancies [225, 226, 227]. A daily intake of 1500 international units of vitamin D has been found to lower cancer mortality rates among men in the US by 30% [228]. However, conflicting results exist on the role of vitamin D against skin cancer. Patients who have acquired higher vitamin D levels through extended sun exposure are at an inevitably greater risk of developing skin cancer. This should be considered when evaluating the association between vitamin D and skin cancers.

6.10 Melanoma Skin Cancer

The term ‘melanoma’ refers to aggressive malignant tumors originating from melanocytes. Upon exposure to UV radiation, genetic alterations activate oncogenes, deactivate tumor suppressor genes, and obstruct DNA repair. Consequently, unchecked growth of melanocytes occurs, causing melanoma [229].

The association between melanoma skin cancer and serum vitamin D levels is controversial. Many studies have identified an association between lower plasma vitamin D levels and (1) the development of melanoma, (2) an increase in the severity of the malignancy, and (3) a reduced survival rate in metastatic melanoma patients [230, 231, 232, 233, 234, 235].

In a retrospective study, higher 25(OH)D levels were associated with lower Breslow thickness of the melanoma at the diagnosis (p = 0.002) and better survival [236]. The highest survival was observed in the intermediate BMI group (24.9 to 29.9), which had the highest vitamin D levels (55 nmol/L). Previous research has observed the loss of vitamin D receptor expression in the cytoplasm and the nucleus of cutaneous melanoma (CM) cells. Vitamin D receptor expression negatively correlates with tumor progression; metastatic melanomas show the lowest cytoplasmic receptor staining out of all types of melanoma. The lack of VDR expression correlated to shorter survival of the patients [237, 238]. However, conflicting evidence also exists [239, 240]. A recent meta-analysis reported that each 12 ng/mL increment in 25(OH)D level was linked to a 42%, 30%, and 41% increase in cutaneous melanoma, keratinocyte cancer, and basal cell carcinoma, respectively [240]. Further evaluation is necessary to confirm whether increased safe sun exposure would reduce these risks.

6.11 Non-Melanoma Skin Cancer (NMSC)

Among skin cancers, non-melanoma skin cancers are the most common type of skin malignancy, particularly in fair-skinned populations of European descent. Most NMSCs are keratinocyte skin cancers, including basal cell carcinoma and squamous cell carcinoma [241]. Previous investigations into the role of vitamin D on NMSC have provided mixed results.

6.12 Basal-Cell Carcinoma (BCC)

Basal cell carcinoma is the most common type of skin malignancy worldwide [242]. UVB radiation has been identified as the most critical risk factor for BCC, especially for Fitzpatrick I, II, and other light skin types [243]. Based on a study conducted in South Africa of BCC and SCC patients, 49.5% had deficient (20 ng/mL), and 41.3% had insufficient vitamin D levels. Moreover, in this study, female gender was identified as a risk factor for vitamin D deficiency (p = 0.047) along with the winter season (p 0.001) [244].

In a comprehensive three-staged study involving 496 patients (mean age: 69 years), Ince et al. [171] observed that a serum vitamin D₃ level above 25 ng/mL could significantly reduce the recurrence rates of BCC. In a study conducted with a cohort of Latvian patients with different primary and recurrent BCC of the head and neck, 94.9% of patients were deficient in vitamin D. Furthermore, an inverse association was observed between serum vitamin D levels and tumor size [245]. When testing in the murine ASZ001 BCC line, potent antitumorigenic activity was detected when 1,25(OH)₂D, 1,20(OH)₂D₃, 1,20,23(OH)₃D₃, 1,20,24(OH)₃D₃, 1,20,25(OH)₃D₃ and 1,20,26(OH)₃D₃ hydroxy derivatives of vitamin D were supplemented. The classical and CYP11A1-derived D₃ hydroxy derivatives, including 1,25(OH)₂D₃, 1,20(OH)₂D_3, and 20(OH)D_3, inhibited the expression of glioma-associated oncogene 1 (GLI1) and \beta-catenin in ASZ001 cells, providing a mechanism for this anticancer potential [246].

However, controversial studies report increased BCC risk at high serum vitamin D₃ levels. Liang et al. [247] reported that the women with >31.4 ng/mL 25(OH)D exhibited more than a 2-fold increased risk of BCC when compared to women with >20.4 ng/mL 25(OH)D (p 0.0001). A linear dose-response meta-analysis by Mahamat-Saleh et al. [240] showed that every 30 nmol/L increment of 25(OH)D was linked with a 41% increase in BCC. A recent review by Abdelwahab et al. [248] suggested keeping the vitamin D₃ level between 15–30 ng/mL for a safer balance. In a study that evaluated the effect of body mass index and 25-hydroxy-vitamin D level on BCC using Mendelian randomization, the authors concluded that vitamin D levels may not be casually associated with the risk of BCC [249].

6.13 Squamous-Cell Carcinoma (SCC)

In a systematic review and meta-analysis of BCC and cutaneous squamous-cell carcinomas (cSCC), Caini et al. [241] suggested a lack of a strong association between the serum vitamin D level and the NMSC risk. Moreover, a statistically significant association between 25(OH)D concentrations and cSCC was not detected among 1192 kidney transplant patients. Another study by de Gruijl et al. [250] observed a clear trend of higher 25(OH)D concentrations with the development of cSCC, possibly linked with the higher level of UV exposure promoting carcinogenesis. However, the intermittent supplementation of cholecalciferol has been proven helpful in enhancing photodynamic therapy-based treatments for SCC [251]. Therefore, further research is needed to uncover the potential of vitamin D supplementation as a monotherapy and/or in combination with other treatments for SCC.

7. Conclusions

The world population is aging, and there is a growing interest in understanding the physiological changes associated with advanced age. The skin undergoes intrinsic age-associated natural changes, such as telomere shortening, reduced DNA repair, oxidative damage to biomolecules, hormonal changes, immunosenescence, inflammation, and damage to ECM components. Extrinsic or environmental factors, such as UV radiation exposure can also cause DNA damage, oxidative stress, inflammation, ECM degradation, pigmentation changes, hyperkeratosis, and altered cell signaling, leading to “photo-aging”. Both intrinsic and extrinsic aging contribute together to the aged appearance of the skin. The physiological, biochemical, and functional changes that occur with aging also contribute to the high prevalence of skin diseases in older people. Both skin aging and cutaneous diseases can impose a physical and psychological burden on geriatric populations, reducing their quality of life.

Despite causing photo-aging, UVB radiation also induces the cutaneous synthesis of vitamin D. Numerous beneficial effects of vitamin D on human health have been reported over the past 15 years [12, 13]. However, the exact impact of this vitamin on skin aging remains poorly understood. Previous research has evidenced the potential of vitamin D derivatives to protect the skin by acting against various aging mechanisms, including oxidative stress, inflammation, activation of MMPs, and degradation of collagen and elastin. Furthermore, Vitamin D deficiency is a risk factor for various dermatological conditions. Studies suggest maintaining adequate levels of vitamin D to protect against the most common age-associated skin diseases. Maintaining the recommended vitamin D concentrations (above 40 ng/mL) via safe sun exposure or supplementation [17, 20] should be considered an effective and affordable strategy for maintaining overall skin health.

References

[1] Lin Y, Cao Z, Lyu T, Kong T, Zhang Q, Wu K, et al. Single-cell RNA-seq of UVB-radiated skin reveals landscape of photoaging-related inflammation and protection by vitamin D. Gene. 2022; 831: 146563.

[2] Lee JH, Park J, Shin DW. The Molecular Mechanism of Polyphenols with Anti-Aging Activity in Aged Human Dermal Fibroblasts. Molecules. 2022; 27: 4351.

[3] Zhang J, Yu H, Man MQ, Hu L. Aging in the dermis: Fibroblast senescence and its significance. Aging Cell. 2024; 23: e14054.

[4] Abdo JM, Sopko NA, Milner SM. The applied anatomy of human skin: A model for regeneration. Wound Medicine. 2020; 28: 100179.

[5] Pfisterer K, Shaw LE, Symmank D, Weninger W. The Extracellular Matrix in Skin Inflammation and Infection. Frontiers in Cell and Developmental Biology. 2021; 9: 682414.

[6] Wong R, Geyer S, Weninger W, Guimberteau JC, Wong JK. The dynamic anatomy and patterning of skin. Experimental Dermatology. 2016; 25: 92–98.

