Glycation is one of the basic root causes of endogeneous (intrinsic) skin ageing and a very challenging one or almost impossible one to reverse. Glycation is an ageing reaction which begins in early life, developing clinical symptoms at around 30, and progressively accumulates in tissues and skin due to the glycated collagens that are difficult to be decomposed. Glycation occurs naturally in the body when sugars react with proteins and lipids to form advanced glycation end products (AGEs). AGEs can be exogenously ingested (through food consumption), inhaled via tobacco or endogenously produced and formed both intracellularly and extracellularly. AGE modifications lead to dermal stiffening, diminished contractile capacity of dermal fibroblasts, lack of elasticity in the connective tissues, contribute to hyperpigmentation and a yellowish skin appearance. The formation of AGEs is amplified through exogenous factors, e.g., ultraviolet radiation. 

AGEs cause changes in the skin through 3 processes:

1. AGEs interact with specific cell receptors, altering the levels of soluble signaling molecules, such as cytokines, hormones, and free radicals.
2. In the process of non-enzymatic glycation reaction, a large number of reactive oxygen radicals are released, creating a state of oxidative stress, leading to a significantly reduced level of glutathione, Vitamin C, and Vitamin E in the body. This causes synthetic disorders of collagen in skin tissues. 
3. AGEs alter the physical and biological properties of the original extracellular matrix proteins, such as collagen. 

Many cells have AGEs receptors on the surface, such as macrophages, mesangial cells, fibroblasts, and endothelial cells, through which their function can be affected. They induce oxidative stress and trigger inflammatory pathways by forming crosslinks, altering protein structure, or by binding to AGEs receptors. AGEs cause cellular dysfunction through the modification of intracellular molecules and accumulate in tissues with ageing. This causes the skin and connective tissue to harden and lose their ability to regenerate healthy cells. They cause damage to extracellular proteins like collagen and elastin fibers, which are crucial for maintaining skin structure and firmness. This damage leads to the breakdown of these fibers. AGEs can also affect intracellular proteins like vimentin. AGEs can act as a catalytic site for free radical formation, exacerbate intracellular oxidative stress, and increase ROS production through a variety of mechanisms, reducing glutathione (skin's own anti-oxidant) storage, and activation of protein kinase C, etc., to accelerate the production and accumulation of AGEs. 

One study published in the Journal of Investigative Dermatology found that levels of AGEs were higher in the skin of older individuals compared to younger ones. The study also showed that there was a correlation between the level of AGEs and the severity of skin ageing. This suggests that inhibiting the production or accumulation of AGEs in the skin is a potential target for anti-ageing interventions or skin ageing management.

AGEs are complex and heterogeneous, more than a dozen AGEs have been detected (however not all) in tissues and can be divided into three categories according to their biochemical properties. 
​AGEs are formed through four pathways:

1. the Maillard reaction (non enzymatic reaction between amino groups of proteins and reducing sugars, binding sugars to proteins)
2. sugars auto-oxidation pathway (metal-catalyzed auto-oxidation of glucose or Wolff pathway) 
3. lipid peroxidation pathway (acetyl alcohol pathway)
4. polyols pathway (glucose is converted into fructose via the polyol pathway, which accelerates the production of AGEs)

GLYCATION INHIBITION IS KEY 
AGEs can be crosslinked through side chains to form a substance of very high molecular weight, which is not easily degraded. The consequences from skin glycation are irreversible. This makes prevention or inhibition of the process the best potential strategy to maintain skin health and ageing skin management. One way to do this is by altering the diet to reduce the intake of sugars and carbohydrates, which are known to contribute to glycation. Several studies have found that reducing sugar intake can result in significant improvements in skin health, including reducing wrinkles and improving skin texture. 

AGE inhibitors
Another potential strategy is the use of topical agents that inhibit the formation or accumulation of AGEs in the skin. One study published in the Journal of Cosmetic Science found that a cream containing carnosine, a peptide that inhibits glycation, improved skin elasticity and reduced the appearance of wrinkles in individuals with ageing skin. Skincare containing NAHP or Acetyl Hydroxyproline inhibits the formation of AGEs significantly (in vitro), most likely through a mechanism where NAHP competes with the proteins for the sugar. Finally, NAHP sacrifices itself in place of the proteins and gets (at least partially) glycated. NAHP also prevents loss of cellular contractile forces in a glycated in vitro dermis model and counteracts the diminished cell-matrix interaction that is caused by glyoxal-induced AGE formation.

