Sustainable Hydroxytyrosol Rich Formulations for Skin Health and Healthy Ageing

1. Introduction

The skin is a dynamic, multifunctional organ essential for maintaining homeostasis through its roles in barrier function, thermoregulation, and immune surveillance, which contribute to overall health [Zhu et al., 2025]. Skin health is closely associated with the integrity of the skin barrier, which provides protection against ultraviolet (UV) radiation, pollutants, and pathogens [Mohania and Chandel, 2017; Fitoussi et al., 2022; Elias, 2008]. Beyond barrier integrity, healthy skin is characterized by adequate hydration, preservation of extracellular matrix (ECM) components such as collagen and elastin, efficient wound healing, and protection against oxidative damage and systemic inflammation. Together, these features contribute to skin elasticity, resilience, and overall appearance. Aging progressively compromises these functions, leading to reduced hydration, impaired repair capacity, and increased skin pH, promoting cutaneous and systemic inflammation via elevated circulating cytokines [Wang et al., 2020; Hu and Mauro, 2017]. Skin ageing is driven by a complex interplay of intrinsic and extrinsic factors, with oxidative stress and chronic low-grade inflammation representing the principal mechanisms underlying progressive structural and functional skin decline [Rinnerthaler et al., 2015; Kammeyer and Luiten, 2015]. Poor nutrition, dehydration, sleep deprivation and hormonal changes, particularly estrogen decline during ageing, may further exacerbate these alterations [Fitzmaurice et al., 2011; Raine-Fenning et al., 2003]. In addition, growing interest has focused on the contribution of microbial ecosystems to skin physiology and ageing. Both the skin microbiome and the gut-skin axis have been increasingly recognized as important components of cutaneous homeostasis and immune regulation [Lunjani et al., 2021; Liu et al., 2023; Millman et al., 2024; Jimenez-Sanchez et al., 2025]. Emerging evidence suggests that alterations in these interconnected systems may influence skin function and contribute to age-related changes and inflammatory skin conditions, highlighting their potential relevance as targets for preventive and therapeutic strategies [Lunjani et al., 2021; Liu et al., 2023; Millman et al., 2024; Jimenez-Sanchez et al., 2025].

These mechanisms have stimulated growing interest in systemic and dietary strategies aimed at supporting skin health and healthy ageing [Jiang et al., 2025]. Among naturally occurring bioactive compounds, hydroxytyrosol (HT), a phenolic compound abundant in olives and olive-derived products, has attracted considerable attention because of its potent antioxidant and anti-inflammatory properties [D’Angelo et al., 2020; Echeverria et al., 2017]. Oral HT supplementation has been associated with improvements in oxidative balance, inflammatory status, and metabolic health, all of which are relevant to skin homeostasis and ageing processes [Frumuzachi et al., 2024; Moratilla-Rivera et al., 2025; Colica et al., 2017].

This review focuses primarily on the evidence supporting oral HT and HT-rich nutraceuticals as potential strategies to promote skin health and healthy ageing. Mechanistic, preclinical, and clinical evidence are critically examined to provide an integrated overview of the biological rationale underlying HT supplementation and its potential implications for skin function. Particular attention is given to animal and human studies evaluating oral HT administration, while current limitations, knowledge gaps, and future research priorities are also discussed.

2. Methods

The literature search was conducted in PubMed/MEDLINE, Scopus, and Google Scholar using combinations of keywords related to hydroxytyrosol (HT), skin health, skin ageing, and the biological pathways involved in skin homeostasis. The primary search terms included: “hydroxytyrosol” AND “oral supplementation”, “hydroxytyrosol” AND “oral administration”, “hydroxytyrosol” AND “dietary supplementation”, “hydroxytyrosol” AND “nutraceutical”, “hydroxytyrosol” AND “skin health”, “hydroxytyrosol” AND “skin ageing”, “hydroxytyrosol” AND “skin aging”, “hydroxytyrosol” AND “photoaging”, “hydroxytyrosol” AND “photoprotection”, “hydroxytyrosol” AND “skin homeostasis”, “hydroxytyrosol” AND “wound healing”, “hydroxytyrosol” AND “skin regeneration”, “hydroxytyrosol” AND “extracellular matrix”, “hydroxytyrosol” AND “collagen”, “hydroxytyrosol” AND “oxidative stress”, “hydroxytyrosol” AND “reactive oxygen species”, “hydroxytyrosol” AND “inflammation”, “hydroxytyrosol” AND “cellular senescence”, “hydroxytyrosol” AND “advanced glycation end products”, “hydroxytyrosol” AND “AGEs”, “hydroxytyrosol” AND “gut-skin axis”, and “hydroxytyrosol” AND “microbiome”. Additional searches were performed using terms related to olive-derived bioactive compounds and nutraceutical formulations, including “olive polyphenols”, “olive oil polyphenols”, “olive phenolics”, “olive-derived polyphenols”, “extra virgin olive oil”, “olive mill wastewater”, “OMWW polyphenols”, and “hydroxytyrosol-rich nutraceuticals”, combined with keywords such as “skin health”, “skin ageing”, “skin aging”, “healthy ageing”, “photoaging”, “skin inflammation”, “oxidative stress”, “wound healing”, “microbiome”, and “gut-skin axis”. Reference lists of relevant original articles and review papers were manually screened to identify additional studies of interest. Studies published in English up to June 2026 were considered. Original articles, clinical studies, animal studies and relevant reviews were included according to their relevance to the scope of the review.

3. Skin Ageing and Alterations in Skin Homeostasis

Clinically, skin ageing is characterized by wrinkles, pigmentation changes, xerosis, epidermal thinning, actinic keratoses, and reduced dermal elasticity. Importantly, the deterioration of skin structure and function extends beyond cosmetic concerns, affecting barrier integrity, immune competence, and susceptibility to disease [Yang and Man, 2023]. Skin ageing is a multifactorial process driven by both intrinsic (chronological) and extrinsic factors, including environmental and lifestyle influences, collectively referred to as the exposome [Thompson et al., 2022]. The exposome plays a major role in accelerating skin ageing, highlighting the need for preventive and targeted interventions [Krutmann et al., 2017]. The skin is highly vulnerable to environmental stressors such as ionizing radiation, pollution, and UV exposure, as well as to lifestyle factors including alcohol consumption and poor diet [Rittié and Fisher, 2015; Farage et al., 2013; Wong and Chew, 2021]. In particular, UV radiation damages the dermal ECM and keratinocyte DNA, leading to structural and cellular alterations that manifest clinically [Rittié and Fisher, 2015]. Intrinsic ageing, by contrast, is an inevitable process driven by genetic and metabolic factors [Zhang and Duan, 2018].

