 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. More research is needed to fully understand the long-term effects of repeated collagen stimulation treatments on skin structure and function. 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
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 Vitamin C is one of the best researched skincare ingredients and is well-known for its significant benefits for the skin. It is the most abundant (primary) anti-oxidant in human skin [1] and necessary for collagen production. However, we are not able to synthesize vitamin C ourselves, as humans lack the enzyme L-gulonolactone oxidase necessary for synthesizing Vitamin C [2]. Thus we rely on food, supplementation or topical application [3]. 10% vitamin C in your serum is 200 x more concentrated than 1 orange. There are many compelling reasons to incorporate vitamin C in your skincare regimen, whether you are twenty or eighty. 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. Vitamin C´s efficacy is dose-dependant, more efficacy in higher concentrations, which range between 3-20%. If you´re considering a collagen stimulating (or biostimulating) aesthetic treatment, it is highly recommended to have vitamin C either in your diet or skincare regimen (day, night or both). This is beneficial for younger, however especially more mature rejuvenators as vitamin C levels are lower in mature or photo-damaged skin [4]. More vitamin C is found in epidermis which is the top layer of the skin compared to the deeper layer or dermis [5]. Oxidative stress (from pollutants or UV irradiation) is associated with depleted vitamin C levels in the epidermal layer [6]. Topical ascorbic acid is favored in the practice of dermatology [1]. Vitamin C has multiple benefits, it enhances production of barrier lipids – decreasing TEWL (transepidermal water-loss) [7] , supports differentiation of keratinocytes (skin regeneration) [8] and protects keratinocytes from apoptosis (cell death), thus increases cell survival [9], supports wound healing, and increases dermal papillae. Dermal papillae provide nutrients and oxygen to the epidermis through their rich vascular network, support epidermal-dermal adhesion, and play a crucial role in regulating hair follicle development and cycling.
 THE ROLE OF VITAMIN C IN COLLAGEN PRODUCTION 1. Transcriptional activation: Vitamin C directly activates transcription factors involved in collagen synthesis. Research indicates that it stabilizes pro-collagen messenger RNA (mRNA), which regulates the expression of type I and type III collagen genes, particularly COL3A1. This stabilization enhances the overall production of collagen in fibroblasts. [10] 2. Hydroxylation: Vitamin C acts as a cofactor for prolyl and lysyl hydroxylases, enzymes necessary for the post-translational modification of collagen precursors. Hydroxylation of proline and lysine residues is essential for the stability and proper folding of collagen molecules. A deficiency in vitamin C leads to improper collagen formation, resulting in weakened connective tissues. [11] 3. Epigenetic regulation: Recent studies suggest that vitamin C can modulate gene expression through epigenetic mechanisms, influencing chromatin structure and accessibility. This regulation allows for enhanced transcription of collagen-related genes, thereby promoting collagen synthesis. [12] THE ROLE OF VITAMIN C IN PREVENTION OF COLLAGEN DEGRADATION Vitamin C not only plays a role in collagen synthesis but also influences its degradation: 1. Inhibition of matrix metalloproteinases (MMPs): Vitamin C has been shown to inhibit the activity of MMPs, particularly MMP-1 and MMP-12, which are responsible for collagen degradation. By reducing MMP activity, vitamin C helps maintain collagen levels in the skin. [13] [14] [15] 2. Oxidative stress reduction: As an antioxidant, vitamin C protects collagen (and other components, cells and our DNA) from oxidative damage caused by free radicals. This protection is vital for preserving the structural integrity of collagen fibers over time. [2] VITAMIN C FORMS IN SKINCARE Vitamin C is a vital ingredient in skincare, celebrated for its antioxidant properties, ability to stimulate collagen production, and other skin benefits. However, various forms of vitamin C differ in their stability, penetration, safety, and effectiveness. 