Promising Functions of Novel Vitamin D Derivatives as Cosmetics: A New Fountain of Youth in Skin Aging and Skin Protection

Abstract

Vitamin D is a natural photoproduct that has many beneficial effects on different organs, including skin. Active forms of vitamin D and its derivatives exert biological effects on skin cells, thus maintaining skin homeostasis. In keratinocytes, they inhibit proliferation and stimulate differentiation, have anti-inflammatory properties, act as antioxidants, inhibit DNA damage and stimulate DNA repair after ultraviolet (UV) exposure. In melanocytes, they also inhibit cell proliferation, inhibit apoptosis and act as antioxidants. In fibroblasts, they inhibit cell proliferation, affect fibrotic processes and collagen production, and promote wound healing and regeneration. On the other hand, skin cells have the ability to activate vitamin D directly. These activities, along with the projected topical application of vitamin D derivatives, are promising for skin care and photo protection and can be used in the prevention or possible reversal of skin aging.

1. Introduction

1.1. Vitamin D

Vitamin D is a natural photoproduct found in plants, as vitamin D2 (D2), or in skin of humans and animals, as vitamin D3 (D3) [1,2,3,4,5,6,7,8,9]. It is formed by ultraviolet B irradiation (UVB) action from its precursors ergosterol or 7-dehydrocholesterol (7DHC), respectively, in fungi and plants or animal and human skin [1,6,7,10,11,12,13,14]. Other forms of vitamin D, D1, D4, and D5, are less important for humans. Chemically, it is a secosteroid with a broken B ring in its structure [1,7,10,11,12]. Since its discovery in 1922, vitamin D has found many applications in medicine and cosmetics [1,7,11,12,15,16]. Not only does it help to prevent rickets and osteomalacia by regulating calcium and bone metabolism, but it also helps to prevent or treat many other diseases and conditions through the regulation of cellular growth and immune and endocrine responses [8,10,17]. All these vitamin D-regulated biological processes are crucial in aging [18,19]. Many cells, especially skin cells, are capable of producing vitamin D in its active forms with specific biological actions on cells dependent on the target organs, thus making it categorized as a pro-hormone and its active forms such as hormones [1,3,11,12,20,21,22,23,24].

Vitamin D can be found in food in the form of D2 (ergocalciferol) or D3 (cholecaciferol) or is produced in the skin [25,26]. In the classical activation pathway, vitamin D pro-hormone is hydroxylated under the action of catalytic enzymes CYP2R1 and CYP27A1 to 25-hydroxyvitamin D3 (25(OH)D3), mainly in the liver [1,7,22,27,28,29] but also in skin cells including keratinocytes and fibroblasts [8,12,22,30,31,32]. This hormone precursor is a form of vitamin D found in the serum and is used to measure the vitamin D status in the body, since its levels in circulation persist longer, lasting 2–3 weeks [33]. The level of 25(OH)D3 varies among people across the globe [2,11,34]. A hormonally active calcitriol or 1,25-dihydroxy-vitamin D (1,25(OH)₂D3) is produced from 25(OH)D3. The production takes place in many tissues or organs, primarily in kidneys, under the action of 1α-hydroxylase, an enzyme regulated by CYP27B1 [1,29,35,36]. The main active form of vitamin D is 1,25(OH)₂D3, primarily regulating bone metabolism and calcium levels. Calcitriol upregulates the CYP24A1 gene, of which the enzymatic product degrades 1,25(OH)₂D3 [37,38]. The levels of 1,25(OH)₂D3 are typically short lasting, up to 15 h, and are closely regulated by parathyroid hormones, minerals calcium and phosphorus, and vitamin D levels.

Many metabolites of vitamin D have been discovered over the years [15,23,39,40]—some of them useful, others not [23,41]. Vitamin D and its analogs are most frequently used for the treatment of osteoporosis, since as suppressing parathyroid hormone (PTH) agents, they increase calcium absorption and bone mineral density [26,41,42]. In skin, these molecules find application in the treatment of psoriasis as potent inhibitors of keratinocytes proliferation and in alopecia as hair growth stimulators [2,3,41]. As an adjuvant therapy, vitamin D metabolites are used against cancer, such as leukemia, as inhibitors of tumor cell growth and metastasis [41,43,44,45], including skin cancer [46,47,48,49,50,51,52].