[7] D’Orazio J, Jarrett S, Amaro-Ortiz A, Scott T. UV radiation and the skin. International Journal of Molecular Sciences. 2013; 14: 12222–12248.

[8] Guan LL, Lim HW, Mohammad TF. Sunscreens and Photoaging: A Review of Current Literature. American Journal of Clinical Dermatology. 2021; 22: 819–828.

[9] Bocheva G, Slominski RM, Slominski AT. The Impact of Vitamin D on Skin Aging. International Journal of Molecular Sciences. 2021; 22: 9097.

[10] Tang X, Yang T, Yu D, Xiong H, Zhang S. Current insights and future perspectives of ultraviolet radiation (UV) exposure: Friends and foes to the skin and beyond the skin. Environment International. 2024; 185: 108535.

[11] Gromkowska-Kępka KJ, Puścion-Jakubik A, Markiewicz-Żukowska R, Socha K. The impact of ultraviolet radiation on skin photoaging - review of in vitro studies. Journal of Cosmetic Dermatology. 2021; 20: 3427–3431.

[12] Wimalawansa SJ. Non-musculoskeletal benefits of vitamin D. The Journal of Steroid Biochemistry and Molecular Biology. 2018; 175: 60–81.

[13] Wimalawansa SJ. Controlling Chronic Diseases and Acute Infections with Vitamin D Sufficiency. Nutrients. 2023; 15: 3623.

[14] Dominguez LJ, Farruggia M, Veronese N, Barbagallo M. Vitamin D Sources, Metabolism, and Deficiency: Available Compounds and Guidelines for Its Treatment. Metabolites. 2021; 11: 255.

[15] Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW. Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proceedings of the National Academy of Sciences of the United States of America. 2004; 101: 7711–7715.

[16] Pike JW, Meyer MB. The unsettled science of nonrenal calcitriol production and its clinical relevance. The Journal of Clinical Investigation. 2020; 130: 4519–4521.

[17] Wimalawansa SJ. Physiological Basis for Using Vitamin D to Improve Health. Biomedicines. 2023; 11: 1542.

[18] Dong AN, Tan BH, Pan Y, Ong CE. The CYP2R1 Enzyme: Structure, Function, Enzymatic Properties and Genetic Polymorphism. Journal of Pharmacy & Pharmaceutical Sciences. 2021; 24: 94–112.

[19] Lehmann B, Meurer M. Extrarenal sites of calcitriol synthesis: the particular role of the skin. Recent Results in Cancer Research. Fortschritte Der Krebsforschung. Progres Dans Les Recherches Sur Le Cancer. 2003; 164: 135–145.

[20] Wimalawansa SJ. Rapidly Increasing Serum 25(OH)D Boosts the Immune System, against Infections-Sepsis and COVID-19. Nutrients. 2022; 14: 2997.

[21] Cave EM, Bhola S, Crowther NJ, Padoa CJ. The association of vitamin D binding protein levels and genotypes with type 1 diabetes in the black South African population. BMC Endocrine Disorders. 2022; 22: 182.

[22] Vieth R. Vitamin D supplementation: cholecalciferol, calcifediol, and calcitriol. European Journal of Clinical Nutrition. 2020; 74: 1493–1497.

[23] Bikle D, Christakos S. New aspects of vitamin D metabolism and action - addressing the skin as source and target. Nature Reviews. Endocrinology. 2020; 16: 234–252.

[24] Olmos-Ortiz A, Avila E, Durand-Carbajal M, Díaz L. Regulation of calcitriol biosynthesis and activity: focus on gestational vitamin D deficiency and adverse pregnancy outcomes. Nutrients. 2015; 7: 443–480.

[25] Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. The American Journal of Clinical Nutrition. 1999; 69: 842–856.

[26] Mostafa WZ, Hegazy RA. Vitamin D and the skin: Focus on a complex relationship: A review. Journal of Advanced Research. 2015; 6: 793–804.

[27] Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G. Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects. Physiological Reviews. 2016; 96: 365–408.

[28] Taracha-Wisniewska A, Parks EGC, Miller M, Lipinska-Zubrycka L, Dworkin S, Wilanowski T. Vitamin D Receptor Regulates the Expression of the Grainyhead-Like 1 Gene. International Journal of Molecular Sciences. 2024; 25: 7913.

[29] Carlberg C. Vitamin D and Its Target Genes. Nutrients. 2022; 14: 1354.

[30] Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, Stewart PM, et al. Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. The Journal of Clinical Endocrinology and Metabolism. 2001; 86: 888–894.

[31] Bikle DD, Patzek S, Wang Y. Physiologic and pathophysiologic roles of extra renal CYP27b1: Case report and review. Bone Reports. 2018; 8: 255–267.

[32] Bikle DD. Vitamin D and the skin: Physiology and pathophysiology. Reviews in Endocrine & Metabolic Disorders. 2012; 13: 3–19.

[33] Seo G, Hyun H, Jeong M, Park Y, Cho J, Win TTM, et al. Lagerstroemia macrocarpa extract inhibits Th2-mediated STAT6 signaling pathway in human keratinocytes. Fitoterapia. 2024; 174: 105859.

[34] Oda Y, Sihlbom C, Chalkley RJ, Huang L, Rachez C, Chang CPB, et al. Two distinct coactivators, DRIP/mediator and SRC/p160, are differentially involved in vitamin D receptor transactivation during keratinocyte differentiation. Molecular Endocrinology. 2003; 17: 2329–2339.

[35] Oda Y, Uchida Y, Moradian S, Crumrine D, Elias PM, Bikle DD. Vitamin D receptor and coactivators SRC2 and 3 regulate epidermis-specific sphingolipid production and permeability barrier formation. The Journal of Investigative Dermatology. 2009; 129: 1367–1378.

[36] Bikle DD, Oda Y, Xie Z. Calcium and 1,25(OH)2D: interacting drivers of epidermal differentiation. The Journal of Steroid Biochemistry and Molecular Biology. 2004; 89–90: 355–360.

[37] Hu L, Bikle DD, Oda Y. Reciprocal role of vitamin D receptor on β-catenin regulated keratinocyte proliferation and differentiation. The Journal of Steroid Biochemistry and Molecular Biology. 2014; 144: 237–241.

[38] Wong QYA, Chew FT. Defining skin aging and its risk factors: a systematic review and meta-analysis. Scientific Reports. 2021; 11: 22075.

[39] Lee S, Ye S, Kim M, Lee H, Jun SH, Kang NG. Fine Wrinkle Improvement through Bioactive Materials That Modulate EDAR and BNC2 Gene Expression. Biomolecules. 2024; 14: 279.

[40] Gunin AG, Petrov VV, Golubtzova NN, Vasilieva OV, Kornilova NK. Age-related changes in angiogenesis in human dermis. Experimental Gerontology. 2014; 55: 143–151.

[41] Assaf H, Adly MA, Hussein MR. Aging and Intrinsic Aging: Pathogenesis and Manifestations. In Farage MA, Miller KW, Maibach HI (eds.) Textbook of Aging Skin (pp. 783–794). Springer Berlin Heidelberg: Berlin, Heidelberg. 2017.

[42] Marcos-Garcés V, Molina Aguilar P, Bea Serrano C, García Bustos V, Benavent Seguí J, Ferrández Izquierdo A, et al. Age-related dermal collagen changes during development, maturation and ageing - a morphometric and comparative study. Journal of Anatomy. 2014; 225: 98–108.

[43] Lain ET, Agrawal N, Ruvolo E, Weise JM, Callender VD. The Role of Coenzyme Q10 in Skin Aging and Opportunities for Topical Intervention: A Review. The Journal of Clinical and Aesthetic Dermatology. 2024; 17: 50–55.

[44] Knoedler S, Hoch CC, Huelsboemer L, Knoedler L, Stögner VA, Pomahac B, et al. Postoperative free flap monitoring in reconstructive surgery-man or machine? Frontiers in Surgery. 2023; 10: 1130566.

[45] Farage MA, Miller KW, Maibach HI. Degenerative Changes in Aging Skin. In Miranda A. Farage KWM, Maibach HI (eds.) Textbook of Aging Skin (pp. 15–30). Springer-Verlag: Berlin Heidelberg. 2017.

[46] Quan T. Molecular insights of human skin epidermal and dermal aging. Journal of Dermatological Science. 2023; 112: 48–53.

