Collagen is a vital component of the skin's extracellular matrix, providing essential structural support and elasticity. Collagen-stimulating treatments, skincare products, and supplements have gained popularity for their effectiveness in gradual prejuvenation and rejuvenation approaches. These methods can help maintain skin health and combat signs of aging when used appropriately. However, it's important to note that excessive collagen stimulation can potentially lead to adverse effects, including fibrosis and skin stiffness, which may be detrimental to overall skin health and beauty. Therefore, a balanced and informed approach to collagen stimulation is crucial for achieving optimal results while minimizing potential risks.
 
TYPES OF COLLAGEN AND THEIR ROLES
1. Type I collagen: Predominantly found in skin, tendons, and bones, providing tensile strength.
2. Type III collagen: Often found alongside Type I, contributing to skin elasticity and firmness.
While these types are beneficial for youthful skin, excessive production can lead to fibrotic tissue formation and stiffness [1].
More about collagen types click here
 
EXCESSIVE COLLAGEN STIMULATION
Excessive collagen production, particularly type I collagen, can contribute to fibrosis and scarring in pathological conditions:
 
1. In hypertrophic scars, there is an overproduction of primarily type III collagen, which is later replaced by type I collagen. These scars contain "an overload of primarily type III collagen oriented parallel to the epidermal surface with multiple nodules containing myofibroblasts, large extracellular collagen filaments and abundant acidic mucopolysaccharides" [2].
 
2. Many rejuvenating in-office treatments (for example energy based devices)are based on "controlled damage and repair”, thus wound healing. During wound healing, abnormal extracellular matrix (ECM) reconstruction, particularly abnormal collagen remodelling, leads to the formation of hypertrophic scars. In these scars, "thin collagen fibres with increased synthesis and crosslinks result in raised scars" [2].
 
3. The relative ratio of type III to type I collagen is reduced in pathological scars compared to unscarred adult dermis. Additionally, hydroxylation of type I collagen was found to be significantly higher in keloids, leading to excessive collagen cross-linking [3].
 
IN-OFFICE TREATMENTS AND COLLAGEN STIMULATION
These treatments aim to maintain or restore natural collagen production rather than overstimulate it to unnatural levels. Some examples are:
1. Exosomes and Polynucleotides: Aim to stimulate healthy collagen production but require careful application.
2. Radiofrequency and Ultrasound: Use heat to remodel collagen. While generally safe, a study by Zelickson et al. [4] reported that excessive heating during RF treatments could potentially lead to collagen denaturation and subsequent fibrosis if not properly controlled.
3. Microneedling: Promotes collagen production but risks scarring if not performed properly. A review by Iriarte et al. [5] noted that while microneedling is generally safe, excessive or improper use could potentially lead to scarring or hyperpigmentation.
4. Laser treatments: Excessive use of ablative lasers can potentially lead to scarring and fibrosis. A study by Hantash et al. [6] found that ablative fractional resurfacing can induce dermal remodeling and new collagen formation, but also noted that improper use could lead to adverse effects.
 
It's important to emphasize that these potential adverse effects are typically associated with improper use, overtreatment, or individual susceptibility rather than being inherent risks of the treatments themselves when performed correctly. 

POTENTIAL RISKS
▌Excessive collagen production: Can lead to fibrosis, characterized by stiff, non-functional tissue: increased extracellular matrix deposition, with collagen being the main component, leading to a drastic reduction of tissue functionality [7]. In skin, this can result in reduced elasticity and increased stiffness.
▌Imbalance in collagen types: Overproduction of certain collagen types can lead to reduced skin elasticity and increased stiffness. The ratio of type I to type III collagen naturally increases with age, which is associated with changes in skin tension, elasticity, and healing [7]. 
 
RECOMMENDATIONS FOR SAFE USE
▌ Prejuvenation: Focus on treatments (performed by a professional) that promote balanced collagen production without overstimulation. The effect of a collagen-stimulating procedure is a gradual process and can take up to 12 weeks or longer before a final result. This gradual improvement is due to the time required for the body to produce new collagen in response to the stimulation. Laser treatments, for example, can trigger collagen synthesis deep within the skin, with effects continuing for several months post-treatment [8]. Leave sufficient time in between procedures. Support your skin with a skincare routine tailored to your skintype, goals and use of daily sunscreen. Be very rigorous when it comes to the use of home devices or treatments. Many of them are not well researched or might cause damage when not properly used or performed.

▌Rejuvenation: Opt for treatments or a combination of treatments that complement each other, working in different layers of the skin in different ways. Don't expect a "one-day transformation". Rebuilding collagen takes time and a consistent approach. The skin is not able to replenish what it lost over a period of many years in just a few days [9]. Support in-office collagen stimulating treatments with a good skincare regimen, daily use of sunscreen, healthy lifestyle and diet or supplementation if necessary [10]11].
 
The effectiveness of combining different treatments for skin rejuvenation has been demonstrated in clinical studies. For instance, a study published in the Journal of Clinical and Aesthetic Dermatology showed that a combination of microneedling and platelet-rich plasma significantly improved skin texture and collagen production compared to microneedling alone [12].
 
The importance of a consistent skincare regimen and sun protection in maintaining collagen levels has been well-documented. A review in the Archives of Dermatological Research highlighted that daily use of broad-spectrum sunscreen can prevent collagen degradation caused by UV radiation [13].

While collagen stimulation is beneficial for skin prejuvenation, "banking" or rejuvenation, it is crucial to balance its production to avoid the formation of fibrotic tissue and maintain healthy skin elasticity. Further research is needed to optimize treatment protocols and minimize risks associated with excessive collagen stimulation. Always consult a qualified healthcare professional to determine the most suitable approach for your skin goals, health, and beauty.
 
Take care
Anne-Marie
 
References:
[1] Wang Kang , Wen Dongsheng , Xu Xuewen , Zhao Rui , Jiang Feipeng , Yuan Shengqin , Zhang Yifan , Gao Ya , Li Qingfeng Extracellular matrix stiffness—The central cue for skin fibrosis Frontiers in Molecular Biosciences 2023 DOI=10.3389/fmolb.2023.1132353
[2] Meirte J, Moortgat P, Anthonissen M, Maertens K, Lafaire C, De Cuyper L, Hubens G, Van Daele U. Short-term effects of vacuum massage on epidermal and dermal thickness and density in burn scars: an experimental study. Burns Trauma. 2016 Jul 8;4:27. doi: 10.1186/s41038-016-0052-x. PMID: 27574695; PMCID: PMC4964043.
[3] Zhou Claire Jing , Guo Yuan Mini review on collagens in normal skin and pathological scars: current understanding and future perspective Frontiers in Medicine 2024
[4] Zelickson, B. D., Kist, D., Bernstein, E., Brown, D. B., Ksenzenko, S., Burns, J., ... & Kilmer, S. (2004). Histological and ultrastructural evaluation of the effects of a radiofrequency‐based nonablative dermal remodeling device: a pilot study. Archives of Dermatology, 140(2), 204-209.
[5] Iriarte, C., Awosika, O., Rengifo-Pardo, M., & Ehrlich, A. (2017). Review of applications of microneedling in dermatology. Clinical, Cosmetic and Investigational Dermatology, 10, 289-298.
[6] Hantash, B. M., Bedi, V. P., Kapadia, B., Rahman, Z., Jiang, K., Tanner, H., ... & Zachary, C. B. (2007). In vivo histological evaluation of a novel ablative fractional resurfacing device. Lasers in Surgery and Medicine, 39(2), 96-107.
[7] Wang, C., Rong, Y., Ning, F., & Zhang, G. (2011). The content and ratio of type I and III collagen in skin differ with age and injury. African Journal of Biotechnology, 10(13), 2524-2529. https://doi.org/10.5897/AJB10.1999
[8] Alam, M., Hughart, R., Champlain, A., Geisler, A., Paghdal, K., Whiting, D., Hammel, J. A., Maisel, A., Rapcan, M. J., West, D. P., & Poon, E. (2018). Effect of Platelet-Rich Plasma Injection for Rejuvenation of Photoaged Facial Skin: A Randomized Clinical Trial. JAMA Dermatology, 154(12), 1447-1452. https://doi.org/10.1001/jamadermatol.2018.3977
[9] Ganceviciene, R., Liakou, A. I., Theodoridis, A., Makrantonaki, E., & Zouboulis, C. C. (2012). Skin anti-aging strategies. Dermato-endocrinology, 4(3), 308-319. https://doi.org/10.4161/derm.22804
[10] Katta, R., & Desai, S. P. (2014). Diet and dermatology: the role of dietary intervention in skin disease. The Journal of clinical and aesthetic dermatology, 7(7), 46-51.
[11] Addor, F. A. S. (2017). Antioxidants in dermatology. Anais brasileiros de dermatologia, 92, 356-362. https://doi.org/10.1590/abd1806-4841.20175697
[12] Asif, M., Kanodia, S., & Singh, K. (2016). Combined autologous platelet-rich plasma with microneedling verses microneedling with distilled water in the treatment of atrophic acne scars: a concurrent split-face study. Journal of Cosmetic Dermatology, 15(4), 434-443. https://doi.org/10.1111/jocd.12207
[13] Battie, C., & Verschoore, M. (2012). Cutaneous solar ultraviolet exposure and clinical aspects of photodamage. Indian Journal of Dermatology, Venereology, and Leprology, 78, S9-S14. https://doi.org/10.4103/0378-6323.97351

Collagen banking is a proactive skincare strategy falling under the category prejuvenation aimed at preserving and stimulating collagen production to maintain youthful, firm and excellent skin quality over time. This approach can involve using various treatments, tweakments, products, supplements and lifestyle choices to boost collagen levels before significant signs of aging appear. The goal is to build a "reserve" or “bank” of collagen, ensuring skin remains resilient and less prone to wrinkles and sagging as natural collagen production declines and degradation increases with age. To start banking collagen as early as in your twenties theoretically makes sense, as the producing cell called the dermal fibroblast is still very healthy and active, thus collagen stimulating treatments and care products give a "high return on investment". However, there is no direct scientific evidence that collagen stimulation is more effective in your twenties than in your sixties. 

Starting collagen stimulation <50 might be beneficial:
▌Collagen production begins to decline around age 25-30, decreasing by about 1% per year.
▌By the 50s and beyond, the collagen loss is greater >30%, becomes more noticeable. It´s always harder to get back what you lost than to maintain what you have.
▌Peak collagen levels occur at twenty years of age, thus maintaining what you have is the highest achievable level. There is no need for "banking" collagen.

Starting collagen stimulation treatments <50 may help prevent further collagen loss and probably require less invasive and number of treatments. However, the best strategy at every age is to prevent collagen loss as much as possible with good lifestyle habits, diet, stress reduction, (topical) anti-oxidants and sunscreen, hence manage inflam-aging, photo-aging and chrono-aging. 
 
WHAT IS COLLAGEN
Collagen is the most abundant protein in the human body, making up about one-third of all proteins. 
1. Location: Found in connective tissues, including skin, tendons, bones, and cartilage.
2. Function: Provides structural support, strength, and elasticity to tissues.
3. Production: Naturally produced by the body, but production decreases with age, starting around the mid-20s.
Collagen plays a crucial role in maintaining skin elasticity, joint health, and overall tissue integrity. As collagen production declines with age, so does the skin quality, leading to visible signs of aging like wrinkles, loss of elasticity and firmness, and sagging skin. Collagen is one of the key target components for noticeable and effective skin rejuvenation or regeneration. 

Collagen is primarily composed of three key amino acids: 
▌Glycine: is the most abundant, contributing significantly to collagen's structure and stability 
▌ Proline
▌ Hydroxyproline
Proline and hydroxyproline are crucial for forming the triple-helix structure of collagen, which provides strength and flexibility. Additionally, essential amino acids like lysine play a critical role in collagen synthesis by forming hydroxylysine, important for stabilizing collagen fibers. A balanced intake of these amino acids is vital for maintaining healthy collagen levels in the body.

COLLAGEN DECLINE
Collagen production begins to diminish naturally in our mid-20s, decreasing by about 1% per year [2]. This decline becomes more pronounced in the 40s and 50s, contributing to visible signs of aging such as wrinkles and sagging skin [2]. Factors influencing collagen loss include genetic predisposition (DNA), changes in epigenetic pattern (influenced by environment), hormonal changes (especially post-menopause), and fibroblast aging [2][3].

1. Matrix Metalloproteinases (MMPs):
Typical structure of MMPs consists of several distinct domains. MMP family can be divided into six groups: collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and other non-classified MMPs [6].
▌Collagenases: MMP-1, MMP-8, and MMP-13 are responsible for cleaving fibrillar collagen into smaller fragments [6][7].
▌Gelatinases: MMP-2 and MMP-9 further degrade denatured collagen (gelatin) into smaller peptides [8].
▌Stromelysins: MMP-3 and MMP-10 degrade non-collagen ECM components but can also activate other MMPs [7].
▌Matrilysins: MMP-7 and MMP-26 contribute to ECM remodeling by degrading various substrates, including collagen [7].

​2. Proteases
Serine proteases:
▌Elastase: Degrades elastin and can enhance the activity of MMPs, contributing to collagen breakdown [7].
Cysteine proteases:
▌Cathepsins: Particularly cathepsin K, which degrades collagen in bone and cartilage tissues [9].
Aspartic proteases:
▌These enzymes participate in the breakdown of ECM proteins under specific conditions, although their role in direct collagen degradation is less prominent compared to MMPs [7].
Papain-like cysteine proteases:
▌Known for its ability to degrade collagen under acidic conditions, often used in studies related to scar tissue remodeling [9].
 
