1 Basic Properties and Structural Basis of Carnosine

1.1 What Is Carnosine?

Carnosine is a naturally occurring histidine-containing dipeptide found in the human body. It is composed of β-alanine and L-histidine, with the molecular formula C₉H₁₄N₄O₃. Carnosine is present at relatively high levels in skeletal muscle, cardiac muscle, and brain tissue. These tissues are metabolically active and prone to oxidative stress; therefore, they require endogenous small molecules to participate in acid–base buffering, redox balance, and protein protection.

In skincare applications, the core value of carnosine is concentrated in three directions:

1.2 Structural Features of Carnosine

The simplified structure of carnosine is as follows:

H₂N-CH₂-CH₂-C(=O)-NH-CH(COOH)-CH₂-imidazole ring

1.3 Why the Imidazole Ring Is Important

The imidazole ring performs three major functions in the carnosine molecule:

Carnosine does not rely on a single functional group to exert its effects. Instead, it intervenes in chemical damage processes related to skin aging through the coordinated reactivity of its free amino group, imidazole ring, carboxyl group, and peptide structure.

2 Oxidative Stress and Carbonyl Stress in Skin Aging

2.1 How Oxidative Stress Affects Collagen

The skin is chronically exposed to ultraviolet radiation, air pollution, inflammatory reactions, and metabolic stress, all of which can lead to excessive production of reactive oxygen species (ROS). ROS can directly attack proteins, lipids, and nucleic acids, and can also trigger lipid peroxidation.

A pathway with major impact on dermal structure is as follows:

Ultraviolet radiation / pollution / inflammation → increased ROS → lipid peroxidation → increased reactive carbonyl species → enhanced protein carbonylation and glycation reactions → collagen cross-linking, stiffening, and reduced elasticity

The key point here is the downstream reaction triggered by ROS. Lipid peroxidation generates a variety of reactive carbonyl species (RCS). These molecules have relatively longer lifetimes and broader diffusion ranges, making them more likely to continuously attack collagen and elastin.

2.2 RCS as Key Intermediates Connecting Oxidation and Glycation

RCS are molecules containing highly reactive carbonyl groups. They can be derived from glycoxidation, lipid peroxidation, and amino acid oxidation. Common RCS include:

RCS can attack lysine, arginine, cysteine, and histidine residues in proteins, leading to protein carbonylation, conformational changes, and cross-link formation. In the skin, collagen and elastin are long-lived structural proteins. Once they are chronically attacked by RCS, structural recovery becomes difficult.

2.3 Metal Ions and the Fenton Reaction

Free iron and copper ions can promote the amplification of oxidative reactions. A typical example is the Fenton reaction, with the classic reaction equation:

Fe²⁺ + H₂O₂ → Fe³⁺ + OH⁻ + ·OH

The hydroxyl radical (·OH) is extremely reactive and can rapidly attack nearby lipids, proteins, and nucleic acids. Copper ions can also participate in similar Fenton-like reactions, for example:

Cu⁺ + H₂O₂ → Cu²⁺ + OH⁻ + ·OH

Metal ions such as iron and copper are not inherently harmful in the skin; they participate in normal physiological processes. The problem arises when free or imbalanced transition metal ions amplify oxidative stress.

3 How Carnosine Intervenes in the Oxidative Damage Chain

3.1 Reducing Oxidative Amplification Through Metal-Ion Coordination

The imidazole ring, free amino group, and carboxyl group in carnosine can participate in metal-ion coordination. Studies have shown that carnosine can form complexes with metal ions such as Cu²⁺, Zn²⁺, and Fe²⁺. In antioxidant mechanisms, the significance of carnosine’s metal-coordinating activity mainly lies in buffering iron, copper, and other metal ions capable of participating in redox cycling, thereby reducing the opportunity for metal-catalyzed oxidative reactions to continue amplifying. Zn²⁺ coordination is more related to competitive coordination or metal homeostasis.

Reduced free transition metal ions → decreased opportunity for metal-catalyzed ROS generation → reduced lipid peroxidation pressure → decreased RCS generation → reduced oxidative and carbonyl attacks on collagen

Carnosine is not equivalent to a strong chelating agent, nor does it completely remove metal elements from the skin. It is better understood as a local chemical buffering molecule that lowers the activity of certain metal-catalyzed reactions through coordination.

3.2 Reducing Downstream Lipid Peroxidation Damage Through Carbonyl Scavenging

When sebum, cell-membrane lipids, or stratum corneum lipids are attacked by ROS, lipid peroxidation occurs, producing RCS such as 4-HNE, MDA, and ACR. These substances can continue to attack proteins, forming a second wave of reactions after oxidative damage.