​Anti-Oxidants
Moreover, I would suggest to combine those ingredients with an ingredient like Licochalcone A. Numerous high ranked publications support that Licochalcone A protects cells from oxidative stress mediated by e.g. UV and HEVIS (blue light) induced reactive oxidative species (ROS). Due to the activation and nuclear translocation of the transcription factor NrF2, the expression of anti-inflammatory, antioxidant and detoxifying enzymes are induced. These enzymes protect the skin cells (like keratinocytes and fibroblasts) from ROS-induced damage, like lipid peroxidation and DNA as well as protein damage. If Licochalcone A is combined with L-Ascorbic Acid, (the most active form of Vitamin C), it supporting skin's own collagen production, provides superior biological cell protection amongst other relevant benefits. My absolute favourite product is Eucerin Hyaluron-Filler Vitamin C Booster which I use daily as a serum in my morning routine.

GLYCATION AND SKIN HEALTH

Acne
In addition to its role in ageing, glycation in the skin has also been linked to a range of skin health problems. One study published in the Journal of Cosmetic Dermatology found that the level of AGEs in the skin was significantly higher in individuals with acne than in those without acne. The study also showed that treating acne with a topical antibiotic significantly reduced the levels of AGEs in the skin.

Atopic Dermatitis
Another study published in the Journal of Investigative Dermatology found that individuals with atopic dermatitis had higher levels of AGEs in their skin than healthy individuals. This suggests that glycation may play a role in the development of inflammatory skin conditions.

Diabetes + Woundhealing
The correlation between high sugar levels and skin ageing can be seen in diabetic patients, where one-third of this population has skin complications. A prominent feature of ageing human skin is the fragmentation of collagen fibers, which severely damages the structural integrity and mechanical properties of the skin. Elevated levels of MMP-1 and MMP-2 and higher crosslinked collagen in the dermis of diabetic skin lead to the accumulation of fragmented and crosslinked collagen, thereby impairing the structural integrity and mechanical properties of dermal collagen in diabetes. Collagen crosslinking makes it impossible for them to easily repair, resulting in reduced skin elasticity and wrinkles. Keratinocytes and fibroblasts are the main cells involved in wound healing, but due to the high glucose (HG) microenvironment in diabetics, the functional state of these cells is impaired, thereby accelerating cellular senescence (programmed cell death).

Conclusion
We can't completely stop the glycation process, therefore it's important that we inhibit it from a young age onwards, hence monitor the sugar intake of our children, use daily SPF and invest in good dermo-cosmetic products containing ingredients like NAHP and powerful anti-oxidants like L-Ascorbid Acid (Vitamin C is needed for the production of collagen) and Licochalcone A (also anti-inflammatory). Preventing signs of ageing, specifically caused by glycation is most effective. If your skin shows (advanced) signs of ageing, you can get visible improvement using skin component (hyaluron, collagen and elastin) bio-stimulating ingredients like Retinol, Bakuchiol, Arctiin, Creatine or Glycine Saponin. Consult your dermatologist if you wish to improve your skin's appearance or skin health issues.

Take care

Special thanks: Ph.D. dr Julia M. Weise Manager Biological Testing & Dorothea Schweiger Lab Manager Facial Skin Biology Beiersdorf HQ Hamburg

Skin boosters using micro-injections with predominantly non-crosslinked hyaluron filler gels like Restylane® Vital, Juvéderm® VOLITE or Belotero® Revive are gaining popularity for very good reasons. Unlike traditional dermal fillers, they are not injected beneath the skin to volumise or shape the face. Instead, they are very fine dermal easily integrated "fillers" that are injected into the skin to hydrate, improve skin quality and give very natural results. They are also gently bio-stimulating, meaning they "stretch" the fibroblasts in the injected area and as a result this cell is producing more collagen. An effective bio-remodeling skin booster using 2 times 5 injection points (bio-aesthetic points - BAP) for a full-face treatment is Profhilo®. However, the recent K-beauty treatment via topical application or micro-injections with bio-remodeling exosomes is gaining popularity.

Exosomes are nano-sized cargos with a lipid bilayer structure carrying diverse biomolecules including lipids, proteins, and nucleic acids. These small extra cellular vesicles are secreted by most types of cells (skin relevant are the keratinocytes and fibroblasts) to communicate with each other. Exosomes circulate through bodily fluids and can transfer information. ​They can be either good or bad, however taken from a healthy young cell they will be sending the best messages. Studies have shown the efficacy of exosomes in skin ageing. They can facilitate skin remodeling (increasing collagen and decreasing senescent cells) leading to skin rejuvenation.

