WO2010101331A1 - External use skin composition which suppresses skin aging - Google Patents

Abstract

The present invention relates to a composition which suppresses aging of skin cells by promoting expression of extracellular matrices such as type I collagen, type III collagen, and fibronectin in skin cells like keratinocytes and skin fibroblasts. The composition of the present invention effectively treats skin wrinkles and suppresses skin aging.

Description

 Skin external composition which suppresses skin aging

 The present invention relates to a composition for inhibiting the aging of skin cells by promoting the expression of extracellular matrix type I collagen, type III collagen and fibronectin in skin cells keratinocytes and skin fibroblasts.

 Degeneration of the extracellular matrix (ECM) during skin aging causes skin wrinkles and decreased elasticity. To date, the main targets of anti-aging have been concentrated on metalloproteases or structural proteins such as collagen and elastin, but recent interactions between cells and extracellular matrix proteins (collagen, fibrillin, fibronectin) have led to the survival and proliferation of cells and reconstruction of tissues. It is known to play an important role. The causes of such skin aging include natural aging, photoaging by ultraviolet rays, aging due to pollution and free radicals, and aging due to other stresses. Among them, photoaging, which is the biggest cause of skin aging, causes acute and chronic skin injury such as skin cancer by continuous exposure to UV. It is divided into three types of UVA (320-400 nm), UVB (290-320 nm) and UVC (200-290 nm), depending on the wavelength range present in sunlight. Among them, UVC is almost completely absorbed by the ozone layer. UVA and UVB reach the surface of the earth and act as lethal factors that cause skin damage. Although shorter than UVA, UVB is known to penetrate the epidermis in the upper part of the dermis, injuring keratinocytes and damaging collagen fibers, resulting in photoaging, skin discoloration and skin cancer.

      Therefore, while the present inventors are studying the mechanism of action that regulates the expression of extracellular matrix protein in keratinocytes and skin fibroblasts, GW501516, which is known as ligand of PPARδ until now, is collagen type I, in human-derived keratinocytes and fibroblasts, By promoting the expression of collagen type III, fibronectin and suppressing aging induced by UV, it was confirmed that skin wrinkle improvement and aging can be suppressed, and thus the present invention has been completed.

 The present invention is to provide a composition for inhibiting the aging of skin cells by promoting the expression of extracellular matrix type I collagen, type III collagen and fibronectin in the skin cells keratinocytes and skin fibroblasts.

 The present invention relates to "GW501516 (2- [2-methyl-4-([4-methyl-2- [4- (trifluoromethyl) phenyl) -1,3-thiazol-5-yl] methylsulfanyl] phenoxy] acetic acid)" It is based on the fact that it has beneficial effects such as prevention of skin aging and wrinkle improvement by activating various skin physiology.

 Since GW501516 is a ligand specific to the peroxisome proliferation-activated receptor (PPAR) beta (β) or delta (δ), a ligand specific for PPARβ or PPARδ is expected to exert the same effect as GW501516. Therefore, the active ingredient in the present invention is a ligand specific for PPARβ or PPARδ.

 Through the present invention, it was observed that the expression of collagen types I and III and fibronectin mRNA in human epidermal keratinocytes and dermal fibroblasts were significantly increased by treatment with GW501516. In addition, the effects of GW501516 on the expression of extracellular matrix proteins were examined in human skin-derived HaCaT (keratinocytes) and Detroit551 (dermis fibroblasts) cell lines, showing collagen type I and III, fibronectin and transforming growth factor-. The expression of beta 1 was confirmed to increase concentration-dependently by treatment with GW501516. The expression of type III collagen in the extracellular matrix protein was elevated in time dependent manner by GW501516 of 50 nmol / L, and it was also found that the protein and promoter activity of type III collagen was increased as well as mRNA. The results suggest that the synthesis of new proteins by GW501516 is essential for the expression of type III collagen. Therefore, the present invention suggests that GW501516 is an essential substance for maintaining skin elasticity as a specific substance that promotes the expression of extracellular matrix protein.

 In addition, GW501516 is thought to contribute to the regeneration of damaged skin and wrinkle improvement by inducing the expression of keratinocyte growth factor (KGF), which accelerates the proliferation of skin cells and promotes the regeneration of skin epidermal cells.

