Life Extension Magazine®

Woman with youthful skin being supported by glycation

Protect Your Skin From Age-Related Glycation

Glycation disrupts collagen metabolism, which leads to wrinkles and sagging. Clinical and lab studies show that five topical nutrients work in complementary ways to block the detrimental effects of glycation and promote dermal regeneration—preserving the skin’s youthful appearance.

Scientifically reviewed by: Dr. Crystal M. Gossard, DCN, CNS, LDN, in August 2023. Written by: Robert Goldfaden and Gary Goldfaden, MD..

At this very moment, a destructive process called glycation is aging your skin from the inside out.1,2 In fact, researchers recently uncovered compelling evidence that stresses “the importance and possibly central role of glycation in skin aging.2

Glycation occurs when sugar molecules bind to proteins like collagen in living tissues, and culminates in the formation of deadly complexes called advanced glycation end products (AGEs).1,3 This in turn significantly disrupts collagen metabolism and paves the way for wrinkles, creping, and loose skin.4,5

That’s why researchers have ramped up their efforts to identify safe and effective ways to target this enemy of healthy skin. In this article, we will explore how five topical compounds protect against the detrimental effects of glycation as we age and promote dermal regeneration.

As part of a comprehensive approach for skin health that includes a reduction in sugar-laden foods and refined carbohydrates, as well as limiting high-temperature cooking methods, these clinically proven compounds can reduce glycation and AGEs formation to retain the skin’s youthful appearance.

Glycation Accelerates Intrinsic Skin Aging

Glycation Accelerates Intrinsic Skin Aging  

When excess sugar, such as fructose6,7 or glucose, floats around the bloodstream, it has a propensity for binding to functional proteins through a chemical process called glycation.1,8

Once glycated, these proteins are rendered dysfunctional and undergo further structural rearrangements to form dangerous advanced glycation end products (AGEs) that accumulate in the brain, kidney, arteries, and skin as we get older.9-11 This is evident in diabetics, whose systemic complications are tied to abnormal AGE levels.12

The dermis, which provides strength and resiliency to skin,13 consists primarily of an extracellular matrix that has a high quantity of the protein collagen, particularly types I and III.14,15 Due to its slow turnover rate and exposure to elevated glucose levels outside of cells, 16,17 collagen falls victim to glycation and AGE formation.18 The result is extensive cross-linking of collagen molecules, turning them from tough and flexible to brittle and stiff.19,20 This decreases skin’s elasticity and sets the stage for the development of wrinkles and sagging skin.

AGE-modified collagen is highly resistant to repair mechanisms, which allows it to accumulate and impair the structural integrity of the dermis. 1,3,16 It has been shown to cause the collapse of specialized cells known as fibroblasts that produce and organize collagen fibers.16 This strongly influences collagen homeostasis and subsequently leads to less collagen production and more breakdown in the skin.3,16 To make matters worse, ultraviolet (UV) exposure21,22 and AGE formation1 itself generate free radicals that further exacerbate this problem by increasing activity of the collagen-degrading enzyme matrix metalloproteinase-1 (MMP-1).23,24

Scientists have grasped the enormity of glycation-related skin damage and therefore have searched for new ways to inhibit glycation reactions and enhance the regeneration of the skin’s matrix. Let’s now take a look at how a variety of topical compounds accomplish this to reveal fresher, younger-looking skin.

Terminalia Chebula Fruit Extract

The fruit of the plant Terminalia chebula is highly revered in traditional Chinese and Ayurvedic medicine for treating a wide range of health conditions, from asthma to heart disease.25,26 These health benefits have been largely attributed to the fruit’s broad spectrum of potent phytochemicals, which include polyphenols, anthocyanins, and alkaloids.25,27,28

The substantial activity of the compounds in Terminalia chebula fruit extract neutralizes free radicals and reduces AGE formation that promotes toxic sugar-protein reactions.29-31 Research demonstrates that this novel extract was seven times more effective at reducing glycation than the well-known glycation inhibitor aminoguanidine.32 Other research indicates that one of its main constituents, chebulic acid, acts as a powerful hammer to break the bond existing between abnormally cross-linked proteins, setting them free and restoring their critical functions in various organs, including the skin.31 By being both an inhibitor and breaker of glycation cross-linking, Terminalia chebula fruit extract offers a unique advantage for fighting or even reversing skin aging.

These impressive findings led to additional research, but this time in humans. Scientists conducted a clinical trial in which a topical formula containing Terminalia chebula fruit extract was applied twice daily to the face of 15 human volunteers aged between 41 and 65. At the end of the 12-week study, participants significantly reduced wrinkle depth by 22% and skin roughness by 24% compared to baseline. Dermatological evaluation also revealed improvements for skin brightness, tone, and dryness.33

What You Need To Know
Prevent Skin Glycation With Topical Nutrients

Prevent Skin Glycation With Topical Nutrients

  • Glycation refers to a spontaneous reaction between sugar, such as fructose and glucose, and proteins like collagen that reside in the skin’s vital matrix.
  • This culminates in the formation of advanced glycation end products (AGEs) that cause damage to collagen molecules, leading to wrinkles, creping, and loose skin.
  • Scientists have identified topical nutrients, including Terminalia chebula fruit extract, pentapeptide-34 trifluoroacetate, blueberry extract, hexapeptide-3, and pomegranate extract, that work in complementary ways to protect the skin against the detrimental effects of glycation as we age and promote dermal regeneration.
  • As part of a comprehensive approach that includes reducing sugary foods and refined carbohydrates, as well as proper cooking methods, these compounds, proven clinically or in the lab, reduce glycation and AGE formation to preserve the skin’s youthful appearance.