Cells sleep because they don't get enough bio-stimulation: messages. Better messages is better skin architecture. This is why exosomes are so important. At the World Stem Cell Summit it used to be 90% about stem cells (they only life 28 days) and 10% about exosomes, now it is 50/50. The reason is called heterochronic parabiosis. 1. One of the most robust methods of improving the function of ageing tissues is that of heterochronic parabiosis,. The effect was shown in a study with a surgical procedure whereby a young and old mouse are joined together so the share one circulatory system. 2 This study according to dr Kate Goldie AMWC 2023 Monaco is proof that it is not the cells, but the messages they give that is transforming lots of different tissues, which has the ability to profoundly regenerate tissues. That is why people are so interested in exosomes. Exosomes taken from a very young cell give potentially the best messages as they "send the message" of youth. EV (Extra-cellular Vesicle) is the actual correct term as messages come as micro-vesicles and exosomes and form 2 different messages from the cell. 3 We start to understand active ingredients. In exosomes one of the most important ingredients is RNA and is part of the future of regenerative aesthetics. Messenger RNAs up-regulate and Micro-RNAs down-regulate. They physically go into the cell and change how the cells works. So we have to be cautious. In this study "The therapeutic and commercial landscape of stem cell vesicles in regenerative dermatology" dr Kate Goldie et al. assessed all available exosomes in the (UK) market.

Most exosomes used in-office are extracted from human stem cells and frozen to keep them as stable. Unlike actual stem cells, exosomes don't have a nucleus and therefore they are safe to use. Exosome therapy is the application of topical exosomes after in-office treatments which disrupt the skin barrier, like laser resurfacing, chemical peelings or microneedling. Exosomes are also used in micro-injections as a stand-alone skin boosting treatment and in a few skin care products. Be aware that as usual, not all products are alike. The way exosomes are sourced (origin), size, their content (can be growth factors) and function determine largely their efficacy and the price of the product. 

One of the challenges is that we do not really know what is in the exosomes. They are like small packages with a lot of messengers. The use of exosomes looks promising for several indications: regenerative aesthetic medicine, healing, scar treatment, burns and atopic dermatitis, however their safety is not yet fully established and no official registration for their use granted.



​Take care

1. Cell Cycle. 2012 Jun 15; 11(12): 2260–2267. Heterochronic parabiosis for the study of the effects of aging on stem cells and their niches
Irina M. Conboy 
2. Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types Methodios Ximerakis
3. J Cell Biol. 2013 Feb 18; 200(4): 373–383. Extracellular vesicles: Exosomes, microvesicles, and friends Graça Raposo et al

The fibroblast is one of the most important cells involved in ageing skin. You can find it in the lower layer of the epidermis and the dermis. It has many functions, one of which is the production of key components like hyaluron (filling + hydration), collagen (strength + structure) and elastin (flexibility + stretch). It particularly has to work hard to replenish hyaluronic acid or hyaluron as this filling component only has a half-life in the skin of several hours up to a day. Good quality collagen can last 15 years and elastin up to 70 years. It is also believed to be involved in the clean-up of dysfunctional components, like for example broken elastin, which is visible photodamage-damage and called solar elastosis. Fibroblast senescence (agedness) does also increase the risk of age spots. In proper ageing skin management, the fibroblast is a key target-cell.
 
Many aesthetic in-office treatments like ultrasound, radio-frequency, chemical peelings, laser etc. are based on causing controlled damage to the skin provoking wound-healing. This is the base of their rejuvenating or aesthetic impact. The number of new fibroblasts (myofibroblasts) is increased during the wound-healing process. Some injectables, like for example hyaluron-fillers cause the fibroblasts at the injection site to stretch and bio-stimulate collagen production. There are specific bio-stimulating injectable treatments. The most popular ones are Sculptra®, Radiesse®, Ellanse®, and a new one which combines hyaluron-filling and bio-stimulation is HArmonyCa®.
 
As we age the fibroblast is undergoing some changes because of intrinsic and extrinsic factors. It loses it’s production power, it flattens, loses mechanical tension and therewith the ability to interact with other cells in the skin. It is becoming “tired and deaf”. My hypothesis was that injecting large droplets of hyaluron into the dermis might cause the fibroblast to become “lazy” via a negative feedback mechanism: when something is present in abundance, the fibroblast might not be stimulated enough to work hard to replenish it. This is not yet scientifically proven.
 