 In particular, the present invention demonstrates that GW501516 effectively inhibits the activity of beta-galactosidase, a major marker of aging generated when UV is irradiated to human epidermal keratinocytes. Active oxygen species known to damage cells caused by the aging process by UV irradiation have also been shown to be effectively removed by GW501516. UV irradiation promotes the migration of Rac-1 to the cell membrane in the cytoplasm, and NADPH Oxidase is known to produce reactive oxygen species. GW501516 inhibits the migration of Rac-1 to the cell membrane by UV irradiation. It will contribute to aging control.

 In conclusion, the present invention shows that GW501516 increases the expression of extracellular matrix proteins, induces keratinocyte growth factors, and improves skin elasticity, wrinkle improvement, and inhibition of aging by inhibiting skin aging factors caused by UV. It is characterized by the effective adjustment.

 Accordingly, the present invention relates to a composition for inhibiting the aging of skin cells by promoting the expression of extracellular matrix type I collagen, type III collagen and fibronectin in skin cells keratinocytes and skin fibroblasts. The active ingredient of the composition is a ligand specific for PPARβ or PPARδ.

 The composition containing the active ingredient of the present invention may be formulated into a conventional preparation for transdermal administration. Such formulations include, but are not limited to, ointments, gels, creams, linens, lotions, and the like.

 One embodiment of the formulation for transdermal administration of the present invention is an ointment, which can be prepared by appropriately blending the ointment, other additives and the like based on the active ingredient and what is known in the art. The ointment agent is, for example, a higher fatty acid or esters thereof (e.g. adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, sebacic acid). Dimethyl, hexyl laurate, cetyl isooctanoate), lead (e.g. mercury, beeswax, selesin), surfactants (e.g. polyoxyethylene alkyl ether phosphate esters), higher alcohols (e.g. cetanol, stearyl alcohol, Cetostearyl alcohol), silicone oils (e.g. dimethylpolysiloxane, methylphenylpolysiloxane, glycolmethylpolysiloxane, silicone glycol polymers), hydrocarbons (e.g. hydrophilic wasserine, white wasserine, purified lanolin, liquid paraffin), water, humectant (e.g. , Glycerin, propylene glycol, butylene glycol, sorbitol), and an anti-infective agent may be appropriately selected.

 Another embodiment is a gel agent, which can be prepared by appropriately blending the gel base, other additives and the like based on the active ingredient and what is known in the art. Gel bases are, for example, lower alcohols (e.g. ethanol, isopropyl alcohol), water, gelling agents (e.g. carboxyvinyl polymers, hydroxyethyl cellulose, ethyl cellulose, carboxymethyl cellulose, alginate propylene glycol esters), neutralizing agents ( E.g., triethanolamine, diisopropanolamine, sodium hydroxide), surfactants (e.g., sesquioleate sorbitan, threoleate sorbate, monosorbate monooleate, sorbate monostearate, sorbitan monolaurate, monostearate Polyethyleneglycone, polyoxyethylene nonyl phenyl ether, polyoxyethylene lauryl ether), an anti-infective agent, etc. are mentioned, These can be suitably selected from these.

 Another embodiment is a cream agent, which may be prepared by appropriately blending a cream base, other additives, and the like based on the active ingredient and what is known in the art. Cream bases are, for example, higher fatty acid esters (e.g., myristic acid esters, palmitic acid esters, diethyl sebacate, hexyl laurate, cetyl isooctanoate), lower alcohols (e.g. ethanol, isopropanol), carbohydrates (E.g. liquid paraffin, squalane), polyhydric alcohols (e.g. propylene glycol, 1,3-butylene glycol), higher alcohols (e.g. 2-hexyldecanol, cetanol, 2-octyldodecanol), emulsifiers ( Examples thereof include polyoxyethylene alkyl ethers, fatty acid esters, polyethylene glycol fatty acid esters, preservatives (e.g., paraoxybenzoic acid esters), infection inhibitors, and the like.

 Suitable dosages of the compositions according to the invention depend on a number of factors, including the condition and weight of the patient, the extent of the disease, the form and duration of the formulation, and may be appropriately selected by those skilled in the art. However, the composition of the present invention may be administered at 0.01 to 1000 mg, preferably 0.1 to 500 mg per kg of body weight per day. Administration may be administered once a day or divided into several times depending on symptoms.

 The active ingredient of the present invention may be provided as a cosmetic composition by mixing with a dermatologically acceptable carrier.

