Tag Archives: Dermis

Forget the Collagen Supplements for Skin Health – It’s All Pay to Play When the Studies Are Analyzed

A new study analyzing 23 randomized clinical trials with 1474 participants has found that “collagen supplements” significantly improved skin hydration, elasticity, and wrinkles only if you include data from physician-investigators who were paid by pharmaceutical/supplement companies. However, an analysis of studies not receiving funding from pharmaceutical companies revealed no effect of collagen supplements for improving skin hydration, elasticity, and wrinkles, while those receiving funding from pharmaceutical companies did show significant effects. Similarly, high-quality studies of “collagen supplements” revealed no significant effect in all categories, while low-quality studies revealed a significant improvement in elasticity.

No evidence that collagen supplements improve skin health

First, “collagen supplements” don’t contain collagen – they contain hydrolyzed collagen, otherwise known as amino acids. Moreover, most “collagen supplements” contain many ingredients other than the hydrolyzed collagen. A new meta-analysis by scientists at two major universities casts doubt on the effectiveness of “collagen supplements” for improving signs of skin aging, raising questions about the role of industry-funded research in shaping health and wellness trends. As the authors conclude, “There is currently no clinical evidence to support the use of “collagen supplements” to prevent or treat skin aging.” This is nothing new. Many studies in the pharmaceutical and supplement industries are flawed, frequently using fraudulent data, to sell their products that actually don’t work.

Often times, pharma and supplement companies hire ghostwriters to perform and write-up the study. Then the company finds a physician who will put their name on the byline. The physician didn’t have anything to do with the study and had nothing to do with writing the study. Ghostwriting is a big problem, and growing. For example, “first author” of a medical paper on Vioxx, Jeffrey Lisse, M.D., has said in an interview that “Merck designed the trial, paid for the trial, ran the trial…Merck came to me after the study was completed and said, ‘We want your help to work on the paper.’ The initial paper was written at Merck (ghostwritten), and then it was sent to me for editing.” In other words, Mr. Lisse was not an author of the study but was paid to pretend he was. Not only were his actions immoral, they were dangerous. Vioxx was later removed from the market because it significantly increases cardiovascular adverse events – people died from heart attacks. As physician Adriane Fugh-Berman, M.D., professor at Georgetown University School of Medicine and PharmedOut, has said about ghostwriting, “But there’s also the fact that this is so common that it’s not considered unusual. There’s no shame attached to it.” The point here is that many studies of drugs and supplements are flawed, some are fraudulent, and the studies of collagen supplements seem to be highly flawed.

Collagen and its importance to skin function and health

From: Han et al (2021) Recent advances in skin collagen: functionality and non-medical applications

Skin Collagen is a scleroprotein (not water soluble) and a major structural protein found throughout the body, including in skin (Fig. 2), hair, nails, tendons and bones. Much collagen in the body, including in the skin, is long-lived. One estimate of human skin collagen half-life suggested 14.8 years. Specifically, type I and type III collagen are found in abundance in the skin. Elastic fibers also play an important structural role within the dermis. Elastic fibers are composed of elastin and fibrillin microfibrils. In contrast to collagen, the biochemical configuration of elastin allows for gliding, stretching, and recoiling of fibers. The reticular dermis comprises thick elastic fibers. Two subtypes of elastic fibers are noteworthy: elaunin and oxytalan fibers. Elaunin fibers are horizontally arranged elastic fibers found near the junction of the papillary and reticular dermis. Oxytalan fibers are perpendicular elastic fibers found in the papillary dermis. Fibers work alongside substances like glycosaminoglycans (GAGs), such as hyaluronic acid, to maintain skin elasticity, volume, and moisture. While the body naturally produces collagen using amino acids from foods like beans and tofu, production declines with age and can be further reduced by sun exposure and poor diet.

From Alcaide-Ruggiero et al (2021). Schematic representation of collagen biosynthesis. (1) Gene transcription. (2) Formation of α-chains. (3) Formation of triple helix procollagen and secretion into extracellular space. (4) Procollagen processing and formation of tropocollagen (non-soluble form of collagen). (5) Association of tropocollagen molecules to form collagen structures.