Blueberry Extract

Blueberries have long been known for remarkable anti-inflammatory and free-radical fighting properties, which can be credited to their wealth of phenolic compounds known as anthocyanins.34-39 By combating free radicals and reducing the release of proinflammatory cytokines,39,40 blueberries can safely break the self-perpetuating cycle of AGEs and oxidative stress that underlies intrinsic skin aging.41-43

When researchers tested the anti-glycation activity of various fruits, blueberries ranked as one of the highest.44 In addition, blueberries protect against collagen breakdown by inhibiting matrix metalloproteinases (MMPs) that occur as a response to UV exposure.45,46

In human studies, blueberry extracts have been shown to improve the undesirable skin changes that accompany aging.47,48 In a study of 20 diabetic females older than 55 years with elevated skin AGEs, a topical preparation containing blueberry extract significantly improved skin tone and smoothness, fine lines, crepiness, and firmness after 12 weeks with excellent tolerability. Although no changes in skin AGEs was observed, researchers believe that a study with a longer duration might have produced a different result.47

In another clinical trial, six weeks of supplementation with an oral mixture containing blueberry extract in 62 women aged 45-73 significantly increased skin elasticity by 9% over a placebo, and after 12 weeks significantly decreased skin roughness by 6% compared to the control group.48

Pentapeptide-34 Trifluoroacetate

The fat-soluble compound coenzyme Q10 (CoQ10) is an essential component in mitochondrial energy production49 that fuels processes that repair and regenerate skin, including collagen synthesis and DNA repair.50,51 In skin cells, CoQ10 defends against UV induced damage and oxidative stress.52 Since CoQ10 levels decline with age,49 scientists have developed a novel peptide called pentapeptide-34 trifluoroacetate that enhances the skin’s own capacity to produce CoQ10.53 This effect was observed in vitro as skin cells exposed to pentapeptide-34 trifluoroacetate exhibited a 46% rise in endogenous CoQ10.53

By replenishing depleted CoQ10 levels, pentapeptide-34 trifluoroacetate protects and energizes the skin, leading to visible anti-aging effects in humans. In a double-blind clinical study on 10 women aged 48-59, applying pentapeptide-34 trifluoroacetate twice daily around crow’s feet for 28 days reduced fine lines and wrinkles compared with a placebo.53


Since collagen is the most abundant structural protein in the skin,54-56 it stands to bear the brunt of glycation reactions. But research shows that, with aging, other key dermal proteins like fibronectin are not immune either.57 Fibronectin is a glycoprotein that attaches to matrix components and controls vital functions such as cell adhesion, differentiation, and migration.58 Once glycated, fibronectin has difficulty binding to and interacting with matrix elements, compromising reparative processes that maintain the skin’s youthful structure and appearance.59

Hexapeptide-3 has been shown to mimic the beneficial effects of fibronectin to promote matrix remodeling and repair.60 Results from human clinical trials show that when applied topically, hexapeptide-3 improves several parameters of skin health, with one study reporting an increase in skin hydration of 100% and skin smoothness by 425% in just one hour!60,61

Pomegranate Extract

Research has shown that pomegranate extract can regenerate the dermis by stimulating type I collagen,62 inhibiting protein-destroying matrix metalloproteinase-1,62 and preventing fibroblast apoptosis (cell death).63 It also counteracts the age-related thinning of the epidermis by increasing its thickness to protect against UV radiation,62 and in vitro studies have demonstrated that compounds in pomegranate inhibit the formation of AGEs.64-66 Together, this research shows that pomegranate extract induces favorable changes in different layers of the skin to enhance its healing capacity.


Glycation and AGEs deteriorate the skin’s vital matrix to accelerate skin aging that manifests itself as wrinkles, creping, and loose and dry skin. Scientists have identified topical nutrients, including Terminalia chebula fruit extract, pentapeptide-34 trifluoroacetate, blueberry extract, hexapeptide-3, and pomegranate extract that safeguard the skin against the detrimental effects of glycation as we age and promote dermal regeneration. As part of a comprehensive approach that includes a reduction in sugar-laden foods and refined carbohydrates, as well as limiting high-temperature cooking methods, these clinically proven compounds can reduce glycation and AGE formation to preserve the skin’s youthful appearance.

If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.

Gary Goldfaden, MD, is a clinical dermatologist and lifetime member of the American Academy of Dermatology. He is the founder of Academy Dermatology in Hollywood, FL, and Cosmesis Skin Care. Dr. Goldfaden is a member of the Life Extension® Foundation’s Medical Advisory Board. All Cosmesis products are available online.


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