PracticalDermatology

SkinCeuticals has launched a modernized ingredient technology of their anti-aging product—A.G.E. Interrupter Advanced—to deliver a multimodal anti-glycation skincare that targets all phases of the glycation process. Its original formula, A.G.E. Interrupter, debuted and pioneered anti-glycation skincare in 2009. It was evaluated on advanced glycation end products (AGEs) and was found effective in reducing signs of aging seen in patients with diabetes, a cohort of patients specifically prone to AGEs.^1,2 The newer version, A.G.E Interrupter Advanced, has harnessed more than 15 years of glycation expertise and new anti-glycation science, resulting in a modernized ingredient technology.¹

While visible signs of aging stem from a range of causes such as exposure to UV rays and pollution, substantial research supports the role of glycation as a key factor that influences the normal aging process and contributes to premature aging as well.3-5

“In its simplest form, glycation is the binding of glucose to protein,” said Zoe Diana Draelos, MD, a clinical and research dermatologist based in High Point, North Carolina. Glycation degrades skin’s collagen. Glycation, also known chemically as the Maillard reaction, is a multi-phase biological process in which sugars bind to proteins, like collagen, to form byproducts known as AGEs. AGEs cause collagen to become brittle and weaken its reparative ability, degrading its overall integrity and resulting in signs of aging.3

Accumulation of AGEs and degradation of collagen in the skin can lead to the appearance of wrinkles and laxity, dullness and sallowness, and inflammation.4 “As the sugar binds to the protein [such as collagen], the protein becomes more rigid because it’s cross-linked and bound, and this structural hardening of the protein translates into decreased function, which translates into premature aging,” Dr. Draelos explained.

The impact of AGEs increases when glycated collagen becomes resistant to matrix-degrading enzymes, while normal and healthy collagen becomes vulnerable. Studies have shown that glycation promotes stimulation of matrix-degrading enzymes which impacts normal degradation and synthesis of the extracellular matrix (ECM), leading to visible effects.5

As the new product name reflects, A.G.E. Interrupter Advanced aims to interrupt this process to prevent future AGEs formation, correct existing damage, and optimize collagen matrix integrity.¹

The Impact of AGEs

Premature aging due to AGEs is distinct from the effects of typical UV-induced photoaging, Dr. Draelos said. However, the oxidative stress resulting from UV exposure also increases AGEs, as do other extrinsic factors including smoking, alcohol, and diet. Research has revealed that 10% to 30% of AGEs from foods—dietary AGES (dAGEs)—are absorbed in the body after ingestion, and a 2020 study linked higher dAGEs intake with higher AGEs content in the skin, as indicated by assessment of skin autofluorescence.6,7

Drier, high-temperature cooking methods such as frying and grilling result in greater production of dAGEs⁵—especially when cooking animal-derived foods—compared to stewing, boiling, and other methods that are lower in heat and higher in moisture.6

Diet also affects intrinsic aging, according to Dr. Draelos. “Intrinsic aging is related to the reactive oxygen species issues that are created, for example, during digestion and through the synthesis of hormones, so intrinsic aging is in part related to metabolic processes, and AGEs coming from the diet are partly related to intrinsic aging.”

AGEs have been implicated in various age-related diseases, including diabetes, kidney disease, atherosclerosis, and Alzheimer disease.4 There is evidence that AGEs can also affect the different structures and physiological functions of the skin.5

Over time, the progressive accumulation of AGEs results in substantial changes in the structure and appearance of the skin.5 Among other cutaneous effects, higher AGEs content has been linked to yellowing and browning, reduced elasticity, and deeper wrinkles in volunteer study participants. In vitro studies have demonstrated that AGEs decrease proliferation and increase apoptosis and premature senescence of skin cells, while increasing the expression of proinflammatory mediators.8

Although glycation and AGEs formation is a normal physiological process during aging, the appearance of glycated collagen can be first seen at the age of 20.8 Dr. Draelos points to its occurrence in people with diabetes to underscore the impact of glycation on the aging of numerous organ systems. “Glycation occurs to a greater degree in diabetes than in any other disease, due to elevated circulating serum glucose levels,” she said. “Glycation products occur throughout life, but they’re accelerated in diabetes, so diabetes is kind of a model of accelerated aging.”

