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The skin acts as the body's first line of defense against external threats. However, as we age, the epidermis -- the outermost layer of skin -- gradually becomes thinner and loses its protective strength. About 90% of the cells in this layer are keratinocytes, which originate from deeper layers of the epidermis and migrate upward, ultimately forming the skin's protective barrier. To combat aging's impact on skin, numerous studies have emphasized the benefits of vitamin C (VC), a vitamin well known for its role in skin health and antioxidant properties.
Now, researchers in Japan have discovered that VC helps thicken the skin by directly activating genes that control skin cell growth and development. Their findings, published online in the Journal of Investigative Dermatology on April 20, 2025, suggest that VC may restore skin function by reactivating genes essential for epidermal renewal.
This study was led by Dr. Akihito Ishigami, Vice President of the Division of Biology and Medical Sciences at Tokyo Metropolitan Institute for Geriatrics and Gerontology (TMIG), Japan, in collaboration with Hokuriku University, and ROHTO Pharmaceutical Co., Ltd. Associate Professor Ayami Sato from TMIG (currently at the Toyo University); Associate Professor Yasunori Sato, Professor Toshiyuki Kimura, and Mr. Hideki Tanaka (currently at the University of Fukui Hospital) from Hokuriku University; and Ms. Florence, Ms. Akari Kuwano, Mr. Yasunari Sato, and Mr. Tsuyoshi Ishii from ROHTO Pharmaceutical Co., Ltd also co-authored the study.
"VC seems to influence the structure and function of epidermis, especially by controlling the growth of epidermal cells. In this study, we investigated whether it promotes cell proliferation and differentiation via epigenetic changes," explains Dr. Ishigami, while talking about this study.
To investigate how VC affects skin regeneration, the team used human epidermal equivalents, which are laboratory-grown models that closely mimic real human skin. In this model, skin cells are exposed to air on the surface while being nourished from underneath by a liquid nutrient medium, replicating the way human skin receives nutrients from underlying blood vessels while remaining exposed to the external environment.
The researchers used this model and applied VC at 1.0 and 0.1 mM -- concentrations comparable to those typically transported from the bloodstream into the epidermis. On assessing its effect, they found that VC-treated skin showed a thicker epidermal cell layer without significantly affecting the stratum corneum (the outer layer composed of dead cells) on day seven. By day 14, the inner layer was even thicker, and the outer layer was found to be thinner, suggesting that VC promotes the formation and division of keratinocytes. Samples treated with VC showed increased cell proliferation, demonstrated by a higher number of Ki-67-positive cells -- a protein marker present in the nucleus of actively dividing cells.
Importantly, the study revealed that VC helps skin cells grow by reactivating genes associated with cell proliferation. It does so by promoting the removal of methyl groups from DNA, in a process known as DNA demethylation. When DNA is methylated, methyl groups attach to cytosine bases, which can prevent the DNA from being transcribed or read, thereby suppressing gene activity. Conversely, by promoting DNA demethylation, VC promotes gene expression and helps cells to grow, multiply, and differentiate.
The study suggests that VC supports active DNA demethylation by sustaining the function of TET enzymes (ten-eleven translocation enzymes), which regulate gene activity. These enzymes convert 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC), a process in which Fe2+ is oxidized to Fe3+. VC helps maintain TET enzyme activity by donating electrons to regenerate Fe2+ from Fe3+, enabling continued DNA demethylation.
The researchers further identified over 10,138 hypomethylated differentially methylated regions in VC-treated skin and observed a 1.6- to 75.2-fold increase in the expression of 12 key proliferation-related genes. When a TET enzyme inhibitor was applied, these effects were reversed, confirming that VC functions through TET-mediated DNA demethylation.
These findings reveal how VC promotes skin renewal by triggering genetic pathways involved in growth and repair. This suggests that VC may be particularly helpful for older adults or those with damaged or thinning skin, boosting the skin's natural capacity to regenerate and strengthen itself.
"We found that VC helps thicken the skin by encouraging keratinocyte proliferation through DNA demethylation, making it a promising treatment for thinning skin, especially in older adults," concludes Dr. Ishigami.
This study was supported by grants from the Japan Society for the Promotion of Science (JSPS) KAKENHI: grant number 19K05902.