Hyaluronic Acid
What is Hyaluronic Acid?
Hyaluronic acid (HA, also called hyaluronan) is a linear, unbranched glycosaminoglycan composed of repeating disaccharide units of D-glucuronic acid and N-acetyl-D-glucosamine linked by alternating β-1,4 and β-1,3 glycosidic bonds (Iaconisi, G. N. et al., 2023). Unlike other glycosaminoglycans, HA is nonsulfated, is not attached to a core protein, and is synthesised at the plasma membrane by hyaluronan synthases (HAS1-3) (Bravo et al.,2022). In vivo, HA is present throughout connective, epithelial, and neural tissues; over half of the total body HA is located in the skin (Chylińska & Maciejczyk, 2025). The extracellular matrix (ECM) is a structural network of proteins and glycosaminoglycans that surrounds dermal cells, providing mechanical support, hydration, and tissue integrity. Within the dermis, HA is a key extracellular matrix (ECM) component that fills the interstitial space, binding large amounts of water due to its highly anionic, hydrophilic nature. This water binding gives HA its characteristic viscosity and contributes to tissue turgor and resistance to physical stress (Iaconisi, G. N. et al., 2023). HA also forms a “mesh” or pericellular coat around many cell types, supporting cell migration and acting as a barrier against pathogens (Chylińska & Maciejczyk, 2025). HA is biocompatible and biodegradable (identical across species), which underlies its broad use in medical and cosmetic applications. To keep it simple, Hyaluronic acid is a naturally occurring substance in the body known for its ability to retain moisture, making it beneficial for skin hydration, joint lubrication, and wound healing.
Age-Related Decline and Skin Ageing
HA levels in skin decline with age and environmental exposure. Clinical studies report that elderly individuals have far less dermal HA than young adults – for example, one study found 75-year-old skin has <25% of the HA content of 19-year-old skin (Maria et al., 1987). The biosynthetic activity of HA synthases (HAS1 and HAS2) is known to fall in ageing skin, and UV irradiation accelerates HA breakdown, compounding depletion. As skin HA falls, its water-binding capacity is reduced, causing drier, less elastic skin. Clinically, this manifests as loss of plumpness, sagging, a rough texture, and the formation of wrinkles (Chylińska & Maciejczyk, 2025). Age-related HA depletion also impairs wound healing; older skin shows slower repair, partly because the HA-rich provisional matrix is diminished. Because HA is so central to dermal hydration and ECM structure, its decline is considered a key driver of intrinsic skin ageing. In view of this, supplementing HA (via injections, topical products, or oral “nutricosmetics”) has become a common anti-ageing strategy (Chylińska & Maciejczyk, 2025).
Mechanistic Roles of HA in Skin
Hydration and ECM Integrity
HA’s principal role in skin is to bind and retain water, maintaining dermal hydration and volume. Its high molecular weight polymer chains can trap up to 1000 times their weight in water via hydrogen bonding, creating a viscous gel within the ECM. This HA-hydrated matrix resists compression and provides structure to connective tissues (Iaconisi, G. N. et al., 2023). HA also interacts with other ECM components (collagen, proteoglycans) and cell-surface receptors to modulate matrix assembly. CD44 is a transmembrane adhesion receptor that binds hyaluronic acid to regulate fibroblast attachment, cytoskeletal organisation and migration. RHAMM (Receptor for Hyaluronan-Mediated Motility) is a hyaluronan-binding receptor involved in mechanotransduction and cell motility, enabling HA-dependent fibroblast migration and wound repair. For example, through CD44 and RHAMM receptors, HA can influence fibroblast adhesion and migration (Bravo et al.,2022). By stabilising the ECM and supporting fibroblast function, HA indirectly promotes collagen and elastin homeostasis (Bukhari et al., 2018). In ageing skin, loss of HA undermines this matrix integrity, leading to collagen fragmentation and tissue laxity.