The transcriptional activity of hormonally active 1,25(OH)₂D3 starts with its binding to the vitamin D receptor (VDR) that forms heterodimers with the retinoid receptor (RXR), a complex activating transcription of target genes through binding to the VDR binding element (VDRE) in the nucleus [1,53,54,55,56]. The activity of vitamin D goes beyond classical bone mineral metabolism. These activities include regulation of cell proliferation and differentiation, metabolism of lipids, apoptosis, immune functions, and protection against oxidative damage and aging, etc.

1.2. Vitamin D Metabolism in the Skin

Vitamin D metabolites are also activated in the skin cells [20,30], including fibroblasts [32,57] and keratinocytes [31]. Skin is also a target organ where vitamin D regulates many skin cells functions, thus making it a unique organ within the endocrine system [11]. The formation of vitamin D in the skin involves UVB-induced transformation of 7DHC to pre-vitamin D3, with further transformation to D3 configuration that is accelerated by an increased temperature [1,11,25,26]. Keratinocytes and fibroblasts produce 25(OH)D3 [12] and the hormonally active form of vitamin D3, 1,25(OH)₂D3 [26], through the pathway shown in Figure 1.

The alternative pathways of vitamin D activation in the skin include the metabolism of vitamin D by the CYP11A1 enzyme [23,24,32,58,59,60] and the production of many different vitamin D hydroxymetabolites (Figure 1). Hydroxylation of the side chain of vitamin D3 by CYP11A1 generates new vitamin D hydroxyderivatives, such as 20(OH)D3 [61] and 20,23(OH)₂D3 [62]. Hydroxylation of these new metabolites of vitamin D3 under the CYP27B1 enzyme generates even more potent vitamin D3 hydroxyderivatives: 1,20(OH)₂D3 [63] and 1,20,23(OH)₃D3 as examples [23,62]. As tested on rats and mice, 20(OH)D3 is non-calcemic even at high doses, which is in contrast to 1,25(OH)₂D3 inducing hypercalcemia and attendant toxicity [64,65,66]. These novel secosteroids are biologically active, similarly to 1,25(OH)₂D3, yet they have lower toxicity and do not cause the calcemic effect, which makes them safer than 1,25(OH)₂D3 for pharmacological use [40].

2. Skin and Photo-Aging

2.1. The Damaging Effects of UV Radiation on Skin Cells

Skin is the organ that protects the body from external factors, acting as a barrier between the environment and the internal milieu [67,68,69]. Skin consists of three layers; the epidermis is the outer layer, the dermis is the inner layer, and the hypodermis is composed of subdermal adipose tissue. Keratinocytes and melanocytes are predominant components of the epidermis, while fibroblasts are predominant cells in the dermis. Keratinocytes undergo a precise differentiation program forming a skin barrier [70,71,72]. Melanocytes are less abundant being found in the basal layer of the epidermis, hair follicles and partially in the dermis in nevi [73]. Melanocytes produce melanin pigment that absorbs UV energy, thus protecting the skin from its damaging effect [74,75]. Skin fibroblasts are located in the dermis and play an important role in wound healing, tissue fibrosis, inflammation, collagen turnover, etc. They produce extracellular matrix (ECM) components, such as collagen and elastin, as well as a variety of other important molecules, such as fibronectin and laminin [76]. The most abundant collagen in the skin is type I collagen. Matrix degrading enzymes, such as metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), regulate collagen processing and are also produced by fibroblasts [77]. Collagen and elastin provide structure and support for the dermis.

The skin maintains its homeostasis via a cutaneous neuroendocrine system [78,79]. The loss of this homeostasis leads to many skin pathologies and to skin aging or cancer over time [69,80,81,82]. A meta-analysis of skin aging showed that the most common causes are solar exposure and smoking, while the most common signs of skin aging are wrinkling, followed by pathological pigmentation, sagging and telangiectasia [83,84,85]. The loss of the internal skin barrier is caused by internal factors, such as the metabolism of the cells and genetics [86,87,88,89]. The loss of the external skin barrier is caused by external factors, such as radiation, UVA (315–400 nm), UVB (280 to 315 nm), UVC (190–280 nm), infrared (IR) (750 nm–1000 μm), blue light (400–500 nm) [90,91] and chemicals [86,92,93]. An integral part of this process is the prolonged exposure of the skin to UVA, UVB or blue light causing photo-aging, characterized by loss of skin elasticity, wrinkling and skin hyperpigmentation, primarily on the face [69,86,94,95]. Harmful effects of UVC rays are usually blocked by the ozone layer and the upper layers of the epidermis [91,96,97]; therefore, UVC irradiation is not considered as a photo-aging factor [98].