[47] Fenske NA, Lober CW. Structural and functional changes of normal aging skin. Journal of the American Academy of Dermatology. 1986; 15: 571–585.

[48] Farage MA, Miller KW, Elsner P, Maibach HI. Characteristics of the Aging Skin. Advances in Wound Care. 2013; 2: 5–10.

[49] Zargaran D, Zoller F, Zargaran A, Weyrich T, Mosahebi A. Facial skin ageing: Key concepts and overview of processes. International Journal of Cosmetic Science. 2022; 44: 414–420.

[50] He T, Fisher GJ, Kim AJ, Quan T. Age-related changes in dermal collagen physical properties in human skin. PLoS ONE. 2023; 18: e0292791.

[51] Liu Z, Song S, Luo W, Elias PM, Man MQ. Sun-induced changes of stratum corneum hydration vary with age and gender in a normal Chinese population. Skin Research and Technology. 2012; 18: 22–28.

[52] Sato N, Kitahara T, Fujimura T. Age-related changes of stratum corneum functions of skin on the trunk and the limbs. Skin Pharmacology and Physiology. 2014; 27: 181.

[53] Norman RA. Xerosis and pruritus in the elderly: recognition and management. Dermatologic Therapy. 2003; 16: 254–259.

[54] Fluhr JW, Moore DJ, Lane ME, Lachmann N, Rawlings AV. Epidermal barrier function in dry, flaky and sensitive skin: A narrative review. Journal of the European Academy of Dermatology and Venereology. 2024; 38: 812–820.

[55] Seyfarth F, Schliemann S, Antonov D, Elsner P. Dry skin, barrier function, and irritant contact dermatitis in the elderly. Clinics in Dermatology. 2011; 29: 31–36.

[56] Bonifant H, Holloway S. A review of the effects of ageing on skin integrity and wound healing. British Journal of Community Nursing. 2019; 24: S28–S33

[57] Kurban RS, Bhawan J. Histologic changes in skin associated with aging. The Journal of Dermatologic Surgery and Oncology. 1990; 16: 908–914.

[58] Wulf HC, Sandby-Møller J, Kobayasi T, Gniadecki R. Skin aging and natural photoprotection. Micron. 2004; 35: 185–191.

[59] García-Piqueras J, García-Mesa Y, Cárcaba L, Feito J, Torres-Parejo I, Martín-Biedma B, et al. Ageing of the somatosensory system at the periphery: age-related changes in cutaneous mechanoreceptors. Journal of Anatomy. 2019; 234: 839–852.

[60] Zlotogorski A. Distribution of skin surface pH on the forehead and cheek of adults. Archives of Dermatological Research. 1987; 279: 398–401.

[61] Man MQ, Xin SJ, Song SP, Cho SY, Zhang XJ, Tu CX, et al. Variation of skin surface pH, sebum content and stratum corneum hydration with age and gender in a large Chinese population. Skin Pharmacology and Physiology. 2009; 22: 190–199.

[62] Varani J, Dame MK, Rittie L, Fligiel SEG, Kang S, Fisher GJ, et al. Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation. The American Journal of Pathology. 2006; 168: 1861–1868.

[63] Li Y, Lei D, Swindell WR, Xia W, Weng S, Fu J, et al. Age-Associated Increase in Skin Fibroblast-Derived Prostaglandin E2 Contributes to Reduced Collagen Levels in Elderly Human Skin. The Journal of Investigative Dermatology. 2015; 135: 2181–2188.

[64] Pittayapruek P, Meephansan J, Prapapan O, Komine M, Ohtsuki M. Role of Matrix Metalloproteinases in Photoaging and Photocarcinogenesis. International Journal of Molecular Sciences. 2016; 17: 868.

[65] Green EM, Mansfield JC, Bell JS, Winlove CP. The structure and micromechanics of elastic tissue. Interface Focus. 2014; 4: 20130058.

[66] Shek N, Choy AM, Lang CC, Miller BE, Tal-Singer R, Bolton CE, et al. Accelerated elastin degradation by age-disease interaction: a common feature in age-related diseases. Npj Aging. 2024; 10: 15.

[67] Heinz A. Elastases and elastokines: elastin degradation and its significance in health and disease. Critical Reviews in Biochemistry and Molecular Biology. 2020; 55: 252–273.

[68] Watanabe M, Sawai T, Nagura H, Suyama K. Age-related alteration of cross-linking amino acids of elastin in human aorta. The Tohoku Journal of Experimental Medicine. 1996; 180: 115–130.

[69] Dobberstein RC, Tung SM, Ritz-Timme S. Aspartic acid racemisation in purified elastin from arteries as basis for age estimation. International Journal of Legal Medicine. 2010; 124: 269–275.

[70] Uitto J, Bernstein EF. Molecular mechanisms of cutaneous aging: connective tissue alterations in the dermis. The Journal of Investigative Dermatology. Symposium Proceedings. 1998; 3: 41–44.

[71] Mora Huertas AC, Schmelzer CEH, Hoehenwarter W, Heyroth F, Heinz A. Molecular-level insights into aging processes of skin elastin. Biochimie. 2016; 128–129: 163–173.

[72] Schmidt MD, Notley SR, Meade RD, Akerman AP, Rutherford MM, Kenny GP. Revisiting regional variation in the age-related reduction in sweat rate during passive heat stress. Physiological Reports. 2022; 10: e15250.

[73] Hou X, Wei Z, Zouboulis CC, Ju Q. Aging in the sebaceous gland. Frontiers in Cell and Developmental Biology. 2022; 10: 909694.

[74] Seiberg M. Age-Induced Hair Graying and Oxidative Stress. In Farage MA, Miller KW, Maibach HI (eds.) Textbook of Aging Skin (pp. 319–330). Springer Berlin Heidelberg: Berlin, Heidelberg. 2017.

[75] Park S. Biochemical, structural and physical changes in aging human skin, and their relationship. Biogerontology. 2022; 23: 275–288.

[76] Jakubczyk K, Dec K, Kałduńska J, Kawczuga D, Kochman J, Janda K. Reactive oxygen species - sources, functions, oxidative damage. Polski Merkuriusz Lekarski: Organ Polskiego Towarzystwa Lekarskiego. 2020; 48: 124–127.

[77] Ambagaspitiya SS, Appuhamillage GA, Dassanayake RS. Impact of vitamin D on ultraviolet-induced photoaging and skin diseases. Exploration of Medicine. 2024; 5: 363–383.

[78] Nakai K, Tsuruta D. What Are Reactive Oxygen Species, Free Radicals, and Oxidative Stress in Skin Diseases? International Journal of Molecular Sciences. 2021; 22: 10799.

[79] Rinnerthaler M, Bischof J, Streubel MK, Trost A, Richter K. Oxidative stress in aging human skin. Biomolecules. 2015; 5: 545–589.

[80] Zhang J, Wang X, Vikash V, Ye Q, Wu D, Liu Y, et al. ROS and ROS-Mediated Cellular Signaling. Oxidative Medicine and Cellular Longevity. 2016; 2016: 4350965.

[81] Koundouros N, Poulogiannis G. Phosphoinositide 3-Kinase/Akt Signaling and Redox Metabolism in Cancer. Frontiers in Oncology. 2018; 8: 160.

[82] Lu MC, Ji JA, Jiang ZY, You QD. The Keap1-Nrf2-ARE Pathway As a Potential Preventive and Therapeutic Target: An Update. Medicinal Research Reviews. 2016; 36: 924–963.

[83] Schallreuter KU, Wood JM. Thioredoxin reductase - its role in epidermal redox status. Journal of Photochemistry and Photobiology. B, Biology. 2001; 64: 179–184.

[84] Pelle E, Maes D, Huang X, Frenkel K, Pernodet N, Yarosh DB, et al. Protection against UVB-induced oxidative stress in human skin cells and skin models by methionine sulfoxide reductase A. Journal of Cosmetic Science. 2012; 63: 359–364.

[85] Lee SH, Lee NY, Choi SH, Oh CH, Won GW, Bhatta MP, et al. Molecular mechanism of the anti-inflammatory and skin protective effects of Syzygium formosum in human skin keratinocytes. Food Science and Biotechnology. 2023; 33: 689–697.