Many forms of collagen, such as type I, are abundant through a range of tissues and are fundamental structural building blocks. Type I collagen is the main component of fibrils that provide tissues with tensile strength. Type I collagen is a heterotrimeric protein assembled from the two α1(I) and one α2(I) polypeptides when they fold into a triple helix. After secretion of procollagen into the extracellular space, the terminal domains are removed by proteolytic cleavage and the rodlike triple helices of the central domain polymerize into fibrils and are covalently cross-linked.

Type I collagen is the most abundant collagen type in the skin, accounting for 80–85% of the dermal ECM. Other subtypes, like type III and type V collagen, can be found in skin, but type I collagen is fundamental to skin structure; it supplies considerable tensile strength and helps to determine the structure and durability of the dermis. As skin ages, there is a progressive loss, damage, and fragmentation of dermal collagen fibrils, leading to reduced skin thickness and biomechanical strength.

Type I collagen is also one of the longest-lasting of the long-lived protein in humans, and is a major fibrillar component of connective tissues such as skin, bone, and tendons. It has a triple-helix structure composed of two α1 chains encoded by the Collagen type I alpha 1 chain (COL1A1) gene and one α2 chain encoded by the Collagen type I alpha 2 chain (COL1A2) gene. Among these, COL1A1 expression has been identified as a biomarker of skin aging, as its levels decline with age. This organization of collagen along with other fibrils and matrix molecules endows connective tissues with mechanical strength and elasticity.

Collagen genetics

The COL1A1 gene provides instructions for making part of type I collagen. A component of type I collagen called the pro-α1(I) chain is produced from the COL1A1 gene. Collagens begin as rope-like procollagen molecules that are each made up of three chains. Type I collagen is composed of two pro-α1(I) chains and one pro-α2(I) chain (which is produced from the COL1A2 gene).

The triple-stranded procollagen molecules are processed by enzymes in a series of steps inside and outside the cell to create mature collagen. The collagen molecules then arrange themselves into long, thin fibrils that form stable interactions (cross-links) with one another in the spaces between cells. The cross-links result in the formation of very strong type I collagen fibers.

Industry funded pharmaceutical and supplement studies are often flawed

While collagen drinks, supplements, topical products and even prescription pharmaceuticals have gained market traction for their promised skin benefits, the stark difference between the overall results and the subgroup findings underscores how industry funding and study quality can sway outcomes, a longstanding concern in nutrition, pharmaceutical, and supplement research. Sadly, many medicines and supplements don’t work, including those for dermatological use. Allen Rogers, PharmD, worldwide vice president of genetics at Glaxo SmithKline, is reported on the front page of the Independent (8 December, p 1) as saying: “Our drugs don’t work on most patients.”

Confounding these studies of collagen, most of the trials used commercially available supplements that contained more than hydrolyzed collagen (amino acids), including vitamins, minerals, antioxidants, coenzyme Q10, hyaluronic acid and chondroitin sulfate were among the additional ingredients.

Too much amino acid consumption is bad for health, including heart health

Scientists have discovered a molecular mechanism by which excessive dietary protein could increase atherosclerosis risk. For example, amino-acid-mediated mammalian target of rapamycin (mTOR) signalling in macrophages has been implicated in the pathogenesis of ischemic cardiovascular disease. Specifically, ingestion of protein or amino acids in excess of ∼22% of dietary energy requirements drives atherosclerosis.

Further, an unbalanced, unnatural increased intake of one or more amino acids can cause imbalance in amino acid concentrations in the body, increase concentrations of its metabolites, and affect the transport of a group of amino acids into cells due to competition for a carrier at the cell membrane. The phenomenon of carrier competition can affect absorption of other amino acids in the gut and subsequently their appearance in the blood, transport across the blood-brain barrier, and supply for protein synthesis. Proteinopathies may result, leading to degenerative disorders. For example, too much leucine consumption can decrease autophagy in the brain. Autophagy, a cellular process of waste and debris removal, is known to decrease proteinopathy, and therefore too much leaucine may potentially lead to the buildup of toxic metabolites and neurodegeneration.

Summary

Skip the supplements made from hydrolyzed collagen. Eating a variety of plant-based protein sources—such as beans, soy, legumes and quinoa—means your body will have the amino acids it needs to make collagen, while also providing Vitamin C and antioxidants, all of which are important to the health status of the skin, particularly collagen formation and protection of the long-lived collagen.