1. L-Ascorbic Acid (LAA) ▌Penetration: High; penetrates the skin effectively but requires a low pH for optimal absorption. [16] ▌Stability: Prone to oxidation; degrades quickly when exposed to light and air. [17] ▌Safety and tolerability: Can cause irritation, especially at higher concentrations (esp. above 20%). [18] ▌Mode of action: Directly stimulates collagen synthesis and acts as a potent antioxidant. [19] ▌Effect on collagen: Increases collagen production by stabilizing pro-collagen mRNA and activating transcription factors involved in collagen synthesis. [20] LAA enhances the expression of collagen genes, particularly COL3A1, contributing to improved skin firmness and elasticity. [16] ▌Antioxidative capacity: Excellent; neutralizes free radicals effectively. ▌Other benefits: Brightens skin tone, reduces hyperpigmentation, increases dermal pappilae, smoother skin texture and reduced roughness thus enhance overall skin texture, hydration, reduce inflammation [21], can improve the effectiveness of sunscreens [22] Pros: Highly effective; significant evidence supporting its efficacy. Cons: May irritate sensitive skin; requires careful storage.  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: Good; provides antioxidant protection but less effective than LAA. ▌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. Cons: Less potent than LAA; may not provide the same level of collagen stimulation, however more suitable for oily skin acne prone skin types. 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.  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.  Closeup of a proteasome core complex with ubiquitin molecules
After "deep-diving" into autophagy and impaired autophagy, one of the twelve hallmarks of aging, it makes sense to shine some light on its equally important (however not so famous) partner in cellular housekeeping: the proteasome. It ́s primary function is breaking down proteins that are no longer needed, damaged, or misfolded [1]. Similar to autophagy, it is our body's and skin's very own trash and recycling system, working 24/7 to keep our cells healthy and functioning [2]. The human body is composed of approximately 16-20% protein by weight. This percentage can vary based on factors like age, sex, and overall body composition. Skin, is particularly rich in proteins, about 25-30% of the total protein in the human body is found in the skin and the dry weight of skin is approximately 70% protein. Loss of proteostasis (balance of protein synthesis, folding, and degradation) is one of the twelve hallmarks of aging and the proteasome is an important mechanism within the proteostasis network [3].
THE PROTEASOME The proteasome is a large, barrel-shaped protein complex found in all eukaryotic cells, responsible for the degradation of intracellular proteins [4]. It plays a crucial role in maintaining cellular homeostasis by selectively breaking down short-lived, damaged, or misfolded proteins [5]. The 26S proteasome consists of a 20S core particle and one or two 19S regulatory particles [6]. Proteins targeted for degradation are typically tagged with ubiquitin molecules, which are recognized by the 19S regulatory particle, allowing the protein to be unfolded and fed into the 20S core for proteolysis [7]. The ubiquitination process provides a highly selective mechanism for targeting proteins for degradation in comparison to other systems like lysosomes. Proteasomal degradation is an ATP-dependent process:
This process is crucial for:
▌Maintaining protein quality control [12] ▌Regulating cellular processes by controlling protein levels ▌Recycling amino acids for new protein synthesis The proteasome is involved in numerous vital cellular processes (see illustration), including: ▌Cell cycle regulation ▌Transcriptional control ▌Immune responses ▌Neuronal plasticity Its proper function is essential for cellular health, and dysfunction of the proteasome system has been implicated in various diseases, including neurodegenerative disorders and cancer. The proteostasis network The proteostasis network (PN) is a complex system of cellular machinery that maintains the integrity of the proteome consisting of collaborating systems to ensure proper protein folding, repair damaged proteins and eliminate those beyond repair. ▌Molecular chaperones and co-chaperones ▌The ubiquitin-proteasome system (UPS) ▌Autophagy machinery ▌Translational machinery 
PROTEASOME VS AUTOPHAGY