[86] Kim SR, Park JW, Lee BH, Lim KM, Chang TS. Peroxiredoxin V Protects against UVB-Induced Damage of Keratinocytes. Antioxidants. 2023; 12: 1435.

[87] Shindo Y, Witt E, Han D, Epstein W, Packer L. Enzymic and non-enzymic antioxidants in epidermis and dermis of human skin. The Journal of Investigative Dermatology. 1994; 102: 122–124.

[88] Hadshiew IM, Eller MS, Gilchrest BA. Skin aging and photoaging: the role of DNA damage and repair. American Journal of Contact Dermatitis. 2000; 11: 19–25.

[89] Tiwari V, Wilson DM, 3rd. DNA Damage and Associated DNA Repair Defects in Disease and Premature Aging. American Journal of Human Genetics. 2019; 105: 237–257.

[90] Buckingham EM, Klingelhutz AJ. The role of telomeres in the ageing of human skin. Experimental Dermatology. 2011; 20: 297–302.

[91] Favrot C, Beal D, Blouin E, Leccia MT, Roussel AM, Rachidi W. Age-Dependent Protective Effect of Selenium against UVA Irradiation in Primary Human Keratinocytes and the Associated DNA Repair Signature. Oxidative Medicine and Cellular Longevity. 2018; 2018: 5895439.

[92] Kciuk M, Marciniak B, Mojzych M, Kontek R. Focus on UV-Induced DNA Damage and Repair-Disease Relevance and Protective Strategies. International Journal of Molecular Sciences. 2020; 21: 7264.

[93] Laughery MF, Wilson HE, Sewell A, Stevison S, Wyrick JJ. The Surprising Diversity of UV-Induced Mutations. Advanced Genetics. 2024; 5: 2300205.

[94] Douki T, Sage E. Dewar valence isomers, the third type of environmentally relevant DNA photoproducts induced by solar radiation. Photochemical & Photobiological Sciences. 2016; 15: 24–30.

[95] Rastogi RP, Richa, Kumar A, Tyagi MB, Sinha RP. Molecular mechanisms of ultraviolet radiation-induced DNA damage and repair. Journal of Nucleic Acids. 2010; 2010: 592980.

[96] Budanov AV. The role of tumor suppressor p53 in the antioxidant defense and metabolism. Sub-Cellular Biochemistry. 2014; 85: 337–358.

[97] Rufini A, Tucci P, Celardo I, Melino G. Senescence and aging: the critical roles of p53. Oncogene. 2013; 32: 5129–5143.

[98] Jagoda SV, Dixon KM. Protective effects of 1,25 dihydroxyvitamin D₃ and its analogs on ultraviolet radiation-induced oxidative stress: a review. Redox Report: Communications in Free Radical Research. 2020; 25: 11–16.

[99] Lee CH, Wu SB, Hong CH, Yu HS, Wei YH. Molecular Mechanisms of UV-Induced Apoptosis and Its Effects on Skin Residential Cells: The Implication in UV-Based Phototherapy. International Journal of Molecular Sciences. 2013; 14: 6414–6435.

[100] Tang Z, Tong X, Huang J, Liu L, Wang D, Yang S. Research progress of keratinocyte-programmed cell death in UV-induced Skin photodamage. Photodermatology, Photoimmunology & Photomedicine. 2021; 37: 442–448.

[101] Reichrath J, Reichrath S, Vogt T, Römer K. Crosstalk Between Vitamin D and p53 Signaling in Cancer: An Update. Advances in Experimental Medicine and Biology. 2020; 1268: 307–318.

[102] Polefka TG, Meyer TA. Cutaneous Oxidative Stress and Aging. In Farage MA, Miller KW, Maibach HI (eds.) Textbook of Aging Skin (pp. 651–676). Springer Berlin Heidelberg: Berlin, Heidelberg. 2017.

[103] Schwarz D, Lipoldová M, Reinecke H, Sohrabi Y. Targeting inflammation with collagen. Clinical and Translational Medicine. 2022; 12: e831.

[104] Salminen A, Kaarniranta K, Kauppinen A. Photoaging: UV radiation-induced inflammation and immunosuppression accelerate the aging process in the skin. Inflammation Research. 2022; 71: 817–831.

[105] Ansary TM, Hossain MR, Kamiya K, Komine M, Ohtsuki M. Inflammatory Molecules Associated with Ultraviolet Radiation-Mediated Skin Aging. International Journal of Molecular Sciences. 2021; 22: 3974.

[106] Ansel J, Perry P, Brown J, Damm D, Phan T, Hart C, et al. Cytokine modulation of keratinocyte cytokines. The Journal of Investigative Dermatology. 1990; 94: 101S–107S.

[107] Vicentini FTMC, He T, Shao Y, Fonseca MJV, Verri WA, Jr, Fisher GJ, et al. Quercetin inhibits UV irradiation-induced inflammatory cytokine production in primary human keratinocytes by suppressing NF-κB pathway. Journal of Dermatological Science. 2011; 61: 162–168.

[108] Starr ME, Saito M, Evers BM, Saito H. Age-Associated Increase in Cytokine Production During Systemic Inflammation-II: The Role of IL-1β in Age-Dependent IL-6 Upregulation in Adipose Tissue. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2015; 70: 1508–1515.

[109] Chung JH, Seo AY, Chung SW, Kim MK, Leeuwenburgh C, Yu BP, et al. Molecular mechanism of PPAR in the regulation of age-related inflammation. Ageing Research Reviews. 2008; 7: 126–136.

[110] Antonicelli F, Hornebeck W. Chapter 21 - Matrix Metalloproteinases and Skin Inflammaging. In Rahman I, Bagchi D (eds.) Inflammation, Advancing Age and Nutrition (pp. 255–265). Academic Press: San Diego. 2014.

[111] Bosch R, Philips N, Suárez-Pérez JA, Juarranz A, Devmurari A, Chalensouk-Khaosaat J, et al. Mechanisms of Photoaging and Cutaneous Photocarcinogenesis, and Photoprotective Strategies with Phytochemicals. Antioxidants. 2015; 4: 248–268.

[112] Fisher GJ, Varani J, Voorhees JJ. Looking older: fibroblast collapse and therapeutic implications. Archives of Dermatology. 2008; 144: 666–672.

[113] Luchian I, Goriuc A, Sandu D, Covasa M. The Role of Matrix Metalloproteinases (MMP-8, MMP-9, MMP-13) in Periodontal and Peri-Implant Pathological Processes. International Journal of Molecular Sciences. 2022; 23: 1806.

[114] Cabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosa C, Ramirez-Acuña JM, Perez-Romero BA, Guerrero-Rodriguez JF, et al. The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases. International Journal of Molecular Sciences. 2020; 21: 9739.

[115] Hornebeck W. Down-regulation of tissue inhibitor of matrix metalloprotease-1 (TIMP-1) in aged human skin contributes to matrix degradation and impaired cell growth and survival. Pathologie-biologie. 2003; 51: 569–573.

[116] Fisher GJ, Datta SC, Talwar HS, Wang ZQ, Varani J, Kang S, et al. Molecular basis of sun-induced premature skin ageing and retinoid antagonism. Nature. 1996; 379: 335–339.

[117] Saarialho-Kere U, Kerkelä E, Jeskanen L, Hasan T, Pierce R, Starcher B, et al. Accumulation of matrilysin (MMP-7) and macrophage metalloelastase (MMP-12) in actinic damage. The Journal of Investigative Dermatology. 1999; 113: 664–672.

[118] Pozzo LD, Xu Z, Lin S, Wang J, Wang Y, Enechojo OS, et al. Role of epigenetics in the regulation of skin aging and geroprotective intervention: A new sight. Biomedicine & Pharmacotherapy. 2024; 174: 116592.

[119] Zheng W, Li H, Go Y, Chan XHF, Huang Q, Wu J. Research Advances on the Damage Mechanism of Skin Glycation and Related Inhibitors. Nutrients. 2022; 14: 4588.

[120] Romano F, Serpico D, Cantelli M, Di Sarno A, Dalia C, Arianna R, et al. Osteoporosis and dermatoporosis: a review on the role of vitamin D. Frontiers in Endocrinology. 2023; 14: 1231580.

[121] Chaiprasongsuk A, Janjetovic Z, Kim TK, Jarrett SG, D’Orazio JA, Holick MF, et al. Protective effects of novel derivatives of vitamin D₃ and lumisterol against UVB-induced damage in human keratinocytes involve activation of Nrf2 and p53 defense mechanisms. Redox Biology. 2019; 24: 101206.