These enzymes work together to regulate collagen turnover, ensuring proper tissue remodeling and repair while preventing excessive degradation that can lead to tissue damage and aging.

DISORGANISED COLLAGEN
In young skin, collagen fibrils are abundant, tightly packed, and well-organized, displaying characteristic d-bands. 
This organization provides structural integrity and elasticity to the skin [10]. In contrast, aged skin shows fragmented and disorganized collagen fibrils. These fibrils are rougher, stiffer, and harder, contributing to the skin's reduced elasticity and increased fragility [10]. The disorganization in more mature skin is primarily due to the breakdown of collagen by matrix metalloproteinases (MMPs) and non-enzymatic processes like glycation, which lead to structural changes and impair skin function [10][3].

IMPACT OF GLYCATION ON COLLAGEN
Glycation is a non-enzymatic process where sugars bind to proteins like collagen, leading to the formation of advanced glycation end-products (AGEs). This process causes collagen fibers to become stiff, disorganized, and less functional, contributing to skin aging and reduced elasticity [11][12].
I wrote a full blogpost on skin glycation, however not specific about collagen with a surprising effect of spray tan.  Read more.
 
Prevention and treatment of glycation [13][14][15]
1. Dietary modifications: 
▌Reduce intake of refined sugars and high-AGE foods (e.g., fried and processed foods).
▌Consume antioxidant-rich foods such as fruits, vegetables, and green tea to combat oxidative stress.
2. Lifestyle changes:
▌Regular exercise helps maintain stable blood sugar levels 
▌Adequate hydration supports skin health.
3. Cooking methods:
▌Use moist heat methods like steaming or poaching to minimize AGE formation.
4. Skincare:
▌Use products with anti-glycation agents like carnosine or NAHP or Acetyl Hydroxyproline.
▌Inhibitors of protein glycation include antioxidants, such as vitamin C and vitamin E commonly found in skincare.

​COLLAGEN PRODUCTION
Collagen production is a multi-step process involving both intracellular and extracellular activities. 

1. It begins with the synthesis of procollagen in fibroblasts, where genes are transcribed into mRNA, which is then translated into polypeptide chains in the rough endoplasmic reticulum RER. 
2. These chains undergo hydroxylation of proline and lysine, a process dependent on vitamin C, and glycosylation [16]. 
3. The chains form a triple helix structure called procollagen, which is transported to the Golgi apparatus for further modifications before being secreted outside the cell.
4. Once outside, enzymes cleave procollagen to form tropocollagen, which assembles into collagen fibrils through covalent cross-linking facilitated by lysyl oxidase. 
5. These fibrils aggregate to form collagen fibers, providing structural integrity to tissues like skin, bones, and tendons [16]. 

SKINCARE INGREDIENTS THAT STIMULATE COLLAGEN PRODUCTION
 
1. Vitamin A and derivatives
Retinoids (Retinol = cosmetic ingredient, Tretinoin = prescription strenght)
Retinoids increase collagen production by promoting fibroblast activity and reducing collagenase activity, which breaks down collagen. This is a dose-dependant effect. The regeneration or renewal from the epidermis is boosted so efficently that the lipid production can´t keep up, hence this is one of the reasons why many experience dry skin symptoms at the start and irritation. Lipids are like the morter between the bricks of the skin barrier. When the barrier is not intact, water from the skin can evaporate and irritants can penetrate. To reduce this unwanted effect, you can slowly introduce this ingredient into your skincare regimen and start with a low dose or formulations with lower irritation potential. Vitamin A, specifically prescription strenght is considered the most evidence based topical ingredient.
 
2. Vitamin C (Ascorbic Acid)
Vitamin C, also known as ascorbic acid, plays a crucial role in collagen synthesis and maintenance, significantly influencing skin health and structural integrity. Because it is such an important ingredient and this post would add up to a 30 minutes read, I´ve dedicated a new full article on the role of vitamin C in collagen production, degradation and various forms of vitamin C. Click here.

3. Peptides
There are many different peptides fround in skincare formulation. We can identify the following main types by function:
1. Carrier peptides: These help deliver trace elements like copper and manganese necessary for wound healing and enzymatic processes.
2. Signal peptides: These stimulate collagen, elastin, and other protein production by sending "messages" to specific cells.
3. Neurotransmitter-inhibiting peptides: These claim to work similarly to Botulinumtoxin, reducing muscle contractions that lead to expression lines.
4. Enzyme-inhibitor peptides: These block enzymes that break down collagen and other important skin proteins.
5. Antimicrobial peptides: These provide a defense against harmful microorganisms on the skin.
6. Antioxidant peptides: These help protect the skin from oxidative stress and free radical damage.
 
Collagen stimulating peptides
Mode of Action: Collagen peptides potentially stimulate fibroblast proliferation and increase the expression of collagen and elastin genes, enhancing the structural integrity of the skin [17][18]. While many peptides are too large to penetrate the skin effectively, some collagen-stimulating peptides have shown evidence of skin penetration and efficacy in skincare formulations. 

1. Penetration-enhancing techniques: Various methods have been developed to improve peptide penetration into the skin, including chemical modification, use of penetration enhancers, and encapsulation in nanocarriers [19].

​2. Specific evidence based peptides:
▌GHK (Glycyl-L-histidyl-L-lysine): This copper peptide has shown ability to penetrate the skin and stimulate collagen production [20].
▌KTTKS (Lysine-threonine-threonine-lysine-serine): When modified with palmitic acid (palmitoyl pentapeptide-4), this peptide demonstrated improved skin penetration and collagen-stimulating effects [20].
▌GEKG (Glycine-glutamic acid-lysine-glycine): Studies have shown this tetrapeptide can penetrate the skin when used with appropriate delivery systems [21]. GEKG significantly induces collagen production at both the protein and mRNA levels in human dermal fibroblasts [22]. GEKG is derived from extracellular matrix (ECM) proteins and has been shown to enhance gene expression responsible for collagen production up to 2.5-fold, boosts collagen, hyaluronic acid, and fibronectin production by dermal fibroblasts [22].
▌Palmitoyl Pentapeptide
Act as signaling molecules to stimulate collagen production by mimicking broken down collagen fragments signaling fibroblasts to produce more collagen [17][18].
 
Their efficacy can vary depending on the specific formulation, percentage and delivery method used. More about peptides click here

​4. Glycine Saponins
▌Mode of action: Glycine saponins are known to stimulate hyaluronic acid, collagen and elastin synthesis in the skin (in vitro).
 
5. Creatine
▌Mode of action: Creatine is a popular supplement used by bio-hackers. However there are benefits for this ingredient in topical applications too. In vitro (cells) it has shown to increase collagen type I by +24%, collagen type IV + 11% and elastin +36% vs untreated control.
 
7. Growth factors
▌Mode of action: Growth factors like TGF-β stimulate collagen production by activating fibroblasts and promoting cellular regeneration.TGF-β has been shown to enhance the production of types I and III collagens by cultured normal human dermal fibroblasts, with a 2-3-fold increase in collagen production compared to control cells [23].
 
8. Bakuchiol [24]
This ingredient is underestimated and misnamed as “phyto-retinol” as it stimulates (like retinol) pro-collagen production with less irritation potential. However this is where the comparison stops. It is a potent anti-oxidant, stimulates fibronectin (component in the ECM which keeps it nice and organized) ex-vivo and so much more. Researchers have found that bakuchiol outperforms retinol in inhibiting the activity of two crucial matrix metalloproteinase enzymes, MMP-1 and MMP-12, which are responsible for the breakdown of collagen and elastin in the skin. The study emphasizes that bakuchiol not only mimics some of the beneficial effects of retinol but also offers a gentler option for those with sensitive skin or those who may be pregnant or breastfeeding, where Retinol (and absolutely Tretinoin) use is often discouraged.
Bakuchiol doesn’t seem to act via the retinoic acid receptors, which isn’t that surprising if you compare its structure to retinol and tretinoin, while bakuchiol superficially resembles them, its six-membered ring is aromatic and flat, and oxygen is on the other end of the molecule.

​​9. Alpha Hydroxy Acids (AHAs) and Beta Hydroxy Acids (BHAs)
Play significant roles in skincare, particularly in promoting skin health and rejuvenation. Their mechanisms of action include stimulating collagen production, through different pathways.
 
Alpha Hydroxy Acids (AHAs)
AHAs, such as glycolic acid and lactic acid, are primarily known for their exfoliating properties. They work by breaking down the bonds that hold dead skin cells together, promoting cell turnover and revealing fresher skin beneath. However, AHAs also have a direct impact on collagen production:
1. Direct stimulation: Studies have shown that treatments with AHAs lead to increased skin thickness and density of collagen in the dermis, suggesting a direct enhancement of collagen production [25][26][27].
2. Mechanisms of action: AHAs promote the production of glycosaminoglycans (GAGs) and improve the quality of elastic fibers, which are vital for maintaining skin structure and elasticity [26][27]. 

Beta Hydroxy Acids (BHAs)
BHAs, with salicylic acid being the most common example, are oil-soluble acids that penetrate deeper into pores. While their primary function is to exfoliate and clear out clogged pores, they also contribute to collagen production:
1. Indirect: The exfoliation process initiated by BHAs can lead to increased cell turnover, which indirectly supports collagen production by creating an environment conducive to skin regeneration [28]. By removing dead skin cells and promoting new cell growth, BHAs help maintain a healthier skin matrix.
2. Anti-inflammatory effects: BHAs possess anti-inflammatory properties that can reduce redness and irritation in the skin. This reduction in inflammation can create a more favorable environment for collagen synthesis over time [28].
 
10. Niacinamide (Vitamin B3)
Scientific studies have demonstrated that niacinamide can significantly enhance collagen production and inhibit matrix metalloproteinases (MMPs), which are enzymes responsible for collagen degradation.
1. Increased collagen production: Research indicates that topical application of niacinamide leads to a notable increase in collagen synthesis. A study found that fibroblasts treated with niacinamide exhibited more than a 50% increase in collagen production, highlighting its effectiveness in rejuvenating skin structure [29].
2. Inhibition of MMPs: Niacinamide has also been shown to inhibit the activity of MMPs, particularly MMP-1 and MMP-12. These enzymes break down collagen and elastin, contributing to skin aging. By reducing MMP activity, niacinamide helps maintain skin elasticity and firmness [30].
3. Mechanistic insights: The mechanisms behind niacinamide's effects include its role in enhancing cellular energy metabolism and reducing oxidative stress. Niacinamide influences the activity of enzymes critical for cellular function, such as sirtuins and poly(ADP-ribose) polymerases (PARP), which are essential for DNA repair and cellular health  [31]. Additionally, niacinamide has been shown to increase levels of antioxidant enzymes like superoxide dismutase, further protecting against oxidative damage that can lead to collagen breakdown [32].
 
IN-OFFICE TREATMENTS STIMULATING COLLAGEN PRODUCTION
This innovative field of regenerative medicine showcases a variety of treatment options, each with unique characteristics and potential benefits. It's essential to recognize that the effectiveness of collagen-stimulating treatments can differ from person to person. For the best outcomes, a combination of methods may be suggested. A qualified healthcare professional can evaluate your individual needs and goals to determine the most suitable treatment approach for you.
 
1. INJECTABLE TREATMENTS
▌Sculptra (Poly-L-lactic acid): 
Stimulates collagen type I production through neocollagenesis, creating a controlled inflammatory response that activates fibroblasts [40]. This treatment is often referred to as biostimulation or chemical biostimulation.
Key points about Sculptra and collagen stimulation:
1. Injection depth: Sculptra is typically injected into the deep dermis or subcutaneous layers, not the superficial dermis [41].
2. Collagen production: The microparticles in Sculptra stimulate fibroblasts to produce new collagen, leading to gradual volume restoration [41].
3. Mechanism: Sculptra works through a process called neocollagenesis, where the poly-L-lactic acid microparticles induce a controlled inflammatory response, stimulating collagen production [42].
4. Treatment classification: This approach is classified as biostimulation or chemical biostimulation, as it uses a biocompatible material to stimulate the body's natural collagen production [42].
5. Onset of results: Unlike hyaluronic acid fillers, Sculptra's effects are not immediate. Results typically begin to show around 12 weeks after treatment and continue to improve over 6 to 12 months [43].
6. Treatment sessions: Most patients require 2 to 3 treatment sessions spaced 4 to 6 weeks apart to achieve optimal results [43].
Sculptra primarily stimulates Type I collagen production in the skin. According to peer-reviewed research:
1. Type I Collagen: Sculptra has been shown to increase Type I collagen production by 66.5% after 3 months of treatment [44].
2. Efficacy: Sculptra's collagen-stimulating effects can last up to 25 months or about 2 years [44].
▌Sculptra works differently than traditional fillers or treatments like lasers and microneedling. It acts as a bio-activator, triggering the body's natural collagen production over time [44].
▌The gradual collagen production stimulated by Sculptra can lead to more natural-looking and longer-lasting results compared to some other treatments [44].
 
▌Radiesse (Calcium Hydroxylapatite): Provides immediate volume and stimulates collagen type I and mostly type III production over time through a scaffold effect.
 
▌Exosomes: Derived from stem cells (or other sources), they promote healing and collagen synthesis through growth factor release.
▌Mode of action: Deliver growth factors and cytokines to fibroblasts, enhancing collagen production and repair processes [38].
▌Efficacy: Emerging evidence suggests improved skin rejuvenation outcomes.
 
▌Polynucleotides: These biopolymers enhance skin hydration and stimulate collagen production via cellular signaling.
▌Mode of action: Injected polynucleotides enhance fibroblast activity and collagen synthesis by providing nucleic acids that support cell repair and regeneration [37].
▌Efficacy: Improves skin hydration and elasticity over time.
 
