Reversing Glycation with a Dietary Supplement Containing Rosemary Extract

J Clin Aesthet Dermatol. 2025;18(2):44–49.

by Zoe Draelos, MD; Vivian Bucay, MD; Jacqueline Watchmaker, MD; and Giuseppe Valacchi, PhD 

Dr. Draelos is with Dermatology Consulting Services, PLLC in High Point, North Carolina. Dr. Bucay is with Bucay Center for Dermatology and Aesthetics in San Antonio, Texas. Dr. Watchmaker is with Southwest Skin Specialists in Scottsdale, Arizona. Dr. Valacchi is with North Carolina State University, Plants for Human Health Institute in Kannapolis, North Carolina; Kyung Hee University Department of Food and Nutrition in Seoul, Korea; and University of Ferrara Department of Environment and Prevention Science in Ferrara, Italy.

FUNDING: Funding for this article was provided by skinbetter science, Inc.

DISCLOSURES: Dr. Draelos is a researcher and consultant for skinbetter science, Inc. Drs. Bucay, Watchmaker, and Valacchi report no conflicts of interest relevant to the content of this article.

ABSTRACT: Objective: The authors sought to explore the skin deglycation ability of rosemary extract dietary supplements to support skin health and improve the signs of skin aging. Methods: A PubMed literature search for English-language articles on rosemary extract effects on glycation and skin aging in clinical and/or preclinical settings was conducted. Results: Endogenous and exogenous glycative stress and reactive oxygen species lead to the accumulation of advanced glycation endproducts (AGEs), accelerating skin aging. Rosemary extract, and its active polyphenol, rosmarinic acid (RA), exhibit antiglycative and antioxidant effects, preventing AGE formation. Rosemary reduces reactive intermediates in the glycation pathway, decreases protein carbonylation, and protects against environmental stressors. Rosemary has shown potential in reversing glycation, benefiting skin health by protecting collagen and elastin. Both topical and oral delivery methods have been investigated and have shown to be beneficial. Manufacturing and extraction methods are critical in preserving essential and synergistic components of the extract when optimizing formulation development. Limitations: As a narrative review, the selection of the literature was not fully comprehensive, thus introducing a potential for bias. However, our aim was to provide insights into the impacts of glycation and RA on skin quality and health. Conclusion: Rosemary extract and RA appear to exhibit antiglycative effects, both interrupting AGE formation and AGE-protein crosslinks, making them promising compounds for skin health. However, further research is needed to fully understand their mechanisms and therapeutic potential.

Keywords: Glycative stress, advanced glycation endproducts (AGEs), skin aging, skin health, rosemary extract, rosmarinic acid, antiglycative effects, antioxidant properties, nutraceuticals

Introduction

Skin aging manifests through visible changes in skin quality, including wrinkles, dryness, dullness/sallowness, roughness, erythema, uneven pigmentation, enlarged pores and loss of elasticity. Multiple endogenous processes involving excessive free radical production and glycative stress (glycation and the progressive accumulation of advanced glycation endproducts [AGEs]), gene mutations, immune system alterations and cellular senescence, and reduced proliferation play roles. Additionally, external factors such as ultraviolet (UV) exposure, pollutant exposure, dietary patterns (especially diets high in baked goods and fried or grilled foods), and smoking impact skin health and contribute to skin aging.¹ 

Improving skin health should include strategies to slow skin aging, like eating a healthy diet, limiting exposure to pollutants and UV radiation, and avoiding smoking. Supplementation with bioactive compounds, such as plant extracts (a mixture of various compounds extracted from plant tissues) or individual purified components, whether applied topically or taken orally, can help visibly improve skin quality and signs of skin aging.² Oral and topical routes of administration each have their own set of benefits and drawbacks, and additive or synergistic effects may be possible by combining them.² The choice between them may depend on individual preferences, skin type, specific skin concerns, and lifestyle. Starting at an early age with preventive measures is preferable to mitigate extrinsic cutaneous damage.