The Benefits of Topical Retinoids on the Skin

NeoGenesis uses Hydroxypinacolone retinoate (HPR), a newer retinoid that is less irritating than tretinoin and has been found to be as effective in vitro at promoting collagen production. HPR is also more stable than other retinoids in the presence of sunlight and air. Unlike retinol, HPR directly binds to the retinoid receptors and is therefore more effective and less irritating than retinol. The efficacy of HPR is similar to retinoic acid. However retinoic acid (tretinoin) can cause significant irritation of the skin, and is available only by a physician’s prescription. Retinoids can provide great benefit to aging skin. In this blog, I’ll explore some of the mechanisms by which retinoids benefit both the epidermis and the dermis. (Christine Preston contributed to this blog).

From Quan (2023) Epidermal and dermal aging of human skin. Skin aging includes the thinning of both the epidermis and dermis.

Over time, many alterations occur within the epidermis, collectively known as epidermal aging. These changes in time are characterized by the thinning of the epidermal layer and the flattening of rete ridges (as depicted in Fig 1, on the right). Rete ridges (RR) form an interdigitated surface area that reinforces cohesion between the epidermis and dermis, and this structure demonstrates plasticity, responding dynamically to stimuli such as UV irradiation. RR adapts to disruptions of its boundary during wound repair when cells lose hyper-adhesiveness, allowing the skin to appropriately remodel itself. The principal cause of epidermal aging can be traced to a reduction in the proliferation and turnover of keratinocytes, linked partially to the depletion of interfollicular epidermal (IFE) stem cells and dysfunctional Rete Ridges, leading to poor healing and thinning of the epidermis.

Collagen type, COL17A1 has been of particular interest due to its role in maintaining the homeostasis of the skin stem cells. COL17A1 is a structural element within the dermal–epidermal basement membrane, and it is synthesized by epidermal keratinocytes, not fibroblasts (Xiang et al, 2022). COL17A1 is primarily expressed in the uppermost extensions of the rete ridges area, where the niches for IFE stem cells are located. Research results have suggested a reduction in the expression of COL17A1 in human skin affected by both intrinsic and extrinsic aging factors, including human skin exposed to acute UV irradiation. The decrease in COL17A1 levels within the area specific to the rete ridges can reduce the adherence of IFE stem cells to their designated locations, leading to their removal from the skin. Consequently, the reduction of collagen protein, COL17A1, results in decreased rates of keratinocyte renewal and the development of thinner epidermal layers, the primary morphological characteristic of aging skin.

Human skin has developed two main defense mechanisms to guard against the damaging effects of UV: 1. epidermal thickening, 2. and the stimulation of melanin synthesis, however, photoprotection through increased melanogenesis is more important. As we think about retinoids and what they do for the skin, think about how retinoids help to maintain the normal structure of the skin, can actually thicken the epidermis and dermis, and how important this is for skin function and protection, including protection against UV.

Retinoids, which refer to a group of vitamin A derivatives, are among the most-extensively studied ingredients in skincare for combatting aging and enhancing the appearance of mature skin. Retinoids can stimulate collagen synthesis, inhibit MMP (Matrix metalloproteinases – too much of this activity can break-down proteinaceous tissues) activity, reduce oxidative stress, and modulate gene expression (Quan, 2023). Retinoids have exhibited efficacy in ameliorating the visual manifestations of both intrinsic and extrinsic aging, such as wrinkles, fine lines, and irregular pigmentation. The mechanisms of retinoid’s action may involve the activation of retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which regulate gene transcription and cell differentiation. Retinoids may also modulate the activity of growth factors and cytokines involved in ECM turnover and inflammation. Retinoic acid (RA) is the active form of vitamin A and its precursor is called retinol (ROL). ROL can be converted into its active metabolite within human skin. When retinol is applied topically to human skin, it can penetrate the skin and undergo sequential conversion to retinaldehyde and then to retinoic acid

Skin-equivalent cultures have been used to investigate the regulatory role of retinoids in collagen homeostasis. Typically, these simplified skin constructs feature stratified and differentiated keratinocytes, representing the epidermal layer, layered atop a collagen lattice primarily comprising Type I collagen. Dermal fibroblasts are embedded within this lattice to mimic the dermal layer. When subjected to retinoic acid treatment, these skin-equivalent cultures exhibit a thickened epidermis with a substantial increase in the number of keratinocyte layers and elicit a dermal response akin to the effects observed when retinoic acid is topically applied to human skin in vivo. Consequently, skin-equivalent cultures hold significant potential as a valuable model for delving into the mechanisms by which retinoids enhance the appearance of aging skin in humans.