Ageing is also associated with alterations in the skin microbiome and immune function, which may contribute to barrier dysfunction, chronic inflammation, and impaired tissue repair [Yang et al., 2024]. In women, menopause further accelerates skin ageing through estrogen decline, resulting in reduced collagen synthesis, impaired elasticity, decreased hydration, thinning of the epidermis and dermis, and delayed wound healing [Viscomi et al., 2025]. Both extrinsic and intrinsic factors contribute to ageing by increasing reactive oxygen species (ROS) production and activate inflammatory pathways [Vierkötter et al., 2010]. ROS accumulation promotes ECM degradation, collagen breakdown, cellular senescence, and progressive loss of skin function, contributing to the visible signs of ageing. Moreover, skin barrier dysfunction is increasingly recognized as a potential driver of systemic inflammaging, a chronic low-grade inflammatory state associated with systemic consequences [Agrawal et al., 2023; Zhang et al., 2025]. This process involves glycation, reduced autophagy, mitochondrial dysfunction, telomere shortening, immune dysregulation, and diminished regenerative capacity [Agrawal et al., 2023; Buckingham and Klingelhutz, 2011; He et al., 2024; Ge et al., 2020].

Beyond its role in physiological ageing, oxidative stress also contributes to the pathogenesis of inflammatory skin disorders. In psoriasis, for example, redox imbalance promotes keratinocyte hyperproliferation and immune activation, establishing a self-perpetuating cycle between oxidative stress and inflammation [Dobrică et al., 2022]. UV radiation and other environmental stressors further amplify oxidative damage through lipid peroxidation, protein oxidation, and DNA injury in keratinocytes and fibroblasts [Rinnerthaler et al., 2015; Kammeyer and Luiten, 2015]. These alterations impair cellular function, accelerate cellular senescence, and increase matrix metalloproteinase (MMP) expression, ultimately promoting ECM degradation [Gilchrest et al., 1999; Yaar et al., 2007]. Sustained activation of inflammatory pathways also results in overproduction of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, further exacerbating tissue damage [Pillai et al., 2005; Quan and Fisher, 2015]. In parallel, ageing of the skin immune system reduces pathogen defense, impairs clearance of senescent cells, and promotes dysregulated inflammatory responses, thereby increasing susceptibility to infections, inflammatory disorders, and delayed wound healing [He et al., 2024].

Among the intrinsic drivers of ageing, advanced glycation end products (AGEs) have attracted considerable attention. AGEs are formed through non-enzymatic reactions between reducing sugars and macromolecules and originate from both endogenous metabolism and dietary sources [Singh et al., 2001; Scheijen et al., 2016]. In the skin, AGEs accumulate in collagen and elastin fibers, increasing stiffness, reducing elasticity, and disrupting ECM turnover [Fan et al., 2025; Gkogkolou and Böhm, 2012; Chen et al., 2022]. They also promote fibroblast apoptosis, reduce collagen content, and enhance dermal fragmentation [Chen and Guo, 2021]. Furthermore, AGEs contribute to oxidative stress and inflammation by increasing ROS production and inducing mitochondrial dysfunction [Twarda-Clapa et al., 2022]. Their biological effects are mediated through protein crosslinking, ROS generation, and activation of receptor-mediated pathways, particularly the receptor for advanced glycation end products (RAGE), which triggers NF-κB-dependent inflammatory signaling and cytokine production [Chrysanthou et al., 2022; Twarda-Clapa et al., 2022]. Although autophagy normally contributes to AGE clearance, excessive glycation impairs autophagic function, creating a vicious cycle that promotes further AGE accumulation and cellular dysfunction [Takahashi et al., 2017; Gómez et al., 2021]. Conversely, activation of autophagy has been shown to facilitate AGE removal and improve cellular homeostasis [Laughlin et al., 2020].

The gut-skin axis is increasingly recognized as a key contributor to skin ageing and inflammatory skin disorders through the interplay between the gut microbiota, immune responses, and circulating metabolites [Jimenez-Sanchez et al., 2025]. Among the mechanisms underlying this connection, oxidative stress appears to play a central role. Increased ROS levels can impair intestinal barrier integrity, promoting microbial translocation and systemic inflammatory responses. In turn, gut dysbiosis may further enhance oxidative stress through immune dysregulation and the production of pro-inflammatory metabolites, creating a self-perpetuating cycle that contributes to chronic inflammation, disruption of tissue homeostasis, and progression of inflammatory skin conditions [Pleńkowska et al., 2020; Ni and Zhang, 2022].

Increasing evidence highlights the importance of preserving skin barrier integrity, reducing oxidative stress, and modulating inflammation not only to maintain skin health but also to mitigate systemic ageing processes [Haykal et al., 2026]. Consequently, plant-derived phytochemicals are increasingly being explored as therapeutic and preventive strategies for inflammatory skin conditions, both as topical agents and nutritional supplements. These compounds may modulate inflammatory pathways, provide photoprotective effects, and support skin barrier function with fewer adverse effects than conventional pharmacological approaches [Nisar and Jagtap, 2023; Chaiprasongsuk and Panich, 2022; Assaf and Kelly, 2024; Albini et al., 2025]. Among these bioactive compounds, HT has emerged as a particularly promising candidate due to its combined antioxidant, anti-inflammatory, and metabolic effects, which target several of the biological pathways involved in skin ageing and skin homeostasis.

4. Hydroxytyrosol: Bioavailability and Mechanistic Pathways

4.1. HT Bioavailability

HT is a small, highly polar phenolic alcohol naturally present in olives, olive oil, and olive-derived products [D’Angelo et al., 2020; Echeverria et al., 2017]. It can also be generated endogenously through the metabolism of oleuropein (OLE), the major secoiridoid found in olive leaves and unripe olive fruits. Structurally, HT contains a catechol moiety that underlies its potent radical-scavenging activity and high reactivity toward ROS [Omar, 2010]. One of the most relevant characteristics of HT is its excellent oral bioavailability. Following ingestion, HT is efficiently absorbed in the small intestine and rapidly metabolized into glucuronide and sulphate conjugates that retain significant antioxidant and anti-inflammatory activity [Soldevila-Domenech et al., 2019; Feng et al., 2024]. Peak plasma concentrations are generally reached within 30-60 minutes after administration, supporting the rapid onset of systemic biological effects observed in acute intervention studies [Muriana et al., 2017]. HT bioavailability is influenced by several factors, including formulation, lipid matrix, dose, timing of administration, and the presence of other polyphenols [Silva et al., 2020; Di Renzo et al., 2023]. These characteristics make HT particularly suitable for oral supplementation strategies aimed at targeting systemic pathways involved in oxidative stress, inflammation, and tissue homeostasis.

4.2. HT Mechanistic Pathways

At the mechanistic level, HT exerts its biological activity through a combination of antioxidant, anti-inflammatory, metabolic, and microbiota-modulating effects [Moratilla-Rivera et al., 2026; Gao et al., 2025]. Rather than acting solely as a direct scavenger of reactive oxygen species, HT primarily functions as a regulator of endogenous cellular defense systems. A central mechanism involves activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, which promotes the expression of antioxidant enzymes and enhances cellular resilience to oxidative stress [Tebay et al., 2015].