Cosmetics prepared from the cosmetic composition containing the active ingredient of the present invention can be prepared in the form of a general emulsion formulation and solubilized formulation. Cosmetics of the emulsified formulations include nutrient cosmetics, creams, essences, etc., and cosmetics of the solubilized formulations are flexible cosmetics. In addition to cosmetics containing the active ingredient of the present invention, by containing a dermatologically acceptable medium or base may be prepared in the form of adjuvants that can be used topically or systemically applied commonly used in the field of dermatology.

Suitable cosmetic formulations include, for example, emulsions, suspensions, microemulsions, microcapsules, microgranules or ionics (liposomes), nonionics obtained by dispersing an oil phase in a solution, gel, solid or pasty anhydrous product, aqueous phase. It may be provided in the form of a vesicle dispersant, in the form of a cream, skin, lotion, powder, ointment, spray or conceal stick. It may also be prepared in the form of a foam or in the form of an aerosol composition further containing a compressed propellant.

 “Dermatologically acceptable carriers” that can be used according to the desired formulation include purified water, oils, waxes, fatty acids, fatty alcohols, fatty acid esters, surfactants, humectants, thickening agents, antioxidants, and viscosity stabilizers. Examples include, but are not limited to, topical stabilizers, chelating agents, buffers, preservatives, lower alcohols, and the like, and their types and concentrations are varied and modifications may be made by those skilled in the art without departing from the spirit and scope of the present invention. And parts that can be changed. If necessary, a whitening agent, a moisturizer, an anti-inflammatory agent, an antibacterial agent, an antifungal agent, a vitamin, a sunscreen agent, an antibiotic, an anti-acne agent, a perfume, a dye may be included, and these are cosmetic compositions according to the present invention in amounts commonly used in the cosmetic field Can be included. Suitable from 0.001 to 50% by weight per total weight of the composition.

Specifically, the oil may be hydrogenated vegetable oil, perm oil, cottonseed oil, olive oil, palm oil, jojoba oil, avocado oil, wax, wax, carnauba, candelilla, montan, ceresin, liquid paraffin as wax. Lanolin may be used. Stearic acid, linoleic acid, linolenic acid, oleic acid may be used as the fatty acid, cetyl alcohol, octyl dodecanol, oleyl alcohol, pantenol, lanolin alcohol, stearyl alcohol, hexadecanol may be used as the fatty acid. As the fatty acid ester, isopropyl myristate, isopropyl palmitate, butyl stearate and the like may be used, but is not limited thereto.

Examples of the surfactant include anionic surfactants such as sodium stearate, sodium cetyl sulfate, polyoxyethylene laurylether phosphate, sodium N-acyl glutamate; Cationic surfactants such as stearyldimethylbenzylammonium chloride and stearyltrimethylammonium chloride; Amphoteric surfactants such as alkylaminoethylglycine hydrochloride and lecithin; Glycerine monostearate, sorbitan monostearate, propylene glycol monostearate, polyoxyethylene oleyl ether, polyethylene glycol monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene coconut fatty acid monoethanol arnide (monoethaolarnide ), Polyoxypropylene glycol, polyoxyethylene castor oil, nonionic surfactants such as polyoxyethylene lanolin and the like.

Glycerin, 1,3-butylene glycol, propylene glycol may be used as the moisture absorbent, and ethanol or isopropanol may be used as the lower alcohol. Examples of thickeners include sodium alginate, sodium caseate, gelatin agar, xanthan gum, starch, cellulose ethers (e.g. hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxy propylmethyl cellulose), polyvinyl pyrrolidone, Polyvinyl alcohol, polyethylene glycol, sodium carboxymethyl cellulose, and the like, but are not limited thereto. As antioxidants, butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, citric acid, ethoxyquin can be used, and chelating agents include disodium edetate and ethane hydroxy diphosphate. Citric acid, sodium citrate, boric acid, borax, disodium hydrogen phosphate are available as buffers, and methyl parahydroxybenzoate, ethyl parahydroxybenzoate, dihydro as preservatives. Acetic acid, salicylic acid, benzoic acid are available, but are not limited to these.

 According to the present invention, GW501516 effectively promotes the expression of extracellular matrix proteins such as type I collagen, type III collagen and fibronectin in keratinocytes and dermal fibroblasts and inhibits the production of reactive oxygen species produced by UV irradiation. It can improve skin wrinkles and aging.