Increasing the Thickness of the Epidermis and the Vascularity of the Dermis in Aged Human Skin In Vivo Using Topical Retinoids: Stimulating the Growth of Epidermal Keratinocytes and Dermal Endothelial Cells

Topical application of retinoids to aged human skin in a live setting has been found to significantly enhance the thickness of the epidermis by stimulating the proliferation of epidermal keratinocytes, and increasing the number of Rete Ridges. In addition to improving epidermal thickness, topical retinoid has shown a notable increase in the proliferation of endothelial cells and blood vessels in the papillary dermis. These findings suggest that the topical application of retinoids results in the thickening of the epidermal layer and the development of fresh blood vessels within the dermis. The AP-1 transcription factor is critical to enabling the proliferation of keratinocytes in response to growth factors, cytokines, and various stimuli. The AP-1 complex consists of c-Jun and c-Fos, and it has been observed that topical retinoids significantly increases the expression of the epidermal-specific c-Jun protein, leading to a substantial increase in epidermal thickness. There is also evidence that the expression of c-Fos protein increases with retinoid treatment. These findings suggest that topical retinoids enhance the activity of the epidermal-specific c-Jun, and possibly c-Fos transcription factors, thereby stimulating the proliferation of epidermal keratinocytes in aged human skin in vivo.

Topical Retinoids Improve the Dermal ECM Microenvironment by Promoting the Production of Collagenous ECM in Aged Human Skin In Vivo

Topical retinoid treatment increases Type I collagen expression, which constitutes 80–85% of the dermal ECM, while collagen type III constitutes about 8–11%.  Topical retinoid also significantly enhances the expression of fibronectin and tropoelastin. In aged human skin in vivo, topical retinoid effectively activates dermal fibroblasts, leading to the substantial production of collagenous ECM through the activation of the TGF-β/Smad pathway, which is a key regulator of ECM production. Topical retinoid administration causes a significant increase in TGF-β1 mRNA expression and a decrease in inhibitory Smad7, while other components of the TGF-β pathway remain unaffected. Additionally, topical retinoid leads to an increase in the expression of connective tissue growth factor (CTGF/CCN2), which is substantially reduced in the dermis of aged individuals and contributes to the decline in collagen production associated with aging. These findings provide evidence that topical retinoid stimulates the production of ECM by dermal fibroblasts through the upregulation of the TGF-β/CTGF pathway in aged human skin.

In addition to the upregulation of TGF-β/CTGF pathway, retinoic acid significantly reduces CCN1 gene expression in both naturally aged and photoaged human skin in vivo. CCN1 is a negative regulator of collagen homeostasis by inhibiting the TGF-β/CTGF pathway and stimulating MMPs’ induction. These data suggest that the mechanism by which topical ROL improves aged skin, through increased collagen production and inhibition of MMPs, may involve the downregulation of CCN1. Thus, retinoids are acting through multiple pathways, inhibiting some and activating others.

In aging skin, decreased vascularity and thinning of the dermis and epidermis are substantial factors contributing to skin fragility and hindered wound healing. Blood flow to the skin, the largest organ in the body, is reduced by 40% between the ages of 20 to 70 years. Topical retinoids not only enhances ECM production, but also improves the dermal microenvironment by promoting the expansion of vasculature through endothelial cell proliferation in aged human skin. An age-related reduction in cutaneous vasculature has been reported. The increased vascularity of the dermis induced by topical retinoids can improve skin blood flow and create a more-favorable microenvironment for the homeostasis of the epidermis and dermis. Further, the promotion of epidermal keratinocyte proliferation and the restoration of ECM production by topical retinoid could create a supportive environment for the growth of endothelial cells and the development of dermal blood vessels. Epidermal keratinocytes are a significant source of vascular endothelial growth factor (VEGF), a powerful factor in promoting angiogenesis. Furthermore, increased production of dermal ECM has been demonstrated to stimulate the proliferation of endothelial cells. As a result, the augmented dermal vascularity facilitated by retinoids may have a significant impact on the homeostasis of both the epidermis and dermis.