In parallel, HT modulates inflammatory responses through inhibition of key signaling pathways, including NF-κB and cyclooxygenase-2 (COX-2). These effects result in reduced production of pro-inflammatory mediators such as C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6, together with increased expression of anti-inflammatory mediators including IL-10 [Alblihed, 2021; Yonezawa et al., 2019; Fuccelli et al., 2018]. Clinical studies further support the broad anti-inflammatory activity of HT [Richard et al., 2013].

Growing evidence also indicates that HT influences cellular quality-control mechanisms involved in ageing and tissue homeostasis. In particular, HT has been shown to regulate apoptosis, autophagy, and immune responses while interacting with lipid metabolism and epigenetic signaling pathways [Moratilla-Rivera et al., 2026]. In primary rat chondrocytes exposed to oxidative and inflammatory stress, HT enhanced autophagic activity through a Sirtuin 1 (SIRT1)-dependent mechanism, increasing the expression of key autophagy-related proteins, including LC3-II and ATG5/7, while reducing p62 accumulation. These effects were accompanied by reductions in ROS production, NADPH oxidase (NOX)2 and NOX4 expression, and inflammatory mediators including IL-6, TNF-α, and MMP-13, ultimately improving cellular viability under stress conditions [Sun et al., 2019]. Importantly, inhibition of either autophagy or SIRT1 abolished these protective effects, confirming the central role of this pathway.

Beyond intracellular signaling, HT exerts beneficial systemic effects that are highly relevant to ageing-related processes. Cardiovascular protection represents one of the most extensively documented areas of research. HT improves endothelial function, enhances nitric oxide bioavailability, reduces the level of low-density lipoprotein (LDL) oxidation, and attenuates inflammatory signaling, thereby contributing to improved vascular homeostasis and reduced cardiovascular risk [Noguera-Navarro et al., 2023].

Emerging evidence also suggests that HT may influence microbiota composition and gut barrier function, contributing to modulation of the gut-skin axis and systemic inflammatory responses [Gao et al., 2025]. These activities are particularly relevant in the context of skin ageing, where oxidative stress, chronic inflammation, metabolic dysfunction, and microbiome alterations interact to drive progressive deterioration of skin structure and function.

Overall, HT displays a favorable safety profile and appears particularly effective under conditions characterized by increased oxidative stress and chronic inflammation [Wang et al., 2025]. Through the coordinated modulation of antioxidant defenses, inflammatory pathways, cellular quality-control mechanisms, and systemic metabolic processes, HT targets several of the biological mechanisms implicated in skin ageing and impaired skin homeostasis.

4.3. Systemic Effects of Hydroxytyrosol-Rich Formulations and Purified Hydroxytyrosol

Olive oil contains a variety of bioactive constituents that can be broadly classified into two fractions: the unsaponifiable (non-polar) fraction, which includes squalene, triterpenes, sterols, tocopherols, and pigments, and the polar fraction, which comprises phenolic compounds, including HT [Covas et al., 2015]. In addition to olive oil, HT and other phenolic compounds are highly concentrated in olive mill wastewater (OMWW), the aqueous by-product generated during extra virgin olive oil production. Despite being biodegradable, OMWW poses significant environmental challenges. Its high phenolic content and acidic pH contribute to phytotoxic effects, while its lipid-rich composition can reduce dissolved oxygen levels, adversely affecting aquatic ecosystems [Sciubba et al., 2020]. Advances in extraction and purification technologies have enabled the recovery of polyphenol-rich fractions from OMWW, transforming an agricultural waste stream into a valuable and sustainable source of nutraceutical compounds within a circular economy framework [Albini et al., 2023]. One example is OliPhenolia^®, a phytocomplex obtained from OMWW through concentration, reverse osmosis, and mechanical filtration processes. Besides HT, OliPhenolia^® contains verbascoside, tyrosol, p-coumaroyl secoiridoids, and other minor polyphenols, suggesting that its biological activity may result from the combined action of multiple compounds rather than HT alone [Cuffaro et al., 2023]. The process of preparation of OliPhenolia^® is depicted in Figure 1.

4.3.1. Evidence from HT-Rich Formulations

The first human studies investigating OMWW-derived formulations primarily focused on bioavailability and antioxidant activity. In a pilot crossover study involving healthy volunteers, Bender et al. demonstrated that HT-rich formulations derived from OMWW (OliPhenolia^®) were rapidly absorbed after oral administration, as evidenced by the urinary excretion of HT. In parallel, in vitro experiments showed significant antioxidant activity, including reductions in reactive oxygen species, lipid peroxidation, and advanced glycation end-product formation, together with stimulation of endogenous antioxidant defenses [Bender et al., 2021].

The bioavailability of OliPhenolia^® was confirmed in a randomized, double-blind, placebo-controlled study conducted in healthy recreationally active adults. Following ingestion of a single dose, plasma HT concentrations increased rapidly and remained elevated for several hours. During a subsequent exercise challenge designed to induce oxidative stress, supplementation resulted in modest but significant antioxidant effects, including increased glutathione levels and reduced superoxide dismutase activity following exercise, suggesting improved redox balance and recovery capacity. However, no significant effects were observed for several other oxidative stress biomarkers, indicating that the physiological impact was relatively modest [Roberts et al., 2022].

A more detailed pharmacokinetic characterization of olive-derived HT formulations (OliPhenolia^®) was subsequently provided by Bender et al. in a randomized, controlled, blinded crossover study in 12 healthy volunteers. Using serial blood and urine sampling over 12 h after a single dose, the authors tracked both free HT and its major metabolites in plasma and urine, showing rapid absorption, a peak plasma concentration at approximately 30 min, dose-dependent bioavailability, and extensive phase II/metabolic conversion. By integrating plasma kinetics with urinary excretion data, this study provided a mechanistic basis for subsequent efficacy analyses in the same experimental setting [Bender, Strassman et al., 2023]. Additional evidence for short-term antioxidant activity was provided by the analysis of biomarkers of lipid oxidation, including plasma oxidized LDL (oxLDL) and urinary F2-isoprostanes, which showed a reduction following supplementation. Interestingly, these effects appeared more pronounced in participants with higher baseline oxidative stress, suggesting that the benefits of supplementation may be greater under conditions of increased oxidative burden [Bender et al., 2023]. Although the study was designed around cardiovascular markers rather than dermatological endpoints, these findings remain of interest in a beauty-from-within context because F2-isoprostanes are robust markers of in vivo lipid peroxidation [Roberts and Morrow, 2000; Milatovic et al., 2011], while oxidative stress-related lipid damage has also been documented in skin under oxidative challenge and is implicated in skin aging and age-related tissue damage [Rinnerthaler et al., 2015]

Beyond antioxidant activity, HT-rich formulations have shown promising effects on metabolic health. In a pilot longitudinal intervention study involving 29 adults presenting characteristics associated with metabolic syndrome, supplementation with OliPhenolia^® (25 mL twice daily for 30 days) was associated with favorable changes in several cardiometabolic parameters, including reductions in blood pressure, fasting glucose, insulin levels, and LDL cholesterol. Improvements were also observed in hydration status, while metabolomic analyses suggested modulation of pathways related to vitamin D metabolism, homocysteine metabolism, and inflammation. Importantly, no clinically relevant adverse effects were reported [Aiello et al., 2024]. A secondary analysis of the same cohort further explored body composition and muscle-related outcomes. Supplementation was associated with modest increases in skeletal muscle mass and muscle mass percentage, reductions in fat mass, and improvements in hydration status. These changes were accompanied by increased antioxidant capacity, reflected by higher protein thiol concentrations and Trolox equivalent antioxidant capacity, suggesting a potential role for OMWW-derived polyphenols in supporting muscle health and counteracting early sarcopenic changes in individuals at metabolic risk [Morelli et al., 2026].