Complementary cleaning and recycling systems While the proteasome primarily handles short-lived and soluble proteins, autophagy is responsible for degrading long-lived proteins, protein aggregates, and even entire organelles [13]. The proteasome plays critical roles in cell cycle control, gene expression, protein quality control, and immune responses, while other systems like autophagy are more involved in bulk degradation and cellular remodeling. The systems are not entirely independent and often work together to maintain cellular health [14]. The ubiquitin-proteasome system (UPS) and autophagy interact through various mechanisms:
PROTEASOME AND EPIGENETICS The proteasome also plays a significant role in epigenetics - the study of heritable changes in gene expression that don't involve changes to the underlying DNA sequence and recognised as one of the hallmarks of aging [19]. The proteasome influences epigenetics through several mechanisms: ▌Histone regulation + modification: The proteasome degrades histones, proteins that package DNA, influencing chromatin structure and gene accessibility [20].. ▌Transcription factor control + regulation: By regulating the levels of transcription factors, the proteasome indirectly affects gene expression patterns [21]. ▌Epigenetic modifier turnover + DNA methylation: The proteasome controls the levels of enzymes that modify histones and DNA, such as histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) [22]. ▌Non-proteolytic functions: Some proteasome subunits have been found to directly interact with chromatin, suggesting a more direct role in gene regulation [23]. These interactions create a complex feedback loop between protein degradation and gene expression, highlighting the proteasome's far-reaching influence on cellular function PROTEASOME AND (SKIN) HEALTH The proteasome is likely present in skin cells and in extracellular fluids associated with skin, such as sweat and plays a vital role in maintaining health and skin quality by regulating the turnover of various proteins. Proteins are fundamental to life for several reasons:
Important proteins in skin and the human body based on their overall impact and prevalence:
Dysfunction of the proteasome in skin cells can lead to various dermatological issues, including ▌accelerated aging of skin cells ▌reduced collagen production and increased breakdown ▌impaired elastin function ▌wrinkles, sagging and loss of elasticity ▌impaired wound healing and barrier function ▌increased susceptibility to UV damage and DNA damage [26] Or more skin conditions like:
PROTEASOME AND CELLULAR SENESCENCE The proteasome plays a crucial role in preventing cellular senescence, a state of permanent cell cycle arrest associated with aging:
PROTEASOME AND IMMUNE FUNCTION The proteasome is integral to immune system function:
Glycosylated proteins Proteins connected to sugar molecules, known as glycosylated proteins, can be targeted by the proteasome: ▌Ubiquitin-Proteasome System (UPS) is capable of degrading many types of glycoproteins [29]. ▌However, hyperglycemia (high blood sugar) can impair proteasome function. Glucose-derived compounds like methylglyoxal (MGO) can modify proteasome subunits, reducing their activity [29]. Amyloids The proteasome's relationship with amyloids (involved in for example Alzheimer's disease) is more complex. The proteasome can degrade some amyloid precursor proteins and smaller amyloid aggregates [30]. However, larger amyloid fibrils often overwhelm or inhibit the proteasome: ▌Amyloid aggregates can clog the entrance to the proteasome's catalytic core. ▌Some amyloids can directly inhibit proteasome activity. INFLUENCERS PROTEASOME ACTIVITY Challenges in protein clearance Several factors can hinder the proteasome's ability to clear modified or aggregated proteins: Glycation: Advanced glycation end products (AGEs) formed in hyperglycemic conditions can modify the proteasome, reducing its activity [29]. Oxidative stress: Often associated with aging and disease, it can damage both proteins and proteasomes [29]. Aging: Proteasome activity generally declines with age, reducing the cell's capacity to clear problematic proteins [30]. The proteasome's activity is sensitive to pH changes: ▌Optimal pH range for proteasome function is typically between 7.5-8.0. ▌Acidic conditions tend to inhibit proteasome activity, while alkaline conditions can enhance it to a certain extent. ▌Skin pH, which is typically slightly acidic (around 4.7-5.75), may influence extracellular proteasome activity. Oxidative stress has complex effects on the proteasome system in skin: ▌Mild