Non-ablative fractional laser 1940-nm treatment modulates epigenetic signatures associated with skin aging in a split-face investigation
Konika Patel Schallen1, Kevin Schomacker1, Cristiana Banila2, Harry Pink2, Nicolle Dest1 & Katherine L. R. Coleman1
Introduction
Skin aging results from the combined effects of intrinsic biological decline and cumulative environmental exposure, leading to structural degradation, pigmentation changes, and reduced regenerative capacity1–3. Intrinsic aging manifests as thinning, fine wrinkles, and slower cellular turnover, while extrinsic aging, driven largely by chronic ultraviolet radiation (UVR) accelerates and intensifies these changes, producing distinct photoaging features4,5. UVR contributes to skin aging through cumulative lifetime exposure via distinct but overlapping mechanisms. UVA penetrates deeply into the dermis and is a major driver of oxidative stress, extracellular matrix (ECM) damage, mitochondrial dysfunction, pigmentary change, and immunomodulation6. By contrast, the more energetic UVB spectrum primarily affects the epidermis, where it induces direct DNA photodamage, inflammation, and mutational burden7.
More broadly, aging is understood to arise from the lifelong accumulation of cellular and molecular damage8 across multiple interconnected hallmarks, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication9. Within this framework, epigenetic dysregulation represents one contributor to age-associated functional decline through changes in DNA methylation, histone modification, and chromatin organization associated with aging and disease10,11. Among these, DNA methylation stands out as a key biomarker, linking environmental exposures to gene expression and capturing the lasting molecular impact of factors such as UVR, pollution, nutrition, and lifestyle12–16.
Age-associated DNA methylation changes, including locus-specific hypermethylation at regulatory regions, mark dysregulation of pathways controlling inflammation, differentiation, tissue repair, oxidative stress, and ECM homeostasis10,17–20. These alterations are not fixed. Increasing evidence shows that targeted modulation of
age-linked methylation states can shift molecular profiles toward those of younger tissues21–25. Here, consistent with prior work25, we define “rejuvenation” as the partial restoration of molecular or epigenetic features characteristic of youthful states, without implying full reversal of biological age or durable anti-aging effects.
Energy-based devices (EBDs) such as non-ablative fractional lasers (NAFL) are widely used for treatment of photoaging and other cutaneous aesthetic concerns through the induction of controlled microthermal zones (MTZs) that stimulate dermal remodeling while largely preserving surrounding tissue integrity. This controlled injury initiates a wound-healing cascade associated with collagen remodeling and clinical improvement in skin texture, pigmentation, and elasticity26. Beyond cosmetic benefit, NAFL treatment has also been associated with reduced incidence of facial keratinocyte carcinomas27 and actinic damage28–31, suggesting broader biological effects beyond structural resurfacing. Early molecular studies further indicate that EBDs modulate pathways involved in inflammation, matrix turnover, pigmentation, and regeneration25,32–36. However, whether these treatment-associated transcriptomic changes are underpinned by durable epigenetic remodeling, particularly at the level of DNA methylation, remains unknown.