Cellular changes occurring during intrinsic skin aging comprise the reduction in cell proliferation, especially in the epidermis that becomes thinner and the reduction in collagen production, which is notable in the dermis. Senescent keratinocytes, melanocytes and fibroblasts may accumulate in the skin as a part of the natural aging process [99,100,101]. Since their discovery [102,103], senescent cells have been considered as an important hallmark of skin aging [104,105,106]. They are characterized by the distinct morphological characteristics, such as enlarged cell size [107]. Under physiological conditions, senescence is a part of homeostasis related to aging, tissue remodeling and repair, wound healing, fibrosis, tumor suppression, etc. [108,109,110]. Under the influence of stress, cells stop dividing and enter so-called premature senescence, which is an irreversible arrested cell cycle [111], or face death [112,113,114]. The pathological conditions create an accumulation of senescent cells, which can further hinder tissue repair and regeneration [115,116,117], as seen in many age-related diseases, such as diabetes and atherosclerosis [118,119,120,121,122]. Cell senescence can cause inflammation, tissue fibrosis or induce tumors [123,124]. It is an important part of tumorigenesis [125,126]. Different types of stress can induce cell senescence, such as chemicals [127], therapeutic agents [128,129,130], UV radiation [131,132,133], pollution [134], or epigenetics factors, etc. [135]. Stress related inflammation and immunosuppression lead to tissue damage and accumulation of the senescent cells in the skin promoting skin aging [81,136,137,138,139,140,141]. Senescent cells can secrete pro-inflammatory cytokines, chemokines, proteases, ECM compounds, and growth factors [142,143,144,145,146]. This senescence-associated secretory phenotype (SASP) can further induce tissue damage [147,148,149]. Senescent cells are detected in all skin layers [132,150,151,152,153,154]. This process is mainly observed in fibroblasts and melanocytes [137,155]. Accumulations of the senescent fibroblasts in the skin leads to a loss of skin elasticity [156,157], hyper-pigmentation such as senile lentigo [158,159] or melasma [160]. Accumulations of the senescent melanocytes in the dermis are observed in melanocytic nevi [150,161] or facial wrinkles [162,163,164]. Accumulation of the senescent keratinocytes in the epidermis can affect actinic keratosis [132,165].

2.1.1. Oxidative Stress in the Skin

UV radiation can have deleterious effects on the skin causing oxidative stress, cancer or premature skin aging [166]. Oxidative stress results from the accumulation of reactive oxygen species (ROS) or reactive nitrogen species (RNS) in the skin cells in response to UV radiation (Figure 2). Under physiological conditions, ROS are produced in cells endogenously in a smaller amount as part of physiological signaling. Excessive ROS production can damage the skin and, over time, causes skin aging [167,168]. On a cellular level, this process leads to an impaired cell proliferation and differentiation, resulting in a thick epidermis [169,170,171]. Besides photo-aging, ROS can contribute to internal aging as well [172].

Oxidative stress triggers the formation of ROS in fibroblasts, which can indirectly stimulate the production of MMP, collagenases that can cause the breakdown of the collagen in skin, thus contributing to the loss of skin structure [155,167] and subsequently resulting in the formation of wrinkles [173,174]. MMPs cause the degradation of ECM, such as collagen, fibronectin, elastin and other skin supportive proteins, thus inducing degenerative changes in skin manifesting as dryness, pigmentation, wrinkling, sagging, etc. (Figure 2). These changes induced by UV radiation are referred to as skin photo-aging changes [175].

Additionally, fibroblasts regulate inflammation. Inflammatory cytokines, such as IL-6, IL-8, IL-33 and TGFβ1, activate fibroblasts and promote differentiation and ECM production [76]. Similarly, so-called fibrotic genes, such as platelet-derived growth factor (PDGF), also stimulate fibroblasts [85].

