Why RNA Is a new target for anti-aging therapy

Skin begins to lose collagen and elastin long before wrinkles become visible — and this process unfolds at the molecular level earlier than we can observe it [1]. For a long time, it was believed that genes, health status (hormones), environmental factors (UV radiation, pollution), and lifestyle (stress, diet) were the primary drivers. However, modern science has revealed an additional layer of regulation between the genome and cellular behavior — the epigenetic layer. A substantial part of it is made up of non-coding RNAs (ncRNAs): molecules that do not encode proteins but actively regulate when and in what quantities those proteins are produced.

Three classes of ncRNA are of particular interest:

1. microRNAs (miRNA),
2. long non-coding RNAs (lncRNA),
3. circular RNAs (circRNA).

Their dysregulation in aging skin has been documented in numerous studies — both in chronologically aged and photoaged skin. This topic forms the subject of a major systematic review published in 2026 in Ageing Research Reviews [1].

Closer look at the three ncRNA сlasses

MicroRNAs (miRNA) are short molecules approximately 22 nucleotides in length. They act as post-transcriptional "switches": by binding to messenger RNAs, they block protein synthesis or accelerate mRNA degradation. In the skin, miRNAs regulate collagen synthesis and its breakdown by matrix metalloproteinases (MMPs), keratinocyte migration, inflammatory responses, and cell proliferation. For example:

• miR-146a controls NAMPT, a key enzyme in NAD+ metabolism, and the activity of sirtuins (SIRT) — proteins directly linked to cellular longevity.

Long non-coding RNAs (lncRNAs) are molecules longer than 200 nucleotides. They act as "molecular sponges," sequestering miRNAs and thereby preventing them from silencing their target genes. They also participate in chromatin remodeling and DNA methylation, influencing gene expression at multiple levels. Examples:

• lncRNA-H19 delays senescence in dermal fibroblasts by sequestering miR-296-5p and sustaining the PI3K/mTOR/AQP3 signaling pathway, which is essential for cell proliferation and skin hydration.
• lncRNA-PVT1 regulates aquaporin AQP3 — a transport channel through which water and glycerol enter the cell, supporting hydration of living cells and the skin overall.

Circular RNAs (circRNAs) are covalently closed-ring molecules distinguished by their high stability relative to linear RNAs; their closed structure protects them from enzymatic degradation, making circRNAs promising biomarkers and therapeutic targets. They also function as miRNA sponges and protein-binding scaffolds, contributing to cellular homeostasis. Examples:

• circRNA-406918 regulates cathepsin D activity — an enzyme involved in the degradation of glycation products in the skin.
• circ_0011129 limits collagen degradation during photoaging by neutralizing miR-6732-5p.

Researchers from Tecnológico de Monterrey (Mexico) and the University of Oslo (Norway) systematically analyzed data on the roles of miRNA, lncRNA, and circRNA in the molecular mechanisms of skin aging [1]. The review covers ncRNA biogenesis and their involvement in five key axes: redox control and extracellular matrix (ECM) integrity; metabolic adaptation and glycation; inflammatory regulation (inflammaging); senescence of fibroblasts and stem cells; and keratinocyte migration and re-epithelialization.

The analysis integrates data from in vitro studies, in vivo preclinical models, and clinical trial findings. The authors note that prior literature on this topic was fragmented, and their goal was to establish a coherent conceptual framework connecting ncRNA biogenesis, mechanistic function, and therapeutic relevance.

Molecules and epigenetic mechanisms of skin aging

The review identifies several molecules with the strongest evidence base. miR-146a is decreased in chronologically aged skin: its deficit disrupts the NAD+/SIRT axis and leads to metabolic "exhaustion" of cells. miR-296-5p, by contrast, is elevated in senescent fibroblasts — it suppresses lncRNA-H19 and growth factor IGF2, accelerating the loss of proliferative capacity.

In the context of photoaging, lncRNA-HULC (whose reduction amplifies the inflammatory response via TLR4 receptor) and lncRNA-SPRY4-IT1, which affects metabolic pathways under UV damage, are highlighted.

A dedicated section addresses the role of ncRNAs in regulating glycation — the excess accumulation of Advanced Glycation End-products (AGEs) formed through non-enzymatic interactions between sugars and proteins. In photoaged skin, the expression level of cathepsin D — a lysosomal enzyme that degrades AGEs in dermal cells — is reduced, leading to their accumulation. Overexpression of circRNA-406918 restores cathepsin D expression, increases cell viability, and enhances autophagic clearance of damaged components.

Also significant is the finding on inflammaging — the chronic low-grade inflammation that accompanies skin aging: ncRNAs modulate key inflammatory pathways (NF-κB, TGF-β, JAK-STAT). Pro-fibrotic molecules such as miR-155 and miR-21 drive fibrosis and scarring, while anti-fibrotic ones — miR-146b-5p and miR-29a-3p — act as molecular brakes.

The authors note that clinical application of ncRNAs remains limited and is associated with several unresolved challenges:

• Pleiotropy: a single miRNA molecule may regulate hundreds of target genes, creating a risk of off-target effects and unpredictable transcriptome remodeling.
• Immune reactivity: synthetic RNAs can activate innate immune receptors.
• Delivery: achieving penetration of ncRNAs through the multilayered skin structures to the target cell type remains a technical challenge.
• Long-term safety: the effects of chronic ncRNA modulation — including its impact on tumor suppression — remain underexplored.

The only compound mentioned in the review to have entered clinical evaluation is Remlarsen (a miR-29 mimic) for the treatment of keloid scarring. In study NCT03601052, it modestly delayed keloid formation but did not reduce its incidence or volume relative to placebo, and caused local reactions (edema, erythema, pain) in some participants. The authors emphasize that clinical research on ncRNAs remains largely focused on oncology, while data for photoaging, wound healing, and dermatological indications are scarce.

Prospects and practical relevance

Non-coding RNAs are real regulators of how quickly skin ages and how effectively it recovers. The review by González-Melgoza et al. demonstrates that behind the same phenotype — wrinkles, sagging, impaired healing — lie specific molecular events amenable to targeted correction.

Despite the preclinical status of most developments, the review outlines concrete strategies under active investigation. For delivering ncRNAs to target skin cells, lipid nanoparticles and microneedle patches show the greatest promise — they can penetrate the stratum corneum and achieve local action without systemic exposure. Exosomal delivery is equally compelling: exosomes enriched with bone marrow-derived miRNA-29b-3p have been shown to stimulate collagen synthesis and reduce MMP activity in dermal fibroblasts.

The authors propose combining ncRNA modulation with established agents — retinoids, metformin (which influences ncRNA networks via AMPK), and antioxidants, including epigallocatechin-3-gallate (EGCG) from green tea. Such combinations may enhance therapeutic efficacy while allowing lower doses of each component.

The diagnostic application is equally relevant: circRNA expression profiles exhibit high stability across tissues and biological fluids, making them strong candidates for monitoring the biological age of the skin.

Clinical use of ncRNAs remains a matter of the future — yet understanding these mechanisms is already reshaping approaches to developing active ingredients and the principles of personalized dermatology.

Reference

González-Melgoza L.L., Méndez-García A., Villegas Ruiz I. et al. Decoding skin aging: Emerging roles of miRNAs, lncRNAs, and circRNAs in mechanisms, therapies, and future horizons. Ageing Res Rev 2026; 118: 103094.