The goal of this paper is to review the effects of glycation on skin health and to explore antiglycative, anti-aging effects of rosemary extract in the context of modulating skin aging. 

Methods

A literature search was conducted using PubMed, searching for keywords such as “rosemary extract,” “rosmarinic acid,” “advanced glycation endproducts,” “glycative stress,” “anti-aging,” “skin aging,” and “reversal of skin aging,” combined with Boolean operators (AND, OR). Articles were included if they were published in English, and specifically investigated the effects of rosemary extract on glycation and/or skin aging in clinical or preclinical settings. Potentially relevant articles were identified by reviews of titles and abstracts; articles not directly related to the topic were excluded. Ultimately 47 articles were selected and included in this review.

Results

Effects of glycation and advanced glycation endproducts on skin health. At the molecular level, the spontaneous, endogenous, non-enzymatic glycation of proteins, DNA, and lipids results in the formation of toxic byproducts called AGEs that create molecular crosslinks between proteins, modifying and impairing their physical properties and functionality.^3–5 AGEs play a significant role in the skin aging process.^4,6,7 AGEs accumulate in the skin over time, with the accumulation of AGEs being directly proportional to the damage they cause.⁸ More than 20 species of AGEs have been identified in human skin.⁹ Each type of AGE has different effects on the skin, but overall, they negatively impact tissue remodeling, leading to matrix accumulation and impaired angiogenesis, which are hallmarks of aging skin.¹⁰ The accumulation of AGEs in the skin is associated with increased dullness, yellowing, fine lines, wrinkles, skin laxity, loss of elasticity, and other skin problems.^9,11 

AGEs have several detrimental effects on the epidermis. They delay wound healing, reduce ceramide and cholesterol content, leading to decreased skin lipid content, destroy keratinocyte cell structure, and promote melanin production in melanocytes.^12,13 AGE-induced crosslinking of extracellular matrix proteins affects skin properties (eg, overall reduction in skin elasticity, increased stiffness and loss of flexibility) and accelerates skin aging.^4,5 When AGEs and collagen are crosslinked, the collagen browns, biomechanical properties change, and the fibers weaken and deform; repair through remodeling is also disturbed.^5,8,12 Elastin fibers become thinner, less rigid, and lose function; and glycated vimentin causes fibroblasts to lose contraction ability and ability to maintain basic cell shape.^5,12 The accumulation of AGEs promotes oxidative stress and inflammation,^8,14,15 which are fundamental to skin aging. AGEs interact with receptors of AGE (RAGE) to activate various molecular pathways involved in inflammation, immune response, cell proliferation, and gene expression.

The process of AGE accumulation is exacerbated by external factors such as UV radiation and pollution.¹¹ UV exposure has been shown to increase the accumulation of AGEs in both senescent and photoaged skin.¹⁶ Keratinocytes increase the production and secretion of AGEs following UV exposure. Greater levels of AGEs cause melanocytes to increase melanogenesis via a RAGE-dependent pathway, leading to photoaging.¹⁷ The formation of AGEs leads to intra- and inter-molecular crosslinks between adjacent proteins, impairing their functionalities and modifying their physical properties.³ Slower turnover proteins, such as collagen, are more greatly impacted by AGEs as there is more time for damage to accumulate.¹³ Collagen glycation leads to crosslinking with adjacent collagen fibers, rendering collagen incapable of being repaired through the usual process of remodeling.⁵ This results in impaired mechanical properties of collagen and a decrease in overall skin elasticity, increased stiffness, and loss of flexibility.^5,8,18

The body has endogenous protections to counteract glycation. Glyoxalases (GLO1 and GLO2) are key antiglycation enzymes that reduce the accumulation of reactive dicarbonyls, thereby suppressing glycative stress. However, these enzymes decrease in levels with chronological age and photoaging.^19,20 Endogenous free-radical scavengers, such as glutathione, carnosine, and superoxide dismutase (SOD), help clear reactive oxygen species (ROS) and neutralize AGEs before they can react with cellular proteins, lipids, and DNA to cause damage. Micronutrients, such as vitamins E and C, also protect the skin against oxidative damage.^2,21