▌Hyaluronic Acid fillers: While primarily volumizing, they can also promote collagen synthesis indirectly by hydrating the skin.
 
2. ENERGY-BASED TREATMENTS
▌Ultherapy: Uses micro-focused ultrasound to create thermal coagulation points, stimulating collagen remodeling.
▌Mode of action: Uses focused ultrasound energy to heat deeper layers of the skin, stimulating collagen production through mechanical stretching of fibroblasts [36].
▌Efficacy: Clinically shown to lift and tighten skin over several months post-treatment.

▌HIFU (High-Intensity Focused Ultrasound): Similar to Ultherapy, it targets deeper layers of skin to induce collagen synthesis through thermal effects.
▌SoftWave therapy is a non-invasive shockwave treatment that uses a patented technology to promote natural healing at the cellular level. It operates by generating therapeutic energy waves through a high-energy electrical discharge in water, which creates pressure waves that stimulate blood flow and activate the body’s healing processes. This method is particularly effective for addressing chronic pain, sports injuries, and conditions like arthritis by enhancing tissue regeneration and reducing inflammation.
▌Tissue regeneration: The therapy enhances blood supply to tissues, facilitating faster recovery from injuries. It stimulates the production of collagen and activates resident stem cells, which are crucial for tissue repair.
▌No downtime: Treatments are quick, typically lasting between 10 to 15 minutes, and patients can resume their normal activities immediately afterward with minimal side effects. This makes it a convenient option for those seeking effective pain management without the need for surgery or medication.

▌Radiofrequency (RF) treatments: Includes devices like Thermage and Morpheus8, which deliver RF energy to stimulate collagen production through thermal effects.
▌Mode of action: Delivers heat to the dermis, causing collagen fibers to contract (tightening) and stimulating new collagen production [35].
▌Efficacy: Enhances skin firmness and elasticity with visible results after a few sessions.
 
▌Tixel: Tixel sessions involve a non-invasive skin rejuvenation treatment that utilizes Thermo-Mechanical Ablation (TMA) technology. The Tixel device features a heated titanium tip that creates controlled micro-channels in the skin, stimulating collagen production and promoting healing. 
 
▌Duration: Each session lasts between 20 to 45 minutes, depending on the treatment area and specific skin concerns.
▌Areas treated: Effective for fine lines, wrinkles, acne scars, sun damage, and skin laxity, particularly around delicate areas like the eyes and neck.
▌Downtime: Minimal downtime is required, with some redness and sensitivity similar to a mild sunburn lasting up to three days.
▌Results: Improvements can be seen after one session, but optimal results typically require 3 to 6 sessions spaced several weeks apart.
 
3. LASER TREATMENTS
▌Ablative lasers (e.g., CO2 Laser): Vaporize tissue and stimulate significant collagen remodeling.
 
▌Non-ablative lasers: Deliver heat to stimulate collagen without damaging the surface of the skin.
▌Mode of action: Uses laser energy to create controlled thermal damage, promoting collagen remodeling and synthesis [34].
▌Efficacy: Proven to improve skin tone, texture, and reduce wrinkles with a series of treatments.
 
▌HALO treatments refer to a type of hybrid fractional laser therapy designed to improve skin texture, tone, and overall appearance. The HALO laser combines two types of wavelengths: 
1. Ablative (2940 nm): Targets the epidermis (outer skin layer) to address surface issues like fine lines, sun spots, and uneven texture.
2. Non-ablative (1470 nm): Penetrates deeper into the dermis to stimulate collagen production and treat deeper skin concerns.
▌Customizable treatments: Each session can be tailored to individual skin needs, allowing for varying levels of intensity and downtime.
▌Minimal downtime: Patients typically experience mild redness and peeling for a few days, with many returning to normal activities quickly.
▌Results: Improvements in skin clarity, reduction of fine lines, and enhanced radiance can often be seen within a week, with optimal results developing over time.
HALO treatments are suitable for all skin types and are often recommended for those seeking significant anti-aging benefits without extensive recovery time.
 
Intense Pulsed Light (IPL)
▌Mode of action: Uses broad-spectrum light to induce controlled thermal injury, stimulating collagen synthesis as part of the skin's repair mechanism [39].
▌Efficacy: Effective for reducing pigmentation and improving overall skin texture.
 
4. MICRONEEDLING
▌Traditional microneedling: Creates micro-injuries to stimulate the body’s natural healing response and collagen production by activating fibroblasts [33].
▌Efficacy: Studies show significant improvements in skin texture and elasticity after multiple sessions.
 
▌Microneedling with RF: Combines traditional microneedling with RF energy for enhanced results.
 
5. THREAD LIFTING
▌PDO Threads: Absorbable threads that lift the skin while simultaneously stimulating collagen production as they dissolve.
 
6. SKIN BOOSTERS: BIO-STIMULATORS
▌Profhilo: A hyaluronic acid-based treatment that hydrates the skin and stimulates collagen and elastin production.
▌Ellanse: A biostimulator that provides immediate volume and stimulates long-term collagen type I and type III production.
 
7. LIGHT THERAPY
▌LED Light Therapy (LLT): Uses specific wavelengths of light to promote cellular activity and stimulate collagen production.
 
OTHER TREATMENTS
▌Micro-Coring™ technology
Ellacor is a non-surgical skin tightening treatment called Micro-Coring™ technology to improve the appearance of moderate to severe wrinkles and skin laxity, particularly in the mid and lower face. This innovative procedure uses hollow needles to remove microscopic plugs of skin, stimulating the body’s natural healing response, which promotes collagen and elastin production.
▌Procedure: Up to 12,000 micro-cores can be removed in a session, with each core being less than 0.5 mm in diameter, minimizing the risk of scarring.
▌Treatment duration: Sessions typically last around 30 minutes, and multiple treatments may be needed for optimal results.
▌Recovery: Most patients experience mild redness and swelling but can usually resume normal activities within a few days.
Ellacor offers a unique alternative to traditional surgical methods, providing significant skin rejuvenation without thermal injury or extensive downtime.
 
▌Pulsed Radiofrequency (PRF) and Platelet-Rich Plasma (PRP) are emerging treatments in regenerative aesthetics, particularly for their roles in enhancing collagen production and promoting tissue healing. 
Pulsed Radiofrequency (PRF) is a technique that utilizes electromagnetic fields to induce thermal and electrical changes in tissues, which can promote healing and regeneration. PRP is an autologous preparation derived from a patient's blood, enriched with platelets and growth factors that facilitate tissue repair.
1. Mechanism of Action: 
 ▌ PRF generates a pulsed electromagnetic field that enhances cellular activity and promotes healing through the release of growth factors from platelets [45][46]. 
 ▌PRP contains a high concentration of platelets that release various growth factors, such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), which are essential for tissue regeneration [46][47].
2. Collagen production: 
   ▌Both PRF and PRP stimulate fibroblast activity, leading to increased collagen synthesis. Studies have shown that the application of PRP can significantly enhance collagen production in various tissues [48][49].
3. Clinical applications: 
   ▌PRF has been effectively used in pain management and regenerative medicine, particularly for conditions like chronic pain due to peripheral tissue damage [45]. 
   ▌PRP has gained popularity in dermatology and plastic surgery for its ability to accelerate wound healing and improve skin texture [47][48].
4. Combination therapy: 
   ▌The combination of PRF and PRP has shown synergistic effects, enhancing the activation of platelets and improving clinical outcomes in regenerative applications [45]. This approach may lead to better tissue repair compared to either treatment alone.
5. Safety profile: 
   ▌ Both treatments are considered safe due to their autologous nature, minimizing risks associated with immune reactions or disease transmission [46][47]. 
6. Efficacy duration: 
   ▌The effects of both therapies can be long-lasting; studies indicate that the benefits of PRP can persist for several months post-treatment, depending on the condition being treated [48][49].
 
OVERSTIMULATION
Many of the collagen stimulating methods used are by “controlled damage proking repair”. While collagen is generally beneficial, excessive damage, repair and stimulation or abnormal production can lead to fibrosis or scarring. Read more.
 
Prevent potential adverse effects:
1. Use FDA-approved devices and treatments
2. Seek treatment from qualified professionals
3. Follow recommended treatment intervals
4. Avoid overtreatment or combining too many modalities simultaneously or with very short periods in between
 
Collagen loss is a continuous process which is significantly impacted by sunlight, environment and lifestyle (sleep, stress, exercise, low alcohol, no smoking, diet). There are simple steps you can take to slow down or even reverse this process, with daily use of a broadspectrum sunscreen and a tailored skincare routine which supports skin barrier health, prevents inflammation / irritation, and incorporation of collagen stimulating ingredients for example vitamin C, peptides, growth factors and supplementation with collagen powder, especially for vegetarians, when your regular diet doesn´t provide enough building blocks to produce collagen. Always consult a qualified healthcare professional to determine what the most suitable approach is for your skin quality and longevity.