2.1.2. DNA Damage in the Skin

Stress activates DNA damage response pathways [176]. Prolonged exposure to UVB causes DNA damage in skin cells in the form of cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4PP) and 8-hydroxy-2′-deoxyguanosine (8-OH-DG) [97,177,178,179,180,181,182,183,184]. The exposure to UVA also causes a formation of so-called “dark CPD” (dCPD), mutations at non-pyrimidine sites, and 8-OH-DG [185,186] (Figure 2). This dCPT accounts for half of all CPDs produced and these are usually formed well after the UVA exposure depending on a pigment called melanin. Damaged DNA can be repaired by the skin nucleotide excision repair system (NER) [187,188], the base excision repair system (BER) [189] or nuclear mitotic apparatus (NuMA) [190]. If this system fails, the cells will undergo apoptosis and the skin will exhibit premature aging signs or pre-cancer changes culminating in cancerogenesis [166,191].

2.1.3. Wound Healing and Fibrotic Process in the Skin

Wound healing leads to the formation of a new tissue involving proliferation of fibroblasts, keratinocytes and endothelial cells in response to tissue injury [192]. These cells rebuild ECM. ECM and collagen are an integral part of tissue granulation and epithelization [193]. Scarring is a natural part of the wound healing localized to the injury site; however, excessive granulation tissue can lead to hypertrophic scars or even keloids [76,194]. A widely spread uncontrolled activity of fibroblasts, so-called fibrosis, can manifests as systemic sclerosis (SS) [195]. Once the wound healing process is finished, fibroblasts undergo senescence, thus limiting formation of excessive fibrosis [196]. However, factors that induce prolonged cell senescence, such as UV radiation, cause inflammation as a tissue response to the injury, which further induces fibroblasts to enter senescence [197,198,199,200,201]. Chronic inflammation and cell senescence decrease proliferation and migration of fibroblasts with subsequent inhibition of wound repair that leads to skin aging [202,203,204]. Accumulation of senescent cells delays wound healing and contributes to chronic wounds [153].

2.2. Endogenous Factors Protecting the Skin against UV Radiation and Photo-Aging

The skin has developed various mechanisms of protection against the UV-induced damage, including pigment production and synthesis of vitamin D and melatonin, as potent antioxidants [85,205,206]. Melanin is produced in melanocytes by the oxidation of L-tyrosine and subsequent conversion to L-dihydroxyphenylalanine (L-DOPA) under the action of the catalytic enzyme tyrosinase [73,75,206,207,208,209,210]. This process is called melanogenesis. Melanin absorbs UV radiation and protects nuclei of keratinocytes by stimulating cornification of keratinocytes [206,211,212,213,214]. As a form of protection against UV radiation, keratinocytes will enter cell-cycle arrest. In the case of prolonged UV exposure, the cell arrest will turn into an early senescence and apoptosis [85]. Although melanin can absorb UV radiation and protect skin, an excess of this pigment in skin forms hyperpigmentation and age spots [212,215]. These dark spots contain primarily eumelanin [212].

UVA is a large part of daily UV rays and is the main source of radiation used in tanning beds. It induces pigmentation that lasts longer than UVB-induced pigmentation, since it can go deeper through the skin beyond the epidermis. Unfortunately, UVA-induced melanin pigmentation does not have protective effects as UVB-induced pigmentation does [216]. DNA damage induced by UVA is primarily in cells located in the dermis, while the damage caused by UVB is more profound and primarily affects the epidermal cell layer [216]. The other, faster occurring mechanism is photo protection by vitamin D and its analogs that are activated in the skin under the influence of UVB [64,177]. According to some authors, vitamin D can induce re-pigmentation in damaged melanocytes (Figure 2). Levels of produced vitamin D correlate with melanin levels [217]. Activated vitamin D metabolites promote the above-described mechanism of skin protection and enhance DNA repair [177,205,218].

2.3. Mechanism of Action of Novel Vitamin D Hydroxyderivatives as Antioxidants and Their Potential in the Treatment of Skin Conditions Associated with Photo-Aging

Novel vitamin D derivatives exert their action in the skin through different molecular pathways. They are involved in DNA repair, oxidative stress and wound healing processes.