Evidence supporting broader cardiometabolic benefits also comes from studies using HT-enriched foods. In a 12-week randomized dietary intervention including 60 adults with overweight/obesity and type 2 diabetes, daily consumption of HT-enriched whole wheat bread within an energy-restricted Mediterranean diet produced greater reductions in fasting glucose, glycated hemoglobin (HbA1c), insulin levels, LDL cholesterol, body fat, and inflammatory markers, particularly TNF-α, compared with conventional whole wheat bread [Binou et al., 2023].

Similarly, a 6-month pilot intervention study conducted in 11 healthy older adults evaluated the effects of olive oils differing in polyphenol content. Participants consuming high-polyphenol extra virgin olive oil, characterized by higher concentrations of HT and tyrosol, showed reductions in arterial inflammation and atherosclerotic microcalcification assessed by positron emission tomography/computed tomography (PET/CT) imaging. In contrast, standard extra virgin olive oil produced no significant changes, while refined olive oil was associated with worsening microcalcification markers. These findings suggest a potential vascular protective effect of olive polyphenols in ageing populations [Zoubdane et al., 2024].

4.3.2. Evidence from Purified Hydroxytyrosol

Compared with HT-rich formulations, clinical evidence specifically evaluating purified HT remains more limited. Nevertheless, available studies generally support the biological effects observed with complex formulations. The strongest evidence currently derives from a randomized, double-blind, placebo-controlled trial involving 49 adults aged 40–70 years with overweight and prediabetes. Participants received either 15 mg/day of purified HT or placebo for 16 weeks. HT supplementation significantly reduced several biomarkers of oxidative stress and inflammation, including oxidized LDL, protein carbonyls, 8-hydroxy-2′-deoxyguanosine (8-OHdG), and interleukin-6, while preserving antioxidant capacity and glutathione peroxidase activity. These findings indicate that HT may be particularly effective under conditions characterized by increased oxidative stress and low-grade inflammation [Moratilla-Rivera et al., 2025].

Overall, current human evidence consistently supports antioxidant, anti-inflammatory, and cardiometabolic effects of both HT-rich formulations and purified HT. However, most studies have evaluated systemic biomarkers and metabolic outcomes rather than dermatological endpoints. Therefore, while these findings provide a strong biological rationale for a potential role of oral HT supplementation in skin health, direct clinical evidence linking HT intake to improvements in skin ageing, skin function, or other dermatological outcomes remains limited.

5. Hydroxytyrosol and Skin Biology: Mechanistic Rationale and Implications for Topical and Oral Supplementation

The biological effects of HT on skin health are supported by a broad body of mechanistic evidence demonstrating its ability to modulate key pathways involved in skin ageing, tissue homeostasis, and repair. These effects encompass oxidative stress regulation, inflammation control, ECM preservation, photoprotection, and tissue regeneration, collectively providing a biological rationale for its potential application in skin health and healthy ageing [Fan et al., 2025]. HT exerts potent antioxidant activity by directly scavenging ROS and by activating endogenous antioxidant defense systems, including Nrf2-dependent pathways. Through these mechanisms, HT helps maintain redox homeostasis and protects skin cells from oxidative injury induced by ageing, environmental stressors, and UV radiation [Fan et al., 2025].

In parallel, HT exhibits significant anti-inflammatory activity. Experimental studies have demonstrated modulation of several signaling pathways involved in cutaneous inflammation, particularly NF-κB-dependent pathways, resulting in reduced production of pro-inflammatory cytokines and attenuation of chronic low-grade inflammation. This activity may be particularly relevant in the context of inflammaging, which contributes substantially to age-related skin deterioration [Aparicio-Soto et al., 2019; Fan et al., 2025].

The integrity of the ECM is a major determinant of skin structure, elasticity, and mechanical resilience. HT contributes to ECM homeostasis by limiting collagen degradation, reducing MMP activity, and supporting collagen preservation. Through these effects, HT may help maintain skin firmness and counteract structural alterations associated with chronological ageing and photoageing [Jeon and Choi, 2018; Menicacci et al., 2017].

These mechanisms are particularly relevant under conditions of UV exposure, where oxidative stress and inflammation accelerate matrix degradation and skin ageing. By reducing oxidative injury and inflammatory responses induced by UV radiation, HT exerts photoprotective effects that may contribute to preserving skin architecture and function under environmental stress [Zwane et al., 2012].

Beyond its anti-ageing properties, HT appears to support tissue repair and regenerative processes. Experimental studies indicate that HT promotes fibroblast proliferation and migration, enhances re-epithelialisation, stimulates ECM remodeling, and supports wound closure. In addition, HT modulates epithelial-mesenchymal transition (EMT) and inflammatory responses involved in tissue repair, potentially facilitating effective healing while limiting excessive fibrosis and pathological remodeling [Batarfi et al., 2023; González-Acedo et al., 2023]. Evidence also suggests that HT activates cytoprotective pathways such as heme oxygenase-1 (HO-1)/Nrf2 signaling, further enhancing cellular resilience and repair capacity under conditions of oxidative stress [Zrelli et al., 2015].

Collectively, these mechanisms provide the biological rationale for both topical and oral administration of HT. Topically applied HT may support skin homeostasis by enhancing epidermal barrier function, promoting tissue regeneration, and reducing cutaneous inflammation through the modulation of pro-inflammatory cytokines [Smeriglio et al., 2019]. On the other side, oral supplementation may contribute indirectly to skin health through systemic antioxidant and anti-inflammatory effects [Fan et al., 2025]. Importantly, although mechanistic and preclinical evidence consistently supports a protective role of HT in skin biology, the strength of evidence varies across outcomes. Direct clinical evidence demonstrating improvements in skin ageing, skin function, or dermatological conditions following oral HT supplementation remains limited and should therefore be interpreted cautiously. Nevertheless, the available mechanistic data strongly support further investigation of HT as a potential strategy for maintaining skin homeostasis, promoting tissue repair, and mitigating age-related skin changes.