 1 (A) shows the expression levels of mRNAs of type I and III collagen and fibronectin when 50 nmol / L of GW501516 was treated to normal human keratinocytes and dermal fibroblasts.

 2 (A) shows the mRNA expression levels of type I and III collagen, fibronectin and TGF-β1 when human HaCaT cells were treated with different concentrations of GW501516.

 Figure 2 (B) shows the mRNA expression of type I and III collagen, fibronectin and TGF-β1 when treated with different concentrations of GW501516 in human Detroit551 cells.

 Figure 3 (A) shows the expression of type III collagen mRNA over time after treatment with 50 nmol / L GW501516 in human HaCaT and Detroit551 cells.

 3 (B) shows the expression level of type III collagen protein when 50 nmol / L of GW501516 was treated to human HaCaT and Detroit551 cells.

 3 (C) shows the degree of promoter activation of type III collagen following treatment with 50 nmol / L of GW501516 in human HaCaT and Detroit551 cell lines.

 FIG. 3 (D) shows the effects of Cyclohexamide, a protein synthesis inhibitor, and Actinomycin D, a transcription inhibitor, on the expression of type III collagen mRNA by GW501516 in human HaCaT and Detroit551 cell lines.

 4 (A) and 4 (B) show the proliferation of cells over time after treatment with 50 nmol / L GW501516 in human HaCaT and Detroit551 cell lines.

 5 (A) and 5 (B) show the expression levels of keratinocyte growth factors according to the time results after treatment with 50 nmol / L GW501516 in normal human dermal fibroblasts.

 Figure 6 (A) shows the effect of GW501516 on the activation of beta-galactosidase upon UV irradiation in normal human keratinocytes.

 Figure 6 (B) is a quantification of the degree of staining of beta-galactosidase shown in 6 (A).

 FIG. 6 (C) shows the survival rate of cells by irradiating UV after concentration-dependent treatment of normal human keratinocytes.

 FIG. 7 (A) measures the effect of GW501516 on the activation of beta-galactosidase by UV irradiation in normal human keratinocytes.

 Figure 7 (B) is to quantify the degree of staining of beta-galactosidase shown in 7 (A).

 Figure 8 (A) shows the effect of GW501516 and NAC on the activity of beta-galactosidase in normal human keratinocytes by UV irradiation.

 Figure 8 (B) is a quantification of the staining of beta-galactosidase shown in 8 (A).

 8 (C) shows the effects of GW501516 and NAC on reactive oxygen species production in normal human keratinocytes by UV irradiation.

 8 (D) shows the effect of GW501516 on migration of Rac-1 to cell membranes by UV irradiation in normal human keratinocytes.

 Hereinafter, the examples are only for illustrating the present invention in more detail, and the scope of the present invention is not limited by these examples in accordance with the gist of the present invention, those skilled in the art to which the present invention pertains. Will be self-evident.

Example 1: Materials and Methods

GW501516, 2 ', 7'-dichlorofluorescein diacetate (H ₂ DCF-DA) was purchased from Calbiochem (La Jolla, CA, USA). Luciferase and beta-galactosidase assay systems were purchased from Promega Co. (Madison, WI). Polyclonal rabbit anti-collagen type I, rabbit anti-fibronectin, goat anti-collagen type III, donkey anti-goat IgG-HRP and goot anti-rabbit IgG-HRP are described in Santa Cruz Biotechnology (Santa Cruz, CA, USA).

 1-1: Cell Culture

 Human primary culture keratinocytes (Welskin, Seoul, Korea) were cultured in keratinocyte growth medium containing keratinocyte growth supplements as recommended by the manufacturer. HaCaT and Detroit551 human cell lines derived from human supercultured skin fibroblasts (Welskin, Seoul, Korea) and skin contain 100 U / mL penicillin and 100 μg / mL streptomycin supplemented with 10% heat inactivated fetal bovine serum DMEM (Dulbecco's modified Eagle's medium) at 37 ° C, 95% air and 5% CO₂Incubated under atmospheric conditions.