[122] Demetriou SK, Ona-Vu K, Teichert AE, Cleaver JE, Bikle DD, Oh DH. Vitamin D receptor mediates DNA repair and is UV inducible in intact epidermis but not in cultured keratinocytes. The Journal of Investigative Dermatology. 2012; 132: 2097–2100.

[123] Wong CT, Oh DH. Vitamin D Receptor Promotes Global Nucleotide Excision Repair by Facilitating XPC Dissociation from Damaged DNA. The Journal of Investigative Dermatology. 2021; 141: 1656–1663.

[124] De Silva WGM, McCarthy BY, Han J, Yang C, Holland AJA, Stern H, et al. The Over-Irradiation Metabolite Derivative, 24-Hydroxylumister-ol₃, Reduces UV-Induced Damage in Skin. Metabolites. 2023; 13: 775.

[125] Gupta R, Dixon KM, Deo SS, Holliday CJ, Slater M, Halliday GM, et al. Photoprotection by 1,25 dihydroxyvitamin D3 is associated with an increase in p53 and a decrease in nitric oxide products. The Journal of Investigative Dermatology. 2007; 127: 707–715.

[126] Chen H, Reed G, Guardia J, Lakhan S, Couture O, Hays E, et al. Vitamin D directly regulates Mdm2 gene expression in osteoblasts. Biochemical and Biophysical Research Communications. 2013; 430: 370–374.

[127] Petersen SV, Oury TD, Ostergaard L, Valnickova Z, Wegrzyn J, Thøgersen IB, et al. Extracellular superoxide dismutase (EC-SOD) binds to type i collagen and protects against oxidative fragmentation. The Journal of Biological Chemistry. 2004; 279: 13705–13710.

[128] Lee MJ, Agrahari G, Kim HY, An EJ, Chun KH, Kang H, et al. Extracellular Superoxide Dismutase Prevents Skin Aging by Promoting Collagen Production through the Activation of AMPK and Nrf2/HO-1 Cascades. The Journal of Investigative Dermatology. 2021; 141: 2344–2353.e7.

[129] Untari U, Anjani G, Fulyani F, Pramono A, Mahati E, Putri SR, et al. The effect of liprotide-encapsulated vitamin D3 on MDA and SOD in rats deficient vitamin D and calcium. Journal of Biomedicine and Translational Research. 2023; 9: 1–6.

[130] Masjedi F, Keshtgar S, Zal F, Talaei-Khozani T, Sameti S, Fallahi S, et al. Effects of vitamin D on steroidogenesis, reactive oxygen species production, and enzymatic antioxidant defense in human granulosa cells of normal and polycystic ovaries. The Journal of Steroid Biochemistry and Molecular Biology. 2020; 197: 105521.

[131] Mastali VP, Hoseini R, Azizi M. The effect of short-term vitamin D on the antioxidant capacity following exhaustive aerobic exercise. African Health Sciences. 2023; 23: 584–591.

[132] de Jager TL, Cockrell AE, Du Plessis SS. Ultraviolet Light Induced Generation of Reactive Oxygen Species. Advances in Experimental Medicine and Biology. 2017; 996: 15–23.

[133] Meephansan J, Komine M, Tsuda H, Ohtsuki M. Suppressive effect of calcipotriol on the induction of matrix metalloproteinase (MMP)-9 and MMP-13 in a human squamous cell carcinoma cell line. Clinical and Experimental Dermatology. 2012; 37: 889–896.

[134] Kim SH, Baek MS, Yoon DS, Park JS, Yoon BW, Oh BS, et al. Vitamin D Inhibits Expression and Activity of Matrix Metalloproteinase in Human Lung Fibroblasts (HFL-1) Cells. Tuberculosis and Respiratory Diseases. 2014; 77: 73–80.

[135] Li S, Niu G, Dong XN, Liu Z, Song C, Leng H. Vitamin D Inhibits Activities of Metalloproteinase-9/-13 in Articular Cartilage In Vivo and In Vitro. Journal of Nutritional Science and Vitaminology. 2019; 65: 107–112.

[136] Hahn J, Cook NR, Alexander EK, Friedman S, Walter J, Bubes V, et al. Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial. BMJ (Clinical Research Ed.). 2022; 376: e066452.

[137] Toniato E, Spinas E, Saggini A, Kritas SK, Caraffa A, Antinolfi P, et al. Immunomodulatory effects of vitamin d on skin inflammation. Journal of Biological Regulators and Homeostatic Agents. 2015; 29: 563–567.

[138] Wimalawansa SJ. Infections and Autoimmunity-The Immune System and Vitamin D: A Systematic Review. Nutrients. 2023; 15: 3842.

[139] Iruretagoyena M, Hirigoyen D, Naves R, Burgos PI. Immune Response Modulation by Vitamin D: Role in Systemic Lupus Erythematosus. Frontiers in Immunology. 2015; 6: 513.

[140] Sîrbe C, Rednic S, Grama A, Pop TL. An Update on the Effects of Vitamin D on the Immune System and Autoimmune Diseases. International Journal of Molecular Sciences. 2022; 23: 9784.

[141] Farage MA, Miller KW, Berardesca E, Maibach HI. Non-neoplastic Disorders of the Aging Skin. In Farage MA, Miller KW, Maibach HI (eds.) Textbook of Aging Skin (pp. 1–24). Springer Berlin Heidelberg: Berlin, Heidelberg. 2014.

[142] Wiegand C, Raschke C, Elsner P. Skin Aging: A Brief Summary of Characteristic Changes. In Farage MA, Miller KW, Maibach HI (eds.) Textbook of Aging Skin (pp. 55–65). Springer Berlin Heidelberg: Berlin, Heidelberg. 2017.

[143] Tan JS, Joseph WS. Common fungal infections of the feet in patients with diabetes mellitus. Drugs & Aging. 2004; 21: 101–112.

[144] Toukabri N, Dhieb C, El Euch D, Rouissi M, Mokni M, Sadfi-Zouaoui N. Prevalence, Etiology, and Risk Factors of Tinea Pedis and Tinea Unguium in Tunisia. The Canadian Journal of Infectious Diseases & Medical Microbiology. 2017; 2017: 6835725.

[145] Flevari A, Theodorakopoulou M, Velegraki A, Armaganidis A, Dimopoulos G. Treatment of invasive candidiasis in the elderly: a review. Clinical Interventions in Aging. 2013; 8: 1199–1208.

[146] Gupta AK, Venkataraman M, Talukder M. Onychomycosis in Older Adults: Prevalence, Diagnosis, and Management. Drugs & Aging. 2022; 39: 191–198.

[147] Abdullah L, Abbas O. Common nail changes and disorders in older people: Diagnosis and management. Canadian Family Physician Medecin De Famille Canadien. 2011; 57: 173–181.

[148] Tétart F, Joly P. Eczema in elderly people. European Journal of Dermatology. 2020; 30: 663–667.

[149] Lima AL, Timmermann V, Illing T, Elsner P. Contact Dermatitis in the Elderly: Predisposing Factors, Diagnosis, and Management. Drugs & Aging. 2019; 36: 411–417.

[150] Sowell J, Pena SM, Elewski BE. Seborrheic Dermatitis in Older Adults: Pathogenesis and Treatment Options. Drugs & Aging. 2022; 39: 315–321.

[151] White-Chu EF, Reddy M. Dry skin in the elderly: complexities of a common problem. Clinics in Dermatology. 2011; 29: 37–42.

[152] Amin R, Lechner A, Vogt A, Blume-Peytavi U, Kottner J. Molecular characterization of xerosis cutis: A systematic review. PLoS ONE. 2021; 16: e0261253.

[153] Garibyan L, Chiou AS, Elmariah SB. Advanced aging skin and itch: addressing an unmet need. Dermatologic Therapy. 2013; 26: 92–103.

[154] Jaul E. Assessment and management of pressure ulcers in the elderly: current strategies. Drugs & Aging. 2010; 27: 311–325.

[155] Lee JJ, Chien AL. Rosacea in Older Adults and Pharmacologic Treatments. Drugs & Aging. 2024; 41: 407–421.

