Method for suppressing yellowing of the skin, method for screening yellowing of the skin inhibitors, and method for evaluating susceptibility to yellowing of the skin.

Abstract

To provide a novel yellow dullness suppression method, a yellow dullness suppressant screening method, and a yellow dullness susceptibility evaluation method.SOLUTION: Provided are; a method of suppressing yellow dullness by increasing PRDX4; a method of screening for yellow dullness suppressant using PRDX4 as an indicator; and a method of evaluating yellow dullness susceptibility.SELECTED DRAWING: Figure 5

Description

Technical Field

[0001] The present invention relates to a method for suppressing sallowness by increasing PRDX4, a method for screening a sallowness inhibitor using PRDX4 as an index, and a method for evaluating sallowness susceptibility.

Background Art

[0002] Yellowing of the skin, so-called sallowness, becomes prominent with ultraviolet rays and aging, and it has been reported that this is caused by glycation, carbonylation, nitration, etc. of skin proteins (Patent Documents 1 to 6, Non-Patent Document 1).

[0003] The degree of sallowness can be evaluated, for example, by hue, lightness, chroma, nitrated protein, carbonylated protein, visual inspection of appearance, a specific evaluation device, etc. (Patent Documents 1 to 6, Non-Patent Document 1). Patent Document 1 discloses a sallowness inhibitor containing a carbonylation inhibitor containing glucosinolate as an active ingredient. Patent Document 2 discloses a skin external preparation for reducing skin sallowness containing hesperetin and / or glycosyl hesperetin as an active ingredient. Patent Document 3 discloses a sallowness generation inhibitor containing apple polyphenol as an active ingredient. Patent Document 4 discloses a sallowness inhibitor containing hibiscus extract. Patent Document 5 discloses a method for measuring and determining the degree of sallowness using nitrated protein as an index and a screening method for sallowness improvement materials. Patent Document 6 discloses a method for estimating the degree of a lively face including sallowness. Patent Document 7 discloses a color improving agent containing ginger extract, etc. Further exploration of sallowness inhibitors and their screening methods is required.

[0004] In addition, regarding the susceptibility to how easily sallowness occurs due to factors such as ultraviolet rays and aging, it is often impossible to predict from the current skin color. Such a tendency varies among individuals, and since there is currently a lack of means to objectively judge, it is difficult to take preventive measures against sallowness in advance. If sallowness susceptibility can be evaluated in advance, it will be easier to prevent sallowness. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] Patent No. 6902392 [Patent Document 2] Japanese Patent Publication No. 2021-73320 [Patent Document 3] Patent No. 6681064 [Patent Document 4] Japanese Patent Publication No. 2021-147335 [Patent Document 5] Patent No. 6474752 [Patent Document 6] Japanese Patent Publication No. 2021-129977 [Patent Document 7] Patent No. 3183741 [Patent Document 8] International Publication No. 2020 / 213743 [Non-patent literature]

[0006] [Non-Patent Document 1] Shiseido News Release: "Shiseido Unravels New Mechanism of 'Yellowish Dullness' in Skin" August 31, 2010 https: / / corp.shiseido.com / jp / newsimg / archive / 00000000001187 / 1187_y7i15_jp.pdf [Non-Patent Document 2] Iwai et al., "Decreased Skin Transparency Due to Carbonylation of Stratum Corneum Proteins," J. Soc. Cosmet. Chem. Jpn. 42 (1) 16-21 (2008) [Non-Patent Document 3] Masuda et al., "Measurement Techniques for Cosmetics and Skin Tone," Color Materials, 76[2], 78-83 (2003) [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] This invention provides a novel method for suppressing yellowing of the skin, a method for screening yellowing of the skin inhibitors, and a method for evaluating susceptibility to yellowing of the skin. [Means for solving the problem]

[0008] As a result of diligent research by the inventors, it has been newly discovered that susceptibility to yellowing of the skin is related to PRDX4, and that yellowing of the skin can be suppressed by PRDX4.

[0009] PRDX4 (Peroxiredoxin 4) is a member of the peroxiredoxin family of antioxidant enzymes, and has been reported to have inhibitory effects on cancer, arteriosclerosis, diabetes, and promote wound healing. However, it was not known that PRDX4 is associated with yellowing of the skin.