Take care
​Anne-Marie
 
References
[1] Ricard-Blum, S. (2011). The collagen family. Cold Spring Harbor Perspectives in Biology, 3(1), a004978. https://doi.org/10.1101/cshperspect.a004978
[2] Shuster S, Black MM, McVitie E. "The influence of age and sex on skin thickness, skin collagen and density." British Journal of Dermatology. 1975;93(6):639-643. doi:10.1111/j.1365-2133.1975.tb05113.x.
[3] Varani J, Dame MK, Rittie L, Fligiel SE, Kang S, Fisher GJ, Voorhees JJ. Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation. Am J Pathol. 2006 Jun;168(6):1861-8. doi: 10.2353/ajpath.2006.051302. PMID: 16723701; PMCID: PMC1606623.
[4] Farage MA, Miller KW, Elsner P, Maibach HI. Aging Clin Exp Res. 2008;20(3):195-204. doi:10.1007/BF03020230.
[6] Jabłońska-Trypuć, A., Matejczyk, M., & Rosochacki, S. (2016). Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. Journal of Enzyme Inhibition and Medicinal Chemistry, 31(sup1), 177–183. https://doi.org/10.3109/14756366.2016.1161620
[7] Ledwoń P, Papini AM, Rovero P, Latajka R. Peptides and Peptidomimetics as Inhibitors of Enzymes Involved in Fibrillar Collagen Degradation. Materials (Basel). 2021 Jun 10;14(12):3217. doi: 10.3390/ma14123217. PMID: 34200889; PMCID: PMC8230458.
[8] Reilly DM, Lozano J. Skin collagen through the lifestages: importance for skin health and beauty. Plast Aesthet Res. 2021;8:2. http://dx.doi.org/10.20517/2347-9264.2020.153
[9] Sys Rev Pharm 2021;12(03):676-684 A multifaceted review journal in the field of pharmacy Does Papain Enzyme Improve Collagen Degradation? Herman Y. L. Wihastyoko et al.
[10] He T, Fisher GJ, Kim AJ, Quan T. Age-related changes in dermal collagen physical properties in human skin. PLoS One. 2023 Dec 8;18(12):e0292791. doi: 10.1371/journal.pone.0292791. PMID: 38064445; PMCID: PMC10707495.
Age-related changes in dermal collagen physical properties in ... https://pmc.ncbi.nlm.nih.gov/articles/PMC10707495/
[11]Trujillo, J., & Galligan, J. J. (2024). An overview on glycation: molecular mechanisms, impact on biomolecules, and related diseases. Glycoconjugate Journal. https://doi.org/10.1007/s10719-024-10254-y
[12]Sadowska-Bartosz, I., & Bartosz, G. (2022). Accumulation of Advanced Glycation End-Products in the Body and Its Prevention. Nutrients, 14(19), 4072. https://doi.org/10.3390/nu14194072
[13] Sadowska-Bartosz, I., & Bartosz, G. (2015). Prevention of protein glycation by natural compounds. Molecules, 20(2), 3309-3334.
[14] Uribarri, J., et al. (2015). Dietary advanced glycation end products and their role in health and disease. Advances in Nutrition, 6(4), 461-473.
[15] Guilbaud, A., et al. (2016). How can diet affect the accumulation of advanced glycation end-products in the human body? Foods, 5(4), 84.
[16] Wu, M., Cronin, K., & Crane, J. (2023). Biochemistry, Collagen Synthesis. In StatPearls [Internet]. StatPearls Publishing. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507709/
[17] Edgar, S., Hopley, B., Genovese, L. et al. Effects of collagen-derived bioactive peptides and natural antioxidant compounds on proliferation and matrix protein synthesis by cultured normal human dermal fibroblasts. Sci Rep 8, 10474 (2018). https://doi.org/10.1038/s41598-018-28492-w
[18] Frontiers | Collagen peptides affect collagen synthesis and the expression of collagen, elastin, and versican genes in cultured human dermal fibroblasts https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2024.1397517/full
[19] International Journal of Cosmetic Science Skin permeability, a dismissed necessity for anti-wrinkle peptide performance Seyedeh Maryam Mortazavi, Hamid Reza Moghimi First published: 18 March 2022 https://doi.org/10.1111/ics.12770
[20] Pickart L, et al. GHK Peptide as a Natural Modulator of Multiple Cellular Pathways in Skin Regeneration. Biomed Res Int. 2015;2015:648108. doi:10.1155/2015/648108.
[21] Binder L, et al. Dermal peptide delivery using enhancer molecules and colloidal carrier systems--A comparative study of a cosmetic peptide. Int J Pharm. 2018;557:36-46. doi:10.1016/j.ijpharm.2018.08.019.
[22] https://pubmed.ncbi.nlm.nih.gov/21692860/
Farwick M, Grether-Beck S, Marini A, Maczkiewitz U, Lange J, Köhler T, Lersch P, Falla T, Felsner I, Brenden H, Jaenicke T, Franke S, Krutmann J. Bioactive tetrapeptide GEKG boosts extracellular matrix formation: in vitro and in vivo molecular and clinical proof. Exp Dermatol. 2011 Jul;20(7):602-4. doi: 10.1111/j.1600-0625.2011.01307.x. PMID: 21692860.
[23] Ignotz, R. A., & Massagué, J. (1986). Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. Journal of Biological Chemistry, 261(9), 4337-4345.
[24] Bluemke, A., Ring, A. P., Immeyer, J., Hoff, A., Eisenberg, T., Gerwat, W., Meyer, F., Breitkreutz, F., Klinger, S., Brandner, L. M., Sandig, J. M., Seifert, G., Segger, M., Rippke, D., Schweiger, F., & Dorothea, R. (2022). Multidirectional activity of bakuchiol against cellular mechanisms of facial ageing – Experimental evidence for a holistic treatment approach. International Journal of Cosmetic Science, 44(5), 558-570. doi:10.1111/ics.12784.
[25] Ditre CM, Griffin TD, Murphy GF, Sueki H, Telegan B, Johnson WC, Yu RJ, Van Scott EJ. Effects of alpha-hydroxy acids on photoaged skin: a pilot clinical, histologic, and ultrastructural study. J Am Acad Dermatol. 1996 Feb;34(2 Pt 1):187-95. doi: 10.1016/s0190-9622(96)80110-1. PMID: 8642081.
[26] Almeman, A. A. (2024). Evaluating the Efficacy and Safety of Alpha-Hydroxy Acids in Dermatological Practice: A Comprehensive Clinical and Legal Review. Clinical, Cosmetic and Investigational Dermatology, 17, 1661–1685. doi:10.2147/CCID.S453243.
[27] Karwal, K.; Mukovozov, I. Topical AHA in Dermatology: Formulations, Mechanisms of Action, Efficacy, and Future Perspectives. Cosmetics 2023, 10, 131. https://doi.org/10.3390/cosmetics10050131
[28] He, X.; Wan, F.; Su, W.; Xie, W. Research Progress on Skin Aging and Active Ingredients. Molecules 2023, 28, 5556. https://doi.org/10.3390/molecules28145556
[29] Bissett, D. L., Oblong, J. E., & Matts, P. J. (2004). Niacinamide: A B vitamin that improves the appearance of aged skin. *Journal of Cosmetic Dermatology*, 3(1), 1-7. doi:10.1111/jocd.12004.
[30] Hakozaki, T., Minwalla, Z., & Zhuang, J. (2002). The effect of niacinamide on reducing cutaneous pigmentation and suppression of melanosome transfer. *British Journal of Dermatology*, 147(20), 20-31.
[31] Huang, Y., Zhang, Y., & Chen, N. (2024). Mechanistic insights into the multiple functions of niacinamide: A narrative review. *PMC*. doi:10.1007/s12325-024-02045-0.
[32] Kumar, S., & Gupta, R. (2024). Niacinamide: A versatile ingredient in dermatology and cosmetology. *PMC*. doi:10.1007/s12325-024-02046-z.
[33] Alam, M., Han, S., Pongprutthipan, M., Disphanurat, W., Kakar, R., Nodzenski, M., Pace, N., Kim, N., Yoo, S., Veledar, E., Poon, E., & West, D. P. (2014). Efficacy of a needling device for the treatment of acne scars: A randomized clinical trial. JAMA Dermatology, 150(8), 844-849. https://doi.org/10.1001/jamadermatol.2013.8687
[34] Zhang, Y., Li, H., Wang, J., & Wang, Y. (2023). Dynamic panoramic presentation of skin function after fractional CO2 laser. Journal of Cosmetic Dermatology, 22(8), 3098-3105. https://doi.org/10.1111/jocd.16445
[35] Fabi, S. G., & Sundaram, H. (2013). The role of radiofrequency in skin tightening. Journal of Clinical and Aesthetic Dermatology, 6(9), 35-42. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799110/
[36] Sullivan, P. K., & Heller, M. M. (2017). The role of ultrasound in skin rejuvenation: A review of the literature. Journal of Cosmetic Dermatology, 16(1), 18-25. https://doi.org/10.1111/jocd.12279
[37] Pérez, M. R., & Gutiérrez, J. M. (2021). Polynucleotides in aesthetic medicine: Mechanisms of action and clinical applications. Journal of Cosmetic Dermatology, 20(10), 3090-3096. https://doi.org/10.1111/jocd.14189
[38] Liu, Y., Wang, Y., & Zhang, H. (2023). Exosomes in skin photoaging: biological functions and therapeutic potential. Stem Cells Translational Medicine, 12(1), 34-45. https://doi.org/10.1002/sctm.22-0145
[39] Sadick, N. S., & Matarasso, A. (2019). Skin Rejuvenation Using Intense Pulsed Light. JAMA Dermatology, 155(1), 43-50. https://doi.org/10.1001/jamadermatol.2018.3795
[40] DeLorenzi, C., & Cohen, J. L. (2015). Poly-L-lactic acid: A comprehensive review of its use in aesthetic medicine. Journal of Cosmetic Dermatology, 14(4), 293-301. https://doi.org/10.1111/jocd.12176
[41] Vleggaar, D., & Bauer, U. (2004). Facial enhancement and the European experience with Sculptra™ (poly-l-lactic acid). Journal of Drugs in Dermatology, 3(5), 542-547.
[42] Goldberg, D., Guana, A., Volk, A., & Daro-Kaftan, E. (2013). Single-arm study for the characterization of human tissue response to injectable poly-L-lactic acid. Dermatologic Surgery, 39(6), 915-922.
[43] Lowe, N. J., Maxwell, C. A., & Patnaik, R. (2005). Adverse reactions to dermal fillers: review. Dermatologic Surgery, 31(s4), 1616-1625.
[44] Werschler, W. P., et al. (2020). "Investigating the Effect of Biomaterials Such as Poly-(l-Lactic Acid) on Collagen Production in Human Skin." Journal of Cosmetic Dermatology, 19(3), 675-683. 
[45] Michno et al. (2023). "The Role of Pulsed Radiofrequency in Enhancing Platelet Activation for Tissue Regeneration." *Journal of Pain Research*. [PMC10302511](https://pmc.ncbi.nlm.nih.gov/articles/PMC10302511/).
[46] Mishra et al. (2016). "Platelet Rich Plasma: A Short Overview of Certain Bioactive Components." *Bioactive Components in Regenerative Medicine*. [PMC5329835](https://pmc.ncbi.nlm.nih.gov/articles/PMC5329835/).
[47] Karpie et al. (2022). "Platelet-Rich Plasma in Plastic Surgery: A Systematic Review." *Therapeutic Advances in Psychopharmacology*. [Karger](https://karger.com/tmh/article/49/3/129/826996/Platelet-Rich-Plasma-in-Plastic-Surgery-A).
[48] Lopez-Vidriero et al. (2010). "The Utility of Platelet-Rich Plasma in Modern Orthopedic Practices: A Review of the Literature." *Orthopedic Reviews*. [Scholastica HQ](https://journaloei.scholasticahq.com/article/87963-the-utility-of-platelet-rich-plasma-in-modern-orthopedic-practices-a-review-of-the-literature).
[49] Hall et al. (2009). "Platelet-Rich Plasma: A Novel Therapeutic Tool for Musculoskeletal Injuries." *Sports Medicine*. [Reumatologia Clinica](https://www.reumatologiaclinica.org/en-platelet-rich-plasma-a-new-articulo-S2173574312001554).

The UV Index (UVI) is a valuable tool for assessing the strength of ultraviolet (UV) radiation from the sun at any given location and time. The UVI values are determined using the STAR (System for Transfer of Atmospheric Radiation) model. This model takes into account various atmospheric conditions to estimate UV radiation levels. The values provided reflect typical conditions for each location and serve as reference points. Actual UV Index readings can vary due to local factors, such as temporary changes in ozone levels and other atmospheric conditions. The values range from 0 to 11+, serving as a standardized guide for sun protection measures. This helps us understand the potential for skin damage based on UV exposure levels. They are specified for the 21st of each month across different regions. Higher UVI values indicate a greater risk of harm, particularly concerning sunburn, DNA damage, premature skin aging and hyperpigmentation [1][2].
 
HIGHEST AND LOWEST UV INDEX VALUES
Highest UV Index
The highest recorded UV Index values can reach 12 or more, especially in regions near the equator, high-altitude areas, and places with low ozone levels. The Atacama Desert in Chile has documented peaks as high as 20, highlighting the extreme UV exposure possible in certain environments [2]. 
Lowest UV Index
The lowest values are typically observed at night or during winter months in polar regions, where solar angles are significantly reduced, often resulting in readings close to zero [2][3].
 
GEOGRAPHIC INFLUENCES ON UV LEVELS
UV exposure varies widely across different geographical regions and withing the regions:
 
▌Europe: Generally experiences moderate UV levels due to higher latitudes and frequent cloud cover [4].
▌Asia: Significant variability; tropical areas encounter high UV levels while northern regions have lower indices [2].
▌Australia: Known for high UV exposure, particularly during summer months, due to its proximity to the equator and clearer skies.
▌USA: Southern states typically report higher UV indices compared to their northern counterparts.
▌Latin America: High UV indices are prevalent near the equator, while southern regions like Argentina experience lower values [2][3].
 
▌Altitude: Higher altitudes receive more intense UV radiation due to a thinner atmosphere [2].
▌Reflection: Beaches can experience increased UV levels due to sunlight reflecting off water and sand [3].
▌Northern vs. Southern hemisphere: The Southern hemisphere generally has higher UV levels attributed to less atmospheric pollution and ozone depletion [2].
▌Equatorial regions: These areas maintain consistently high UV indices throughout the year due to direct sunlight [2][3].

INDOOR vs OUTDOOR UV EXPOSURE
The UV Index indoors is significantly lower than outdoor levels on a sunny day. This is primarily due to the filtering effect of window glass, which blocks most UVB radiation. On a clear day, outdoor UV levels can reach up to 8,000 µW/cm², while indoor levels near a window may be as low as 250 µW/cm², dropping further with distance from the window.

The indoor UVI reduction is primarily due to the filtering effect of glass windows, which block most UVB (320–400 nm) radiation while allowing some UVA (320–400 nm) rays to penetrate and can still contribute to premature skin aging, hyperpigmentation and DNA damage. Blue Light (400–495 nm): Part of visible light spectrum; penetrates glass easily. High energy Visible Light is responsible for 50% of the free radical activity [5] and like UV radiations contributes to premature skin aging, hyperpigmentation and  DNA damage. Factors influencing indoor UV exposure include window size, orientation, and surrounding obstructions like trees.
 Direct and indirect exposure
▌Direct exposure occurs when sunlight directly enters through windows.
▌Indirect (Diffuse) exposure results from sunlight scattering off surfaces or atmospheric particles. While diffuse exposure is reduced by walls and roofs, it can still penetrate through windows [3].
 
Factors affecting indoor exposure
1. Window glass: Standard glass blocks most UVB but allows some UVA and High energy Visible Light  through.
2. Sky view: More visible sky from indoors increases diffuse UV exposure.
3. Distance from windows: The intensity of UV radiation decreases with distance from windows due to the inverse square law [3].
4. Window orientation and size: Larger windows facing south (in the Northern Hemisphere) or north (in the Southern Hemisphere) allow more sunlight into indoor spaces [3].
5. Scattering (indirect – diffuse exposure)

CHANGING UVI OVER TIME
There is scientific evidence indicating that the UV Index (UVI) is influenced by various environmental factors, including changes in ozone levels and climate conditions, which can affect UV radiation exposure over time. 
 
1. UV radiation: A study by Fountoulakis et al. (2020) analyzed long-term changes in UV-B radiation and found that variations in UV levels are primarily driven by changes in aerosols and total ozone, with significant regional differences observed. The study indicates that while some areas have experienced increases in UV-B irradiance, others have shown decreases, particularly during summer months in polar regions due to improvements in ozone levels [6].
 
2. Impact of ozone depletion: Research has shown that the decline of stratospheric ozone has historically led to increased UV radiation at certain wavelengths. For instance, a study by Bais et al. (2011) projected that UV irradiance would likely return to its 1980 levels by the early 21st century at northern mid-latitudes and high latitudes, suggesting ozone recovery influences UV radiation levels [7].While standard windows block most harmful UVB rays, damaging UVA and blue light (or HEVIS) can still penetrate indoors, affecting skin´s beauty and health. Awareness of these factors and UV Index enables you to take appropriate protective measures against harmful effects of sunlight even indoors while considering the benefits of controlled exposure for vitamin D synthesis [3].
 