Carnosine can react with certain α,β-unsaturated aldehydes. Using acrolein as an example, studies show that the reaction between carnosine and acrolein can first form a Schiff base, followed by Michael addition and cyclization steps, ultimately generating carnosine–acrolein adducts. The specific product structures may vary depending on reaction conditions, and the following can be understood as a simplified mechanism:

Carnosine + α,β-unsaturated aldehyde

↓

Schiff base

↓

Michael addition

↓

Stable adduct

↓

Reduced opportunity for RCS to continue attacking proteins

This mechanism explains why carnosine has both antioxidant and anti-glycation significance. It can participate in metal coordination at the early stage of the oxidative chain and also capture RCS generated at later stages of oxidation, thereby reducing protein carbonylation and subsequent cross-linking.

4 Glycation Reactions and Collagen Cross-Linking

4.1 Basic Process of the Maillard Reaction

The Maillard reaction is a non-enzymatic reaction between reducing sugars and free amino groups in proteins, peptides, or amino acids. In food, this reaction can contribute to browning and flavor development; in the skin, similar reactions promote structural aging of collagen and elastin.

The basic pathway of skin glycation is as follows:

Reducing sugar + free amino groups in proteins → Schiff base → Amadori product → dehydration, oxidation, cleavage → α-dicarbonyl compounds and other RCS → AGE formation → collagen cross-linking

Advanced glycation end products (AGEs) are a complex class of products formed at the later stage of glycation reactions. AGEs can bind to long-lived structural proteins, causing collagen fibers to become cross-linked, stiffened, and functionally impaired.

4.2 Effects of AGEs on Skin Structure

Collagen is an important supporting structure in the dermis. Normal collagen fibers need to maintain a certain degree of flexibility and slippage to preserve skin elasticity. After AGEs are formed, they increase abnormal cross-linking between collagen molecules, causing collagen fibers to gradually lose elasticity. The effects of AGEs on the skin include:

RAGE, the receptor for advanced glycation end products, can bind AGEs and further induce ROS, inflammatory factors, and matrix metalloproteinase-related reactions, forming a “glycation–oxidation–inflammation” cycle.

5 Anti-Glycation Mechanisms of Carnosine

5.1 Early Stage: Sharing the Reaction Burden of Reducing Sugars and Early Carbonyl Intermediates

In the early stage of glycation, reducing sugars undergo condensation reactions with protein amino groups, forming Schiff bases and then Amadori products. Lysine and arginine residues in collagen are common reaction sites.

Carnosine contains a free amino group and an imidazole ring, allowing it to react with certain carbonyl or dicarbonyl intermediates. Dicarbonyl compounds such as MGO and GO, as well as aldehydes derived from lipid peroxidation such as MDA, 4-HNE, and ACR, can continue to modify lysine, arginine, cysteine, or histidine residues in proteins, promoting protein carbonylation, AGE precursor accumulation, and cross-link formation. As a small-molecule carbonyl-scavenging substrate, carnosine can consume a portion of reactive carbonyl species, reducing their opportunity to directly attack long-lived structural proteins such as collagen and elastin.

5.2 Middle Stage: Capturing RCS Such as MGO, GO, MDA, 4-HNE, and ACR

As glycation progresses into the middle stage, the focus of damage shifts toward RCS. Highly reactive carbonyl molecules such as MGO, GO, MDA, 4-HNE, and ACR can rapidly modify proteins, inducing carbonylation, cross-linking, and AGE precursor accumulation. The free amino group and imidazole ring in carnosine can form adducts with certain reactive carbonyl species, reducing the intensity of RCS attacks on collagen and elastin.

This stage represents the core of carnosine’s anti-glycation activity:

Glycoxidation / lipid peroxidation → increased RCS → carnosine captures RCS → reduced AGE precursors → decreased pressure for collagen cross-linking

5.3 Late Stage: Reducing the Continued Accumulation of Irreversible Cross-Links

Once AGEs form stable cross-links with collagen, ordinary topical skincare ingredients have difficulty directly breaking down the cross-linked structures that have already formed. Carnosine primarily acts before large amounts of AGEs are formed, reducing the burden of upstream RCS and early glycation intermediates, thereby decreasing the continued accumulation of cross-links. Therefore, under certain concentration and exposure conditions, carnosine can be understood as a sacrificial substrate or carbonyl-scavenging substrate. It can competitively consume some reactive carbonyl species, thereby reducing the opportunity for these substances to continue modifying collagen and elastin.