[0010] This application provides the following invention. (1) A method for cosmetic purposes to suppress yellowing of the target, The method comprising increasing the expression or activity of the target PRDX4. (2) A screening method for a yellowing-causing agent, The method, which uses the expression or activity of PRDX4 in a skin sample as an indicator. (3) A screening method for a yellowing-causing agent, Applying a candidate drug to a skin sample; Measuring the expression or activity of PRDX4 in skin samples before and after application of the candidate drug; and If the expression or activity of PRDX4 in a skin sample treated with the candidate drug increases compared to before treatment, the drug should be evaluated as having an anti-yellowing effect. The method, including the method described above. (4) The method according to any one of (1) to (3), wherein the suppression of yellowing is achieved by inhibiting the carbonylation of collagen with PRDX4. (5) A method for cosmetic purposes to evaluate susceptibility to yellowing, The method comprising evaluating the yellowing susceptibility of the skin of the subject using, as an index, the measured value of the expression or activity of PRDX4 in a skin sample collected from the subject. (6) The method according to (5), wherein the lower the measured value, the higher the yellowing susceptibility of the skin of the subject is evaluated. (7) The method according to any one of (1) to (6), wherein the yellowing is caused by carbonylation of collagen. (8) The method according to any one of (1) to (7), wherein the expression or activity of PRDX4 is promoted by induction or activation of M2 macrophages. (9) A system for evaluating yellowing susceptibility, comprising a database unit that stores data regarding a preset reference value of the expression or activity of PRDX4, a data input unit for inputting data regarding the expression or activity of PRDX4 of a subject, a calculation unit that refers to the reference value of the expression or activity of PRDX4 stored in the database unit and calculates by comparing with the data regarding the expression or activity of PRDX4 of the subject input to the data input unit, an evaluation unit that evaluates yellowing susceptibility based on the calculation result by the calculation unit, the system having a display unit that displays the result evaluated by the evaluation unit. (10) The system according to (9), wherein when the evaluation unit evaluates that the yellowing susceptibility of the subject is high, the display unit further displays a proposal for yellowing suppression. (11) The system according to (10), wherein the proposal is to increase the expression or activity of PRDX4.

Advantages of the Invention

[0011] According to the present invention, it becomes possible to simply and objectively evaluate yellowing susceptibility based on the expression or activity of PRDX4 of a subject. Further, yellowing can be suppressed by increasing the expression or activity of PRDX4. Furthermore, it becomes possible to conduct screening for searching for compounds or compositions for suppressing yellowing using PRDX4 as an index. [Brief explanation of the drawing]

[0012] [Figure 1] Figure 1 shows the results of Experiment 3, illustrating the PRDX4 expression level (log2(CPM)) in fibroblasts when M1 or M2 macrophage culture supernatant was added. [Figure 2] Figure 2 shows the results of Experiment 4, illustrating the immunohistochemical staining of PRDX4 when M1 or M2 macrophage culture supernatant was added to fibroblasts. [Figure 3] Figure 3 shows the results of quantifying the PRDX4 intensity value per cell (PRDX4 / cell) using the image analysis software ImageJ for the immunostained image in Figure 2. **p < 0.01, *p < 0.05 (Tukey-Kramer test) [Figure 4] Figure 4 shows the results of Experiment 5, illustrating how PRDX4 suppresses the yellowing of collagen sponges whose carbonylation was induced by acrolein. [Figure 5] Figure 5 shows the results of quantifying the b* value of the collagen sponge from Experiment 5 using a spectrophotometer CM-2600d. [Modes for carrying out the invention]

[0013] Yellowing is noticeable in skin exposed to ultraviolet light and in aged skin, and is particularly pronounced in photoaged skin. On the other hand, it is known that photoaging can be prevented and improved by adjusting the M1 / M2 balance, such as increasing the ratio of M2 macrophages to M1 macrophages. Macrophages are cells that are localized in various tissues in the body and trigger an immune response to foreign substances and pathogens, differentiating from undifferentiated M0 macrophages into M1 and M2 types. M1 macrophages are known as the inflammatory type, and M2 macrophages are known as the repair type (anti-inflammatory type) (Patent Document 8). However, many aspects of the detailed mechanism between yellowing and M1 and M2 macrophages remain unclear.

[0014] Therefore, the inventors comprehensively analyzed numerous factors whose expression levels change upon the addition of M1 or M2 macrophage culture supernatant to search for factors involved in suppressing yellowing of the skin. As a result of this diligent research, they discovered that PRDX4, whose expression increases upon the addition of M2 macrophage culture supernatant, exhibits a remarkable effect in suppressing yellowing of the skin. The present invention is based on the inventors' novel discovery that yellowing of the skin is related to PRDX4.

