Shiseido discovers that aging increases the risk of hyperpigmentation under UV light exposure during daytime hours, leading to the development of suppression methods

Shiseido discovered that, in the skin with dark spots, the expression of ”interleukin 6 receptor (IL-6R),”*1 an inflammatory factor receptor that is known to be involved in chronic inflammation in age-related diseases, increases more with advancing age in conjunction with UV irradiation during the day. The study revealed that, even when the amount of exposure to UV light is the same, the risk of dark spot formation (hyperpigmentation) and/or worsening may increase because of aging factors, given that the higher the expression of IL-6R in epidermal cells, the higher the activity of melanocytes.*2 In addition, Shikuwasa (Hirami lemon）extract was found to be useful as an agent to suppress inflammatory reactions caused by UV radiation and aging, and its effect to inhibit the activity of melanocytes was confirmed.
Until now, the details have remained unclear regarding the mixed effects of UV radiation and aging in the hyperpigmentation process. The present discovery will make it possible to approach dark spot prevention from the two aspects, i.e., UV radiation as an external factor and aging as an internal factor, demonstrating, once again, the importance of dark spot risk care in the daytime. This knowledge will be applied to future product development. The results of this study were partly presented at the 25th International Pigment Cell Conference (23/5/30–6/2) and the 1st Annual Congress of the Society of Cosmetic Chemists of Japan (SCCJ) (23/12/5–7).
*1 The receptor that receives IL-6, an Inflammatory factor, and transmits the signal in response to inflammation in the cell.
*2 A condition in which the length and number of dendrites of melanocytes increase, and melanin delivery is promoted.

Figure 1. The receptor IL-6R, which triggers inflammatory response, is highly expressed due to aging

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Research background

From early on, Shiseido has pursued studies in the field of dark spot research focused not only on ”melanin production,” which is a localized phenomenon, but also on the ”dark spot-prone skin environment” that increases the risk of hyperpigmentation by promoting melanin production, advocating the company's unique research findings pertaining to dark spots that explain how the skin environment prone to dark spots is created under the condition of inflammation—”chronic micro-inflammation.”*3 Meanwhile, regarding the two major factors of inflammation that lead to the creation of dark spot-prone skin environment, namely, the external factor of UV radiation and the internal factor of aging, their mixed effects have only partly been elucidated. Against this backdrop, the present study was undertaken with the aim to clarify the mechanism of hyperpigmentation from both aspects.
*3 A condition in which weak inflammation continues to occur chronically in the epidermis and dermis

The skin with dark spots shows increased expression of the inflammatory factor receptor IL-6R in epidermal cells

We discovered that, when the inflammatory condition in human skin tissue was compared between areas with hyperpigmentation and without (non-hyperpigmented area), the level of expression of the inflammatory factor receptor IL-6R was higher in the hyperpigmented area (Figure 2). It was speculated that the hyperpigmented area of the skin is in a state prone to ”worsening” dark spots, as inflammation is chronically activated due to an excessive increase in IL-6R, the receptor for the inflammatory factor IL-6.

Figure 2. IL-6R, a receptor for the inflammation-inducing factor, was overexpressed in the hyperpigm

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The increase in IL-6R in epidermal cells due to aging and UV radiation leads to activation of melanocytes

Next, we investigated ”aging” as a factor that influences the expression of IL-6R, which was increased in the hyperpigmented area. Experiments using young or aged human-derived epidermal cells revealed a higher increase in the expression of IL-6R in the cells due to UV light exposure, assuming daytime sunlight, in aged cells (Figure 3). Moreover, when we observed the condition of melanocytes co-cultured with aged epidermal cells in order to investigate whether IL-6R actually affects the activation of melanocytes, the number and length of dendrites, which are indicators of melanocyte activation, increased and elongated compared with those of melanocytes co-cultured with young epidermal cells (Figure 4).
An increase in IL-6R in epidermal cells triggers the activation of melanocytes, and this is potentially prompted by ”aging.”

Figure 3. Increased IL-6R gene expression due to UV radiation and aging

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Figure 4. UV light exposure induces melanocyte activation in aged epidermal cells

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Discovery of an extract effective for suppressing IL-6R expression

This time, upon finding that the risk of developing or worsening hyperpigmentation due to UV radiation is increased via promotion of IL-6R expression due to aging, we searched for an agent that could suppress the expression of IL-6R. As a result, we discovered that the extract of Shikuwasa extract has an effect to suppress the expression of IL-6R in epidermal cells (Figure 5). Moreover, we found that Shikuwasa extract　 has an effect to suppress an increase or extension of the number and length of dendrites of melanocytes co-cultured with aged epidermal cells (Figure 6). We believe that, by suppressing IL-6R expression, it will be possible to realize a new approach to prevent dark spots, i.e., to prevent an increase in the risk of developing or worsening hyperpigmentation even in aged skin.


Under the company vision ”PERSONAL BEAUTY WELLNESS COMPANY” toward 2030, Shiseido has been striving to become a company that people in realizing unique beauty and wellness throughout their lives. In order to provide proactive care for worrisome dark spots and dullness and support one’s own unique beauty and wellness , we will continue to carry out studies with the aim of promoting dark spot and dullness prevention and improvement in a fundamental way.

Figure 5. Shikuwasa extract suppresses IL-6R gene expression

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Figure 6. Shikuwasa extract suppresses the activation of melanocytes after UV light exposure

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