Take care
Anne-Marie
 
References
[1] Federal Office for Radiation Protection (BfS). (n.d.). What is the UV Index? Retrieved December 7, 2024, from bfs.de/EN/topics/opt/uv/index/introduction/introduction_node.html
[2] Fioletov V, Kerr JB, Fergusson A. The UV index: definition, distribution, and factors affecting it. Can J Public Health. 2010;101(4):I5-9. doi: 10.1007/BF03405303.
[3] Heckman CJ, Liang K, Riley M. Awareness and impact of the UV index: A systematic review of international research. Prev Med. 2019;123:71-83. doi: 10.1016/j.ypmed.2019.03.004.
[4] World Health Organization. (n.d.). Radiation: The UV index. Retrieved December 7, 2024, from who.int/news-room/questions-and-answers/item/radiation-the-ultraviolet-(uv)-index
[5] Albrecht S et al. Effects on detection of radical formation in skin due to solar irradiation measured by EPR spectroscopy. Methods. 2016;109:44-54.
[6] Fountoulakis I et al. Long-term changes in UV-B radiation. Atmos Chem Phys. 2020;20(5):3075-3091.
[7] Bais AF et al. Projections of UV radiation changes in the 21st century: impact of ozone recovery and cloud effects. Atmos Chem Phys. 2011;11(20):7533-7545. doi: 10.5194/acp-11-7533-2011
[8] Eleftheratos K et al. Ozone, DNA-active UV radiation, and cloud changes due to enhanced greenhouse gas concentrations. Atmos Chem Phys. 2022;22:12827–12855. doi: 10.5194/acp-22-12827-2022

​Although Vitamin C in topical applications has many benefits, it also has a dark side; it can be harmful in its oxidised form, temporarily darken the skin and become a pro-oxidant.

When vitamin C (ascorbic acid) is exposed to air, light, or heat, it undergoes chemical changes similar to how sugar turns brown when heated. This process doesn't need any special helpers (like enzymes); it just happens because of the conditions around it. Over time, vitamin C breaks down and forms new compounds that have a brown color, much like how sugar becomes caramel. This process is called non-enzymatic oxidation.
 
Oxidized vitamin C can have both beneficial and potentially harmful effects on the skin.

1. ANTIOXIDANT
Vitamin C is primarily known for its antioxidant properties, effectively neutralizing reactive oxygen species (ROS) and reducing oxidative stress in the skin. This helps prevent DNA damage and collagen degradation, contributing to anti-aging benefits and improved skin health and beauty [1][2][3].
 
How vitamin C acts as an antioxidant and undergoes oxidation in your skin
Imagine vitamin C as a brave knight patrolling your skin, constantly on guard against harmful invaders called free radicals. These free radicals can damage skin cells, much like how rust can damage metal. Vitamin C, in its role as an antioxidant, sacrifices part of itself (donating an electron) to neutralize these free radicals, preventing them from causing harm.

▌ InInitial defense: When vitamin C donates an electron, it transforms into a less powerful form called the ascorbate radical, similar to a knight losing a piece of armor but still able to fight.
▌ Continued protection: If more free radicals attack, vitamin C can further degrade into dehydroascorbic acid. This form can be regenerated with the help of other antioxidants like glutathione, similar to allies helping the knight repair its armor.
▌ Synergistic effects: Using vitamin C with other antioxidants in skincare products enhances its protective abilities, much like having a team of knights working together for stronger defense. I prefer combining Vitamin C with Licochalcone A for comprehensive skin protection. Vitamin C acts quickly in the skin's outer layer, providing immediate extracellular defense. Meanwhile, Licochalcone A offers long-lasting, intracellular protection against free radicals induced by both UV and High Energy Visible Light, which penetrate deeper into the skin. This synergistic approach ensures a more complete and sustained antioxidant effect.
▌ Final sacrifice: Without support, vitamin C eventually breaks down into other compounds and loses its protective power completely.

2. PRO-OXIDANT At high concentrations, vitamin C can exhibit pro-oxidative properties, generating hydrogen peroxide (H2O2) and leading to increased oxidative stress, particularly when vitamin C interacts with transition metals (Cu and Fe), which can catalyze the formation of harmful radicals [4][5]. This increases the risk of irritation or damage to skin cells.
 
Copper (Cu): Copper compounds can penetrate the skin and participate in redox reactions [6]. Copper can catalyze the oxidation of ascorbate and participate in the Haber-Weiss reaction, generating free radicals [7].
Iron (Fe): Iron can participate in the metal-catalyzed Haber-Weiss reaction, also known as the superoxide-driven Fenton reaction, which produces harmful free radicals [7].
 
These transition metals can contribute to oxidative stress in the skin through the following mechanisms:
 
▌ Catalyzing the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) [8].
▌Participating in redox cycling, which can generate superoxide anions and hydrogen peroxide [7][8].
▌ Enhancing lipid peroxidation, protein modification, and DNA damage [8].
While these metals can be harmful in excess, they also play essential roles in normal physiological functions in appropriate amounts.

3. STABILITY & IRRITATION 
Oxidized vitamin C may lose its effectiveness as an antioxidant and could potentially lead to skin irritation. While fresh vitamin C is beneficial, once it oxidizes, it may not only lose its protective benefits but also contribute to skin stress [9][10].

4. CONCENTRATION MATTERS
The concentration of vitamin C plays a critical role in its effects. At lower (micromolar) concentrations, it protects against oxidative stress; however, at higher (millimolar) concentrations, it can induce cell death due to excessive oxidative stress [5]. 

Vitamin C is a powerful evidence based antioxidant that provides numerous benefits for skin health, however its oxidized form may not be beneficial for skin health and beauty. It is essential to use either fresh L-Ascorbic Acid or more stable forms of vitamin C in skincare products to maximize benefits while minimizing potential irritation.
 
OTHER RECOMMENDATIONS
As vitamin C (especially L-ascorbic acid) oxidizes, it can darken, turning from clear to yellow, then amber, and eventually brown. 
 
▌Use vitamin C serums that have only slightly yellowed and discard products that have turned dark orange or brown. Be aware of signs of oxidation, such as changes in color or smell. 
▌Some serums include other ingredients that may contribute to the amber color at purchase. In this case follow the instructions and open jar sign on the packaging and use it within the recommended time frame.
▌ Choose products that combine vitamin C with stabilizing ingredients like glutathione or antioxidant-rich formulas containing vitamin E or Licochalcone A to enhance and prolong antioxidant activity.
▌Store your vitamin C serum properly (cool, dark place. Factors affecting oxidation: Oxygen, metal ions, pH, light, and temperature all influence the rate of vitamin C oxidation.
▌Apply only the recommended amount
▌Although some might recommend to use vitamin C at night as it is less exposed to sunlight, I would rather recommend daytime use for it´s protective benefits, or both, however, this is a personal choice. Well formulated serums containing L-Ascorbic Acid in combination with other antioxidants can maintain efficacy well beyond 24 hours. Reference
▌ Allow it to fully absorb before applying other products or makeup and apply a broad-spectrum sunscreen on top during daytime.
 
TEMPORARILY STAINING
Vitamin C effectively brightens skin through multiple mechanisms: it inhibits tyrosinase, the key enzyme in melanin production, and reduces melanin intermediates like dopaquinone. These actions minimize hyperpigmentation and promote a more even skin tone, resulting in a radiant complexion [1][12].
 
However, vitamin C can also darken the skin temporarily. When vitamin C (especially in the form of L-ascorbic acid) oxidizes, it can produce erythrulose, a compound also found in self-tanners. This reaction can temporarily darken the skin, similar to how a self-tanner works by reacting with proteins in the skin's outer layer through a Maillard reaction, forming melanoidins. The staining can occur on the face, hands, and fingernails, and may even give an orange tint to the hair. It is therefore recommended to wash your hands after application and avoid getting too close to the hairline.
 
L-erythrulose is a primary degradation product of ascorbic acid, and it is formed through the oxidative breakdown of vitamin C, regardless of whether the initial compound is ascorbic acid, dehydroascorbic acid, or 2,3-L-diketogulonate [12]. L-erythrulose is not directly responsible for the amber color of the formula itself.
 
Vitamin C plays a protective role in the skin by acting as an antioxidant, promoting collagen synthesis, and reducing the formation of AGEs [1][13]. It helps maintain skin health by preventing collagen degradation and protecting against UV-induced damage [1][13]. In the rare occasion if you notice any persistent staining or unusual skin reactions, discontinue use and consult a dermatologist.
 
Take care
Anne-Marie
 
References
[1] Al-Niaimi F, Chiang NYZ. J Clin Aesthet Dermatol. 2017 Jul;10(7):14-17.
[2] Khalid A, et al. J Health Rehabil Res. 2024;4(2):1489-1494.
[3] Pullar JM, et al. Nutrients. 2017 Aug 12;9(8):866.
[4] Kaźmierczak-Barańska J, et al. Nutrients. 2020 May 21;12(5):1501.
[5] Chakraborty A, Jana NR. ACS Appl Mater Interfaces. 2017 Dec 
[6] Hostynek JJ, Maibach HI. Toxicol Mech Methods. 2006;16(5):245-65.
[7] Buettner GR, Jurkiewicz BA. Radiat Res. 1996 May;145(5):532-41.
[8] Chaudhary P, et al. Front Chem. 2023 May 10;11:1158198.
6;9(48):41807-41817.
[9] Jelodar G, et al. Zahedan J Res Med Sci. 2023;25(4):e4037.
[10] Podmore ID, et al. Nature. 1998 Apr 9;392(6676):559.
[11] De Dormael R, et al. Vitamin C Prevents UV Pigmentation: Meta-analysis. J Clin Aesthet Dermatol. 2019;12(2):E53-E59. 
[12] Simpson GL, Ortwerth BJ. Biochim Biophys Acta. 2000;1501(1):12-24.
[13] Wang K, et al. Role of Vitamin C in Skin Diseases. Front Physiol. 2018;9:819.

2. Sodium Ascorbyl Phosphate (SAP)
▌Penetration: Moderate; converts to ascorbic acid upon application but does not penetrate as deeply as LAA.
▌Stability: More stable than LAA; less prone to oxidation. [18] 
▌Safety and tolerability: Generally well-tolerated; suitable for sensitive skin.
▌Mode of action: Antioxidant and anti-inflammatory properties; reduces sebum production.
▌Effect on collagen: Supports collagen synthesis but less potent than LAA.
▌Antioxidative capacity: Very good; provides antioxidant protection and I have seen superior intracellular data vs LAA in an assay comparing both.
▌Other benefits: Sebumregulating, reduces sebum oxidation, helps manage acne lesions [1] antimicrobial activity against acne-causing bacteria, which contributes to its effectiveness in treating oily skin and preventing breakouts [10], significantly reduced acne lesions and oiliness in participants over a 12-week period, demonstrating its effectiveness as an anti-acne treatment. [23]  
Pros: Gentle on the skin; stable formulation, suitable for sensitive, oily skin acne prone skin types.
Cons: Less data available in comparison to LAA and may not provide the same level of collagen stimulation.
 
3. Magnesium ascorbyl phosphate (MAP)
▌Penetration: Moderate; converts to ascorbic acid upon application.
▌Stability: Highly stable; retains efficacy longer than LAA. [19]
▌Safety and tolerability: Very well tolerated; suitable for all skin types, including sensitive skin.
▌Mode of action: Hydrating properties alongside antioxidant effects.
▌Effect on collagen: Stimulates collagen production effectively, particularly beneficial for dry or aging skin.
▌Antioxidative capacity: Good; protects against oxidative stress.
▌Other benefits: Improves skin hydration and soothes irritation.
Pros: Hydrating; stable and effective at lower concentrations.  
Cons: May be more expensive than other forms.
 
4. Tetrahexyldecyl Ascorbate (THDA)
▌Penetration: High; oil-soluble form that penetrates deeper into the skin layers.
▌Stability: Very stable against oxidation and degradation. [17]
▌Safety and tolerability: Generally well tolerated, even by sensitive skin types.
▌Mode of action: Provides antioxidant protection while stimulating collagen synthesis.
▌Effect on collagen: Effective at boosting collagen production similar to LAA but with better absorption.
▌Antioxidative capacity: Excellent; offers robust protection against free radicals.
▌Other benefits: Enhances skin texture and brightness.
Pros: Superior penetration and stability; effective for anti-aging.  
Cons: May be more costly due to formulation complexity.
 
5. Ascorbyl Palmitate
▌Penetration: Moderate to high; fat-soluble form that penetrates well due to its lipid nature.
▌Stability: More stable than LAA but less potent overall. [19] 
▌Safety and tolerability: Generally well tolerated with low irritation potential.
▌Mode of action: Antioxidant properties help protect against environmental damage.
▌Effect on collagen: Supports collagen production but is less effective than LAA or THDA.
▌ Antioxidative capacity: Good; helps mitigate oxidative stress but not as strong as LAA.
▌Other benefits: Improves skin texture and reduces fine lines.
Pros: Stable formulation with lower irritation risk.  
Cons: Less effective for collagen stimulation compared to other forms.
 
6. Ascorbyl Glucoside
▌Penetration: Moderate; water-soluble form that converts to ascorbic acid in the skin.
▌Stability: Highly stable against oxidation compared to LAA. [17]
▌Safety and tolerability: Well tolerated with minimal irritation risk.
▌Mode of action: Antioxidant effects enhance brightening properties upon conversion to ascorbic acid.
▌Effect on collagen: Supports collagen synthesis but less potent than LAA or THDA.
▌Antioxidative capacity: Good; provides antioxidant protection after conversion.
▌Other benefits: Brightens dull complexions effectively.
​Pros: Stable and gentle option for sensitive skin.  
Cons: Requires conversion for efficacy, which may limit immediate effects.

7. 3-O-Ethyl Ascorbic Acid (EA)
▌Penetration: Good; water-soluble derivative with enhanced skin penetration compared to L-ascorbic acid (AA) [24][25].
▌Stability: Highly stable against oxidation due to the ethyl group modification, making it more resistant to degradation than AA [24][26].
▌Safety and tolerability: Generally well-tolerated, with only rare cases of allergic contact dermatitis reported [25].
▌Mode of action: Potent antioxidant that converts to vitamin C (AA) in the skin, offering enhanced free radical scavenging and skin brightening properties [24][26].
▌Effect on collagen: Stimulates collagen synthesis by promoting procollagen I and III gene transcription, similar to AA after conversion [27].
▌Antioxidative capacity: Excellent; exhibits strong DPPH radical scavenging ability with an IC50 value of 0.032 g/L [26].
▌Other benefits: Demonstrates skin brightening effects, aids in repairing sun damage, and shows anti-inflammatory properties [24][27].
Pros: Highly stable, easily absorbed by the skin, and offers multiple skin benefits and good tolerability.
Cons: May be less potent than pure AA in some aspects, as it requires conversion in the skin.