oxidation (hormesis) can stimulate proteasomal degradation, while severe oxidation inhibits it ▌Oxidative stress can cause the 26S proteasome to disassemble into its 20S core and 19S regulatory components [25] ▌In skin, oxidative stress from UV radiation or environmental pollutants may affect proteasome function ▌Severely oxidized proteins may form non-degradable aggregates that can bind to and inhibit the proteasome [24] ▌Oxidative stress can reduce cellular ATP levels, affecting the ATP-dependent 26S proteasome function [25] ▌Oxidative stress can alter the association of chaperone proteins like HSP70 with the proteasome, affecting its function and assembly [25] Temperature can significantly impact proteasome function: ▌The optimal temperature for proteasome activity is typically around 37°C (human body temperature) [27] ▌Higher temperatures may initially increase proteasome activity but can eventually lead to denaturation and loss of function. ▌Low temperatures reduce proteasome activity by slowing down enzymatic reactions. ▌Skin, being exposed to environmental temperature changes, may experience fluctuations in proteasome activity. MAINTAIN AND IMPROVE PROTEASOME Several strategies can help maintain and improve proteasomal function: Exercise: Regular physical activity has been shown to enhance proteasome activity. Diet: ▌Protein: Ensuring adequate intake of high-quality proteins provides the building blocks for maintaining a healthy proteome ▌Polyphenols: Found in green tea, berries, and red wine, can stimulate proteasome function. ▌Omega-3 fatty acids: May help maintain proteasome activity and reduce oxidative stress. ▌Sulforaphane (found in broccoli sprouts): Activates Nrf2, which enhances proteasome function. ▌Spermidine: This natural polyamine has been shown to enhance autophagy and improve proteostasis. ▌Curcumin: This compound from turmeric has been shown to enhance proteostasis and have anti-aging effects ▌Caloric restriction or intermittent fasting: May enhance proteasome activity and promote cellular health. Stress management: Chronic stress can impair proteasome function, so stress reduction techniques will be beneficial. Sleep: Crucial for cellular repair and protein homeostasis. Skincare + ingredients: ▌Sun protection: Use broad-spectrum sunscreens to protect skin from photo-damage, which can impair proteasome function. ▌Retinoids: May enhance proteasome activity in skin cells. ▌Peptides: Certain peptides have been shown to stimulate proteasome function. ▌Licochalcone A: Activates Nrf2, which in turn enhances proteasome function. ▌Niacinamide: Supports proteasome function and improves skin barrier health. In-office treatments: ▌Low-level laser therapy: May improve proteasome function in skin cells. ▌Chemical peels: Can stimulate cellular renewal and potentially enhance proteasome activity. MISCELLANEOUS PROTEASOME FACTS ▌Ancient origins: Proteasomes are found in all three domains of life (bacteria, archaea, and eukaryotes), suggesting they evolved over 2 billion years ago. ▌Rapid recyclers: A single proteasome can degrade about 2 million proteins over its lifetime. ▌Circadian rhythm regulation: The proteasome plays a crucial role in maintaining our body's internal clock by degrading clock proteins at specific times. ▌Stress response: Under stress conditions, cells can form large assemblies of proteasomes called "proteasome storage granules" to quickly respond to changing protein degradation needs. The role of the proteasome in protein quality control, cellular regulation, interplay with autophagy, epigenetics, telomeres, cell senescence and more, makes it a key player in maintaining our health and beauty and an interesting target for new strategies to enhance longevity [28], health span and beauty span. Always consult a qualified healthcare professional to determine what the most suitable approach is for your needs and rejuvenation or regeneration goals. Take care! Anne-Marie References: [1] Glickman MH, Ciechanover A. Physiol Rev. 2002;82(2):373-428. [2] Lecker SH, et al. Annu Rev Biochem. 2006;75:629-649. [3] López-Otín C, et al. Cell. 2013;153(6):1194-1217. [4] Tanaka K. Proc Jpn Acad Ser B Phys Biol Sci. 2009;85(1):12-36. [5] Goldberg AL. Nature. 2003;426(6968):895-899. [6] Finley D. Annu Rev Biochem. 2009;78:477-513. [7] Pickart CM, Cohen RE. Nat Rev Mol Cell Biol. 2004;5(3):177-187. [8] Hershko A, Ciechanover A. Annu Rev Biochem. 