[156] Deotto ML, Spiller A, Sernicola A, Alaibac M. Bullous pemphigoid: An immune disorder related to aging (Review). Experimental and Therapeutic Medicine. 2022; 23: 50.

[157] Kridin K, Ludwig RJ. The Growing Incidence of Bullous Pemphigoid: Overview and Potential Explanations. Frontiers in Medicine. 2018; 5: 220.

[158] Finn DJ, Graham C, Holt DJ, Kelly R, Rajlawat BP, Yesudian PD. Management of mucous membrane pemphigoid in a joint oral medicine-dermatology clinic. Clinical and Experimental Dermatology. 2020; 45: 685–690.

[159] Brown F, Crane JS. Idiopathic Guttate Hypomelanosis. StatPearls: Treasure Island. 2023.

[160] Calzavara-Pinton P, Calzavara-Pinton I, Rovati C, Rossi M. Topical Pharmacotherapy for Actinic Keratoses in Older Adults. Drugs & Aging. 2022; 39: 143–152.

[161] Sreekantaswamy S, Endo J, Chen A, Butler D, Morrison L, Linos E. Aging and the treatment of basal cell carcinoma. Clinics in Dermatology. 2019; 37: 373–378.

[162] Winter A, Schulz SM, Schmitter M, Müller-Richter U, Kübler A, Kasper S, et al. Comprehensive Geriatric Assessment and Quality of Life Aspects in Patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC). Journal of Clinical Medicine. 2023; 12: 5738.

[163] Macdonald JB, Dueck AC, Gray RJ, Wasif N, Swanson DL, Sekulic A, et al. Malignant melanoma in the elderly: different regional disease and poorer prognosis. Journal of Cancer. 2011; 2: 538–543.

[164] Buja A, Rugge M, Trevisiol C, Zanovello A, Brazzale AR, Zorzi M, et al. Cutaneous melanoma in older patients. BMC Geriatrics. 2024; 24: 232.

[165] Scampoli P, Di Martino G, Cedrone F, Odio C, Di Giovanni P, Romano F, et al. The Burden of Herpes Zoster on Hospital Admissions: A Retrospective Analysis in the Years of 2015-2021 from the Abruzzo Region, Italy. Vaccines. 2024; 12: 462.

[166] Dattola A, Silvestri M, Bennardo L, Passante M, Scali E, Patruno C, et al. Role of Vitamins in Skin Health: a Systematic Review. Current Nutrition Reports. 2020; 9: 226–235.

[167] Meehan M, Penckofer S. The Role of Vitamin D in the Aging Adult. Journal of Aging and Gerontology. 2014; 2: 60–71.

[168] Goetz DW. Idiopathic itch, rash, and urticaria/angioedema merit serum vitamin D evaluation: a descriptive case series. The West Virginia Medical Journal. 2011; 107: 14–20.

[169] Popadic S, Tomanovic M, Minic S. Effectiveness and safety of topical calcipotriol in the treatment of flat seborrheic keratosis on the face. The Australasian Journal of Dermatology. 2023; 64: e171–e174.

[170] Mitsuhashi Y, Kawaguchi M, Hozumi Y, Kondo S. Topical vitamin D3 is effective in treating senile warts possibly by inducing apoptosis. The Journal of Dermatology. 2005; 32: 420–423.

[171] Ince B, Yildirim MEC, Dadaci M. Assessing the Effect of Vitamin D Replacement on Basal Cell Carcinoma Occurrence and Recurrence Rates in Patients with Vitamin D Deficiency. Hormones & Cancer. 2019; 10: 145–149.

[172] Gallo D, Baci D, Kustrimovic N, Lanzo N, Patera B, Tanda ML, et al. How Does Vitamin D Affect Immune Cells Crosstalk in Autoimmune Diseases? International Journal of Molecular Sciences. 2023; 24: 4689.

[173] Ao T, Kikuta J, Ishii M. The Effects of Vitamin D on Immune System and Inflammatory Diseases. Biomolecules. 2021; 11: 1624.

[174] Skowron K, Bauza-Kaszewska J, Kraszewska Z, Wiktorczyk-Kapischke N, Grudlewska-Buda K, Kwiecińska-Piróg J, et al. Human Skin Microbiome: Impact of Intrinsic and Extrinsic Factors on Skin Microbiota. Microorganisms. 2021; 9: 543.

[175] Katsarou A, Armenaka MC, Zafiriou E, Vakirlis E. Atopic Dermatitis in the Aged. In Farage MA, Miller KW, Maibach HI (eds.) Textbook of Aging Skin (pp. 971–989). Springer Berlin Heidelberg: Berlin, Heidelberg. 2017.

[176] Millsop JW, Chang ALS. Major Changes in Skin Function in the Elderly and Their Contributions to Common Clinical Challenges. In Farage MA, Miller KW, Maibach HI (eds.) Textbook of Aging Skin (pp. 1–11). Springer Berlin Heidelberg: Berlin, Heidelberg. 2014.

[177] Huang J, Lei J, Ge A, Xiao W, Xin C, Song Z, et al. Antifungal Effect of Vitamin D₃ against Cryptococcus neoformans Coincides with Reduced Biofilm Formation, Compromised Cell Wall Integrity, and Increased Generation of Reactive Oxygen Species. Journal of Fungi. 2023; 9: 772.

[178] Kherad Z, Yazdanpanah S, Saadat F, Pakshir K, Zomorodian K. Vitamin D₃: A promising antifungal and antibiofilm agent against Candida species. Current Medical Mycology. 2023; 9: 17–22.

[179] Lei J, Xiao W, Zhang J, Liu F, Xin C, Zhou B, et al. Antifungal activity of vitamin D₃ against Candida albicans in vitro and in vivo. Microbiological Research. 2022; 265: 127200.

[180] Xie J, Zhu L, Zhu T, Jian Y, Ding Y, Zhou M, et al. Vitamin D-supplemented yogurt drink reduces Candida infections in a paediatric intensive care unit: a randomised, placebo-controlled clinical trial. Journal of Human Nutrition and Dietetics. 2019; 32: 512–517.

[181] Dai J, Liang Y, Li H, Zhou W, Wang B, Gong A, et al. Vitamin D enhances resistance to aspergillus fumigatus in mice via inhibition of excessive autophagy. American Journal of Translational Research. 2018; 10: 381–391.

[182] Hu S, Dai J, Chen X. Vitamin D reduces autophagy by regulating NF-κB resistance to Aspergillus fumigatus infection. Gene. 2020; 753: 144819.

[183] Li P, Xu X, Cao E, Yu B, Li W, Fan M, et al. Vitamin D deficiency causes defective resistance to Aspergillus fumigatus in mice via aggravated and sustained inflammation. PLoS ONE. 2014; 9: e99805.

[184] Nguyen NLH, Chen K, McAleer J, Kolls JK. Vitamin D regulation of OX40 ligand in immune responses to Aspergillus fumigatus. Infection and Immunity. 2013; 81: 1510–1519.

[185] Farage MA, Miller KW, Berardesca E, Maibach HI. Psychological and Social Implications of Aging Skin: Normal Aging and the Effects of Cutaneous Disease (pp. 1–14). In Farage MA, Miller KW, Maibach HI (eds.) Textbook of Aging Skin. Springer Berlin Heidelberg: Berlin, Heidelberg. 2014.

[186] Ban GY, Kim MY, Yoo HS, Nahm DH, Ye YM, Shin YS, et al. Clinical features of elderly chronic urticaria. The Korean Journal of Internal Medicine. 2014; 29: 800–806.

[187] Nasiri-Kalmarzi R, Abdi M, Hosseini J, Babaei E, Mokarizadeh A, Vahabzadeh Z. Evaluation of 1,25-dihydroxyvitamin D3 pathway in patients with chronic urticaria. QJM: Monthly Journal of the Association of Physicians. 2018; 111: 161–169.

[188] Grzanka A, Machura E, Mazur B, Misiolek M, Jochem J, Kasperski J, et al. Relationship between vitamin D status and the inflammatory state in patients with chronic spontaneous urticaria. Journal of Inflammation. 2014; 11: 2.

[189] Abdel-Rehim ASM, Sheha DS, Mohamed NA. Vitamin D level among Egyptian patients with chronic spontaneous urticaria and its relation to severity of the disease. The Egyptian Journal of Immunology. 2014; 21: 85–90.