Inflammation and Immunomodulation
HA modulates inflammatory signalling in a size-dependent manner. Very high molecular weight (HMW) HA (>1 MDa) tends to exhibit anti-inflammatory properties, as it can inhibit angiogenesis (biological process of forming new blood vessels from existing ones) and suppress the activation of immune cells (Iaconisi, G. N. et al., 2023). In contrast, low molecular weight (LMW) HA fragments (<250 kDa) often act as damage-associated molecular patterns (DAMPs), binding Toll-like receptors and inducing pro-inflammatory cytokines (e.g. IL-1β, TNF-α, IL-8) (Iaconisi, G. N. et al., 2023). During injury or UV exposure, HA is enzymatically or oxidatively cleaved, generating LMW oligosaccharides that recruit immune cells and stimulate granulation tissue formation (Kawano et al., 2021). Over time, chronic HA fragmentation may perpetuate low-grade inflammation in ageing skin (sometimes called “inflammaging”), further degrading the matrix. At the same time, HMW HA coatings on cell surfaces and in healthy ECM help dampen excessive inflammation (Chylińska & Maciejczyk, 2025). Thus, HA plays a complex role in skin immunity, promoting repair while also modulating the inflammatory balance.
Wound Healing and Repair
Keratinocytes are the primary epithelial cells of the epidermis that migrate to resurface and close the wound, and Fibroblasts are dermal connective-tissue cells that migrate into the wound to deposit new extracellular matrix and form granulation tissue. HA is critically involved at all stages of wound repair. In early wounds, HA-rich matrix fills the gap, providing a scaffold that allows keratinocytes and fibroblasts to migrate (Kawano et al., 2021). High levels of HA in the provisional matrix keep the wound moist and facilitate growth factor signalling. As healing proceeds, HA stimulates cell proliferation and angiogenesis. For example, Kawano demonstrated that topically applied HMW HA markedly upregulated VEGF and other genes in keratinocytes, thereby accelerating re-epithelialization (Kawano et al., 2021). VEGF (Vascular Endothelial Growth Factor) is a signalling protein that stimulates the growth of new blood vessels and supports tissue regeneration. Upregulating VEGF in keratinocytes helps improve nutrient supply and accelerates re-epithelialisation during wound healing. HA also promotes fibroblast-to-myofibroblast transition (in concert with TGF-β) to facilitate contraction and collagen deposition during remodelling. Conversely, disrupted HA synthesis impairs healing, illustrating its central role in tissue regeneration. By maintaining hydration and supporting cell signalling, HA ensures effective wound closure and restoration of skin architecture (Kawano et al., 2021).
Fibroblast Function and Collagen Synthesis
HA signals directly to dermal fibroblasts through CD44 and other receptors, influencing their proliferation and matrix production. Inserting HA into aged dermis (e.g. via fillers) mechanically stretches fibroblasts, which respond by increasing collagen synthesis. In a study, injecting cross-linked HA into sun-damaged forearm skin of elderly subjects significantly increased type I procollagen staining and collagen gene expression over a period of 4 to 13 weeks (Wang et al., 2025). Electron microscopy revealed that filler-treated fibroblasts became elongated and developed an abundant rough endoplasmic reticulum, indicating active collagen production (Wang et al., 2025). Thus, HA (particularly stabilised dermal fillers) adds volume and induces the formation of new collagen in the dermis, partially restoring the aged extracellular matrix. In vitro studies have likewise found that exogenous HA can modulate fibroblast proliferation and protein synthesis, depending on its molecular weight, reinforcing that HA is more than a passive filler (Iaconisi, G. N. et al., 2023).
Molecular Weight Variations
HA’s biological effects are strongly influenced by its molecular weight (MW). Native HA in human tissues spans a wide size range (10^5 - 10^7 Da) (Bravo et al.,2022). Manufacturers also produce defined fractions: for convenience, these are often classified as high MW (HMW, >1,000 kDa), medium MW (MMW, ~250 - 1000 kDa), and low MW (LMW, 10 - 250 kDa) (Iaconisi, G. N. et al., 2023). HMW HA forms very viscous gels with strong viscoelastic properties. It acts as an excellent space-filling and lubricating material, forming an occlusive film on the skin surface that prevents transepidermal water loss (Chylińska & Maciejczyk, 2025). However, HMW HA by itself does not readily penetrate the epidermis: it largely stays on the stratum corneum, hydrating the surface. In contrast, LMW HA is less viscous and can permeate the skin more deeply. Studies indicate that 50 - 200 kDa HA fragments can diffuse through the epidermis to reach the dermis. Accordingly, topical products often combine HA of multiple weights: HMW forms an external barrier to seal in moisture, while LMW fractions penetrate to deliver hydration and bioactivity internally (Chylińska & Maciejczyk, 2025).
