Shiseido elucidates cellular senescence mechanism underlying age spots through optical real-time FLIM analysis for the first time in the world

Shiseido has uncovered a mechanism underlying the exacerbation of age spots through an innovative approach that challenges conventional knowledge in age spot research. Using FLIM*1, which allows observation of the living human skin in real time, the company has established a method for evaluating cellular metabolism at the site of age spots for the first time in the world*2. This led to capturing of the time frame of how age spots worsen, the ”lifecycle of age spot,” which has been difficult to observe until now. By utilizing this method, a cellular senescence occurring at the site of age spots was identified as the root cause of exacerbation of age spots, and unique triple active ingredients was developed to address the worsening of age spots (Figure 1). Focusing on the “lifecycle of age spot,” we will devise innovative solutions to address the root cause of age spot exacerbation, challenging conventional knowledge in current age spot research.
The results of this groundbreaking research won the top award in the Podium Presentation Basic Research category at the IFSCC Congress*3, the world's largest, prestigious research conference for cosmetics technology, achieving high acclaim as a next-generation cosmetic technology. The study was also presented at the 32nd Annual Meeting of the Japanese Society for Pigment Cell Research (2024/11/2-11/3). Moving forward, we will continue to aim for the development of innovative solutions through application of advanced research findings.
*1 FLIM: Fluorescence Lifetime Imaging Microscopy, an observation method for imaging based on fluorescence lifetime, which is an inherent property of fluorescent molecules.
*2 This is the world's first method to evaluate cellular metabolism at the site of age spots in the epidermis via a specific electron transport component using FILM (as researched by Clarivate, September 2024)
*3 IFSCC: The International Federation of Societies of Cosmetic Chemists. Shiseido won Top Award for the results of this research at the 34th IFSCC Congress 2024 Brazil, Iguazu Falls (2024/10/14-10/17)

Figure 1. Cellular senescence mechanism specific to age spots and its solution

Download Small Image[183KB]

Research background

Through more than 100 years of skin research and advanced age spots research, Shiseido has revealed various factors related to the formation of age spots using multiple approaches to examine age-spot’s microenvironment, where excessive melanogenesis and melanin-deposition occur. We came to think that the observation of the internal structure of the skin is important to elucidate age spots. To this end, we strived to develop solutions by identifying factors specific to age spots: the condition of melanin deposition in age spots, abnormal capillary formation, darkening spiral that promotes excessive generation of melanin, and chronic micro-inflammation. Meanwhile, we have found that it is necessary to capture the dynamic changes occurring inside the skin, which are linked to these specific factors of age spots, at the cellular level in the same environment as the actual skin. However, it was difficult to analyze the inside of living age spots at the cellular level and in real time. In order to solve the fundamental problem of age spots, we needed to focus on the “lifecycle of age spot” and understand it as the activity state occurring within the lifecycle of skin cells, that is, metabolic changes in cells. This time, using FLIM, we established a new technique to observe the living skin, and observed mitochondrial metabolism in age spots for the first time in the world, taking on a challenge to verify the associated metabolic state.

Established a new technique for evaluating cellular metabolism at the site of age spots by applying FLIM, and elucidated the cellular senescence mechanism specific to age spots

FLIM-based analysis led to a finding that the mitochondrial metabolism in epidermal cells was reduced at the site of age spots in the living human skin compared with the no-age-spot site (Figure 2). It was also confirmed that this decrease in mitochondrial metabolism was caused by the excessive deposition of melanin (Figure 3), which further induced cellular senescence (Figure 4). These findings suggest that, at the site of age spots, mitochondrial metabolism is reduced because of the deposition of melanin, causing cellular senescence; this worsens age spots. In other words, there exists a source of age spot exacerbation, i.e., a vicious cycle of formation and spread of age spots.

Figure 2. Mitochondrial metabolism in epidermal cells is reduced at the site of age spots compared with the non age-spot site
Figure 3. Excessive melanin deposition lowers mitochondrial metabolism
Figure 4. Excessive melanin deposition causes cellular senescence deposition lowers mitochondrial metabolism

Figure 2

Download Small Image[138KB]

Figure 3

Download Small Image[110KB]

Figure 4

Download Small Image[94.5KB]

Shiseido's unique triple active ingredients improves the cellular senescence mechanism specific to age spots

A formulation containing Shiseido's unique triple active ingredients was continuously applied to human skin for 6 weeks. As a result, we found that mitochondrial metabolism in age spots was enhanced with the application of the triple complex formulation (Figure 5). In addition to suppressing the decrease in mitochondrial activity, which is one of the major factors of cellular senescence, it also suppressed GROα*4, a SASP factor*5 secreted by senescent cells that further exacerbates cellular senescence (Figure 6).
*4 One of SASP factors secreted by epidermal keratinocytes. It is also known to be involved in the process of melanocytes transformation to melanoma.
*5 General term for various factors including inflammatory factors secreted by senescent cells, called senescence-associated secretory phenotype (SASP).

Figure 5. Continuous application of the triple active ingredients-containing formulation increases mitochondrial metabolism at age spots
Figure 6. Triple active ingredients-containing formulation suppressed GROα

Figure 5

Download Small Image[83.6KB]

Figure 6

Download Small Image[73.8KB]

Future prospects

Shiseido aims to realize healthy beauty unique to each individual throughout his/her life under the company’s vision toward 2030: ”Personal Beauty Wellness Company.” In order to respond to a variety of skin problems and support the pursuit of individual beauty, we will deepen our research toward a profound understanding of skin problems such as age spots and skin dullness and development of solutions.

About our R＆D strategy:
We conducted this research under ”Skin Beauty INNOVATION,” one of the three pillars of Shiseido's R＆D strategy, to elucidate the causes of ”permanent skin concerns”, including age spots/skin dullness, wrinkles, sagging, and pores, that our customers have been expressing for many years and develop solutions.