Nuclear factor erythroid 2-related factor 2 (Nrf2) and Klotho are important factors involved in the regulation of the anti-oxidative response. Klotho, or alpha-Klotho, is an antiaging gene partially regulated by vitamin D3 that plays a beneficial role in aging [219]. Nrf2 is located in the cytoplasm of the cells in its inactive state bound to Kelch-like ECH-associated protein 1 (Keap1) [220]. When cells are undergoing oxidative stress, Nrf2 translocates to the nucleus and binds to the antioxidant responsive element (ARE), thus activating target genes and the process of detoxification [220,221,222]. Nrf2 is involved in removing ROS, chemical detoxification, reducing inflammation in wound healing, skin protection, photo protection and pigmentation [221]. Nrf2 increases synthesis of detoxifying enzymes, such as glutathione peroxidase (GPx), superoxide dismutase (SOD), glutathione S-transferase (GST), gluthathione (GSH), catalase (CAT), heme oxygenase 1 (HO-1), NAD(PH):quinone oxidoreductase (NQO1,), etc. These enzymes further detoxify ROS products, such as peroxide (H₂O₂) and superoxide anion (O₂) [221]. Nrf2 deficiency in mice leads to the development of precancerous and cancerous states [221]. In summary, Nrf2 protects skin from photo-aging by decreasing cytotoxicity and senescence of skin cells, keratinocytes, melanocytes and fibroblasts, and reducing oxidative stress [166,223,224]. Overexpression of Nrf2 in melanocytes leads to the inhibition of melanin production [225] and stimulation of epidermal differentiation [222]. Epidermal differentiation is stimulated by the Nrf2-AhR (aryl hydrocarbon receptor) complex [226]. The AhR controls the expression of the genes involved in epidermal differentiation, such as loricrin and involucrin, and the expression of CYP enzymes [226,227,228]. Stimulation of the Nrf2-AhR complex has been proposed for the treatment of atopic dermatitis, a skin disorder characterized by the dysfunctional skin barrier [226,229]. Of note, AhR has been identified as a receptor for vitamin D derivatives and melatonin [230,231,232,233], all having photo protective activities.

UV induces damage to melanocytes and inhibits Nrf2. Accordingly; products that act as antioxidants and stimulate production of Nrf2 protect melanocytes from UVA/B damage [234,235]. UV induced accumulation of ROS in cells activates nuclear factor kappa B (NF-kB), along with Nrf2 and AhR, crucial transcription factors involved in prevention of premature aging (Figure 2). NF-kB is an immune response regulator [236]. DNA damage can activate p53 and induce apoptosis [187]. Both, DNA damage and oxidative stress can activate p53, which can lead to cell senescence, aging or cancer [237,238,239,240,241,242]. NF-kB can inhibit p53, thus affecting DNA damage, cell metabolism and inflammatory and immune responses, through the process of cell-cycle arrest and apoptosis [236].

It was reported that 1,25(OH)₂D3 and other vitamin D metabolites protect skin keratinocytes against UV-induced damage by modulating DNA damage or repair processes, reducing ROS, CPD, 6-4PPs, 8-OH-DG, and enhancing NER [49,177,243,244,245,246,247]. Similarly, novel secosteroids can protect human keratinocytes and melanocytes against UV-induced damage. For example, the topical application of 20(OH)D3 protects murine skin from UVR-induced damage [205,243,244,245]. Novel secosteroids can reduce levels of CPD and stimulate p53-phosphorylation in UV-exposed human keratinocytes and melanocytes [243]. Further, they increase the levels of inhibitory kappa-B protein (IκB) [248] to inhibit ROS-mediated NF-κB p65 translocation to the cell nucleus of keratinocytes and melanocytes [249,250,251]. The described signaling process controls the levels of p53. Novel secosteroids induce phosphorylation of p53 that activates p53 to induce DNA repair or inhibit ROS productions [243]. They also reduce the levels of H₂O₂ and NO and increase the levels of detoxifying enzymes, such as GSH, thus enhancing DNA repair similarly to melatonin [252]. Novel D3-hydroxyderivatives inhibit UVB-mediated DNA damage by the activation of the Nrf2 pathway and DNA repair as a response to UV-induced damage in skin cells [235] (Figure 2).

Vitamin D plays an important role in wound healing [253,254] and is shown to be effective in the prevention of hypertrophic scars [255,256] and systemic sclerosis [195]. Vitamin D regulates pro-inflammatory cytokines by increasing the levels of anti-inflammatory cytokines, such as IL-10, as part of the wound healing process [255]. An intact VDR is required for normal wound healing, since its ligand, 1,25(OH)₂D3, regulates keratinocytes proliferation, differentiation and wound healing processes through VDR [257]. In addition, a lack of VDR induces skin fibrosis and scleroderma in mice [258].