Hydroxypinacolone Retinoate (HPR) for Anti-Aging, Photodamage, and Acne

Hydroxypinacolone retinoate (HPR) has demonstrated positive effects as a topical anti-aging ingredient, the authors of the study writing, “Together these data suggest that HPR is an effective alternative to ATRA and other less potent retinoids in the treatment of aging skin without the detrimental side-effects. And the combination of retinoids and salicylic acid can be used to ameliorate the signs of photoaging.

Data have confirmed past studies indicating that topical retinoids are under-used for acne. Further, HPR has been successfully used to treat comedonal-papular, mild to moderate acne of the face. In this study, papain was also used, in addition to HPR, as an exfoliant, and in many cases acne patients may benefit from combination therapies, such as the use of retinoids (HPR) with salicylic acid to better treat acne.

Carotenoids, Like Beta-Carotene, Convert to Retinoids When Topically Applied

You’ll notice on the label of NeoGenesis Skin Restore Serum, that in addition to HPR, carotenoids, including beta-carotene, are included in the product. While topically applied carotenoids absorb into the skin and are converted to retinoids in the skin, the carotenoids also provide antioxidant benefit to the skin. The beautiful yellow color of the vitamin A product, Skin Restore Serum, reflects the yellow pigmented carotenoid antioxidants loaded into the serum.

The amount of carotenoids in the skin depends on dietary intake, and their bioavailability from various foods, with fruits and vegetables as an important source.. After absorption in the gut and transportation into the skin, carotenoids accumulate in the skin, including the adipocytes in the hypodermis. The skin protective benefits of carotenoids, especially from those residing in the epidermis, are many, including protection from UV and air pollution.

Retinoids and Photosensitivity

Photosensitivity to retinoids appears to be a rare event, and quite to the contrary, retinoids have been found to successfully treat some forms of skin photosensitivity. First, let’s dispel the somewhat common belief that topical retinoids enhance UV-induced inflammation. Smit et al (1999) evaluated the minimal erythema dose (MED) for UVB irradiation on topical all-trans RA (tretinoin cream 0.05%) pre-treated skin compared with vehicle cream pre-treated skin and untreated skin. Their study found no significant difference for the MED values either 24 or 48 h after UVB irradiation between the all-trans RA cream treated skin, and the vehicle cream treated skin and untreated skin. In other words, topical retinoid caused no enhanced inflammation when the skin is exposed to UV.

Second, Actinic folliculitis (AF) is a rare recurrent seasonal photodermatosis, relatively newly characterized by nonpruritic, monomorphic pustules and papules appearing 4-24 h after exposure to sunlight. Lesions usually affect the face but also appear on the upper chest and arms. Resolution normally occurs within 7-10 days with cessation of sunlight exposure. AF is resistant to standard treatments used for acne vulgaris and acne rosacea, with only oral retinoids previously being reported as effective. Academic dermatologists in the UK have reported that AF responding extremely effectively to a topical retinoid.

Discussing photosensitivity, be clear that HPA is relatively stable in light and in the air. Applying and using HPA in normal lighting conditions will not degrade the product.

Long Term and Overuse of Retinoids

While a significantly higher concentration of retinol (0.4%) is required to attain similar outcomes as observed with topical retinoic acid, retinol triggers similar histological alterations (epidermal thickening and dermal ECM production) as retinoic acid. However, inappropriate or excessive use of topical retinoids or retinoic acid may also result in potential side effects. These commonly include skin dryness, redness, and peeling, which can cause discomfort. However, these side effects typically diminish over time as the skin adjusts to the product. Evidence suggests that HPR will induce fewer adverse side-effects than the other retinoids.

Long-term use of retinoids (studied for up to 2 years) have found beneficial effects to the skin throughout the treatment period, and a good safety profile. While most of the benefit is seen within 6 months following onset of the treatment, long term use can maintain the positive effects.

Summary

Topical retinoids (TR) are a safe and effective addition to one’s skin care routine, especially for aged skin. TR provides major benefits to the skin, including increased thickness of the epidermis and dermis, and enhanced blood flow to the skin. There are few side effects of retinoids, and if chosen properly, retinoid products, such as those that use HPR, are well tolerated by those with sensitive skin. Photosensitivity is not an issue, and their use with vitamin C/antioxidant products, such as those using gentle liposomal vitamin C (liposomal ascorbic acid), provides extra benefit.