5.1. Studies Relevant to Skin Biology

The mechanistic rationale supporting the role of HT in skin health is supported by a growing body of experimental, preclinical, and clinical evidence. Studies conducted in cellular and animal models have consistently demonstrated that HT modulates biological processes directly involved in skin ageing and tissue homeostasis, including oxidative stress, inflammation, ECM remodeling, wound healing, and photoprotection. These findings are complemented by a limited number of clinical studies investigating the effects of HT-containing formulations in selected dermatological conditions. The available evidence is heterogeneous with respect to study design, HT source, and outcomes evaluated. Some studies have investigated purified HT, whereas others have examined HT-rich extracts or complex olive-derived formulations containing additional bioactive polyphenols. Therefore, the results should be interpreted considering the specific intervention tested. To facilitate interpretation, the evidence is presented according to the level of investigation, moving from in vitro studies to animal models and, finally, clinical studies evaluating skin-related outcomes.

5.1.1. In Vitro Evidence

A substantial body of in vitro evidence supports the role of HT in protecting skin cells against oxidative stress, inflammation, ECM degradation, and cellular senescence.

Several studies have investigated the anti-photoaging properties of HT. Using a UVA-induced photoaging model in human dermal fibroblasts (HDFs), Jeon and Choi demonstrated that purified HT (>90% purity) was non-cytotoxic up to 30 μM and significantly attenuated cellular senescence, as evidenced by reduced senescence-associated β-galactosidase activity. HT also downregulated MMP-1 and MMP-3, key mediators of collagen degradation, while reducing the expression of the pro-inflammatory cytokines IL-1β, IL-6, and IL-8 in a dose-dependent manner [Jeon and Choi, 2018].

Additional evidence supporting anti-aging activity was provided by Li et al., who investigated purified HT and OLE. Both compounds exhibited moderate inhibitory activity against elastase and collagenase, with HT showing inhibition ranging from 12.6-31.0% and 11.6-31.9%, respectively. When combined at a 1:1 ratio, OLE and HT exerted synergistic elastase inhibition, confirmed by combination index analysis, enzyme kinetics, and molecular docking studies. Furthermore, HT reduced H₂O₂-induced cytotoxicity and intracellular ROS production in human dermal fibroblasts, while OLE–HT combinations produced synergistic reductions in ROS levels, suggesting enhanced cytoprotective activity [Li et al., 2022].

The anti-senescence activity of HT has also been demonstrated in chronically treated human fibroblasts. Menicacci et al. evaluated HT and OLE in pre-senescent lung (MRC5) and dermal (NHDF) fibroblasts and observed reductions in senescence-associated β-galactosidase activity, p16 expression, IL-6 production, COX-2 expression, NF-κB activation, and MMP activity. These findings suggest attenuation of both the senescence-associated secretory phenotype (SASP) and ECM degradation [Menicacci et al., 2017].

The anti-inflammatory properties of HT have been extensively investigated in keratinocyte models. Aparicio-Soto et al. demonstrated that HT and HT acetate significantly reduced the expression of thymic stromal lymphopoietin (TSLP), IL-6, IL-8, and TNF-α in primary human keratinocytes stimulated with IL-1β or toll-like receptor (TLR)3 ligands. Mechanistically, these effects were mediated through inhibition of NF-κB activation, preventing IκB degradation and NF-κB nuclear translocation [Aparicio-Soto et al., 2019].

Similarly, Chen et al. employed a psoriasis-like model using HaCaT keratinocytes stimulated with an M5 cytokine cocktail (TNF-α, IL-17A, IL-1α, IL-22, and oncostatin M). Treatment with purified HT significantly reduced the expression of IL-6, IL-8, and TNF-α, suppressed antimicrobial proteins, and inhibited keratinocyte proliferation, supporting a potential role for HT in inflammatory skin disorders such as psoriasis [Chen et al., 2023].

A growing body of evidence also supports a role for HT in wound healing and tissue regeneration. Zrelli et al. demonstrated that HT upregulates HO-1 expression in vascular endothelial cells through activation of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways. This effect was associated with Nrf2 activation, enhanced antioxidant defenses, and accelerated wound closure, highlighting a potential pro-repair mechanism [Zrelli et al., 2015].

Consistent with these findings, Batarfi et al. reported that HT modulates EMT in human dermal fibroblasts by increasing E-cadherin expression and reducing vimentin expression, thereby limiting excessive fibroblast transformation and fibrosis. HT also promoted fibroblast proliferation and migration while attenuating NF-κB-mediated inflammation, resulting in accelerated wound healing [Batarfi et al., 2023].

Finally, González-Acedo et al. demonstrated that HT significantly enhanced proliferation and migration of CCD-1064Sk human skin fibroblasts. HT increased fibronectin and α-actin expression without altering cell-cycle progression, supporting its role in ECM formation, tissue repair, and skin regeneration [González-Acedo et al., 2023].

5.1.2. In Vivo Evidence

Animal studies provide important translational evidence supporting the biological activity of HT in skin health. Compared with in vitro models, animal studies allow the evaluation of complex interactions between oxidative stress, inflammation, immune responses, tissue remodeling, and systemic metabolic pathways that collectively influence skin structure and function. Fan et al. employed a mouse model of skin ageing induced by a high-AGE diet, which resulted in impaired skin structure, reduced hydration, oxidative stress, systemic inflammation, and disruption of intestinal barrier function. Oral supplementation with purified HT (25-50 mg/kg/day for 16 weeks) improved skin hydration, dermal and epidermal thickness, and hydroxyproline content, while reducing inflammatory cytokines and oxidative stress markers. HT also enhanced intestinal barrier integrity through increased expression of the tight-junction proteins ZO-1 and occludin, suggesting a potential role of the gut-skin axis in mediating its protective effects against glycative skin ageing [Fan et al., 2025].

The anti-psoriatic potential of HT was investigated by Liu et al. using both imiquimod-induced psoriasis-like dermatitis in BALB/c mice and M5-stimulated HaCaT keratinocytes. Oral HT administration (10-50 mg/kg/day) significantly improved psoriasis-like lesions, reducing Psoriasis Area and Severity Index (PASI) scores, epidermal hyperplasia, inflammatory infiltration, and keratinocyte proliferation. HT also decreased local and systemic levels of TNF-α, IL-1β, IL-6, IL-17A, IL-22, and IL-23 while inhibiting ERK and NF-κB signaling pathways. These findings support HT as a promising candidate for the management of psoriasis-associated inflammation [Liu et al., 2025].

5.1.3. Clinical Evidence

While the mechanistic rationale and preclinical evidence supporting the effects of HT on skin biology are substantial, clinical studies specifically evaluating dermatological outcomes remain relatively limited. Most available human investigations have been exploratory in nature, involving small populations and heterogeneous interventions, ranging from purified HT to olive-derived polyphenol-rich formulations. Although direct clinical evidence linking HT supplementation to skin outcomes remains limited, the existing studies provide preliminary evidence suggesting potential benefits in inflammatory skin disorders, pigmentation abnormalities, and wound healing processes, thereby supporting further clinical investigation.