[190] Rasool R, Masoodi KZ, Shera IA, Yosuf Q, Bhat IA, Qasim I, et al. Chronic urticaria merits serum vitamin D evaluation and supplementation; a randomized case control study. The World Allergy Organization Journal. 2015; 8: 15.

[191] Li Y, Cao Z, Guo J, Li Q, Su J. Effects of Serum Vitamin D Levels and Vitamin D Supplementation on Urticaria: A Systematic Review and Meta-Analysis. International Journal of Environmental Research and Public Health. 2021; 18: 4911.

[192] Hattangdi-Haridas SR, Lanham-New SA, Wong WHS, Ho MHK, Darling AL. Vitamin D Deficiency and Effects of Vitamin D Supplementation on Disease Severity in Patients with Atopic Dermatitis: A Systematic Review and Meta-Analysis in Adults and Children. Nutrients. 2019; 11: 1854.

[193] McCarthy RL, Tawfik SS, Theocharopoulos I, Atkar R, McDonald B, Dhoat S, et al. Vitamin D deficiency and atopic dermatitis severity in a Bangladeshi population living in East London: A cross-sectional study. Skin Health and Disease. 2024; 4: e358.

[194] Mansour NO, Mohamed AA, Hussein M, Eldemiry E, Daifalla A, Hassanin S, et al. The impact of vitamin D supplementation as an adjuvant therapy on clinical outcomes in patients with severe atopic dermatitis: A randomized controlled trial. Pharmacology Research & Perspectives. 2020; 8: e00679.

[195] Camargo CA, Jr, Ganmaa D, Sidbury R, Erdenedelger K, Radnaakhand N, Khandsuren B. Randomized trial of vitamin D supplementation for winter-related atopic dermatitis in children. The Journal of Allergy and Clinical Immunology. 2014; 134: 831–835.e1.

[196] Amestejani M, Salehi BS, Vasigh M, Sobhkhiz A, Karami M, Alinia H, et al. Vitamin D supplementation in the treatment of atopic dermatitis: a clinical trial study. Journal of Drugs in Dermatology. 2012; 11: 327–330.

[197] Javanbakht MH, Keshavarz SA, Djalali M, Siassi F, Eshraghian MR, Firooz A, et al. Randomized controlled trial using vitamins E and D supplementation in atopic dermatitis. The Journal of Dermatological Treatment. 2011; 22: 144–150.

[198] Imoto RR, Uber M, Abagge KT, Lima MN, Rosário NA, Carvalho VOD. Vitamin D supplementation and severity of atopic dermatitis: pre-post assessment. Allergologia et Immunopathologia. 2021; 49: 66–71.

[199] Raj KAP, Handa S, Narang T, Sachdeva N, Mahajan R. Correlation of serum vitamin D levels with severity of pediatric atopic dermatitis and the impact of vitamin D supplementation on treatment outcomes. The Journal of Dermatological Treatment. 2022; 33: 1397–1400.

[200] Aldaghi M, Tehrani H, Karrabi M, Abadi FS, Sahebkar M. The effect of multistrain synbiotic and vitamin D3 supplements on the severity of atopic dermatitis among infants under 1 year of age: a double-blind, randomized clinical trial study. The Journal of Dermatological Treatment. 2022; 33: 812–817.

[201] Adly MA, Assaf HA, Hussein MR. Expression of the heat shock protein-27 in the adult human scalp skin and hair follicle: hair cycle-dependent changes. Journal of the American Academy of Dermatology. 2006; 54: 811–817.

[202] Borzutzky A, Iturriaga C, Pérez-Mateluna G, Cristi F, Cifuentes L, Silva-Valenzuela S, et al. Effect of weekly vitamin D supplementation on the severity of atopic dermatitis and type 2 immunity biomarkers in children: A randomized controlled trial. Journal of the European Academy of Dermatology and Venereology. 2024; 38: 1760–1768.

[203] Lu’o’ng KVQ, Nguyễn LTH. The roles of vitamin D in seborrhoeic keratosis: possible genetic and cellular signalling mechanisms. International Journal of Cosmetic Science. 2013; 35: 525–531.

[204] Aulia I, Wibawa LP, Suseno LS, Manikam NRM. Correlation Among Serum Calcidiol, Sun Index, and Vitamin D Intake in Individuals With Seborrheic Keratoses Living in Coastal Area. Dermatology Practical & Conceptual. 2024; 14: e2024037.

[205] Maryam Y, Leyla N, Hassan G, Ehsan A, Rayhaneh R, Behrooz B. Eficacy of calcipotriol in the treatment of seborrheic keratosis: a pilot study. Iranian Journal of Dermatology. 2013; 16: 132–136.

[206] Herron MD, Bowen AR, Krueger GG. Seborrheic keratoses: a study comparing the standard cryosurgery with topical calcipotriene, topical tazarotene, and topical imiquimod. International Journal of Dermatology. 2004; 43: 300–302.

[207] Ekiz O, Balta I, Sen BB, Dikilitaş MC, Ozuğuz P, Rifaioğlu EN. Vitamin D status in patients with rosacea. Cutaneous and Ocular Toxicology. 2014; 33: 60–62.

[208] Sharma A, Kroumpouzos G, Kassir M, Galadari H, Goren A, Grabbe S, et al. Rosacea management: A comprehensive review. Journal of Cosmetic Dermatology. 2022; 21: 1895–1904.

[209] Park BW, Ha JM, Cho EB, Jin JK, Park EJ, Park HR, et al. A Study on Vitamin D and Cathelicidin Status in Patients with Rosacea: Serum Level and Tissue Expression. Annals of Dermatology. 2018; 30: 136–142.

[210] Mao R, Zhou G, Jing D, Liu H, Shen M, Li J. Vitamin D Status, Vitamin D Receptor Polymorphisms, and the Risk of Incident Rosacea: Insights from Mendelian Randomization and Cohort Study in the UK Biobank. Nutrients. 2023; 15: 3803.

[211] Akdogan N, Alli N, Incel Uysal P, Candar T. Role of serum 25-hydroxyvitamin D levels and vitamin D receptor gene polymorphisms in patients with rosacea: a case-control study. Clinical and Experimental Dermatology. 2019; 44: 397–403.

[212] Algarin YA, Pulumati A, Jaalouk D, Tan J, Nouri K. The role of vitamins and nutrients in rosacea. Archives of Dermatological Research. 2024; 316: 142.

[213] Huang L, Sun W, Ye Z, Liu Y, He K, Li S. Changes in epidermal thickness and their correlation with clinical characteristics in patients with vitiligo. Archives of Dermatological Research. 2024; 316: 519.

[214] Hussein AFA, Shams AS, Hosny N, Elrosasy A, Kobtan M, Shafik YA, et al. A meta-analysis of therapeutic trials of topical ruxolitinib cream for the treatment of vitiligo: therapeutic efficacy, safety, and implications for therapeutic practice. Archives of Dermatological Research. 2024; 316: 518.

[215] Thng S, Chuah SY, Gan EY. Age and Vitiligo: Childhood, Pregnancy and Late-Onset Vitiligo. In Picardo M, Taïeb A (eds.) Vitiligo (pp. 141–151). Springer International Publishing: Cham. 2019.

[216] Beyzaee AM, Goldust M, Patil A, Rokni GR, Beyzaee S. The role of cytokines and vitamin D in vitiligo pathogenesis. Journal of Cosmetic Dermatology. 2022; 21: 6314–6325.

[217] Kim TE, Kim SK, Shin MK, Jeong KH, Lee MH. Serum 25-Hydroxy Vitamin D Levels and Association of Vitamin D Receptor Gene Polymorphisms in Vitiligo. Journal of Korean Medical Science. 2022; 37: e110.

[218] Alshiyab DM, Al-Qarqaz FA, Heis LH, Muhaidat JM, Eddin WS, Atwan AA. Assessment of Serum Vitamin D Levels in Patients with Vitiligo in Jordan: A Case-Control Study. Dermatology Research and Practice. 2019; 2019: 2048409.

[219] Karagün E, Ergin C, Baysak S, Erden G, Aktaş H, Ekiz Ö. The role of serum vitamin D levels in vitiligo. Postepy Dermatologii i Alergologii. 2016; 33: 300–302.