Glycation in the organs contributes to diabetes-related conditions including diabetic neuropathy, diabetic retinopathy, and early-onset kidney disease and coronary artery disease. In addition, studies have identified AGEs as a factor in the pathogenesis of diabetes-related skin complications such as non-healing wounds.5

“Many of the things that we associate with diabetes are actually signs of premature aging,” Dr. Draelos added. Increased production of AGEs also occurs with normal aging and contributes to senescence of the skin and other organs in advanced age.9

Interrupting the Process

The Maillard reaction causes browning of food when cooked with heat and similarly causes browning of the skin in a process involving initiation, propagation, and advanced stages. In the early stages, appropriate intervention may inhibit collagen glycation and protect the collagen environment. However, the process is irreversible once it reaches the advanced stage.1

Within the collagen protein backbone, early glycation reactions can occur in which glucose reacts in a non-enzymatic and reversible manner with free amino groups of lysine.10 “Although this reaction is reversible, with cumulative oxidative stress, the combination of glycation and oxidation forms irreversible adducts with the protein, which ultimately become AGEs, including certain biomarker AGEs specifically as carboxymethyllysine and pentosidine adducts.”10

In the advanced stage, AGE formation results in damaged, brittle, cross-linked collagen and involves an autocatalytic reaction with the receptors of AGEs (RAGEs), which further increases AGE production and reduces the regenerative ability of collagen and elastin.1

Thus, a “primary target for aging is to inhibit glycation, and that’s why anti-aging products are being developed to interrupt the cross-linking of sugars to protein” in the skin, Dr. Draelos noted. “We now recognize that AGEs are an important part of premature aging and the aging process itself, so a full anti-aging regimen has to address this issue as well.”

A.G.E. Interrupter Advanced

In a study published in 2009 in the Journal of Cosmetic Dermatology, Dr. Draelos investigated the original formulation of the A.G.E. Interrupter product by SkinCeuticals in a single-center study with 20 females with type II diabetes aged 55 years or older with mild to moderate fine lines, wrinkles, and pigmentation on the face and hands.9

Participants applied the product to their face, hand, and inner forearm twice daily for 12 weeks, and various signs of aging were graded on a 4-point ordinal scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). The results showed statistically significant improvements in fine lines, firmness, skin tone and smoothness, creping, radiance, and overall appearance, with no reported tolerability issues.

Compared to the original product, A.G.E. Interrupter Advanced contains a higher concentration of the anti-aging ingredient Proxylane™, a molecule derived from the beechwood tree via green chemistry and developed by L’Oréal labs in 2006.1 This ingredient was shown to stimulate the production of type VII collagen and glycosaminoglycans, which may contribute to greater skin firmness and elasticity.1 Proxylane™ is 20% more concentrated in the new formulation compared to the original version.1

Additionally, the wild fruit flavonoids in the updated product are 12.5% more concentrated with the addition of pomegranate extract to the blueberry extract contained in the original formulation.1 These flavonoids have been shown to help inhibit glycation while fortifying the ECM to guard against damage induced by the production of free radicals. Key findings have shown that the new combination of the two wild fruit flavonoids have a synergistic effect and demonstrates significant inhibition of UV-induced protein glycation in ex vivo skin, whereas blueberry extract alone did not show significant AGE inhibition.

Another new key ingredient in A.G.E. Interrupter Advanced is glycyrrhetinic acid, an anti-inflammatory ingredient that is a main bioactive compound found in licorice root. In addition to promoting skin brightening, several studies indicate that glycyrrhetinic acid may inhibit the function of RAGEs and the resulting oxidative stress and inflammation.^11,12

“When the product was first introduced, the concept of AGEs was relatively new, and optimization has occurred in our understanding since then,” due to further research, Dr. Draelos stated. “The newer formulation incorporates a higher concentration of cosmeceutical ingredients, providing additional AGE protection.”

With ingredients that would affect tolerability, she said, A.G.E. Interrupter Advanced would be appropriate for patients of all ages and skin types — including those with sensitive skin — as part of an individualized skin regimen.

According to the product recommendations, the cream can be used alone, or it may be applied following a SkinCeuticals vitamin C antioxidant serum and before applying sunscreen if used in the morning or after retinol application at night.2

Comprehensive Approach

Dr. Draelos emphasizes that topical anti-aging products should be combined with healthy lifestyle choices that maintain healthy levels of circulating blood glucose and minimize the impact of extrinsic factors that can exacerbate glycation, including UV light and pollution exposure, smoking, alcohol, and diet.