It is important to keep the fibroblast in good shape and biologically active. We can stimulate it’s biological activity with skincare containing bio-stimulators, or ingredients which activate the production of important skin components by the fibroblast. On the other side we need to protect the cell from damage.
 
Bio-stimulating active ingredients in skincare which have shown to particularly stimulate the fibroblast* are for example:

• Creatine (bio-stimulation of collagen I and IV by + 35%  and elastin with +36%)
• Glycine Saponin (bio-stimulation of hyaluron production +256% and collagen +49%) which is also a powerful anti-oxidant
• Arctiin (bio-stimulating collagen production)

Protection from photo-damage we can achieve with a combination of sunscreen and anti-oxidants, more specifically Licochalcone A. Licochalcone A has a proven broad ability to protect the skin from damaging free-radicals or oxidative stress from UVA, UVB and HEVIS (High Energy Visible Light) affecting keratinocytes and fibroblasts.

I am not yet aware of skincare ingredients which increase the number of (new) fibroblasts, like the semi or minimal invasive in-office treatments. It’s an interesting field to explore if this is possible without injury, inflammation or irritation. However, you probably get "more bang for your buck" by starting a a skincare routine with focus on bio-stimulation and protection of the fibroblast pre- and post minimal and semi invasive aesthetic treatments. This could be something we will proof with a clinical study.

Take care
​
*in vitro

After about spending some time in bathtub or in the pool, we can notice that our skin on particularly finger tops and toes start to wrinkle up. This wrinkling effect is believed to have a function.

When wet, things tend to be more slippery and our sophisticated skin is designed to counteract this by wrinkling up in a pattern optimised to provide a drainage network that improves grip, much like the tires on a car according to a study. Link to original publication. However, other studies would contradict that there would be a functional benefit for so called aquatic wrinkles.

The osmosis theory
Water molecules moving trough a semipermeable membrane from a low concentration area to a high concentration area is a process called osmosis. The shrinking and expanding effects of osmosis takes place simultaneously outer layer of the skin, causing wrinkles.

The skin's outermost layer is also known as stratum corner could be responsible for this wrinkly reaction, The top layer of our skin consists of dead corneocytes. The longer these cells are attached to the skin, the bigger they are. The size of the corneocytes we actually use to objectively measure the skin's renewal and desquamation (shedding of cells) process. These dead (keratin containing) skin cells may absorb water and swell. The lower layer with living cells doesn't swell up. As top layer (which is increased in size) is still attached to the layer beneath, a wrinkly pattern is formed. The layer of dead skin cells is thicker at the palms of our hands and soles of our feet, the wrinkling effect is more evident. This response occurs more quickly in freshwater than seawater. Moreover, when we are exposed to water for a longer time, the water-repelling film on top of the outer layer of the skin may get impaired.

The sympathetic nervous system / microcirculation theory
It's known that there is a relationship between the wrinkling-effect and blood vessels constricting (narrowing) below the skin. When hands and feet are soaked in water, the nerve fibres in the skin shrink and the body temperature regulators loses volume. Therewith the top layer of the skin is pulled downward and the wrinkling pattern is formed. It is proven that wrinkling-effect response is impaired, if the nerves and/or blood vessels are damaged. Therewith the wrinkling effect can even be used to determine proper functioning of the sympathetic nervous system and/or skin's microcirculation. There is evidence that the wrinkling effect is impaired in patients suffering from diabetes: link to article. 

Regardless the cause, aquatic wrinkles disappear fast and the skin returns to normal once the water has evaporated.
​
Take care.

Facial oils are a trending skin care product at the moment, loved and recommended by many "beauty guru's" and skin care experts. This is why I found it very interesting to read a comment written by a well respected dermatologist claiming that face oils would stifle skin renewal and exfoliation and would make skin dull over time. She must have a reason why she is saying this, and that's why I looked into this a little bit deeper.

To start with, I've done own research (not just me) with a facial oil, included many testers and found many benefits and no draw backs during the duration of the study. Moreover, I jumped out of my chair (literally) when I saw the visible results from the clinical photography, no joke! We've found that the oil (a combination of Argan oil and Lady's Thistle oil) improves moisture, elasticity and firmness, supports skin resilience, making the skin feel smooth and look more radiant. There was even a reduction of comedones detected. The results were published in a poster, accepted by the European Academy of Dermatology and Venereology in 2016.