CYP11A1-derived secosteroids can inhibit proliferation of human keratinocytes and melanocytes [61,62,63,64], stimulate cell differentiation [259,260], decrease inflammation [249,250,260] and prevent pathological skin fibrosis [261,262] similarly to 1,25(OH)₂D3 (Figure 2). However, they can act through different receptors. Novel secosteroids exert their biological activity through VDR [259], the aryl hydrocarbon receptor (AhR) [230] and liver X receptors (LXRα and β) [231,263], yet at the same time, they acts as inverse agonists on retinoid-related orphan receptors (RORα and RORγ) in murine [262] and human skin cells [264]. Similarly to 1,25(OH)₂D3 [253], they show inhibitory effects on induced fibrotic activities in fibroblasts [265]. They inhibited genes involved in fibrosis, such as fibronectin (FN1), a growth factor for fibroblasts, ACTA1 (smooth muscle actin protein), as well as inflammatory genes, such as IL-1, IL-8, IL-33 and TGFB1.

2.4. Current and Future Applications of Vitamin D Hydroxyderivatives in the Treatment of Skin Conditions and as Cosmetic Products

Vitamin D and its derivatives protect the skin against aging by counteracting oxidative stress [19]. In addition, novel D3 hydroxyderivatives stimulate the expression of so-called “anti-aging” genes in human keratinocytes [266], such as Nrf2. The main target for anti-aging skin products is an increase in collagen and elastin in skin to prevent formation of wrinkles. Vitamin D affects collagen turnover by repairing and replacing collagen. Vitamin D decreases collagenase, an enzyme that degrades collagen, and stimulates collagen production [19,253]. Hence, vitamin D can be classified as both an antioxidant and an anti-aging pharmacological agent. This dual feature makes vitamin D a promising target for skin care products or “anti-wrinkle” creams. In addition, Nrf2 activators can be used in treatment of vitiligo, a skin condition where melanocytes have impaired Nrf2-ARE signaling and are prone to oxidative damage [234]. Other skin conditions for which these activators are useful include the treatment of atopic dermatitis [226], UV-induced skin pigmentation [223], aging, wound healing, etc. [220]. Analogs of vitamin D are used for the treatment of vitiligo since they can restore pigment production in melanocytes and have anti-inflammatory effects [267,268]. Novel vitamin D metabolites can stimulate Nrf2 [205], and therefore, they could potentially be used in the treatment of vitiligo or atopic dermatitis [269]. Vitamin D analogs, calcipotriol (available as an ointment and cream) and tacalcitrol, are used for the topical treatment of plaque psoriasis [270]. These lesions are characterized by hyper-proliferation and impaired differentiation of keratinocytes in a response to inflammation. Novel secosteroids are also potent inhibitors of keratinocytes proliferation and stimulators of differentiation [64,250]. These molecules could be applied topically in the treatment of psoriasis in addition to UVB therapy. In addition, antifibrotic biological activities of vitamin D hydroxyderivatives make these molecules good candidates for the treatment of fibrosis and fibrogenesis in scleroderma [271,272,273]. The possible role of novel vitamins D in preventing or delaying the formation of senescent cells or reducing senescent cell viability, such as senolytic drugs [274,275,276,277,278], is not yet explored but isworth testing [279].

Compared to different anti-aging strategies, such as botox and fillers, vitamin D can be delivered into the skin topically [280,281]. Topical application, including transdermal delivery [282], is effective, safe and pain-free [283,284]. The main concern with the use of vitamin D is the potential for increasing calcium levels in blood [285]. These methods of delivery circumvent possible side effects and provide continuous drug delivery, as shown in a randomized controlled trial using vitamin D on the skin [284]. Topical application of vitamin D improves skin hydration and symptoms of dry skin [286]. Many clinical trials proved the efficacy and the safety of topical vitamin D analogs [287]. Topical oral vitamin gel has been described to alleviate oral mucositis in patients undergoing radiation [288]. The topical application of novel secosteroid derivatives is a promising skin anti-aging strategy and should be explored in more depth. It is also important to note that these molecules are present in natural products [289] and can be a safe ingredient for a growing global demand of halal cosmetics [290].