For instance, researchers have observed elevated levels of AGEs in the skin of smokers compared to non-smokers and in skin exposed to UV rays and pollution.6

“Pollution and cigarette smoke contain nanoparticles produced through combustion or burning, and the extrinsic aging produced by these nanoparticles touching the skin is due to the generation of reactive oxygen species,” Dr. Draelos explained. “Wearing a protective film over your face traps nanoparticles and prevents oxidative damage. Thus, a moisturizer or sunscreen film will minimize the damage created by pollution and cigarette smoke.”

Adequate intake of dietary vitamins, especially A, C and E, is important as “vitamins C and E are the primary antioxidant vitamins of the skin, so if you don’t consume these vitamins in your diet, they are not available in the skin to provide endogenous antioxidant protection,” Dr. Draelos said. She also points to the need to prioritize low-glycemic foods, which is especially important for patients with diabetes but also advisable for the general population. People with diabetes may “have to focus on low-glycemic foods to help keep their sugars in check, but a low-glycemic diet is also an anti-aging diet,” she noted.

Across various studies, adherence to a low AGE diet was associated with lower circulating serum AGE levels and inflammatory biomarkers as well as improved insulin resistance in research participants both with and without diabetes.6

Components of a low AGE diet include reducing consumption of dAGEs through modification of cooking techniques; increasing intake of fresh, polyphenol-rich, and high-antioxidant foods such as fruits and vegetables; and using herbs and spices with antiglycation properties, including parsley, thyme, cinnamon, curcumin, and clove.6

Limiting alcohol consumption may reduce AGEs formation, as studies have found AGEs and AGE precursors in alcoholic beverages, including beer.13

“It may not be possible to stop the formation of AGEs, but it may be possible to decrease their formation through lifestyle choices and with the addition of topical products to allow the skin to remain healthier,” Dr. Draelos stated.

1. SkinCeuticals. Data on file.

2. PR Newswire. SkinCeuticals announces the launch of A.G.E. Interrupter Advanced. April 19, 2023. Accessed May 9, 2023.

3. Chaudhuri J, Bains Y, Guha S, et al. The role of advanced glycation end products in aging and metabolic diseases: bridging association and causality. Cell Metab. 2018;28(3):337-352. doi:10.1016/j.cmet.2018.08.014

4. Zheng W, Li H, Go Y, Chan XHF, Huang Q, Wu J. Research advances on the damage mechanism of skin glycation and related inhibitors. Nutrients. 2022;14(21):4588. doi:10.3390/nu14214588

5. Chen CY, Zhang JQ, Li L, et al. Advanced glycation end products in the skin: molecular mechanisms, methods of measurement, and inhibitory pathways. Front Med (Lausanne). 2022;9:837222. doi:10.3389/fmed.2022.837222

6. Garay-Sevilla ME, Rojas A, Portero-Otin M, Uribarri J. Dietary AGEs as exogenous boosters of inflammation. Nutrients. 2021;13(8):2802. doi:10.3390/nu13082802

7. Chen J, Waqas K, Tan RC, et al. The association between dietary and skin advanced glycation end products: the Rotterdam Study. Am J Clin Nutr. 2020;112(1):129-137. doi:10.1093/ajcn/nqaa117

8. Gkogkolou P, Böhm M. Advanced glycation end products: key players in skin aging? Dermatoendocrinol. 2012;4(3):259-270. doi:10.4161/derm.22028

9. Draelos ZD, Yatskayer M, Raab S, Oresajo C. An evaluation of the effect of a topical product containing C-xyloside and blueberry extract on the appearance of type II diabetic skin. J Cosmet Dermatol. 2009;8(2):147-151. doi:10.1111/j.1473-2165.2009.00428.x

10. Reilly DM, Lozano J. Skin collagen through the lifestages: importance for skin health and beauty. Plast Aesthet Res. 2021;8:2. doi:10.20517/2347-9264.2020.153

11. Kowalska A, Kalinowska-Lis U. 18β-Glycyrrhetinic acid: its core biological properties and dermatological applications. Int J Cosmet Sci. 2019;41(4):325-331. doi:10.1111/ics.12548

12. Li ZY, Tung YT, Chen SY, Yen GC. Novel findings of 18β-glycyrrhetinic acid on sRAGE secretion through inhibition of transient receptor potential canonical channels in high-glucose environment. Biofactors. 2019;45(4):607-615. doi:10.1002/biof.1517

13. Del Castillo MD, Iriondo-DeHond A, Iriondo-DeHond M, et al. Healthy eating recommendations: good for reducing dietary contribution to the body’s advanced glycation/lipoxidation end products pool? Nutr Res Rev. 2021;34(1):48-63. doi10.1017/S0954422420000141