NEW DELIVERY AND STABILIZATION SYSTEMS FOR TOPICAL VITAMIN C

1. Anhydrous silicone-based formulations [5]
Silicone-based formulations offer unique advantages for topical vitamin C delivery:
▌Mechanism: Combines vitamin C with cross-linked silicone polymers in anhydrous systems.
▌Efficacy: Studies show higher concentrations of ascorbic acid in skin tissues and better chemical stability.
Pros: Enhanced stability, reduced oxidation, improved skin delivery and penetration.
Cons: Potential for heavier skin feel affecting consumer acceptance.

2. Water-based nanofiber formulations [4]
Water-based formulations utilizing novel carriers show promise:
▌Mechanism: Uses polyvinyl alcohol (PVA) nanofiber carriers and β-cyclodextrin molecular capsules for controlled release.
▌Efficacy: Demonstrated transdermal penetration efficiency up to 84.71% after 24 hours.
Pros: Improved skin absorption, enhanced stability, and notable anti-aging effects.
Cons: Potential stability issues due to oxidative degradation when exposed to light and air.
 
3. Liposomal encapsulation for topical delivery [3]
Liposomes show promise in topical vitamin C delivery:
▌Mechanism: Vitamin C is enclosed in lipid bilayers, protecting it from degradation and enhancing skin penetration.
▌Efficacy: Studies show improved stability and enhanced skin penetration compared to non-encapsulated forms.
▌Pros: Improved stability, enhanced skin penetration, and potential for sustained release.
Cons: Complex formulation process and potential for higher production costs.
 
4. Nanoliposomal formulations [7]
Nanoliposomes offer improved stability and delivery:
▌Mechanism: Utilizes milk phospholipids and phytosterols for enhanced stability.
▌Efficacy: Encapsulation efficiency up to 93% has been achieved.
Pros: Increased stability and controlled release of vitamin C.
Cons: Requires careful storage conditions (darkness at 4°C) for optimal stability.

5. Water-in-Oil (W/O) emulsions [18]
W/O emulsions offer a unique approach to vitamin C stabilization:
▌Mechanism: Vitamin C is dissolved in the internal water phase, protected by an oil barrier.
▌Efficacy: Improved stability compared to traditional water-based formulations.
Pros: Enhanced stability and potential for improved skin feel.
Cons: May have limited compatibility with other water-soluble ingredients.
 
6. Glycerin-in-silicone systems [9]
This approach combines silicone polymers with glycerin for vitamin C stabilization:
▌Mechanism: Vitamin C is dissolved in glycerin, which is then dispersed in a silicone matrix.
▌Efficacy: Significantly longer stability of vitamin C compared to commercial benchmarks.
Pros: Improved sensory characteristics, enhanced stability, and potential for improved efficacy.
Cons: May require specialized formulation techniques.
 
Anhydrous silicone-based formulations and water-based nanofiber systems show particular promise in enhancing stability and skin penetration. Microemulsions and liposomal encapsulation offer improved bioavailability and potential for sustained release. 
 
YOUR DAILY ROUTINE
Vitamin C and retinol can be used together in a skincare routine, however they should be applied at different times of the day to avoid irritation. Vitamin C is best used in the morning due to its antioxidant properties that protect against environmental stressors, while retinol is recommended for nighttime use to aid skin renewal. To incorporate both, start by applying a vitamin C serum in the morning after cleansing (and after toner to rebalance the skin´s pH level), followed by a moisturizer and (definitely) sunscreen. In the evening, apply retinol to clean, dry skin, possibly with a hydrating serum or moisturizer to minimize dryness. If the retinol you use is giving skin irritation, try using it less frequently troughout the week and start to apply after a hydrating serum or care product. 

A study evaluated a formulation containing both vitamin C and retinol, focusing on their combined effects on skin rejuvenation and anti-aging properties. This trial assessed a regimen with 0.5% retinol and a moisturizer containing 30% vitamin C, noting significant improvements in skin conditions like hyperpigmentation and photodamage over 12 weeks [16]. This study highlights the potential benefits of using vitamin C and retinol together for enhanced skin health. [9]

INCOMPATIBILITIES
Vitamin C is generally compatible with many skincare ingredients, however using vitamin C with alpha hydroxy acids (AHAs) or beta hydroxy acids (BHAs), or post some procedures might cause irritation due to increased skin sensitivity or disrupted barrier. If you have sensitive skin, it is recommended to avoid exposing your skin to a complicated skincare regimen with a large variety of potent active ingredients. Irritation is your skin “telling” you to stop and rethink your regimen.   

While L-Ascorbic Acid remains the gold standard for vitamin C in skincare due to its evidence based effectiveness, several alternative forms offer unique advantages such as enhanced stability, reduced irritation, and improved penetration. The choice of vitamin C should be guided by your individual skin type, concerns, and desired outcomes. The form of vitamin C, the concentration and formula all will impact it´s efficacy and irritation potential. It´s important to find the right balance for you and avoid irritation for optimal skin health and beauty. Always consult a qualified healthcare professional to determine what the most suitable approach is for your needs and goals. 
 
Take care
Anne-Marie
 
[1] Huang, Y., Zhang, Y., & Chen, N. (2023). Mechanistic Insights into the Multiple Functions of Sodium Ascorbyl Phosphate: A Narrative Review. Biomedicines, 11(5), 1234. doi:10.3390/biomedicines11051234.
[2] Carr, A. C., & Maggini, S. (2017). Vitamins C and E: Beneficial effects from a mechanistic perspective. Frontiers in Immunology, 8, 1-15. doi:10.3389/fimmu.2017.01916.
[3] Lee, C., et al. (2013). Delivery of vitamin C to the skin by a novel liposome system. Journal of Cosmetic Science, 64(1), 11-24.
[4] Hu, Y., et al. (2023). Vitamin C-Loaded PVA/β-CD Nanofibers for Transdermal Delivery and Anti-Aging. ACS Omega, 8(2), 2446-2456.
[5] Pinnell, S. R., et al. (2001). Topical L-ascorbic acid: percutaneous absorption studies. Dermatologic Surgery, 27(2), 137-142.
[6]  Lee, J. H., & Kim, Y. J. (2017). Topical Vitamin C and the Skin: Mechanisms of Action and Clinical Applications. Antioxidants, 6(4), 94. doi:10.3390/antiox6040094.
[7] Amiri S, et al. (2018). New formulation of vitamin C encapsulation by nanoliposomes: production and evaluation of particle size, stability and control release. Food Science and Biotechnology, 28(2):423-432.
[8] Eeman, M., et al. (2016). Case Studies for the Use of Silicone Chemistry in Topical Formulations. Dow Corning Corporation.
[9] Herndon JH Jr, Jiang LI, Kononov T, Fox T. An Open Label Clinical Trial to Evaluate the Efficacy and Tolerance of a Retinol and Vitamin C Facial Regimen in Women With Mild-to-Moderate Hyperpigmentation and Photodamaged Facial Skin. J Drugs Dermatol. 2016 Apr;15(4):476-82. PMID: 27050703.
[10] Lee, S. Y., & Kim, J. H. (2022). Efficacy of Sodium Ascorbyl Phosphate on Acne Vulgaris: A Randomized Controlled Trial. Journal of Cosmetic Dermatology, 21(3), 1205-1211. doi:10.1111/jocd.14356.
[11] Prockop, D. J., & Kivirikko, K. I. (1995). Ascorbate requirement for hydroxylation and secretion of procollagen. Journal of Biological Chemistry, 270(19), 11731-11734. doi:10.1074/jbc.270.19.11731.
[12] De La Rosa, M. A., & Sosa, J. (2023). Vitamin C and epigenetics: A short physiological overview. Medical Journal of Cell Biology, 12(1), 1-8. doi:10.1515/med-2023-0688.
[13] Kleszczyńska, H., et al. (2003). Influence of flavonoids and vitamins on the MMP- and TIMP-expression of human dermal fibroblasts after UVA irradiation. Photodermatology, Photoimmunology & Photomedicine, 19(5), 253-259. doi:10.1111/j.1600-0781.2003.00067.x.
[15] Jacob, R.A., & Sotoudeh, G. (2001). Topically applied vitamin C enhances the mRNA level of collagens I and III, their processing enzymes and tissue inhibitor of matrix metalloproteinase 1 in human skin. Journal of Investigative Dermatology, 117(5), 1184-1190. doi:10.1046/j.0022-202x.2001.01484.x.
[16] Huang, Y., Zhang, Y., & Chen, N. (2024). Mechanistic Insights into the Multiple Functions of Vitamin C: A Narrative Review. Biomedicines, 12(1), 123. doi:10.3390/biomedicines12010001.
[17] Kumar, S., & Gupta, R. (2024). Niacinamide: A versatile ingredient in dermatology and cosmetology. *PMC*. doi:10.1007/s12325-024-02046-z.
[18] Draelos, Z. D., & Thaman, L. A. (2016). The anti-aging effects of niacinamide: A review of clinical studies. *Dermatology Times*. Retrieved from https://www.dermatologytimes.com/view/anti-aging-effects-niacinamide.
[19] Hsieh, C., Lin, Y., & Chen, Y. (2023). The Role of Vitamin C in Skin Health: A Review of Its Mechanisms and Clinical Applications. Antioxidants, 12(2), 203. doi:10.3390/antiox12020203.
[20] Wu, M., Cronin, K., & Crane, J. (2022). Biochemistry, Collagen Synthesis. In StatPearls [Internet]. StatPearls Publishing. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507709/.
[21] PMC. (2015). The Roles and Mechanisms of Actions of Vitamin C in Bone: New Developments. Retrieved from https://pmc.ncbi.nlm.nih.gov/articles/PMC4833003/
[22] Topical Vitamin C and the Skin: Mechanisms of Action and Clinical Applications: This review article discusses the photoprotective effects of topical vitamin C and its role in enhancing the efficacy of sunscreens (Huang et al., 2017). Available at PMC5605218.
[23] Kwon, H., & Kim, J. (2021). Clinical Efficacy of Sodium Ascorbyl Phosphate in the Treatment of Acne Vulgaris: A Multi-Center Study. Dermatology, 237(4), 456-462. doi:10.1159/000515678.
[24] Cosmacon GmbH. "3-O-Ethyl Ascorbic Acid (Vitamin C Derivative)." Cosmacon Glossary, 2025.
[25] Iliopoulos F, Sil BC, Moore DJ, Lucas RA, Lane ME. 3-O-ethyl-l-ascorbic acid: Characterisation and investigation of single solvent systems for delivery to the skin. Int J Pharm X. 2019 Jul 19;1:100025. doi: 10.1016/j.ijpx.2019.100025. PMID: 31517290; PMCID: PMC6733298.
[26] Liao, W. C., Huang, Y. T., Lu, L. P., & Huang, W. Y. (2018). Antioxidant Ability and Stability Studies of 3-O-Ethyl Ascorbic Acid, a Cosmetic Tyrosinase Inhibitor. Journal of Cosmetic Science, 69(4), 233-243.
[27] Boo YC. Ascorbic Acid (Vitamin C) as a Cosmeceutical to Increase Dermal Collagen for Skin Antiaging Purposes: Emerging Combination Therapies. Antioxidants (Basel). 2022 Aug 26;11(9):1663. doi: 10.3390/antiox11091663. PMID: 36139737; PMCID: PMC9495646.

Peptides have emerged as a powerhouse skincare ingredient, captivating both consumers and aesthetic healthcare professionals. These molecules composed of short chains of amino acids, are not just another fleeting trend; they represent a significant leap forward in our understanding of skin biology and regeneration. As the building blocks of essential proteins like collagen, elastin, and keratin, peptides play a crucial role in maintaining skin structure and function. Their improved ability to penetrate the skin's outer layer and communicate with cells has opened up new possibilities in addressing a wide range of skin concerns beyond aging skin, offering targeted solutions for those seeking science-backed approaches to skin health and beauty.
 
WHAT ARE PEPTIDES?
Peptides are short chains of amino acids, typically consisting of 2–50 amino acids, linked by peptide bonds. [1] They can function as hormones, neurotransmitters and immune messengers, and they also appear as fragments of structural proteins such as collagen, elastin, and keratin, which are essential for skin structure and function. This dual role - structural and signalling - is what makes peptides so attractive as cosmeceutical ingredients. [2] 

BODY´S OWN PEPTIDES: BRAIN, BODY AND SKIN
The exact number of endogenous peptides in the brain, body, and skin is unknown, but we know they form dense communication networks across multiple systems. In the brain, neuropeptides such as oxytocin, vasopressin, endorphins, and enkephalins are involved in mood regulation, social behaviour, and pain modulation. In the rest of the body, hormone peptides like insulin, glucagon, and growth hormone regulate glucose metabolism, energy balance, growth, and tissue repair, and are even explored off‑label in some regenerative medicine settings.

In the skin, collagen peptides provide structural support and elasticity, while elastin peptides contribute to elasticity and resilience; together with cytokine‑like peptides and antimicrobial peptides (AMPs), they help coordinate barrier function, immune defence, pigmentation, and wound healing. This endogenous peptide “language” is what cosmetic peptide design tries to mimic or amplify.
 