[0015] Yellowing of the skin refers to the yellowing of the skin's color. Yellowing of the skin can be caused by glycation, carbonylation, or nitration of skin proteins. Carbonylation refers to the carbonization of skin proteins by the addition of carbonyl compounds such as acrolein, which is a metabolite of lipid peroxides. It is known that skin proteins denature when they undergo carbonylation, and that this denaturation causes them to turn yellow. In particular, it has been reported that proteins in the stratum corneum and dermis undergo carbonylation due to ultraviolet rays and reactive oxygen species, and that factors such as excessive lipid intake and dryness also promote yellowing of the skin (Non-patent documents 1, 2, Patent documents 1-6). In one aspect of the present invention, yellowing of the skin is caused by the carbonylation of skin proteins such as collagen and elastin. In one aspect of the present invention, the carbonylation of skin proteins is caused by oxidizing substances such as hydrogen peroxide and carbonyl compounds such as acrolein.

[0016] The degree of yellowing can be measured, for example, on the target skin or acquired skin image using specific indices obtained from yellowness indicators such as b* value, hue, lightness, saturation, carbonylated protein, wavelength, fluorescence intensity, and RGB color channel data, or by devices such as spectrophotometers, colorimeters, and image analysis devices. Alternatively, it can be evaluated by visual inspection by a trained evaluator (Non-Patent Documents 1-3, Patent Documents 1-6).

[0017] The present invention provides a method for suppressing yellowing of the target skin, comprising increasing the expression or activity of the target PRDX4.

[0018] The inventors have discovered that PRDX4 expression increases in M2 macrophage culture supernatant. Therefore, increasing the expression or activity of the target PRDX4 may be achieved by adjusting the M1 / M2 balance by increasing the number of M2 macrophages or increasing the ratio of M2 macrophages to M1 macrophages. Since the adjustment of the M1 / M2 balance can be achieved using components and methods as described in Patent Document 8, these may also be used. Furthermore, the inventors have discovered that herbal medicines such as Zingiber aromaticum and Zingiber purpureum Roscoe. increase PRDX4 in skin cells such as fibroblasts using a screening method described later, so these herbal medicines can also be used. It has also been confirmed that herbal medicines such as Zingiber aromaticum and Zingiber purpureum Roscoe. have the effect of increasing cells with nuclear localized YAP (Yes-associated protein), which decreases in aged skin due to physical stimulation. This can also be achieved by using a composition containing PRDX4 at appropriate concentrations, such as approximately 0.1 μg / ml to approximately 1000 μg / ml, approximately 1 μg / ml to approximately 100 μg / ml, or approximately 10 μg / ml. Other methods may include, but are not limited to, taking measures that are recognized to be related to the expression or activity of PRDX4, or ingesting a yellowing-causing agent obtained by the screening method described later.

[0019] Furthermore, this application provides a screening method for yellowing-causing agents that use the expression or activity of PRDX4 in skin samples as an indicator. The screening method for yellowing-causing agents may include: applying a candidate drug to a skin sample; measuring the expression or activity of PRDX4 in the skin sample before and after application of the candidate drug; and evaluating that the drug has a yellowing-causing agent effect if the expression or activity of PRDX4 in the skin sample applied to the candidate drug increases compared to before application of the drug.

[0020] Furthermore, the screening method of the present invention may include adding a candidate drug to a skin sample, culturing it for a certain period of time with or without the candidate drug as a control, comparing the expression or activity of PRDX4 when the candidate drug is added with the expression or activity of PRDX4 when the candidate drug is not added, and evaluating that the drug has a yellowing-suppressing effect if the expression or activity of PRDX4 in the skin sample treated with the candidate drug is higher than that of the control.

[0021] The skin sample used in the screening method of the present invention may be a skin sample after collection, for example, an ex vivo skin sample collected from an animal such as a human, or it may be an in vitro sample such as a monolayer or stratified culture of skin cells collected from an animal such as a human, cultured keratinocyte or cultured fibroblast. Alternatively, it may be an artificial skin sample such as a 3D skin model. The skin sample is not limited as long as the expression or activity of PRDX4 can be measured.