[220] Hassan I, Bhat YJ, Majid S, Sajad P, Rasool F, Malik RA, et al. Association of Vitamin D Receptor Gene Polymorphisms and Serum 25-Hydroxy Vitamin D Levels in Vitiligo - A Case-control Study. Indian Dermatology Online Journal. 2019; 10: 131–138.

[221] Varikasuvu SR, Aloori S, Varshney S, Bhongir AV. Decreased circulatory levels of Vitamin D in Vitiligo: a meta-analysis. Anais Brasileiros De Dermatologia. 2021; 96: 284–294.

[222] Colucci R, Conti R, Dragoni F, Cammi A, Cianferotti L, Brandi ML, et al. Evidence of a possible therapeutic role of vitamin D in a cohort of adult Caucasian vitiligo patients. International Journal for Vitamin and Nutrition Research. 2020; 90: 200–204.

[223] Kim JC, Kim HR, Park JS, Lee SY, Kim HO, Park CW, et al. Vitamin D supplementation can enhance therapeutic effects of excimer laser in patients with vitiligo. Journal of Cosmetic Dermatology. 2024; 23: 839–848.

[224] Liu X, Yao Z, Wang Y, Chai L, Zhou X. Vitamin D analogs combined with different types of phototherapy in the treatment of vitiligo: A systematic review of randomized trials and within-patient studies. International Immunopharmacology. 2022; 109: 108789.

[225] Seraphin G, Rieger S, Hewison M, Capobianco E, Lisse TS. The impact of vitamin D on cancer: A mini review. The Journal of Steroid Biochemistry and Molecular Biology. 2023; 231: 106308.

[226] Sluyter JD, Manson JE, Scragg R. Vitamin D and Clinical Cancer Outcomes: A Review of Meta-Analyses. JBMR Plus. 2020; 5: e10420.

[227] Muñoz A, Grant WB. Vitamin D and Cancer: An Historical Overview of the Epidemiology and Mechanisms. Nutrients. 2022; 14: 1448.

[228] Gilaberte Y, Aguilera J, Carrascosa JM, Figueroa FL, Romaní de Gabriel J, Nagore E. Vitamin D: evidence and controversies. Actas Dermo-sifiliograficas. 2011; 102: 572–588.

[229] Hasan N, Nadaf A, Imran M, Jiba U, Sheikh A, Almalki WH, et al. Skin cancer: understanding the journey of transformation from conventional to advanced treatment approaches. Molecular Cancer. 2023; 22: 168.

[230] Cattaruzza MS, Pisani D, Fidanza L, Gandini S, Marmo G, Narcisi A, et al. 25-Hydroxyvitamin D serum levels and melanoma risk: a case-control study and evidence synthesis of clinical epidemiological studies. European Journal of Cancer Prevention. 2019; 28: 203–211.

[231] Fearfield L, Nobbs J, Petruckevitch A, Harland C. Severe vitamin D deficiency associated with BRAF-mutated melanoma. The British Journal of Dermatology. 2019; 181: 1343.

[232] Timerman D, McEnery-Stonelake M, Joyce CJ, Nambudiri VE, Hodi FS, Claus EB, et al. Vitamin D deficiency is associated with a worse prognosis in metastatic melanoma. Oncotarget. 2017; 8: 6873–6882.

[233] Moreno-Arrones OM, Zegeer J, Gerbo M, Manrique-Silva E, Requena C, Traves V, et al. Decreased vitamin D serum levels at melanoma diagnosis are associated with tumor ulceration and high tumor mitotic rate. Melanoma Research. 2019; 29: 664–667.

[234] Nürnberg B, Gräber S, Gärtner B, Geisel J, Pföhler C, Schadendorf D, et al. Reduced serum 25-hydroxyvitamin D levels in stage IV melanoma patients. Anticancer Research. 2009; 29: 3669–3674.

[235] Bade B, Zdebik A, Wagenpfeil S, Gräber S, Geisel J, Vogt T, et al. Low serum 25-hydroxyvitamin d concentrations are associated with increased risk for melanoma and unfavourable prognosis. PLoS ONE. 2014; 9: e112863.

[236] Newton-Bishop JA, Beswick S, Randerson-Moor J, Chang YM, Affleck P, Elliott F, et al. Serum 25-hydroxyvitamin D3 levels are associated with breslow thickness at presentation and survival from melanoma. Journal of Clinical Oncology. 2009; 27: 5439–5444.

[237] De Smedt J, Aura C, Van Kelst S, Janssen L, Marasigan V, Boecxstaens V, et al. Clinical and genetic determinants of vitamin D receptor expression in cutaneous melanoma patients. Melanoma Research. 2024; 34: 125–133.

[238] Brożyna AA, Jozwicki W, Janjetovic Z, Slominski AT. Expression of vitamin D receptor decreases during progression of pigmented skin lesions. Human Pathology. 2011; 42: 618–631.

[239] Vojdeman FJ, Madsen CM, Frederiksen K, Durup D, Olsen A, Hansen L, et al. Vitamin D levels and cancer incidence in 217,244 individuals from primary health care in Denmark. International Journal of Cancer. 2019; 145: 338–346.

[240] Mahamat-Saleh Y, Aune D, Schlesinger S. 25-Hydroxyvitamin D status, vitamin D intake, and skin cancer risk: a systematic review and dose-response meta-analysis of prospective studies. Scientific Reports. 2020; 10: 13151.

[241] Caini S, Gnagnarella P, Stanganelli I, Bellerba F, Cocorocchio E, Queirolo P, et al. Vitamin D and the Risk of Non-Melanoma Skin Cancer: A Systematic Literature Review and Meta-Analysis on Behalf of the Italian Melanoma Intergroup. Cancers. 2021; 13: 4815.

[242] Rogers HW, Weinstock MA, Feldman SR, Coldiron BM. Incidence Estimate of Nonmelanoma Skin Cancer (Keratinocyte Carcinomas) in the U.S. Population, 2012. JAMA Dermatology. 2015; 151: 1081–1086.

[243] Vornicescu C, Ungureanu L, Șenilă SC, Vesa ȘC, Cosgarea R, Baican CI, et al. Assessment of sun-related behavior and serum vitamin D in basal cell carcinoma: Preliminary results. Experimental and Therapeutic Medicine. 2020; 20: 187.

[244] van Deventer L, Kannenberg SMH, du Toit J. Vitamin D status in adult patients with nonmelanoma skin cancer in Cape Town, South Africa: a cross-sectional study. International Journal of Dermatology. 2018; 57: 922–927.

[245] Moisejenko-Goluboviča J, Groma V, Svirskis Š Ivanova A. Serum Vitamin D Levels Explored in the Latvian Cohort of Patients with Basal Cell Carcinoma Linked to the Sonic Hedgehog and Vitamin D Binding Protein Cutaneous Tissue Indices. Nutrients. 2022; 14: 3359.

[246] Slominski AT, Brożyna AA, Kim TK, Elsayed MM, Janjetovic Z, Qayyum S, et al. CYP11A1 derived vitamin D hydroxyderivatives as candidates for therapy of basal and squamous cell carcinomas. International Journal of Oncology. 2022; 61: 96.

[247] Liang G, Nan H, Qureshi AA, Han J. Pre-diagnostic plasma 25-hydroxyvitamin D levels and risk of non-melanoma skin cancer in women. PLoS ONE. 2012; 7: e35211.

[248] Abdelwahab R, Huang R, Potla S, Bhalla S, AlQabandi Y, Nandula SA, et al. The Relationship between Vitamin D and Basal Cell Carcinoma: A Systematic Review. Cureus. 2022; 14: e29496.

[249] Chen X, Song S, Shi J, Wang Z, Song W, Wang J, et al. Evaluating the effect of body mass index and 25-hydroxy-vitamin D level on basal cell carcinoma using Mendelian randomization. Scientific Reports. 2023; 13: 16552.

[250] de Gruijl FR, Wolterbeek R, Pavel S, de Fijter JW, Hamdy NAT, Bouwes Bavinck JN. Low wintertime pre-diagnostic vitamin D status is associated with an increased risk of internal malignancies in kidney transplant recipients. Photochemical & Photobiological Sciences. 2018; 17: 1946–1955.

[251] Anand S, Rollakanti KR, Horst RL, Hasan T, Maytin EV. Combination of oral vitamin D3 with photodynamic therapy enhances tumor cell death in a murine model of cutaneous squamous cell carcinoma. Photochemistry and Photobiology. 2014; 90: 1126–1135.