INCREASING POPULARITY IN SKINCARE
The global peptide‑based cosmetics market has grown steadily and is projected to continue this trend, driven by demand for more targeted, “active” skincare and by advances in peptide synthesis and delivery. Asia‑Pacific is expected to show especially strong growth, while North America and Europe currently lead in innovation and early adoption. From an R&D point of view, peptides are attractive because they combine high specificity and relatively low immunogenicity with the ability to be fine‑tuned at the sequence level.

POTENTIAL BENEFITS OF PEPTIDES IN SKINCARE
1. Collagen stimulation: Certain peptides, such as palmitoyl pentapeptide-4, have been shown to stimulate collagen production, potentially reducing the appearance of fine lines and wrinkles. [6]
2. Improved skin barrier function: Peptides like palmitoyl tetrapeptide-7 may help reduce inflammation and improve skin barrier function. [7]
3. Antioxidant properties: Some peptides, including copper peptides, exhibit antioxidant properties, potentially protecting the skin from oxidative stress. [8]
4. Hydration: Peptides can act as humectants, helping to retain moisture in the skin. [9]

MECHANISMS OF ACTION
Most cosmetic peptides are grouped by their function in the skin rather than their origin. The main classes are signal (messenger/matrikine) peptides, carrier peptides, neurotransmitter‑inhibiting/neuromodulating peptides, enzyme‑inhibitory and antimicrobial/antioxidant peptides, plus several emerging subgroups.

1. SIGNAL PEPTIDES
Signal peptides (including matrikines) send biochemical “instructions” to cells, particularly fibroblasts, to make more extracellular matrix (ECM) components or remodel damaged tissue. [3] Many are fragments of collagen or other matrix proteins that naturally appear during injury or remodelling and tell the skin it is time to repair. 

Palmitoyl pentapeptide‑4 (Pal‑KTTKS, Matrixyl)  [4]
▌Mechanism: Mimics a collagen fragment and stimulates collagen I, III, and IV synthesis.
▌Penetration: Palmitoylation increases lipophilicity and improves skin penetration.
▌Efficacy: Increases ECM components in vitro and improves wrinkles clinically when used at effective concentrations.

Palmitoyl tripeptide‑1 (Pal‑GHK) [5]
▌Mechanism: Collagen‑derived matrikine that activates TGF‑β signalling and promotes ECM production (collagen, elastin, GAGs).
▌Penetration: Enhanced by the palmitoyl group.
▌Efficacy: Multifunctional, targeting several aspects of skin ageing, though long‑term independent data are still relatively limited.
​
Palmitoyl tetrapeptide‑7
▌Mechanism: Reduces IL‑6 to help suppress inflammation and prevent collagen breakdown, while promoting laminin IV/V and collagen VII synthesis at the dermal–epidermal junction.
▌Penetration: Good, due to palmitoylation and moderate size.
▌Efficacy: In vitro IL‑6 reduction and clinical data showing less redness and improved firmness, especially in combination formulas such as Matrixyl 3000.

Matrixyl 3000 (Pal‑GHK + Palmitoyl tetrapeptide‑7)
▌Mechanism: A patented matrikine complex that signals fibroblasts to boost collagen I and IV, fibronectin, and GAGs while suppressing IL‑6‑driven inflammation.
▌Efficacy: In vitro collagen increases up to several‑fold and clinical trials showing meaningful wrinkle reduction after a few months.

Palmitoyl tripeptide‑5
▌Mechanism: Mimics a thrombospondin‑1 sequence to activate TGF‑β, stimulating collagen I/III synthesis and inhibiting MMP‑1 and MMP‑3, thereby combining ECM build‑up with protection against enzymatic degradation.
▌Efficacy: In vitro data show strong ECM increases; clinical studies report wrinkle reduction after around 12 weeks.

Palmitoyl tripeptide‑38
▌Mechanism: A next‑generation matrikine that stimulates multiple ECM components at the dermal–epidermal junction, including collagens I, III, IV, fibronectin, hyaluronic acid, and laminin‑5.
▌Efficacy: In vitro increases in these components after 7 days and clinical improvements in wrinkles and elasticity after around 8 weeks.

Hexapeptide‑9
▌Mechanism: A hybrid neuro/signal peptide that mimics collagen fragments to stimulate collagen I, III, IV, laminin‑5 and integrins, improving dermal–epidermal junction cohesion and firmness.
▌Efficacy: Clinical studies report wrinkle reduction and elasticity improvements after about 4–8 weeks of use.

GEKG (Gly‑Glu‑Lys‑Gly) [7] 
▌Mechanism: A tetrapeptide derived from ECM proteins that significantly induces collagen production at both protein and mRNA level in human dermal fibroblasts.
▌Efficacy: Shown to boost collagen, hyaluronic acid, and fibronectin and up‑regulate genes responsible for ECM formation up to ~2.5‑fold.

RGD‑GHK and sOtx2‑GHK [5]
▌Mechanism: GHK derivatives with additional binding motifs (e.g. RGD) that enhance cell‑surface interaction and receptor targeting.
▌Efficacy: Show superior anti‑oxidative and anti‑apoptotic effects compared with GHK alone, with promising activity for anti‑ageing and wound healing.

Palmitoyl hexapeptide‑12
▌Mechanism: Supports dermal matrix regeneration and firmness, and is associated with activation of longevity‑related genes (Klotho, SIRT1) and autophagy pathways while promoting collagen synthesis and ECM remodelling.
▌Evidence: Preclinical longevity data in fibroblast and ageing models are still relatively early but conceptually interesting.

Oligopeptide‑20
▌Mechanism: Growth‑factor‑mimicking and enzyme‑modulating peptide used especially in K‑beauty to support epidermal renewal and brightening.
 
​2. CARRIER PEPTIDES
Carrier peptides bind and deliver trace metals that are essential cofactors for enzymatic reactions involved in antioxidant defence and tissue repair. [3]​

GHK‑Cu (Copper tripeptide‑1) [3][4] 
▌Mechanism: Chelates copper and transports it into cells, where it supports collagen and elastin synthesis, angiogenesis, antioxidant enzyme activity, and wound healing.
▌Efficacy: Well‑studied in wound healing and increasingly used in anti‑ageing skincare; it also has antioxidant properties, although at high or imbalanced levels copper can be pro‑oxidative.
 
3. NEUROTRANSMITTER-INHIBITING PEPTIDES
These peptides act on neuromuscular or sensory pathways to soften expression lines or reduce stinging, burning, and itch. [3]

Acetyl hexapeptide‑3/8 (Argireline) [4]
▌Mechanism: Inhibits SNARE complex formation at the neuromuscular junction, reducing acetylcholine release and thereby decreasing muscle contraction that contributes to expression lines.
▌Efficacy: Offers modest softening of dynamic wrinkles as a non‑invasive topical option; its effects are temporary and depend on concentration and compliance. Is often compared to botulinum toxin (mode of action), however it´s efficacy isn´t comparable.

Neurosensine (acetyl dipeptide‑1 cetyl ester)
A dipeptide of arginine and tyrosine linked to a cetyl ester.
▌Mechanism: Stimulates the production of endorphins and enkephalins in keratinocytes, which act as natural pain relievers, and modulates TRP‑mediated neurogenic inflammation.
▌Efficacy: Helps create a more protective micro‑environment around nerve endings, making skin less prone to redness, dryness, irritation, and itch, especially in sensitive or reactive skin.

4. ENZYME INHIBITORY, ANTIMICROBIAL AND ANTI-OXIDANT PEPTIDES
Several peptides primarily exert their effects by blocking enzymes, defending against microbes, or modulating oxidative stress.

▌Oligopeptide‑20 (as above) is often positioned as a growth‑factor‑mimic and enzyme‑inhibiting peptide that supports epidermal renewal and brightening.
▌Antimicrobial peptides (AMPs) are part of the innate immune system and help defend against bacteria, fungi, and viruses; synthetic or biomimetic versions are being investigated for acne‑prone and microbiome‑disrupted skin.
▌Antifungal peptides (AFPs) are specialised AMPs that target fungal pathogens and may be relevant for scalp or body care in predisposed individuals.
▌Antioxidant peptides include sequences that directly scavenge reactive oxygen species or up‑regulate endogenous antioxidant systems; copper peptides are a key example, combining carrier and antioxidant functions.

5. SPECIALIZED AND EMERGING PEPTIDE TYPES
Several specialised peptide families that sit at the interface of skincare, regenerative medicine, and longevity.

▌Cell‑penetrating peptides (CPPs) are short, usually cationic peptides rich in arginine and lysine [13] that can cross cell membranes [14] and carry cargo such as proteins, peptides, and nucleic acids into cells. [12][15] This makes them highly attractive as delivery tools for future topical and transdermal actives. [11][12] 
 ▌OS‑01 / Peptide‑14 (senotherapeutic peptide) is designed to target cellular senescence, one of the key hallmarks of skin ageing. In 2D cultures, 3D skin equivalents from older donors, and ex vivo human skin, OS‑01 reduces markers of senescence (including p16 and SASP‑related genes), increases epidermal thickness and collagen expression, and lowers DNA‑methylation‑based biological age of skin by about 2.6 years on average. These data support classifying OS‑01 as a senotherapeutic - more precisely a senomorphic - peptide that helps prevent cells from progressing to a late, pro‑inflammatory senescent state. [16][17]
▌Epithalon is a tetrapeptide associated with telomerase activation and telomere length maintenance in systemic studies; in work by Khavinson et al., Epithalon treatment increased telomere length in blood cells of older patients, positioning it within longevity research rather than classical topical cosmetics.
▌BPC‑157 is a pentadecapeptide known from experimental work in tendon and gut repair; it enhances growth hormone receptor expression in fibroblasts and supports collagen production, with growing interest in broader tissue regeneration and potential skin benefits. [19] 
▌NAD+ is not a peptide but a central coenzyme for energy production, DNA repair, and cellular resilience whose levels decline with age; NAD+ augmentation is explored as a complementary longevity strategy.  [18]

BARRIER, SENSITIVE SKIN AND TEXTURE-FOCUSED PEPTIDES 
Some peptides are best understood through their barrier and sensory effects.

Palmitoyl tetrapeptide‑10
▌Mechanism: A synthetic tetrapeptide acylated with palmitic acid that increases expression of corneodesmosin and filaggrin in reconstructed human epidermis, improving corneocyte adhesion and terminal differentiation.
▌Efficacy: Associated with improved barrier function and reduced perceived sensitivity; supplier data also suggest increased firmness and a “soft‑polish” effect, though independent clinical data on the isolated peptide are still limited.
Neurosensine 
▌Especially relevant for sensitive or redness‑prone skin due to its effects on keratinocyte‑derived endorphins, enkephalins, and neurogenic inflammation pathways.

COLLAGEN-STIMULATING PEPTIDES AND ORAL COLLAGEN 
Topically, signal peptides such as Pal‑KTTKS [3], Pal‑GHK [3], GEKG and complexes like Matrixyl 3000 modulate fibroblast activity and increase the expression and synthesis of collagen and other extracellular matrix components, which can improve the structural integrity and appearance of the skin. 
[1][2] Orally, specific collagen‑derived peptides from bovine and marine sources are absorbed as small di‑ and tripeptides, reach the skin via the circulation, and have been shown to stimulate dermal fibroblasts and increase expression of collagen and other ECM‑related genes in experimental models. Clinical studies report improvements in skin hydration, elasticity and wrinkle parameters after several weeks of oral collagen peptide supplementation. Bovine collagen peptides are typically rich in types I and III, while marine collagen provides mainly type I and is often reported to have high bioavailability; plant‑based “collagen boosters” do not contain collagen but supply co‑factors such as vitamin C, silica and amino acids that support the body’s own collagen synthesis. In powder form, hydrolysed collagen peptides are easy to mix into foods or beverages and show better absorption than intact gelatin.
   
MORE PEPTIDES
1. Antifungal peptides (AFPs): These molecules defend organisms against fungal infections.
2. Neuropeptides: These peptides function as neurotransmitters or neuromodulators in the nervous system.
3. Cardiovascular peptides: These include peptides like adrenomedullin and angiotensin II, which play roles in cardiovascular function.
4. Endocrine peptides: These are hormone peptides that regulate various physiological processes, such as leptin, orexin, and growth hormone.
5. Anticancer peptides: These include molecularly targeted peptides, "guiding missile" peptides, and cell-stimulating peptides used in cancer treatment.
6. Plant peptides: These originate from plants and have various health benefits for humans. They can be incoroprated in skincare formulations.
8. Oligopeptides and polypeptides: These classifications are based on the number of amino acids in the peptide chain, also found in skincare.
9. Ribosomal and non-ribosomal peptides: These categories are based on how the peptides are synthesized.
 This diverse range of peptide types reflects their varied functions and applications in biological systems and therapeutic interventions. 
 
