The search for natural molecules that can slow skin aging remains a priority in dermatology and aesthetic medicine. Among the exogenous factors accelerating this process, advanced glycation end-products (AGEs)—compounds formed by non-enzymatic reactions between sugars and proteins or lipids—play a special role [1, 2]. AGEs enter the body through food, being particularly abundant in thermally processed diets, and accumulate endogenously during metabolism [5]. Their impact on the skin is multifaceted: they cross-link collagen and elastin fibers, reducing dermal elasticity; degrade the extracellular matrix, stimulate fibroblast apoptosis; and trigger chronic inflammation [2, 5].

Against this background, hydroxytyrosol (HT)—a polyphenol found predominantly in the fruits and leaves of the olive tree (Olea europaea L.) and its processed products—attracts attention as a promising natural agent with a broad spectrum of biological activity [3]. Its antioxidant potential is due to a specific chemical structure that provides effective free radical scavenging [3]. Beyond direct antioxidant action, HT enhances the function of endogenous protective enzymes and suppresses inflammatory signaling pathways [4].

Study design: model, groups, doses

Researchers from Peking University set out to evaluate the efficacy of HT against skin aging induced by a high-AGE diet and to uncover the mechanisms of its protective action [1]. An original experimental model was developed for this purpose: 48 male C57BL/6J mice aged 8 months (corresponding to middle age in humans) were fed a diet enriched with AGEs through thermal processing at 128 °C for 3 hours. The AGE marker content in this feed increased 7-fold compared to the unprocessed diet (p < 0.05). A group of young mice (6 weeks old) was additionally used as a reference.

The animals were divided into four groups:

• control — standard diet;
• model — high-AGE diet;
• HT25 — high-AGE diet + 25 mg/kg/day HT orally;
• HT50 — high-AGE diet + 50 mg/kg/day HT orally.

The intervention lasted for 16 weeks. Upon completion, dorsal skin, blood serum, and ileum samples were collected from the animals.

The following parameters were assessed:

• skin moisture — by weighing the skin specimen before and after drying;
• epidermal and dermal thickness — histological staining with hematoxylin and eosin, morphometry;
• hydroxyproline (HYP) as a collagen marker — ELISA;
• antioxidant status — superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activity, malondialdehyde (MDA) levels as an indicator of lipid peroxidation;
• proinflammatory cytokines in serum — interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) — ELISA;
• intestinal barrier integrity — expression of tight junction proteins occludin and ZO-1 (zonula occludens-1) by immunohistochemistry.

Results: from skin structure to the intestinal barrier

Chronic consumption of high-AGE food led to significant changes in the model group. The high dose of HT (HT50) restored most parameters to levels comparable to the control.

Skin structure and moisture:

• moisture content decreased from 71.00 ± 1.95% to 65.20 ± 3.73% in the model group; HT50 restored it to 70.94 ± 3.53% (p < 0.05);
• epidermal thickness in the model group decreased by 25% compared to the control; HT50 restored it to control values (p < 0.05);
• dermal thickness in the model group decreased by 16% compared to the control; HT50 significantly restored it (p < 0.05);
• The hydroxyproline content in the HT50 group was significantly higher than in the model group (1.506 ± 0.233 μg/mg vs. 1.057 ± 0.128 μg/mg; p < 0.05), indicating the preservation of the collagen matrix.

Antioxidant status:

• In the model group, SOD and GSH-Px activities decreased significantly, while MDA levels increased (p < 0.05).
• HT50 normalized all three indicators: SOD activity increased by 44.6%, GSH-Px by 200%, and MDA levels decreased by 46.6% compared to the model group (p < 0.05).

Inflammation:

• in the model group, levels of IL-6 increased 3.8-fold, TNF-α 2.5-fold, and IL-1β 4.7-fold compared to the control (p < 0.05);
• Both HT doses—HT25 and HT50 — significantly reduced the concentrations of all three cytokines to near-control levels (p < 0.05).

Intestinal barrier:

• In the model group, the expression of occludin decreased from 77.5 ± 7.9% to 65.8 ± 4.5%, and ZO-1 from 41.3 ± 6.6% to 22.8 ± 7.1% (p < 0.05);
• Both HT doses significantly restored the expression of both proteins (p < 0.05).

