Study Examines How Vitamin C Shapes Skin Health Through TET-Mediated Demethylation

Vitamin C could combat aging’s impact on the skin by directly activating genes that control skin cell growth and development. The findings, published by investigators in the Journal of Investigative Dermatology, suggest that vitamin C could restore skin function by reactivating genes that are essential for epidermal renewal, ultimately thickening the skin.^1,2

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“Vitamin C seems to influence the structure and function of the epidermis, especially by controlling the growth of epidermal cells. In this study, we investigated whether it promotes cell proliferation and differentiation via epigenetic changes,” Akihito Ishigami, vice president of the division of biology and medical sciences at Tokyo Metropolitan Institute for Geriatrics and Gerontology (TMIG), Japan, said in a news release.²

Vitamin C's Influence on Function of Epidermis

Vitamin C is known for its antioxidant properties and has been shown to enhance collagen synthesis, mitigate UV damage, inhibit melanin deposition, and prevent epidermal atrophy. The epidermis is a multi-layered tissue that is primarily composed of keratinocytes, which differentiate and migrate upwards from the basal layer to the skin surface.¹

The study authors noted that previous research suggests that vitamin C regulates epidermal cell proliferation and differentiation, possibly by influencing DNA methylation. While vitamin C’s role in DNA methylation has been established in other cell types, its impact on epidermal cell proliferation and differentiation through this mechanism requires further research.¹

Vitamin C and Skin Regeneration

The researchers conducted a study based in Japan using human epidermal equivalents—laboratory-grown models that closely imitate real human skin—which are exposed to air on the surface while receiving nourishment from a liquid nutrient medium underneath. The study authors noted that this was done to mimic how human skin obtains nutrients from underlying blood vessels while also being exposed to the external environment. Vitamin C was administered at 1.0 mM and 0.1 mM concentrations.¹

The results demonstrated that on skin treated with vitamin C, a thicker epidermal cell layer was present without the effect of stratum corneum on day 7 of the study. Following, on day 14, the inner layer was even thicker, and the outer layer was thinner. These initial findings suggest that vitamin C promotes the formation and division of keratinocytes—whose roles remained unclear during epidermal tissue formation.^1,2

Further results revealed that vitamin C promotes the removal of methyl groups from DNA, known as DNA demethylation, which helps the skin cells grow by reactivating genes. In this process, vitamin C also promotes gene expression and helps cells to grow, multiply, and differentiate.^1,2

Furthermore, the study indicated that vitamin C aids active DNA demethylation by maintaining the function of ten-eleven translocation (TET) enzymes. These enzymes convert 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), a process that oxidizes Fe²⁺ to Fe³⁺. Vitamin C helps regenerate Fe²⁺ by donating electrons, ensuring TET enzyme activity and continued DNA demethylation. The researchers found that vitamin C treatment led to over 10,000 hypomethylated differentially methylated regions in the skin, boosting the expression of 12 proliferation-related genes by 1.6 to 75.2 times. Blocking TET enzymes reversed these effects, which confirmed vitamin C’s role in TET-mediated DNA demethylation.^1,2

The findings suggest that vitamin C could be helpful for older adults or those with damaged or thinning skin to help naturally strengthen and regenerate itself.^1,2

“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,” Ishigami concluded.²

REFERENCES

1. Sato Y., Sato A., Ishigami A. et al. Vitamin C Promotes Epidermal Proliferation by Promoting DNA Demethylation of Proliferation-Related Genes in Human Epidermal Equivalents. Journal of investigative Dermatology. April 20, 2025. doi: 10.1016/j.jid.2025.03.040

2. Uncovering the role of vitamin C in skin regeneration. EuerkAlert!. News release. June 25, 2025. Accessed July 2, 2025. https://www.eurekalert.org/news-releases/1088729