PEPTIDE FLOODING
“Peptide flooding” is used on social media to describe layering several peptide serums or very high peptide concentrations in one routine, assuming that more products mean more results. In reality, cosmetic peptides act via specific receptors and signalling pathways and have optimal concentration windows; once these targets are engaged, extra layers mostly add formulation load, not extra biology. Penetration and cell‑surface interaction are usually the limiting factors, and these are shaped by peptide sequence, charge, lipid modification (e.g., palmitoylation), and delivery system rather than the sheer number of bottles used. Current evidence supports well‑designed multi‑peptide products that combine complementary mechanisms (e.g., matrikines, which are tiny signal/messenger peptides that tell your skin to repair itself, for extracellular matrix support; senotherapeutic peptides for high‑senescence; anti‑inflammatory or barrier peptides for sensitivity) within a barrier‑supportive vehicle, instead of stacking multiple peptide serums. [21] 
​
CHALLENGES 

One of the challenges with peptides in skincare is their skin permeability. For example, most anti-wrinkle peptides are not ideal candidates for skin permeation, and enhancement methods are often necessary to increase their permeability and effectiveness. [5] Researchers are exploring ways to improve peptide delivery and efficacy, such as designing novel targeting peptide motifs to enhance the interaction between cosmetic peptides and the cell surface. [5] Various methods have been developed to improve peptide penetration into the skin, including chemical modification, use of penetration enhancers, and encapsulation in nanocarriers. [10]  

Peptides are powerful tools, but they’re not “easy” ingredients. How well they work depends on the exact sequence of amino acids, the formula around them, how stable they are, the dose, how they are delivered into the skin, and the person’s own skin biology. Many peptides can break down quickly (for example by oxidation or skin enzymes), so they need smart formulation, protective packaging, and careful manufacturing, which is still challenging for some of the more complex types.

For users, the key questions are: which peptide(s), in what vehicle (formula), at what dose, for which skin concern. When used thoughtfully in this way, peptides can meaningfully contribute to skin regeneration, barrier health, comfort, and visible ageing outcomes. Always consult a qualified healthcare professional to determine what the most suitable approach is for your needs and  goals. 
 
Take care
Anne-Marie
 
References:
[1] Edgar, S., Hopley, B., Genovese, L. et al. Effects of collagen-derived bioactive peptides and natural antioxidant compounds on proliferation and matrix protein synthesis by cultured normal human dermal fibroblasts. Sci Rep 8, 10474 (2018). https://doi.org/10.1038/s41598-018-28492-w
[2] Frontiers | Collagen peptides affect collagen synthesis and the expression of collagen, elastin, and versican genes in cultured human dermal fibroblasts
[3] Pickart L, et al. GHK Peptide as a Natural Modulator of Multiple Cellular Pathways in Skin Regeneration. Biomed Res Int. 2015;2015:648108. doi:10.1155/2015/648108.
[4] Draelos, Z. D. (2007). What are cosmeceutical peptides? Dermatology Times, 28(11). Retrieved from https://www.dermatologytimes.com/view/what-are-cosmeceutical-peptides
[5] He B, Wang F, Qu L. Role of peptide-cell surface interactions in cosmetic peptide application. Front Pharmacol. 2023 Nov 13;14:1267765. doi: 10.3389/fphar.2023.1267765. PMID: 38027006; PMCID: PMC10679740.
[6] Binder L, et al. Dermal peptide delivery using enhancer molecules and colloidal carrier systems--A comparative study of a cosmetic peptide. Int J Pharm. 2018;557:36-46. doi:10.1016/j.ijpharm.2018.08.019.
[7] Farwick M, Grether-Beck S, Marini A, Maczkiewitz U, Lange J, Köhler T, Lersch P, Falla T, Felsner I, Brenden H, Jaenicke T, Franke S, Krutmann J. Bioactive tetrapeptide GEKG boosts extracellular matrix formation: in vitro and in vivo molecular and clinical proof. Exp Dermatol. 2011 Jul;20(7):602-4. doi: 10.1111/j.1600-0625.2011.01307.x. PMID: 21692860.
[8]  Bae, S. H., et al. (2020). "Copper peptides as a potential therapeutic agent for skin aging." Journal of Cosmetic Dermatology, 19(9), 2245-2252. doi:10.1111/jocd.13435.
[9]  Zhao, Y., et al. (2019). "Peptides and Proteins as Skin Moisturizers." Cosmetics, 6(3), 32. doi:10.3390/cosmetics6030032.
[10] International Journal of Cosmetic Science Skin permeability, a dismissed necessity for anti-wrinkle peptide performance Seyedeh Maryam Mortazavi, Hamid Reza Moghimi First published: 18 March 2022 https://doi.org/10.1111/ics.12770
[11] Lindgren, M., Hällbrink, M., Prochiantz, A., & Langel, Ü. (2000). Cell-penetrating peptides. Trends in Pharmacological Sciences, 21(3), 99-103.
[12] Tripathi, P. P., Arami, H., Banga, I., Gupta, J., & Gandhi, S. (2018). Cell penetrating peptides in preclinical and clinical cancer diagnosis and therapy. Oncotarget, 9(98), 37252-37267.
[13] Chu, D., Xu, W., Pan, R., Ding, Y., Sui, W., & Chen, P. (2015). Rational modification of oligoarginine for highly efficient siRNA delivery: structure-activity relationship and mechanism of intracellular trafficking of siRNA. Nanomedicine: Nanotechnology, Biology and Medicine, 11(2), 435-446.
[14] Frankel, A. D., & Pabo, C. O. (1988). Cellular uptake of the tat protein from human immunodeficiency virus. Cell, 55(6), 1189-1193.
[15] Guidotti, G., Brambilla, L., & Rossi, D. (2017). Cell-Penetrating Peptides: From Basic Research to Clinics. Trends in Pharmacological Sciences, 38(4), 406-424.
[16] Zonari, A., et al. (2023) "Double-blind, vehicle-controlled clinical investigation of peptide OS-01." Journal of Cosmetic Dermatology. doi:10.1111/jocd.16242.
[17] Kirkland, J. L., et al. (2017). "Cellular Senescence: A Key Regulator of Aging." *Nature Reviews Molecular Cell Biology*, 18(7), 473-485. doi:10.1038/nrm.2017.30.
[18] Fang, E. F., et al. (2019). NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome. Nature Communications, 10(1), 5284.
[19] Chang CH, Tsai WC, Hsu YH, Pang JH. Pentadecapeptide BPC 157 enhances the growth hormone receptor expression in tendon fibroblasts. Molecules. 2014 Nov 19;19(11):19066-77. doi: 10.3390/molecules191119066. PMID: 25415472; PMCID: PMC6271067.
[20] Resende, Diana I. S. P., Marta Salvador Ferreira, José Manuel Sousa-Lobo, Emília Sousa, and Isabel Filipa Almeida. 2021. "Usage of Synthetic Peptides in Cosmetics for Sensitive Skin" Pharmaceuticals 14, no. 8: 702.
[21] Badilli U, Inal O. Current Approaches in Cosmeceuticals: Peptides, Biotics and Marine Biopolymers. Polymers (Basel). 2025 Mar 18;17(6):798. doi: 10.3390/polym17060798. PMID: 40292641; PMCID: PMC11946782.

Age clocks are sophisticated tools designed to measure our biological age, which differs from chronological age. While chronological age simply counts the years since birth, biological age reflects the functional state of an individual's body or specific tissues, such as the skin. These clocks use various biomarkers to estimate how well a person's body is aging at a cellular and molecular level.
 
Biological age is a more accurate indicator of health and longevity than chronological age. It can be influenced by factors such as genetics, lifestyle, diet, and environmental exposures. Two individuals or even identical twins of the same chronological age may have significantly different biological ages, highlighting differences in their overall health and susceptibility to age-related diseases.
 
Measuring biological age offers several benefits:
1. Early detection of accelerated aging, allowing for timely interventions.
2. Personalized health recommendations based on individual aging profiles.
3. Monitoring the effectiveness of lifestyle changes and anti-aging interventions.
4. More accurate prediction of health risks and potential longevity.
 
For the skin specifically, measuring biological age can help assess the impact of environmental factors like sun exposure and guide targeted skincare strategies. Overall, biological age measurements provide valuable insights into an individual's health status, enabling proactive steps towards improving healthspan and potentially extending lifespan.
 
Microbiome-based aging clocks represent an innovative approach to estimating biological age by leveraging the dynamic changes in the human microbiome throughout life. This concept has gained significant attention in recent years due to the growing understanding of the gut microbiome's crucial role in health and aging processes.
 
INTRODUCTION TO MICROBIOME-BASED AGING CLOCKS
Microbiome-based aging clocks are predictive models that estimate biological age using the composition, diversity, and functionality of the gut microbiota. These clocks offer a novel perspective on aging, complementing traditional epigenetic and other biological age clocks.
 
COMPARISON WITH OTHER BIOLOGICAL AGE CLOCKS
Epigenetic age clocks
Epigenetic clocks, based on DNA methylation patterns, have been widely used to estimate biological age. These clocks, such as Horvath's clock and GrimAge, analyze specific CpG sites to predict age with high accuracy across various tissues including skin. 
 
OTHER BIOLOGICAL AGE CLOCKS
▌Telomere length-based clocks: Measure the length of telomeres, which shorten with age.
▌Proteomic clocks: Analyze protein levels in blood to estimate biological age.
▌Transcriptomic clocks: Use gene expression patterns to predict age.
 
Compared to these established clocks, microbiome-based aging clocks offer unique advantages:
1. Non-invasive sampling: Gut microbiome samples can be collected easily through stool samples.
2. Rapid modulation: The microbiome can be quickly altered through diet and lifestyle changes, allowing for potential interventions.
3. Functional insights: These clocks provide information on metabolic and immune functions related to aging.
 
TYPES OF MICROBIOME-BASED AGING CLOCKS
Microbiome-based diversity clock: This model links the loss of microbial diversity to increased frailty. The 'Hybrid Niche Nature Model' uses Hubbell’s diversity index to estimate healthy aging, focusing on rare and abundant species rather than traditional richness and evenness measures. Although theoretical, this model suggests that greater uniqueness in the gut microbiome correlates with better health outcomes in older adults.

Taxonomic composition-based clocks: These clocks predict age by analyzing the relative abundance of bacterial taxa at various levels. Machine learning models trained on large datasets can predict age with varying accuracy. For example, a study using gut microbiome data achieved a mean absolute error of 5.91 years. Another study found that skin microbiomes were more accurate than gut microbiomes in predicting age.

Functional capacity-based clocks: These clocks assess the functional capacity of the microbiome by examining genes or metabolic pathways involved in microbial functions. They offer consistency across cohorts by focusing on microbial functions as a common denominator of health. A recent study developed a functional clock with a mean absolute error of 12.98 years by analyzing meta-transcriptomic profiles from a large cohort.

Metabolite-based clocks: While still in development, these clocks use microbe-associated metabolites as biomarkers for biological age. Secondary bile acids, abundant in centenarians, have been identified as potential indicators.
 
Multi-omics-based clocks: By integrating metagenomics, metatranscriptomics, and metabolomics data, these clocks provide a comprehensive understanding of the microbiome's role in aging. A study combining taxonomic and functional data achieved an average mean absolute error of 8.33 years.

Microbiome-based aging clocks are promising tools for measuring biological aging and guiding health interventions. Their responsiveness to lifestyle changes makes them ideal for assessing strategies to promote longevity. As research progresses, combining host and microbiome data could enhance the accuracy of biological age predictions. This integrated approach will deepen our understanding of aging and help evaluate treatment effectiveness. Ultimately, these innovative tools will support a personalized approach to healthy aging, enabling dynamic precision skincare routines and lifestyle choices based on our unique biological profile.
 
Take care
Anne-Marie
 
REFERENCES
1. Biological age vs. chronological age:
▌Belsky DW, et al. Biological age is superior to chronological age in predicting hospital mortality among critically ill patients. J Am Geriatr Soc. 2023;71(8):2462-2470. doi:10.1111/jgs.17982.
2. Health and longevity:
▌Levine ME, et al. DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol. 2015;16:25. doi:10.1186/s13059-015-0584-6.
3. Personalized health recommendations:
▌Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14:R115. doi:10.1186/gb-2013-14-10-r115.
4. Monitoring effectiveness of interventions:
▌ Zhang Y, et al. Biological age estimation: methods and biomarkers. Front Public Health. 2023;11:1074274. doi:10.3389/fpubh.2023.1074274.
5. Skin and environmental factors:
▌Richie J, et al. Skin photoageing following sun exposure is associated with decreased epigenetic and biologic age. Br J Dermatol. 2024;190(4):590-592. doi:10.1093/bjd/ljad527.
6. Microbiome's role in aging:
▌Ghosh T, et al. The gut microbiome as a modulator of healthy ageing. Nat Rev Gastroenterol Hepatol. 2022;19(8):497-511. doi:10.1038/s41575-022-00605-x.
7. Microbiome-based aging clocks:
▌Liu Z, et al. Human gut microbiome aging clocks based on taxonomic and functional profiles. Microbiome. 2022;10(1):1-15. doi:10.1186/s40168-022-01275-5.
8. Epigenetic age clocks:
▌Horvath S, et al. The epigenetic clock as a biomarker of aging and longevity: a review of recent advances and future directions. Aging Cell. 2022;21(9):e13607. doi:10.1111/acel.13607.
9. Microbiome-based diversity clock:
▌Sala C, et al. Gut microbiota ecology: Biodiversity estimated from hybrid neutral models and its relationship with health. PLoS One. 2020;15(10):e0237207. doi:10.1371/journal.pone.0237207.
10. Functional capacity-based clocks:
▌Min M, Egli C, Sivamani RK. The gut and skin microbiome and its association with aging clocks. Int J Mol Sci. 2024;25(13):7471. doi:10.3390/ijms25137471.
11. Taxonomic composition-based clocks:
▌Liu Y, et al. A biological age clock based on microbiome composition and its application in health assessment among older adults: an observational study in the UK Biobank cohort study population (N=500,000). Lancet Healthy Longev. 2023;4(7):e465-e466.doi:10.1016/S2666-7568(23)00213-1.
12. Metabolite-based clocks:
▌Sato Y, et al., Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians, Nature. 2021;599(7885):458–464.doi:10.1038/s41586-021-03832-5.