Reducing glycative stress and reversing glycation as an approach to improving skin health. When endogenous defense systems are overwhelmed by glycative stress and ROS, damage in the form of toxic AGE byproducts accumulates, leading to the various detrimental effects associated with skin aging. Numerous molecules have been shown to inhibit the glycation process, leading to a slow reduction of glycated proteins, mostly proteins with medium or fast turnover, but with less impact on slow-turnover proteins. Discovering safe molecules capable of deglycating AGE crosslinked proteins would represent a unique approach and substantial progress toward the improvement of conditions related to aging. Various approaches targeting the AGE process are of interest and may be of clinical importance in reducing, preventing, and possibly even reversing the damage.

Lifestyle and diet. A preventive strategy to reduce exposure to factors driving the glycation processes in the skin or to limit exogenous AGEs can be adopted by employing several lifestyle modifications. It is crucial to advise patients to limit sun exposure, reduce exposure to pollutants, refrain from smoking, and moderate consumption of sugary and heat-treated foods like fried and baked items. Alongside dietary restrictions, augmenting diet with fruits, vegetables, herbs and various plant extracts with antioxidant and/or antiglycative properties are a proactive approach. Nutritional supplements such as vitamins B6, C, D, and E, collagen, or various plant polyphenols are potential interventions that have gained increasing popularity and traction in research as they offer promising avenues for improving skin health.

Pharmaceutical. There has been research into potential pharmaceutical compounds. Alagebrium (ALT-711), a promising antiglycation agent in the early 2000s, was found to protect against reactive sugar metabolites and break AGE crosslinks. In several animal models, it was shown to improve skin hydration, elasticity and wound healing, as well as to exert positive effects in animal models of several cardiometabolic diseases.^22–24 However, challenges associated with its development and regulatory hurdles lead to the termination of its clinical trials, highlighting the importance of exploring alternative treatments.

Extracts of natural polyphenols. Polyphenols, that occur naturally in many plants, exhibit antioxidant properties that can quench ROS production and impede AGE formation.²⁵ For example, in vitro evidence suggests that blueberry anthocyanin extracts can scavenge glycosylated intermediates (Schiff base, fructosamine, and α-dicarbonyl compounds) and inhibit AGE/RAGE-induced secretions of nitric oxide and pro-inflammatory cytokines (IL-6, MCP-1, and TNF-α).²⁶ Blueberry extract has also been shown to prevent inflammatory and oxidative skin damage induced by ozone, a toxic environmental pollutant that interacts with cutaneous lipids in the stratum corneum to generate ROS that trigger an inflammatory response.²⁷ Rosemary (Rosmarinus officinalis) and lemon balm (Melissa officinalis) are two herbs sharing antiglycative effects and common active ingredients, rosmarinic acid (RA) and caffeic acid.^28,29 Rosemary also has high levels of carnosic acid (CA) and carnosol.²⁹ These compounds found in rosemary and lemon balm have antioxidant, antiglycative and anti-inflammatory properties that can fight free radicals and protect against damage by environmental stressors to soothe skin, reduce inflammation and redness and fight skin aging thereby improving skin quality.^29–32

RA and CA inhibit the formation of AGEs by reducing reactive intermediates in the glycation pathway, decreasing protein carbonylation, and retarding the formation and oxidation of protein adducts.²⁸ RA has shown deglycating activity (ie, in reversing glycation and breaking AGE-protein bonds) in vitro.^3,33 This ability to reverse glycation could be particularly advantageous for skin health, given the presence of proteins like collagen and elastin, which have slow turnover rates and are vulnerable to AGE-related damage.²⁸ 