 1-2: Northern Blot Analysis

5 μg of total RNA was thermally denatured at 65 ° C. for 15 minutes in running buffer (40 mM MOPS, 10 mM sodium acetate and 1 mM EDTA, pH 7.0) containing 50% formamide and containing 2.2 M formaldehyde. Electrophoresis was performed on one 1% agarose gel. The RNA fractionated according to size was transferred to the Hybond-N ⁺ nylon membrane (Amersham Biosciences UK Ltd, UK) overnight by capillary action and labeled at ³² P with QuikHyb solution (Stratagene, La Jolla, CA, USA) at 68 ° C. Reaction with specific probes. After washing the membrane, radioactive signals were detected with a Fuji BAS-2500 Bioimaging Analyzer (Tokyo, Japan). The membrane was again reacted with a ³² P-labeled GAPDH cDNA probe. CDNA probes for COL3A1, COL1A1, fibronectin, TGF-β1 were prepared by PCR using primers amplifying the respective base sequences 105-447, 555-896, 436-760 and 1039-1297.

 1-3: Western blot analysis

The cells treated with the reagents were washed with cold phosphate-buffered saline (PBS) and lysed in PRO-PREP Protein Extraction Solution (iNtRON Biotechnology, Seoul, Korea). Some of the cell lysates were electrophoresed on SDS-polyacrylamide gels and then transferred to Hybond-P ⁺ polyvinylidene difluoride membrane (Amersham Biosciences UK Ltd, UK). Proteins were detected using specific antibodies by general methods on the membrane.

 1-4: Determination of beta-galactosidase activity, an aging marker of cells

       Kits for measuring the activity of beta-galactosidase, an aging marker of cells, were purchased from Sigma-Aldrich (St. Louis, MO, USA). Cultured cells washed with 1 × PBS were fixed for 7 minutes in 1 × fixative (2% formaldehyde, 0.2% glutaraldehyde). After the fixed solution was removed, the cells were washed three times with 1 × PBS, and then cultured in a dark room at 37 ° C. for 17 hours with carbon dioxide removed by a staining mixture (10x Staining solution, Reagent B, Reagent C, and X-gal solution). It measured by.

 1-5: Cell Counting

Cells seeded at 1 × 10 ⁴ cells / well density in 24-well culture dishes were treated with GW501516 or DMSO for 1-6 days after incubation for 18-24 hours. 100 μl of cell suspension was mixed with 100 μl of trypan blue dye (0.4%) (Sigma, Korea) to measure only live cells (trypan blue blocked) using Neubauer chamber (MARIENFELD, Germany).

 1-6: Reactive Oxygen Species

Cells seeded at a density of 2 × 10 ⁵ cells in a 6 cm culture dish were pretreated with GW501516 and NAC for 24 hours, and then cultured for 24 hours by irradiation with 40 mJ / cm ² UVB. Cells were treated with 5 μM H ₂ DCFDA (DCF-DA, Calbiochem, San Diego, Calif.) And incubated for 30 minutes, washed twice with cold PBS and centrifuged with an absorbance assay (Infinite F200, TECAN). Measured.

 1-7: Cell Membrane / Cytoplasmic Separation

Cells washed with cold PBS were collected with scraper and suspended in Lysis buffer (5 mM Tris-HCl [pH 7.4], 2 mM EDTA and protease inhibitor). After ultrasonic disruption for 5 minutes, the supernatant was stored in the cytoplasmic fraction by centrifugation for 15 minutes, the remaining pallet was suspended again in Lysis buffer and centrifuged for 90 minutes. After removing the supernatant, the remaining pallet was suspended twice with Lysis buffer, centrifuged and the supernatant was removed again. The remaining pallet was suspended in resuspension buffer (75 mM Tris-HCl [pH 7.4], 12.5 mM MgCl _2, 5 mM EDTA), reacted at -80 ° C for 1 day, and then centrifuged to use the supernatant as a cell membrane fraction. .

Example 2: GW501516 Induces mRNA Expression of Extracellular Matrix Related Genes

 The effects of GW501516 on normal human keratinocytes and dermal fibroblasts were investigated. Treatment with GW501516 significantly increased mRNA expression of extracellular matrix proteins type I and III collagen and fibronectin (FIG. 1). In addition, when GW501516 was treated with HaCaT cells derived from human keratinocytes and Detroit551 derived from human dermal fibroblasts, expression of type I collagen, type III collagen, fibronectin, and TGF-β1 mRNA was dependent on GW501516 concentration. Significantly induced (FIG. 2). Maximum expression was observed in cells treated for 38 hours in GW501516 at 50-100 nmol / L.