6 Limitations of Topical Carnosine: Stability, Skin Penetration, and Enzymatic Hydrolysis

6.1 Skin-Penetration Limitations Caused by Hydrophilicity

Carnosine is a hydrophilic dipeptide containing an amino group, carboxyl group, peptide bond, and imidazole ring, giving it relatively strong overall polarity. The outermost layer of the skin, the stratum corneum, consists of corneocytes and a lipid matrix, which restricts the free diffusion of hydrophilic molecules. Factors affecting the topical performance of carnosine include:

6.2 Carnosinase-Related Hydrolysis

The human body contains enzyme systems capable of hydrolyzing carnosine and related dipeptides, mainly including:

CNDP2 protein expression can be detected in human skin, including varying levels of expression in basal-layer cells, spinous-layer cells, eccrine sweat glands, endothelial cells, fibroblast-related cells, and melanocytes. This indicates that once topical carnosine enters the skin, it may be affected by the cutaneous enzymatic environment, potentially reducing its effective exposure time.

It should be noted that CNDP2 protein expression in the skin does not mean that topical carnosine will necessarily be rapidly inactivated. The actual degree of hydrolysis still needs to be evaluated in relation to whether the ingredient enters the relevant skin layers, local enzyme activity, formulation residence time, and skin penetration–metabolism experiments.

7 Decarboxy Carnosine: Structural Modification to Improve Resistance to Enzymatic Hydrolysis

7.1 What Is Decarboxy Carnosine?

Decarboxy Carnosine generally refers to carcinine, also known as β-alanyl-histamine. It can be viewed as a structural analogue of carnosine: the carboxyl group at the histidine end of carnosine is removed, converting that portion into a histamine structure.

Decarboxy Carnosine / Carcinine

Free-base molecular formula: C₈H₁₄N₄O

H₂N-CH₂-CH₂-C(=O)-NH-CH₂-CH₂-imidazole ring

Common cosmetic names include Decarboxy Carnosine HCl, or decarboxy carnosine hydrochloride. The hydrochloride form can improve stability, solubility, and usability in raw-material processing and formulation applications.

7.2 Why Decarboxylation Makes It Less Readily Recognized by Carnosinase

Carnosinase recognition of carnosine depends on its specific dipeptide structure, carboxyl-group position, spatial conformation, and charge distribution. Decarboxy Carnosine removes the carboxyl group at the histidine end, changing the terminal structure and charge distribution of the molecule so that it no longer fully matches the preferred substrate features of carnosinase. The structural changes lead to the following effects:

The design logic of Decarboxy Carnosine is to retain the imidazole ring and nitrogen-containing reactive sites while changing the substrate-recognition features preferred by carnosinase, thereby improving resistance to enzymatic hydrolysis. Existing literature indicates that structural modifications such as decarboxylation, acetylation, or methylation can improve the enzymatic hydrolysis stability of carnosine-related molecules. However, actual stability in specific topical formulations still needs to be evaluated using formulation and skin-model experiments.

7.3 Enhanced Positive Charge and Skin Retention

Ordinary carnosine contains a carboxyl group and tends to exhibit zwitterionic characteristics under physiological pH conditions. After decarboxylation, the negatively charged carboxyl group is reduced, and the molecule becomes more cationic overall. Some phospholipids, proteoglycans, cell-membrane surfaces, and extracellular matrix components in the skin carry negative charges. With enhanced cationic characteristics, Decarboxy Carnosine may interact more strongly with these structures, thereby increasing the opportunity for local adsorption and retention.

Skin penetration depth cannot be determined solely by charge. Molecular size, polarity, lipophilicity/hydrophilicity balance, salt form, formulation carrier, release rate, and skin-barrier status all influence final penetration performance. Decarboxy Carnosine has improved resistance to enzymatic hydrolysis; however, its actual penetration depth needs to be evaluated in combination with the specific formulation and skin-penetration experiments.

8 Liposomal Encapsulation: Improving Carnosine Delivery and Skin Retention

8.1 Structure of Liposomes

Liposomes are vesicular structures formed by phospholipid bilayers, with a hydrophilic core and a lipid bilayer shell. They can encapsulate hydrophilic ingredients and can also improve the compatibility of ingredients with the skin’s lipid barrier. Carnosine is a hydrophilic small peptide and can be encapsulated in the aqueous region of liposomes. The significance of liposomal encapsulation lies in improving the stability of carnosine in formulations and on the skin surface, while enhancing opportunities for skin retention and penetration.

8.2 Effects of Liposomes on Carnosine

Liposomes support carnosine mainly through four aspects:

An in vitro skin-penetration study showed that skin penetration of carnosine was not detected in a conventional carnosine reference formulation, whereas the cumulative permeation of three types of carnosine liposomes was approximately 6% of the applied dose. In terms of skin retention, the liposome groups reached approximately 20%–30%, while the conventional carnosine gel reached approximately 2%–4%. These data support that liposomes can improve skin retention and in vitro penetration performance of carnosine. The role of liposomes is to increase the opportunity for carnosine to reach its site of action in the skin; it does not mean that all carnosine is guaranteed to directly enter the dermis.