Bioactive based dietary supplements or cosmeceuticals to reduce glycative stress. Plants with various biologic activities have long been utilized in traditional herbal medicine and are now being explored for therapeutic activity either by oral ingestion (dietary supplement) or topical application (cosmeceutical). One promising anti-aging strategy involves inhibiting the accumulation of AGEs, leading to the development of novel nutraceutical and cosmetic compounds.⁸ 

Topical delivery methods include oils, creams, lotions, ointments, gels, foams, sprays, and shampoos. These localized treatments target specific skin areas and may offer quick benefits such as hydration or soothing effects. For example, a topically applied blueberry extract that inhibits AGE and glycosaminoglycan synthesis improved fine lines, firmness, radiance, smoothness, creping, and skin tone in a study of 20 female diabetics.³⁴ However, the impact of topical agents is limited to the application site and can be hindered by poor skin penetration, and the received dose may vary depending on adequacy and frequency of application. Frequent administration may be necessary to maintain the effect. Topical application of RA may result in epidermal accumulation, but insignificant dermal concentrations, formulation considerations affecting bioaccessibility and bioavailability are crucial to ensure adequate delivery to skin layers.^7,35

Oral supplements are a familiar and easy route of administration, usually safe and effective, providing systemic benefits and effecting all areas of skin on the body from the inside-out. Oral supplements may face challenges such as breakdown during digestion, limited absorption, and hepatic metabolism, leading to low bioavailability. For example, plant polyphenols and anthocyanins undergo extensive metabolism when ingested. However, active metabolites with higher concentrations and longer half-lives may contribute to biological activity.^35,36 Low bioavailability can be managed by increasing the administered dose or using formulations that increase stability and bioavailability.³⁷ Oral administration provides systemic benefits, targets all skin areas, and offers more consistent dosing but may take longer for effects to be visible. Topical administration targets specific skin areas and offers quick benefits, but effects are localized and may require frequent application. Given the benefits and drawbacks of each route of administration, a combination approach may be beneficial.²

Another issue considered by clinicians and patients alike is whether to use a plant extract or individual purified bioactive components. Plant extracts contain multiple bioactive compounds that can work together synergistically,³⁷ potentially enhancing their overall effectiveness to provide a broader range of biological activities and benefits. For example, rosemary extract was found to have greater deglycating activity than pure RA (authors, personal communication), likely due to the presence of other compounds. Plant extracts are also closer to their natural form, which may be more appealing to consumers seeking natural or holistic treatments. The challenge with extracts is consistency as the concentration of active compounds can vary between batches due to differences in plant growth conditions, harvest times, extraction methods and different locations.^29,31 This can be managed by standardizing the extract for the key active ingredient(s). In contrast, purified ingredients offer a consistent concentration of the active compound, ensuring uniformity in dosage and effects and remove unwanted compounds, but may lose the synergistic effects offered by the plant extract. The purification process can be expensive, potentially increasing the cost of the final product.

The potential of rosemary extract and rosmarinic acid. Traditional uses of rosemary include helping to alleviate muscle pain, improving memory, boosting the immune and circulatory systems, and promoting hair growth. Rosemary and its main bioactive compound, RA, have been extensively investigated for their numerous health benefits across various diseases, including diabetes, cancer, and neurodegenerative diseases (recently reviewed in Azhar⁷ and Nadeem³⁸). RA, CA, and other polyphenolic compounds in rosemary exhibit anti-inflammatory, antioxidant, astringent, antimutagenic, antibacterial, and antiviral properties.⁷ 

In both in vitro and in vivo models of atopic dermatitis, RA has been shown to curtail the production of inflammatory cytokines (IFN-γ and IL-4) by activated T cells, inhibit the development of skin lesions, and reduce T cell infiltration of lesions.³⁹ Additionally, in vitro and in vivo models have demonstrated that RA acts as both an exogenous and endogenous photo-protector by scavenging free radicals, inducing tyrosinase activity to stimulate melanin production,⁴⁰ and reducing the expression of UVB-induced proinflammatory mediators (IL-6, IL-8, MCP-1, and TNFα).³⁹ Clinically, topical RA has been shown to reduce pruritus and transepidermal water loss in patients with mild atopic dermatitis, and to reduce erythema, crusting, edema, and local pruritus in patients with moderate atopic dermatitis.³⁵ 