The size also dictates signalling roles: as noted, HMW HA exerts anti-inflammatory, anti-angiogenic, and immunosuppressive effects, whereas LMW HA tends to be pro-angiogenic and can stimulate cytokines and growth factors (Iaconisi, G. N. et al., 2023). For example, HMW HA increases TGF-β3 expression (which reduces scarring), whereas very small HA oligomers upregulate pro-inflammatory interleukins and TGF-β1/2 (profibrotic growth factors that promote inflammation, fibroblast activation and collagen deposition). Thus, “full-spectrum” HA preparations may aim to harness both barrier hydration (via HMW) and regenerative signals (via LMW) (Nobile et al., 2025). Understanding these size-dependent activities is crucial: for instance, low-MW HA in cosmetics has more anti-wrinkle effect because of dermal penetration, while HMW HA is key in joint viscosupplements and dermal fillers for mechanical support.
Clinical Studies of HA in Skin Ageing
Several clinical trials have evaluated HA supplementation in humans for skin ageing endpoints.
Oral HA
Several placebo-controlled trials have investigated the effects of oral HA ingestion (typically 80 - 240 mg/day) on skin parameters. Hsu conducted a 12-week randomised trial in 40 middle-aged adults taking 120 mg/day oral hyaluronan. They found significant improvements compared to the placebo in wrinkle depth, stratum corneum water content, transepidermal water loss, and skin elasticity (Hsu et al., 2021). By week 12, the HA group showed notably smoother skin and increased hydration compared to controls. Another recent trial by Nobile combined oral HA with topical HA in a 56-day study: subjects receiving both “in & out” HA therapy showed greater gains in skin moisture, firmness, and wrinkle reduction than those receiving either treatment alone or the placebo (Nobile et al., 2025). (All study cohorts using HA showed statistically significant improvements in clinician- and instrument-measured skin parameters, and patients reported better self-perception of ageing.) In general, oral HA trials report enhanced skin hydration and elasticity, as well as reduced wrinkle severity, after 1 - 3 months of daily HA supplementation (Hsu et al., 2021). A recent meta-analysis (seven randomised controlled trials) concluded that oral HA yields modest but significant improvements in skin hydration and wrinkle depth, supporting its nutricosmetic use (Amin et al., 2025). The mechanism is thought to involve increased HA content in the dermis and improved water retention, although precise pharmacokinetics remain under study.
Anti-Aging Outcomes
HA supplementation yields several demonstrable anti-ageing effects on skin. Both oral and injectable HA have been shown to reduce wrinkle depth. Hsu observed significant improvements in wrinkle appearance (measured by imaging) after 8 - 12 weeks of oral HA administration (Chylińska & Maciejczyk, 2025). Nobile similarly reported softer facial lines with oral and topical HA treatment. Injectable HA fillers produce immediate wrinkle effacement and volume restoration, with secondary collagen induction that may enhance results over several months (Wang et al., 2025). Skin elasticity and firmness: Multiple studies document that HA (oral or topical) improves skin elasticity metrics. Hsu observed increased elastometer readings after HA ingestion, and cosmeceutical trials often report statistically significant gains in firmness. The hydrating effect of HA likely allows collagen fibres to recoil more easily, mechanically increasing elasticity.
The most consistent finding across trials is enhanced skin hydration. Oral HA ingestion increases the water content of the stratum corneum and reduces transepidermal water loss (Chylińska & Maciejczyk, 2025). Topical HA provides an immediate increase in skin hydration (often reported to be more than 50%) that can persist with regular use (Wang et al., 2025). Chronic moisturiser use with HA helps replenish the dermal water reservoir, giving a dewy, plump appearance.
Evidence from biopsy studies indicates that HA (especially cross-linked injectables) stimulates the production of new collagen in aged skin (Wang et al., 2025). This effect may translate to gradual improvement of dermal matrix density.
Some small trials have measured biochemical markers; for example, tissue levels of hyaluronan itself rise after HA treatment, suggesting uptake and retention of the substance. To date, there is no direct evidence that HA supplementation affects DNA methylation or other epigenetic markers of ageing. Most benefits appear to be structural and hydrating rather than genomic.
HA (in its various formulations) acts through multiple mechanisms to counteract skin ageing: it restores hydration, reinforces ECM architecture, modulates inflammation, and promotes tissue repair (Chylińska & Maciejczyk, 2025). Clinical trials consistently demonstrate modest yet significant improvements in wrinkles, hydration, and elasticity, with an excellent safety profile (Hsu et al., 2021). These data support HA as a key anti-ageing biomolecule for skin, whether delivered topically, orally, or via injection.