8.3 Division of Roles Between Decarboxy Carnosine and Liposomes

Decarboxy Carnosine represents molecular-structure optimization, while liposomes represent delivery-system optimization. Both approaches point toward the same goal: allowing carnosine-type active ingredients to maintain longer residence time and higher effective exposure in the skin.

9 Skincare Positioning of Carnosine-Type Ingredients

9.1 Core Mechanistic Pathway

The role of carnosine-type ingredients in skin anti-aging can be summarized as follows:

Ultraviolet radiation, pollution, inflammation, and glucose-metabolism stress → increased ROS and RCS → lipid peroxidation, protein carbonylation, and non-enzymatic glycation → AGE formation and abnormal collagen cross-linking → collagen fiber stiffening, reduced elasticity, worsening wrinkles and sagging

Carnosine participates in metal coordination, oxidative buffering, and RCS scavenging → reduced risk of irreversible modification of collagen

9.2 Suitable Skincare Directions

Carnosine-type ingredients are suitable for the following skincare directions:

9.3 What to Consider When Selecting Carnosine-Type Products

When selecting skincare products containing carnosine-type ingredients, attention should also be paid to the following points:

Carnosine-type ingredients are not substitutes for sunscreen, antioxidants, barrier-repair ingredients, or collagen-promoting ingredients; rather, they act at different positions along the aging chain. The main value of carnosine lies in reducing the risk of continued accumulation of oxidative stress, carbonyl stress, and glycation cross-linking, rather than directly breaking down already formed deep collagen AGE cross-links. The effects of topical application are influenced by ingredient concentration, formulation system, delivery technology, skin-barrier status, and duration of use. Specific efficacy still needs to be verified through formulation-level in vitro experiments, skin models, or human efficacy testing.

10 Classification Tables of Representative Chemicals Related to the Skin Anti-Aging Mechanisms of Carnosine

Table 1 Core Carnosine Actives, Structural Analogues, and Structural Building Blocks

Table 2 Glycation Reactions, Reactive Carbonyl Species, and Protein Damage Models

Table 3 Anti-Glycation, Carbonyl-Scavenging, and Antioxidant Reference Compounds

Table 4 Fenton Reaction, Fenton-Like Reaction, Metal Coordination, and Chelation Detection

Table 5 Detection and Analytical Reagents and Liposomal Delivery Materials

Note: The products listed above are representative Aladdin products related to scientific research and formulation studies. For more product specifications, grades, and COA information, please search by “product name / CAS / catalog number” on the Aladdin official website.

References

[1] PubChem. Carnosine | C₉H₁₄N₄O₃ | CID 439224.

[2] Artasensi A, Mazzotta S, Sanz I, Lin L, Vistoli G, Fumagalli L, Regazzoni L. Exploring Secondary Amine Carnosine Derivatives: Design, Synthesis, and Properties. Molecules. 2024;29(21):5083.

[3] de Lima GC, de Araujo-Neto JH, Portes MC, de Oliveira APA, da Costa Ferreira AM. An Investigation into Carnosine as a Coordinating Ligand of Essential Metals, Copper, Zinc and Iron, and Some of Its Biological Activity. Inorganics. 2026;14(3):85.

[4] Bispo VS, de Arruda Campos IP, Di Mascio P, et al. Structural Elucidation of a Carnosine-Acrolein Adduct and its Quantification in Human Urine Samples. Scientific Reports. 2016;6:19348.

[5] Chen CY, Zhang JQ, Li L, Guo MM, He YF, Dong YM, Meng H, Yi F. Advanced Glycation End Products in the Skin: Molecular Mechanisms, Methods of Measurement, and Inhibitory Pathways. Frontiers in Medicine. 2022;9:837222.

[6] The Human Protein Atlas. Tissue expression of CNDP2 in skin.

[7] PubChem. Carcinine | C₈H₁₄N₄O | CID 2574.

[8] Katsogiannis I, Naziris N, Sarika A, Gardikis K, Hatziantoniou S, Boukos N, Dallas P, Fikioris N, Demetzos C. Development and in vitro evaluation of liposomal carnosine for dermatological and cosmeceutical applications. Journal of Drug Delivery Science and Technology. 2024;96:105654.

[9] Pegova A, Abe H, Boldyrev AA. Hydrolysis of carnosine and related compounds by mammalian carnosinases. Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology. 2000;127(4):443–446.

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