Vitamin D is a lipophilic molecule and requires an enhanced drug delivery in the skin, such as nanocarriers [291,292,293,294,295]. Vitamin D is sensitive to external factors, such as light, heat or moisture, which can affect its bioavailability [296]. To overcome this problem, biocompatible nanocarriers have been developed to protect the vitamin D drugs from the induced degradation and ensure appropriate delivery into the skin superior to existing spray or gel formulations [292,295,297,298].

Cosmetic products, such as sunscreens, can protect skin from damaging effects of UV [299]. Dermatologists recommend using sunscreen and avoiding the sun to protect the skin from UV [300]. Unfortunately, many chemicals found in sunscreens are not safe [301] and they can be toxic or absorbed systemically [302,303]. In addition, many sunscreens do not offer protection against UVA, IR, or blue light. On the other side, UVB is necessary for vitamin D production. Some sources show that limiting the exposure to UVB would block conversion of inactive pro-vitamin D (7DHC) to the active form of vitamin D potentially leading to an insufficient vitamin D production in the skin [42,304]. Some sunscreens can block the necessary vitamin D production in the skin [305,306]. This dual role makes exposure to UVB good and bad at the same time [307].

Currently, there are no optimal sun protection agents and no specific recommendations for optimal sunscreen use [308,309,310]. Therefore, there is a need for new active ingredients that are safe and stable when added to the cosmetic formulations [175,311,312] and possibly act as an anti-oxidant molecule [299], such as vitamin D [313]. Sunscreens with antioxidants can suppress ROS formation more efficiently [314] and prevent photo-aging, similar to vitamin D [279]. This natural product offers protection against UVB and UVA as well. Novel secosteroids decrease ROS formation in UVB-irradiated skin cells [205,243,260,315] and UVA-irradiated skin fibroblasts (our unpublished data). Thus, novel vitamin D hydoxyderivatives are potentially a great alternative to the existing sunscreens or other cream formulations designed to protect the skin since they can reduce UVB-caused effects in the skin [177]. Additionally, topical application of calcitrol protected mice exposed to UV radiation from non-melanoma skin cancer development [316]. It was reported that topical vitamin D in combination with other therapy can inhibit melanoma growth [317]. Our data show that novel secosteroids can also inhibit formation or progression of non-melanoma cancers [48] and melanomas as well [318].

Photo-aging, especially caused by UVA and UVB, accelerates the process of ECM degradation, which is the main culprit in UV-induced changes in the skin dermis [85,140].

3. Conclusions

Aging has negative social and emotional influence on people and contributes to an endless forage for the fountain of youth that will prevent or reverse signs of aging, especially in the skin. This review summarizes the influence of novel vitamin D hydroxyderivatives on skin aging via different mechanisms that offer protection against UV-induced cell damage, which causes all skin cells to enter senescence. The pleiotropic effects of vitamin D make this chemical an excellent candidate in the treatment of different skin diseases. Vitamin D and its metabolites regulate cell proliferation and differentiation in skin cells and enhance skin regeneration. They regulate cell signaling and the genes involved in aging, protect against oxidative damage, direct DNA damage and skin aging. Vitamin D, acting as an antioxidant, can prevent photo-aging by preventing or neutralizing ROS formations or inducing skin repair via inhibition of collagenase synthesis. It is also a natural product. Skin care products targeting aging have Nrf2 activity. Vitamin derivatives target both Nrf2 and AhR, and therefore, they could be used to strengthen the skin barrier function and to treat different skin conditions, such as vitiligo, atopic dermatitis, skin aging, and act as photo protective agents in the skin. Vitamin D regulates the interplay between the NF-kB and p53 that can contribute to the development of the novel cosmetics in skin protection. Therefore, new active ingredients that are safe and stable when added to the cosmetic formulations, such as novel vitamin D compounds, are a potential alternatives to existing sunscreen or other cream formulations designed to protect or rejuvenate the skin. They offer stimulation of natural protection through action on keratinocytes, melanocytes and fibroblasts. The prospects of cosmetic applications of vitamin D in the skin is highly promising, especially regarding their safety since they do not cause hypercalcemia. More research is warranted to explore the use of novel vitamin D derivatives in skin care.