[0022] An increase in PRDX4 expression or activity may, for example, be a PRDX4 gene expression level or protein production level that is 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or less, 70% or more, 80% or more, 90% or more, 100% or more, 200% or more, 300% or more, 400% or more, or 500% or more higher compared to before the addition of the candidate drug or to a control without the addition of the candidate drug.

[0023] Furthermore, the present invention also provides a method and / or system for evaluating the susceptibility of a target skin to yellowing using measured values ​​of PRDX4 expression or activity in a target skin sample as an indicator.

[0024] Yellowing susceptibility refers to the tendency for yellowing to occur when exposed to environments where reactive oxygen species increase due to stimuli such as ultraviolet rays and stress, or environments where lipid peroxides tend to increase due to excessive lipid intake. While it is often difficult to predict the degree of susceptibility to yellowing in the future from current skin color, the inventors of this invention have discovered that PRDX4 suppresses the carbonylation of skin proteins such as collagen. This led to the conclusion that individuals with low PRDX4 expression or activity have high yellowing susceptibility, and that their skin is more prone to yellowing than those with high PRDX4 expression or activity, even in equivalent environments. If yellowing susceptibility can be objectively determined, it becomes possible to provide counseling at a consistent level regardless of the counselor's skill or experience, and to proactively suggest lifestyle habits and cosmetics to prevent or improve skin color deterioration, thus enabling proactive measures to prevent yellowing. Therefore, the method and / or system of this invention may be used to provide the above-mentioned advice to subjects evaluated as having high yellowing susceptibility.

[0025] The evaluation may be based on the assumption that the lower the measured value of PRDX4 expression or activity in the subject, the higher the susceptibility of the subject's skin to yellowing. Alternatively, the evaluation may be based on the assumption that the subject's skin is highly susceptible to yellowing if its measured value is lower than a specific value. Furthermore, the evaluation may be based on the assumption that the measured value of PRDX4 expression or activity in the subject is compared to a pre-established reference value for PRDX4 expression or activity, and the assumption that the subject's skin is highly susceptible to yellowing if its measured value is lower than the reference value. The reference value may be based on data of PRDX4 expression or activity in skin samples taken from multiple subjects, with or without the subject. The reference value may also be based on data of PRDX4 expression or activity in skin samples taken from the same subject at a different time than when the target skin sample was taken.

[0026] A measurement value lower than the reference value may mean, for example, that the measured expression or activity of the target PRDX4 is 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more lower than the reference value.

[0027] The skin sample used in the method and / or system for evaluating the susceptibility of target skin to yellowing may be a skin sample after collection, for example, an ex vivo skin sample collected from an animal subject such as a human; a skin sample collected non-invasively by a method as described in Non-Patent Literature 2; or a skin cell culture derived from the subject, for example, in vitro in the form of monolayer or stratified cultured cells, cultured keratinocytes, or cultured fibroblasts. Alternatively, it may be an artificial skin sample such as a 3D skin model created using skin cells derived from the subject. The biological sample is not limited as long as the expression or activity of PRDX4 in the subject can be measured. The expression or activity of PRDX4 may be measured by measuring the expression level of the PRDX4 gene using the above-mentioned skin sample by PCR, or by measuring the amount of PRDX4 protein by immunostaining, ELISA, etc.

[0028] For example, the method of the present application is a method for evaluating yellowing sensitivity performed by one or more computers, and may include a step of obtaining a function that associates the degree of yellowing, which has been determined in advance by a statistical method, with the expression or activity value of PRDX4; a step of obtaining data on the expression or activity of PRDX4 of a target; a step of applying the data on the expression or activity of PRDX4 of the target to the function and performing calculations; a step of statistically evaluating the yellowing sensitivity of the skin based on the results calculated by the calculation step; and a step of displaying the results evaluated by the evaluation step.

[0029] The methods described herein are for cosmetic purposes and may exclude medical procedures performed by doctors or medical professionals. Furthermore, the methods described herein may also be methods that support the cosmetic procedures in question. [Examples]

[0030] The present invention will now be described in more detail with reference to examples. However, the present invention is not limited thereto.