If you are an impatient person, and demand a fast answer, I can spill the tea right now: I've found no data to support that facial oils would stifle skin renewal and exfoliation, but the opposite.

Moisturisers absolutely influence the skin barrier function and TEWL (transepidermal water loss - which is used to measure the skin barrier function). A good barrier function (confirmed by low TEWL), positively contributes to the skin cell renewal process, which includes skin exfoliation process. Very dry skin has an increased TEWL, and so does very well hydrated skin. There is simply more water on the skin surface to evaporate. A high TEWL with very well hydrated skin can therefore give the impression of an impaired barrier function and thus give a "false positive". This phenomenon is nicely explained in a publication by Marie Loden "Effect of moisturizers on epidermal barrier function".

Looking at non fragrance plant oils also called fixed oils, there are many and they are all different, so it's impossible to generalise. Many plant oils, like almond, jojoba, soybean and avocado oils mostly remain on the skin surface. Even without penetrating deeper into the outer layer of the skin (called epidermis), the occlusive effect of plant oils will reduce water evaporation from the skin and help the growth of the cells of the top layer called keratinocytes. They actually support the skin barrier and therewith skin cell renewal. Part of the skin cell renewal is a process called desquamation, which is skin's natural exfoliation of dead skin cells. Helping this process will make skin appear more radiant and smooth, not duller.

​The benefits of plant oils are supported in many publications, one of which is found in the International Journal of Molecular Sciences anti inflammatory skin barrier repair effects by Tzu-Kai Lin 2017. 

Argan oil
One of the most popular and well researched fixed oils is organ oil. It contains oleic and linoleic fatty acids. Both are part of our skin's natural intercellular lipid-enriched matrix or skin barrier. Linoleic acid (an omega 6 fatty acid) is in fact the most abundant polyunsaturated fatty acid. Our skin barrier is protecting our skin from water loss and penetration of external agressors. Thus the skin barrier keeps the good stuff in and bad stuff out.
Linoleic acid plays a direct role in maintaining the integrity of this skin barrier. Some research shows that oleic acid may indeed disrupt the skin barrier and act as an permeability enhancer, helping other ingredients to penetrate deeper. When oleic acid is continuously applied, it could lead to barrier problems. Another ingredient in argan oil is tocopherol or vitamin E.  Tocopherol is well known for it's antioxidative effect (neutralising damaging free radicals from pollution or sun which cause premature ageing) and lesser known for supporting the skin barrier. Daily topical application of argan oil (the finished product which contains multiple ingredients) has shown to improve skin elasticity (firmness), improve the skin hydration by restoring the barrier function and maintaining water-holding capacity. Furthermore it has a softening and relaxing effect on skin. 

Lady's Thistle oil
The oil of the Milk Thistle plant (also known as Silybum Marianium) is a common ingredient in anti-aging skincare. It contains skin barrier supporting Linoleic acid and is known to nourish skin and improve radiance. 

Facial oils are certainly not for everybody, but in general skin will benefit from a cold pressed fixed plant oil or a mixture. Don't smother skin with oils, just apply a few drops by itself on the skin prior or after your moisturiser, or mix a few drops with your moisturiser of foundation. 

Hope you enjoy radiant skin & take care.

Understandably we want to get rid of pimples as soon as possible and sometimes apply harsh products to our skin in order to shrink them.

Depending on which ingredient is used, you might inflict injury to the skin and it's barrier which is very comparable to a mild burn. There is even a phenomenon called "toothpaste burn". During the healing process there is a risk of scarring. A study published by Tan J. et al in JJD 2017 shows that up to >87% of patients with mild to moderate acne reports atrophic scarring (sunken scar) to some degree.

​A healthy skin barrier and well hydrated skin will support a the healing process. However, as the barrier is impaired and the skin dried out, the skin's regeneration and healing process will take longer.

Therefore be careful with "shrinking" pimples. The same applies for "popping" pimples, as this method by definition will cause injury to the skin. Picking and squeezing pimples will further irritate the skin tissue and delay proper healing. The risk of scarring is increased when the tissue is inflamed. A recent study of prevalence and risk factors of acne scarring confirmed that there is a relationship between the time between onset and effective treatment. Acne scars can be more difficult to treat than acne! It's better to seek expert advice if you have problematic skin. 

Take care.