Mechanism: how hydroxytyrosol protects the skin

AGEs damage the skin through several interrelated mechanisms: they generate reactive oxygen species (ROS), activate inflammatory signaling pathways, and degrade the collagen matrix [2]. HT interrupts this pathological cascade at multiple levels simultaneously [3, 4]:

• Antioxidant protection (direct and indirect): HT not only acts as a potent free radical scavenger, neutralizing ROS, but also restores the activity of the cells' own protective enzymes (superoxide dismutase and glutathione peroxidase), halting destructive lipid peroxidation.
• Suppression of skin inflammation: the molecule specifically inhibits the production of aggressive proinflammatory cytokines (interleukins IL-1β, IL-6, and tumor necrosis factor TNF-α), which are typically produced in abundance in tissues in response to AGE accumulation.
• Dermal matrix protection: by mitigating oxidative stress and inflammation, HT protects collagen fibers from degradation, as evidenced by maintenance of normal hydroxyproline levels and preservation of dermal thickness.
• Modulation of the gut-skin axis: a fundamentally important systemic effect. Dietary AGEs can damage the ileal mucosa, increasing its permeability. HT stimulates the synthesis of tight junction proteins (occludin and ZO-1), literally "sealing" the intestinal barrier. This prevents the leakage of inflammatory molecules into systemic circulation, thereby reducing the inflammatory burden on the entire body and protecting the skin from within [1].

Study limitations

The authors highlight several limitations: a mechanistic analysis focused solely on the physical intestinal barrier, without evaluating the microbiome's role; the long-term effects of HT withdrawal were not studied; and the research was conducted exclusively in a mouse model, warranting caution when extrapolating to humans.

Future perspectives

The findings open several practical avenues. First, HT is of interest as a nutraceutical for the prevention and correction of age-related skin changes associated with dietary glycation. Second, its multilevel mechanism of action—antioxidant, anti-inflammatory, and barrier-enhancing—makes it an attractive active ingredient for anti-aging cosmetic products, including topical formulations [3]. Third, the identified role of the gut-skin axis aligns with modern nutricosmetic concepts, highlighting perspectives for comprehensive strategies, such as combining oral and topical administration of olive polyphenols [4].

At the same time, it is necessary to consider that this study was conducted on an animal model, and clinical data on the use of HT for anti-glycation skin protection in humans remain limited.

Conclusion

The study conducted by specialists at Peking University convincingly demonstrates that hydroxytyrosol can counteract accelerated skin aging caused by dietary AGEs. Its protective effect is achieved by reducing oxidative stress, suppressing systemic inflammation, and strengthening the intestinal barrier—together, these actions preserve the skin's structural integrity, moisture, and collagen matrix. The obtained data form an evidence base for developing nutraceutical strategies to prevent glycation-induced skin aging. Hydroxytyrosol is one of the few natural polyphenols for which the mechanism of anti-glycation skin protection has been comprehensively studied in an experimental design, making it a promising candidate for both nutraceutical and cosmetic developments [3, 4].

References

1. Fan R., Ma Y., Sun M. et al. Improvement effect and mechanism of hydroxytyrosol on skin aging induced by advanced glycation end products. Nutrients 2025; 17(17): 2810. https://doi.org/10.3390/nu17172810
2. Twarda-Clapa A., Olczak A., Białkowska A.M., Koziołkiewicz M. Advanced glycation end-products (AGEs): Formation, chemistry, classification, receptors, and diseases related to AGEs. Cells 2022; 11(8): 1312.
3. Bertelli M., Kiani A.K., Paolacci S. et al. Hydroxytyrosol: A natural compound with promising pharmacological activities. J Biotechnol 2020; 309: 29–33.
4. Velotti F., Bernini R. Hydroxytyrosol interference with inflammaging via modulation of inflammation and autophagy. Nutrients 2023; 15(8): 1774.
5. Nguyen H.P., Katta R. Sugar sag: Glycation and the role of diet in aging skin. Ski Ther Lett 2015; 20(6): 1–5.