Example 3: GW501516 Induces Type III Collagen Expression at the Transcription Level in HaCaT and Detroit551 Cell Lines

 The mRNA of type III collagen in human HaCaT and Detroit551 cell lines was observed to be markedly time-dependently induced by GW501516 (FIG. 3A). Induction of this mRNA was also consistent with protein expression of type III collagen (FIG. 3B). In addition, it can be seen that the induction of type III collagen by GW501516 occurs at the transcription level by confirming that the promoter activity of type III collagen is significantly increased by GW501516 (FIG. 3C). On the other hand, it was confirmed in the study using the transcription inhibitor Actinomycin D and the protein synthesis inhibitor Cyclohexamide that the type III collagen expression is essential for the synthesis of new proteins in the cell prior to the collagen expression by GW501516 (Fig. 3D).

Example 4 GW501516 Induces Proliferation of Skin Cells

 To investigate the effect of GW501516 on the proliferation of skin cells, human HaCaT and Detroit551 cell lines were treated with 50 nmol / L GW501516. As a result, it was confirmed that cell proliferation was significantly induced in both cell lines in the group treated with GW501516 compared to the control group (Vehcle) (FIG. 4).

Example 5: GW501516 Induces KGF mRNA Expression

 Keratinocyte growth factor (KGF) is a factor responsible for the regeneration and growth of keratin, which restores the skin's exchange cycle slowed down due to skin aging. Thus, when GW501516 was treated to confirm the effect of GW501516 on normal human dermal fibroblasts, it was confirmed that mRNA expression of keratinocyte growth factor was induced depending on the time and concentration of GW501516 (FIG. 5).

Example 6: GW501516 Inhibits Aging Induced by UV

 Beta-galactosidase activity, an important indicator of aging, was measured to investigate the effect of GW501516 on photoaging induced by UV irradiation of human keratinocytes. UV irradiation induced cell aging in a concentration-dependent manner, in which aging induced by UV irradiation was significantly inhibited by the treatment of GW501516 (FIGS. 6A and 6B), and the reduction of viable cell rate following UV irradiation was also observed in the treatment of GW501516. Was recovered (FIG. 6C). This effect was once again demonstrated by confirming that beta-galactosidase activity increased by UV decreased concentration dependently upon treatment with GW501516 (FIGS. 7A and 7B).

Example 7: GW501516 inhibits the production of reactive oxygen species by inhibiting intracellular migration of Rac-1 to inhibit cell aging by UV

 Reactive oxygen species (ROS), which are generated by UV, slowly destroy cells and cause aging. NADPH Oxidase present in the cell membrane is an important reactive oxygen species generating protein for the generation of such reactive oxygen species. Activation of NADPH Oxidase by the migration of Rac-1 to the cell membrane in the cytoplasm is essential for its activation. Therefore, in order to investigate the effect of GW501516 on the production of such reactive oxygen species, it was compared with the active oxygen inhibitor N-acetylcysteine (NAC). UV-induced aging and production of reactive oxygen species were inhibited by treatment with GW501516, which effect was similar to that inhibited by NAC (FIGS. 8A, 8B and 8C). In addition, it was confirmed that UV migration of Rac-1 to the cell membrane was also suppressed depending on the concentration of GW501516 (FIG. 8D). The above results suggest that GW501516 inhibits cellular aging by inhibiting the activity of NADHP Oxidase by UV and inhibiting the generation of reactive oxygen species by interfering with intracellular migration of Rac-1.

 The composition of the present invention can be used to improve skin wrinkles and aging.

Claims (5)

1.  A composition for inhibiting skin aging comprising a ligand specific for peroxysome proliferation activation receptor beta (PPARβ) or delta (PPARδ).
2.  The method of claim 1,

    The skin aging is a composition, characterized in that caused by UV irradiation.
3.  The method of claim 1,

    Wherein said ligand promotes expression of an extracellular matrix protein consisting of type I collagen, type III collagen and fibronectin.
4.  The method of claim 1,

    The ligand is a composition characterized in promoting the expression of TGF-beta (transforming growth factor-beta) and keratinocyte growth factor (keratinocyte growth factor) in skin cells keratinocytes and skin fibroblasts.
5.  The method of claim 1,

    The ligand is GW501516 (2- [2-methyl-4-([4-methyl-2- [4- (trifluoromethyl) phenyl) -1,3-thiazol-5-yl] methylsulfanyl] phenoxy] acetic acid) Characterized in that the composition.

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