[0031] Experiment 1: Culture of human monocyte-derived cell line THP-1 and collection of M1 / M2 culture supernatant. Following the method described in the Journal of the American College of Cardiology, Vol. 62, No. 20, 2013, November 12, 2013:1890-901, THP-1, a human-derived cell line, was differentiated into M1 and M2 macrophages. THP-1 cells were cultured in 10% FBS-RPMI (Nacalai Tesque, 30263-95) in T175 flasks. After confirming that the cells had proliferated to subconfluence, they were harvested and conditioned in 4 ml / well of 10% FBS-RPMI supplemented with PMA (100 nM), 2 × 10⁶ cells. 6 Cells were seeded in a 6-well plate at a concentration of cells / well. After 24 hours, 1 ml / well of 10% FBS-RPMI supplemented with IFN-γ (20 ng / mL) and LPS (100 ng / mL) was added to stimulate differentiation into M1 macrophages, and 1 ml / well of 10% FBS-RPMI supplemented with IL-4 (20 ng / mL) and IL-13 (20 ng / mL) was added to stimulate differentiation into M2 macrophages. After 24 hours, the medium in each well was aspirated, washed with PBS, and replaced with 5 ml / well of 0.5% FBS-RPMI. After culturing in 5 ml / well of 0.5% FBS-RPMI for 48 hours, the entire culture supernatant was collected and used as the M1 and M2 macrophage culture supernatant for Experiment 3 below. For the control, a medium with the same composition except for the macrophage culture (0.5% FBS-RPMI without macrophage culture) was collected.

[0032] Experiment 2: Culture of human neonatal-derived fibroblasts Human neonatal-derived fibroblasts were cultured in 10% FBS-DMEM (Thermo Fisher Science, 11885084) in T175 flasks. After confirming that the cells had grown to subconfluence, 0.025% trypsin was added, and the cells were incubated at 37°C for 3 minutes. The cells were then detached, the reaction was stopped with 10% FBS-DMEM, and the cells were collected. After centrifugation, the number of cells was counted, and the cells were used in Experiment 3 below at an appropriate cell concentration.

[0033] Experiment 3: Comprehensive analysis of genes whose expression changes upon addition of M1 / M2 macrophage culture supernatant. The M1 and M2 macrophage culture supernatants obtained in Experiment 1 were added to fibroblasts cultured in Experiment 2, and genes whose expression changed upon addition of M1 or M2 macrophage culture supernatant were searched for by the following comprehensive analysis. Specifically, RNA-seq reads were mapped to the human genome (hg19) using STAR. After filtering out low-expression genes from the obtained count data, size correction and log2 conversion were performed between each sample. For the log2 (CPM) calculated for each sample using the above method, a quasi-likelihood F-test was performed for comparison between two groups using glmQLFit and glmQLFTest, functions of the R package edgeR, and then the q-value was calculated by performing multiple comparison test correction using the Benjamini-Hochberg method.

[0034] Experiment 3 revealed that many genes showed altered expression upon addition of M1 or M2 macrophage culture supernatant, with a particularly significant increase in PRDX4 expression upon addition of M2 macrophage culture supernatant (Figure 1). Therefore, to confirm the increase in PRDX4 protein levels upon addition of M2 macrophage culture supernatant, immunostaining was performed using the following method.

[0035] Experiment 4: Immunostaining

[0036] The fibroblasts cultured in Experiment 2 were placed in 1 ml / well of 10% FBS-DMEM, 0.8 × 10⁶ cells. 5Cells were seeded in a 4-well chamber at a concentration of cells / well. After 24 hours, 1 ml / well of M1 / M2 macrophage culture supernatant supplemented with 0.5% FBS and 500 μM ascorbic acid was added. The control culture medium had the same composition except that it did not contain macrophage supernatant. After 48 hours, the medium was replaced with 0.5 ml / well of 0.5% FBS-DMEM. After another 24 hours, the medium was replaced with 4% PFA and fixed overnight. Subsequently, the cells were permeabilized by replacing the medium with 0.1% Triton X-100 / PBS for 3 minutes. After blocking at room temperature for 20 minutes using DAKO Protein Block Serum-Free Ready-To-Use, immunofluorescence staining was performed using an antibody against PRDX4 (Proteintech, 10703-1-AP). Washing with PBS was performed between each step after fixation.

[0037] The immunohistochemical staining results obtained from Experiment 4 are shown in Figure 2. Furthermore, Figure 3 shows the results of quantifying the PRDX4 brightness value of this immunohistochemical staining using the image analysis software ImageJ. It was confirmed that adding M2 macrophage culture supernatant to fibroblasts significantly increased the amount of PRDX4 protein compared to the control and M1 macrophage culture supernatant.