The strongest evidence currently comes from inflammatory skin disorders. In a pilot randomized, double-blind, placebo-controlled trial involving 30 patients with mild-to-moderate psoriasis, supplementation with an HT-enriched olive polyphenol nutraceutical (Alyvium^®) for 12 weeks significantly reduced PASI scores and affected body surface area compared with placebo, suggesting potential adjunctive benefits in psoriasis management [Acosta and Suárez-Pérez, 2016].

A randomized, double-blind, placebo-controlled pilot study involving 42 women with melasma evaluated both oral and topical HT administration over 90 days. Oral supplementation resulted in significant reductions in melasma severity scores (mMASI) and melanin index after 60 days, whereas topical treatment produced more modest improvements. Although between-group differences were not statistically significant, oral HT showed the most consistent depigmenting and anti-inflammatory effects [de Toledo Bagatin et al., 2020].

Evidence supporting wound repair has also been reported. Duarte et al. investigated the effects of extra virgin olive oil and HT in diabetic wound healing models combining animal and cellular experiments. HT accelerated wound closure, enhanced collagen deposition, reduced oxidative stress and inflammation, and promoted a shift toward an anti-inflammatory microenvironment characterized by increased IL-10 and anti-inflammatory macrophages. In vitro, HT further enhanced fibroblast migration and contraction, supporting tissue repair processes [Duarte et al., 2024].

A summary of the studies is presented in Table 1 and a schematic representation of HT and HT-enriched supplements beneficial effects on skin health and ageing are depicted in Figure 2 and Figure 3.

Collectively, available evidence indicates that HT exerts antioxidant, anti-inflammatory, anti-photoaging, and regenerative effects across multiple experimental models. However, direct clinical evidence remains limited and is largely restricted to small pilot studies and specific dermatological conditions. Further well-designed clinical trials are required to determine whether the promising mechanistic and preclinical findings translate into meaningful benefits for skin ageing and skin health in humans.

Beyond skin ageing and inflammatory skin disorders, growing evidence indicates that the antioxidant and anti-inflammatory mechanisms underlying the beneficial effects of HT may also contribute to protection against UV-induced photodamage and skin carcinogenesis. The following section summarizes the emerging preclinical evidence supporting the role of HT in photoprotection and skin cancer prevention.

6. Hydroxytyrosol: Emerging Evidence on Photoprotection and Skin Cancer Prevention

UV radiation is the principal environmental factor responsible for skin photoaging and a major contributor to skin carcinogenesis. Both UVA and UVB induce excessive production of ROS, leading to oxidative stress, DNA damage, chronic inflammation, activation of mitogen-activated protein kinase (MAPK), NF-κB, and activator protein-1 (AP-1) signaling pathways, extracellular matrix degradation through increased MMP expression, and dysregulation of cell survival and apoptotic pathways. Together, these molecular events promote photodamage, accelerate skin aging, and contribute to skin cancer development [Wei et al., 2024]. Consequently, compounds capable of limiting UV-induced cellular damage may also contribute to skin cancer prevention. HT, the major phenolic compound of olive oil, has attracted considerable attention because, besides its antioxidant and anti-inflammatory properties, it exerts photoprotective activities and direct anticancer effects by inducing apoptosis and cell cycle arrest, suppressing angiogenesis and metastasis, and modulating oncogenic signaling pathways, including PI3K/Akt/mTOR, MAPK, NF-κB, and vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR). These mechanisms provide the biological rationale for investigating HT as a multifunctional agent for both photoprotection and skin cancer prevention [Guo et al., 2010; Kumar et al., 2024].

6.1. Photoprotective Effects

Owing to its potent antioxidant and anti-inflammatory properties, HT has been investigated as a potential photoprotective agent in a range of preclinical models evaluating its ability to attenuate UV-induced oxidative damage and photoaging.

Guo et al. subsequently investigated the protective effects of purified HT in an in vitro study using UVB-exposed HaCaT human keratinocytes. HT significantly reduced UVB-induced DNA strand breaks, intracellular ROS production, oxidative DNA damage (8-OHdG), and the expression of the stress-related proteins p53 and NF-κB in a concentration-dependent manner, supporting its antioxidant and photoprotective activity against UVB-induced cellular damage [Guo et al., 2010].

Photoprotective effects have also been demonstrated using HT derivatives. Zwane et al. evaluated a biocatalytically synthesized HT dimer in UVA-exposed HaCaT keratinocytes. Compared with HT alone, the dimer exhibited greater antioxidant activity in DPPH and FRAP assays and enhanced resistance to UV-induced apoptosis through increased Bcl-2 and reduced Bax expression, indicating superior protection against oxidative damage [Zwane et al., 2012].

More recently, Wang et al. investigated the photoprotective effects of a combination of purified HT, oleuropein (OLE), and verbascoside (Verb) in in vitro models of UVB-induced photoaging using human dermal fibroblasts, HaCaT keratinocytes, and a keratinocyte-fibroblast co-culture system. The combined treatment significantly reduced oxidative stress, inflammation, apoptosis, cellular senescence, and collagen degradation induced by UVB exposure. These protective effects were associated with inhibition of the MAPK/NF-κB pathway and activation of the Nrf2 antioxidant pathway, with the combination demonstrating greater efficacy than the individual polyphenols [Wang J et al., 2025].

Evidence from in vivo studies remains limited but encouraging. Wang et al. evaluated the anti-photoaging potential of purified HT delivered through hyaluronic acid-based soluble microneedles using both in vitro and in vivo models. Human skin fibroblasts exposed to UVA radiation and mice subjected to combined UVA/UVB irradiation were treated with HT-loaded microneedles. The transdermal delivery system improved cell viability, reduced ROS production and cellular senescence in fibroblasts, and significantly enhanced skin hydration, elasticity, and collagen content in irradiated mice while decreasing oxidative stress markers and matrix metalloproteinase-1 expression. These findings indicate that purified HT, when delivered through soluble microneedles, effectively protects against UV-induced photoaging through antioxidant, anti-senescent, and extracellular matrix-preserving mechanisms [Wang E et al., 2026].

6.2. Skin Cancer Prevention

Evidence supporting the potential role of HT in skin cancer prevention has primarily been generated in in vitro melanoma models.

One of the earliest studies investigating the anti-melanoma activity of HT was conducted by D’Angelo et al., who evaluated purified HT (DOPET) in an in vitro model of UVA-exposed M14 human melanoma cells. HT significantly reduced ROS generation, lipid peroxidation, and protein oxidation in a dose-dependent manner, demonstrating protection against UVA-induced oxidative damage. At higher concentrations, HT also inhibited melanoma cell proliferation and promoted apoptosis through caspase-3 activation, suggesting concentration-dependent photoprotective and antiproliferative effects [D’Angelo et al., 2005].