The antiglycation activity of rosemary and its bioactive constituents have been extensively investigated in both in vitro and in vivo studies, especially for its promising therapeutic effects on UV-induced photoaging, atopic dermatitis and pollution-induced skin aging.^38,41,42 Rosemary extract, RA, and CA inhibit the formation of AGEs not only by neutralizing free radicals, but also by blocking reaction of reducing sugars with protein and interrupting the polymerization and aggregation of glycated proteins.^3,30,33,43 Furthermore, RA has profound deglycating effects as demonstrated in an in vitro BSA/ribose model (Figure 1).³ This deglycating effect has also been demonstrated in an in vitro lysozyme/ribose model (54% higher deglycation rate vs. control) suggesting that RA might play a major role in AGE regulation, going further than previously discovered AGE inhibitors.³³ RA also decreases DNA glycation and subsequent cellular apoptosis.⁴⁴ Indeed, RA has demonstrated multiple actions on AGEs (Figure 2), which are crucial in skin aging.^3,30,33,43

Regarding skin effects, purified RA and a lemon balm (Melissa officinalis) extract containing RA and related polyphenols have been shown to reduce the in vitro formation of pentosidine, glycation of collagen and elastin, and collagen yellowing.⁴⁵ A six-week course of daily lemon balm extract consumption resulted in reduced red and yellow colors in the skin of healthy human subjects, consistent with the anti-inflammatory and antiglycation properties of RA. Some improvement in female skin elasticity was also noted, supporting the antiglycation effects on collagen and elastin. Additionally, a dietary combination of rosemary and grapefruit (Citrus paradisi) reduced UV-induced facial skin redness and lipoperoxides and improved facial skin wrinkles and elasticity.⁴⁶ 

Rosemary is a non-toxic compound. Short-term use of RA has shown no side effects in humans, and there has been no evidence of serious adverse effects with long-term dosing.^35,47 Incorporation of dietary supplements containing rosemary extract may be a promising, safe, and effective option to counter the effects of AGEs on skin aging.

RA can be extracted from plants by various means, most commonly alcohol extraction.³⁵ The RA content varies between species of the same genus, subspecies of the same species, and even plants collected in different seasons, making quantification of the RA amount present in an extract important and thus, the amount of RA can be used as a parameter for estimating quality.³⁵ This approach has been used for a dietary supplement comprised of rosemary extract to preserve, in a controlled fashion, the important compounds or cofactors that are part of the rosemary leaf (CORExtract^TM). This product uses a proprietary, multi-sequence bioguided extraction process that identifies, isolates and purifies active compounds to create a powder extract that preserves the beneficial components of the leaf. This extraction process leads to an extract that has twice the deglycating effect as pure RA (authors, personal communication). Thus a rosemary extract, which contains additional active components or supportive compounds likely contributes to the extract’s activity and beneficial effects.^35,36

Limitations. As a narrative review, the selection of the literature was not fully comprehensive, thus introducing a potential for bias.

Conclusion

Our review describes the effects of glycation and AGEs on skin health and summarizes the deglycative, antioxidant, anti-inflammatory and anti-aging effects that rosemary extract and RA exhibit, highlighting their potential as dietary supplements improving skin health and mitigating skin aging. Discovering safe molecules that can interrupt AGEs, reversing glycation, is a significant step toward improving the health of aging skin. Given the current evidence, rosemary extract supplements may be considered for use as part of the daily diet to mitigate the effects of AGEs on skin without undue safety issues.³⁸ Further research is needed to demonstrate proof of concept and fully understand the therapeutic potential of rosemary and RA in skin health.

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