[0038] Experiment 5: Yellowing in collagen sponge and the effect of PRDX4 on suppressing yellowing. Collagen sponge Mighty (KOKEN, CSM-50) was placed in a 96-well plate. Three groups were tested: one with acrolein (AccuStandard, M-8015B-5031-03, final concentration 5 mM), one with acrolein (final concentration 5 mM) and PRDX4 (Abcam, ab93947, final concentration 10 μg / ml), and one with a control group (MilliQ). Each group was incubated at 37°C for 24 hours at 200 μl / well. After incubation, the plates were placed on white calibration plates (Konica Minolta, CR-A44) and photographs were taken using the standard camera app on an iPhone 7. The degree of yellowing of these collagen sponges was quantified by measuring the b* value, an indicator of yellowness, using a spectrophotometer CM-2600d (Konica Minolta).

[0039] Figure 4 shows an image of the results of Experiment 5. Figure 5 also shows the results of measuring the b* value of the collagen sponge using the method described above. It was found that although collagen turned yellow when acrolein was administered, the yellowing was suppressed when PRDX4 was administered. Therefore, it was found that PRDX4 has the effect of suppressing yellowing caused by carbonylation of skin proteins.

[0040] These experiments revealed that among numerous factors whose expression changes upon the addition of M1 / M2 macrophage supernatant, PRDX4 was identified as a factor whose gene expression increases (Figure 1), protein levels increase (Figures 2 and 3), and has an inhibitory effect on yellowing of the skin (Figures 4 and 5) upon the addition of M2 macrophage supernatant. These results indicate that subjects with lower PRDX4 levels are more susceptible to yellowing of the skin, and that yellowing is less easily suppressed in environments prone to yellowing, such as those with increased lipid peroxide metabolites and elevated reactive oxygen species. Therefore, using PRDX4 as an indicator allows for a simple and objective prediction of susceptibility to yellowing of the skin. Furthermore, this invention makes it possible to suppress yellowing of the skin by taking measures to increase the expression or activity of PRDX4. This measure is particularly effective for subjects with high susceptibility to yellowing of the skin. Additionally, using PRDX4 as an indicator allows for a simple screening process to find yellowing-inhibiting agents.

Claims

1. A cosmetic method for suppressing yellowing of the target skin, The method, which includes increasing the expression or activity of the target PRDX4, excluding medical procedures performed by physicians or healthcare professionals.

2. A screening method for an agent that suppresses yellowing of the skin, The method, which uses the expression or activity of PRDX4 in a skin sample as an indicator.

3. A screening method for an agent that suppresses yellowing of the skin, Applying a candidate drug to a skin sample; Measuring the expression or activity of PRDX4 in skin samples before and after application of the candidate drug; and If the expression or activity of PRDX4 in a skin sample treated with the candidate drug increases compared to before treatment with the drug, the drug is evaluated as having an anti-yellowing effect; The method, including the method described above.

4. The method according to any one of claims 1 to 3, wherein the suppression of the yellowing of the skin is achieved by inhibiting the carbonylation of collagen with PRDX4.

5. A cosmetic method for evaluating susceptibility to yellowing of the skin, The method, comprising evaluating the susceptibility of the subject's skin to yellowing using measured values ​​of PRDX4 expression or activity in a skin sample taken from the subject as an indicator, excluding medical procedures performed by physicians or healthcare professionals.

6. The method according to claim 5, wherein the lower the measured value, the higher the sensitivity of the target skin to yellowing.

7. The method according to any one of claims 1 to 6, wherein the aforementioned yellowing is caused by the carbonylation of collagen.

8. The method according to any one of claims 1 to 7, wherein the expression or activity of PRDX4 is promoted by induction or activation of M2 macrophages.

9. A system for evaluating susceptibility to yellowing of the skin, A database unit that stores data on pre-set reference values ​​for PRDX4 expression or activity, A data input unit for inputting data regarding the expression or activity of the target PRDX4, A calculation unit that refers to the reference values ​​for PRDX4 expression or activity stored in the database unit and compares them with the data on the expression or activity of the target PRDX4 entered in the data input unit to perform calculations. An evaluation unit that evaluates the susceptibility to yellowing based on the calculation results from the calculation unit, The system having a display unit that displays the results of the evaluation performed by the evaluation unit.

10. The system according to claim 9, wherein the display unit further displays suggestions for suppressing yellowing if the evaluation unit evaluates that the target has a high susceptibility to yellowing.

11. The proposed system according to claim 10, wherein the proposed system increases the expression or activity of PRDX4.

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