Schlupp et al. evaluated a phenol-enriched purified OMWW containing HT together with other olive polyphenols in HaCaT keratinocytes, normal human epidermal keratinocytes (NHEK), A375 melanoma cells, and a three-dimensional melanoma skin model. Besides reducing ROS production and inflammatory responses in keratinocytes, the extract reduced the size and growth of A375 melanoma nodules without impairing normal keratinocyte viability, suggesting that HT-enriched olive polyphenol extracts may exert both photoprotective and chemopreventive effects [Schlupp et al., 2019].

Costantini et al. investigated the antitumor activity of purified HT in an in vitro study using metastatic human melanoma cell lines. HT reduced melanoma cell viability in a dose- and time-dependent manner by inducing apoptosis, increasing intracellular ROS, upregulating p53 and γH2AX expression, downregulating Akt signaling, and suppressing colony formation. These findings indicate that purified HT inhibits melanoma growth by promoting oxidative stress-mediated apoptosis and interfering with survival pathways [Costantini et al., 2020].

Brito et al. evaluated purified HT, together with oleic acid and homovanillyl alcohol, in an in vitro study using A375 and MNT1 human melanoma cell lines. Among the tested compounds, only HT significantly reduced the viability of the glycolytic A375 cells, whereas it had little effect on the more oxidative MNT1 cells. HT also promoted metabolic reprogramming by enhancing detoxification pathways, stimulating the use of alternative energy sources, and inhibiting c-Jun N-terminal kinase (JNK) and ERK signaling, suggesting that its anticancer activity depends on the metabolic phenotype of melanoma cells [Brito et al., 2021].

More recently, Tovar-Parra and Mangion investigated the effects of purified HT using three-dimensional spheroid models of human melanoma (C32) and non-tumorigenic melanocytes (HEMa). HT selectively reduced melanoma spheroid growth, viability, migration, and invasiveness while inducing cell cycle arrest and apoptosis with minimal toxicity toward non-tumorigenic cells. Proteomic analysis further demonstrated suppression of several oncogenic pathways, including erythroblastic leukemia viral oncogene homolog (ERBB)2/3/4, VEGFR-2, PI3K/Akt, and MAPK/ERK, supporting a multitarget mechanism underlying the antitumor activity of HT [Tovar-Parra and Mangion, 2025].

Finally, Gervasi et al. comprehensively reviewed the evidence regarding purified HT and oleuropein as potential anticancer agents. The authors concluded that HT exerts antiproliferative, pro-apoptotic, antioxidant, and anti-inflammatory effects across several cancer types, including melanoma. However, they also emphasized that most of the reported anticancer effects have been observed at concentrations exceeding those achievable through dietary intake, highlighting bioavailability, metabolism, and the dual antioxidant/pro-oxidant properties of HT as major challenges for its translation into clinical practice [Gervasi et al., 2024].

The evidence for HT photoprotective and anti-cancer effects are summarized in Table 2.

7. Translational Challenges and Research Gaps

Despite the promising mechanistic and preclinical evidence, several challenges currently limit the translation of HT into evidence-based dermatological applications. Key knowledge gaps include the identification of optimal dosing regimens, the influence of formulation and bioavailability on biological efficacy, and the lack of standardized biomarkers to objectively assess skin-related outcomes. Furthermore, most clinical studies have focused on systemic endpoints rather than validated dermatological measures, limiting the ability to establish clear cause-effect relationships. Future research should prioritize well-designed randomized controlled trials incorporating standardized HT preparations, pharmacokinetic assessments, objective skin biomarkers, microbiome-related parameters, and clinically relevant dermatological endpoints, including skin hydration, elasticity, firmness, transepidermal water loss, wrinkle morphology, dermal thickness, collagen integrity, and wound-healing outcomes. Such studies will be essential to better define the therapeutic potential of HT for skin health and healthy ageing and to clarify the relationship between its systemic biological effects and clinically meaningful dermatological benefits.

8. Future Directions: Emerging Mechanisms Beyond Antioxidant and Anti-Inflammatory Effects

Beyond its established antioxidant, anti-inflammatory, and regenerative properties, HT may exert additional biological activities that could be relevant to skin health and healthy ageing. However, these emerging mechanisms remain less extensively investigated and should currently be considered exploratory.

One area of growing interest concerns the potential interaction between HT and estrogen-related pathways. Due to structural similarities with estradiol, HT has been proposed to exhibit phytoestrogen-like activity, potentially influencing estrogen receptor signaling [Boss et al., 2016; Imperatrice et al., 2024]. This hypothesis is particularly intriguing in the context of menopause, where estrogen decline contributes to reduced collagen synthesis, impaired skin barrier function, loss of elasticity, and accelerated skin ageing. In a randomized, double-blind, placebo-controlled clinical trial involving 60 postmenopausal women, supplementation with olive leaf extract significantly improved menopause-related quality of life, increased bone mineral density, and improved selected cardiometabolic parameters [Imperatrice et al., 2024]. However, because the intervention consisted of a complex olive-derived extract rather than purified HT and skin-related outcomes were not specifically evaluated, further studies are required before drawing conclusions regarding a potential role of HT in menopause-associated skin ageing.

Another emerging field concerns the possible contribution of HT to skin and gut microbiome homeostasis. A growing body of preclinical evidence suggests that HT and HT-derived compounds possess antimicrobial and anti-biofilm properties against a variety of bacterial species. In vitro and in silico studies have shown that HT extracted from olive leaves exhibits antibacterial activity against both standard and extended-spectrum β-lactamase (ESBL)-producing bacteria through interactions with essential bacterial proteins involved in DNA replication and cell wall synthesis [Ben Hassena et al., 2025]. Similarly, HT-based polymers have demonstrated antioxidant, antibacterial, and anti-adhesive activity against Staphylococcus epidermidis, reducing bacterial adhesion and biofilm formation in vitro [Crisante et al., 2016]. HT acetate has also shown antibacterial activity against Vibrio species through mechanisms involving increased membrane permeability and disruption of bacterial DNA function [Wei et al., 2018].

Although these findings suggest that HT may influence microbial ecosystems relevant to both skin and gut health, current evidence remains largely limited to experimental models. Whether such antimicrobial and microbiome-modulating activities translate into clinically meaningful effects on skin homeostasis, skin ageing, inflammatory skin diseases, or the gut-skin axis remains unknown. Future studies should therefore investigate the impact of HT on microbiome composition and function in humans, as well as its potential implications for skin health and disease prevention.

Overall, these emerging areas highlight the broad biological potential of HT while underscoring the need for dedicated mechanistic and clinical studies to determine their relevance in dermatology and healthy ageing.

9. Discussion

This review summarizes the current evidence regarding the potential role of HT and HT-rich olive-derived formulations in skin health and healthy ageing. Overall, the available literature suggests that HT exerts multiple biological activities that are highly relevant to skin homeostasis, including antioxidant, anti-inflammatory, photoprotective, and regenerative effects. These mechanisms target several key drivers of skin ageing, such as oxidative stress, chronic low-grade inflammation, ECM degradation, cellular senescence, and impaired tissue repair [Agrawal et al., 2023; Yang and Man, 2023; Fan et al., 2025].

One of the major strengths of the current evidence base is the consistency observed across mechanistic and preclinical studies. In vitro investigations have repeatedly demonstrated that HT reduces reactive oxygen species production, attenuates inflammatory signaling, limits MMP activity, preserves collagen homeostasis, and promotes wound-healing processes [Jeon and Choi, 2018; Menicacci et al., 2017; Aparicio-Soto et al., 2019; Li et al., 2022; González-Acedo et al., 2023]. Furthermore, experimental studies have shown that HT modulates key pathways involved in cellular ageing and tissue repair, including NF-κB, Nrf2, PI3K/Akt, and ERK signaling pathways, supporting its role in maintaining skin resilience under conditions of environmental and metabolic stress [Zrelli et al., 2015; Fan et al., 2025; Liu et al., 2025]. More recent evidence also suggests that HT may protect against UV-induced skin damage and contribute to skin cancer prevention. Experimental studies demonstrated that purified HT and HT-rich formulations reduce oxidative DNA damage, inflammation, and cellular senescence following UV exposure, while inhibiting melanoma cell proliferation, migration, and survival through modulation of oncogenic pathways, including PI3K/Akt, MAPK/ERK, and VEGF signaling [Guo et al., 2010; Schlupp et al., 2019; Costantini et al., 2020; Brito et al., 2021; Tovar-Parra and Mangion, 2025]. Although these findings are currently limited to preclinical models, they further support the multifunctional biological activity of HT in skin protection.

The evidence generated in animal models further supports these observations. Oral HT supplementation has been associated with improvements in skin hydration, dermal structure, collagen content, inflammatory status, and oxidative stress markers in models of glycative skin ageing [Fan et al., 2025]. Similarly, HT has demonstrated anti-inflammatory effects in experimental models of psoriasis, reducing epidermal hyperplasia, inflammatory infiltration, and cytokine production through inhibition of NF-κB and ERK signaling pathways [Liu et al., 2025]. Together, these findings provide a coherent biological framework supporting the potential relevance of HT for skin health.

In addition to its direct effects on cutaneous biology, HT has been extensively investigated for its systemic activity. Clinical studies evaluating purified HT and HT-rich formulations consistently report reductions in biomarkers of oxidative stress and inflammation, together with improvements in selected cardiometabolic parameters [Bender et al., 2021; Roberts et al., 2022; Bender et al., 2023; Binou et al., 2023; Aiello et al., 2024; Moratilla-Rivera et al., 2025]. These findings may be particularly relevant because systemic oxidative stress, chronic inflammation, metabolic dysfunction, and vascular impairment are increasingly recognized as important contributors to skin ageing and impaired skin function [Agrawal et al., 2023; Yang and Man, 2023]. Moreover, emerging evidence suggests that HT may influence pathways associated with microbiome homeostasis and the gut-skin axis, although the clinical significance of these observations remains to be established [Pleńkowska et al., 2020; Ni and Zhang, 2022].

Despite the strong mechanistic rationale and encouraging preclinical evidence, direct clinical evidence linking HT supplementation to skin outcomes remains limited. Only a small number of clinical studies have specifically evaluated dermatological endpoints. Preliminary evidence suggests potential benefits in inflammatory skin disorders such as psoriasis [Acosta and Suárez-Pérez, 2016] and pigmentary conditions such as melasma [de Toledo Bagatin et al., 2020]. However, these studies were characterized by relatively small sample sizes, heterogeneous interventions, and short follow-up periods, limiting the strength and generalizability of their findings.

An additional challenge in interpreting the available evidence is the heterogeneity of the interventions investigated. While some studies have evaluated purified HT [Moratilla-Rivera et al., 2025], many clinical investigations have used complex olive-derived formulations containing multiple bioactive compounds, including tyrosol, verbascoside, secoiridoids, and other phenolic constituents [Cuffaro et al., 2023; Albini et al., 2023]. Consequently, the biological and clinical effects observed in these studies may reflect synergistic interactions among different polyphenols rather than the activity of HT alone. Besides this, most clinical evidence regarding OMWW-derived formulations as sources of HT currently derives from a limited number of research groups and requires independent confirmation.

Several emerging research areas also deserve further attention. Preliminary evidence suggests potential roles for HT in wound repair, microbiome modulation, and the management of inflammation-related dermatological conditions [González-Acedo et al., 2023; Duarte et al., 2024; Ben Hassena et al., 2025]. In addition, the proposed phytoestrogen-like activity of HT may have implications for skin ageing in postmenopausal women, although current evidence remains indirect and largely derived from studies evaluating olive-derived extracts rather than purified HT [Boss et al., 2016; Imperatrice et al., 2024]. These hypotheses warrant further mechanistic investigation and dedicated clinical evaluation.

Overall, the available evidence supports HT as a promising bioactive compound capable of influencing multiple pathways involved in skin health and ageing. Nevertheless, the transition from biological plausibility to clinical applicability requires additional well-designed human studies specifically assessing dermatological outcomes.

10. Conclusions

HT is a biologically active olive-derived polyphenol with well-documented antioxidant and anti-inflammatory properties and a growing body of evidence supporting its potential relevance for skin health [Covas et al., 2015; Moratilla-Rivera et al., 2025]. Mechanistic and preclinical studies consistently demonstrate beneficial effects on oxidative stress regulation, inflammation, ECM preservation, photoprotection, cellular senescence, and tissue repair, all of which are highly relevant to skin ageing and skin homeostasis [Jeon and Choi, 2018; Menicacci et al., 2017; Aparicio-Soto et al., 2019; Fan et al., 2025; Liu et al., 2025].

Human studies evaluating purified HT and HT-rich nutraceutical formulations further support its systemic antioxidant and anti-inflammatory activity and suggest potential benefits in selected dermatological conditions [Roberts et al., 2022; Binou et al., 2023; Aiello et al., 2024; Acosta and Suárez-Pérez, 2016; de Toledo Bagatin et al., 2020]. However, direct clinical evidence supporting the use of oral HT supplementation for skin ageing prevention or skin health promotion remains limited. Most available clinical studies have focused primarily on systemic biomarkers and cardiometabolic outcomes, whereas relatively few have incorporated validated dermatological endpoints.

At present, HT should be considered a promising candidate rather than an established intervention for skin health. Future randomized controlled trials should evaluate standardized HT preparations, clearly distinguish between purified HT and HT-rich formulations, include objective measures of skin structure and function, and investigate the relationship between systemic biological effects and clinically meaningful dermatological outcomes. Such studies will be essential to determine whether the encouraging mechanistic and preclinical findings translate into tangible benefits for skin ageing, skin resilience, and overall skin health in humans.