1998;67:425-479. [9] Thrower JS, et al. EMBO J. 2000;19(1):94-102. [10] Smith DM, et al. Mol Cell. 2005;20(5):687-698. [11] Groll M, et al. Nature. 1997;386(6624):463-471. [12] Balch WE, et al. Science. 2008;319(5865):916-919. [13] Mizushima N, Komatsu M. Cell. 2011;147(4):728-741. [14] Dikic I. Trends Biochem Sci. 2017;42(11):873-886. [15] Ding WX, et al. Am J Pathol. 2007;171(2):513-524. [16] Zhao J, et al. Cell Metab. 2015;21(6):898-911. [17] Pandey UB, et al. Nature. 2007;447(7146):859-863. [18] Korolchuk VI, et al. Mol Cell. 2010;38(1):17-27. [19] Greer EL, Shi Y. Nat Rev Genet. 2012;13(5):343-357. [20] Qian MX, et al. Cell. 2013;153(5):1012-1024. [21] Muratani M, Tansey WP. Nat Rev Mol Cell Biol. 2003;4(3):192-201. [22] Gu B, Lee MG. Mol Cell. 2013;49(6):1134-1146. [23] Geng F, et al. Proc Natl Acad Sci USA. 2012;109(5):1437-1442. [24] Bach SV, et al. Biomol Concepts. 2016;7(4):215-227. doi:10.1515/bmc-2016-0016 [25] Bonea D, et al. BMC Plant Biol. 2021;21:486. doi:10.1186/s12870-021-03234-9 [26] Minoretti P, et al. Cureus. 2024;16(1):e52548. doi:10.7759/cureus.52548 [27] Groll M, et al. Nat Struct Biol. 2005;12(11):1062-1069. doi:10.1038/nsmb1006 [28] Galatidou S, et al. Mol Hum Reprod. 2024;30(7):gaae023. doi:10.1093/molehr/gaae023 [29] Queisser MA, et al. Hyperglycemia impairs proteasome function by methylglyoxal. Diabetes. 2010 [28] Mao, Y. Structure and Function of the 26S Proteasome. In: Harris, J.R., Marles-Wright, J. Macromolecular Protein Complexes III. Springer, 2021. [29] Schipper-Krom, S. Visualizing Proteasome Activity and Intracellular Localization. Front. Mol. Biosci. 6, 2019. [30] Lifespan.io. Loss of Proteostasis. Lifespan.io Topics. Accessed 2024. 3/20/2024 Comments Telomeres: tiny caps with big impact
Our DNA is as like precious book of life filled with information and instructions, with telomeres acting like the protective covers. Just as book covers get worn over time, our telomeres naturally shorten as we age. This shortening is like a biological clock, ticking away with each cell division.
Telomere shortening is considered one of the twelve key hallmarks of aging. Those hallmarks all play an important role in longevity, health-span, and skin quality, thus both health and beauty. Telomeres are the protective end-caps of chromosomes, similar to the plastic caps at the end of shoelaces. They maintain genomic stability and prevent chromosomal damage. Telomeres become slightly shorter each time a cell divides, and over time they become so short that the cell is no longer able to successfully divide. They shorten more rapidly in dermal fibroblasts compared to epidermal keratinocytes, hence there are significant differences amongst our cells. Telomeres in skin cells may be particularly susceptible to accelerated shortening because of both proliferation and DNA-damaging agents such as reactive oxygen species and sun exposure. [16]. When a cell is no longer able to divide due to telomere shortening, this can lead to
This consequently affects both health and beauty
FACTORS INFLUENCING TELOMERE SHORTENING Sleep quality Poor sleep quality significantly impacts telomere length:
INTERVENTIONS FOR TELOMERE PRESERVATION 1. Possible strategies to preserve telomere length
Telomerase is an enzyme that plays a crucial role in maintaining the length of telomeres and skin cell function. Telomerase is a ribonucleoprotein enzyme, meaning it contains both protein (TERT plus dyskerin) and RNA components (TER or TERC). Its primary function is to add repetitive DNA sequences (telomeres) to the ends of chromosomes, preventing them from shortening during cell division. Telomerase is active in embryonic stem cells, some adult stem cells, cancer cells, certain skin cells, specifically:
Poor sleep quality is associated with shorter telomere length. Studies have found significant associations between shortened telomere length and poor sleep quality and quantity, including obstructive sleep apnea [17]. Not feeling well rested in the morning was significantly associated with shorter telomere length in older adults [18]. Sleep loss and poor sleep quality may activate DNA damage responses and cellular senescence pathways [17]. Poor sleep can increase oxidative stress and inflammation, which may accelerate telomere shortening [17]. Disruption of circadian rhythms due to poor sleep may negatively impact telomere maintenance [17]. Improving sleep quality through lifestyle changes and sleep hygiene practices may help preserve telomere length. [19]
A study showed that diet, exercise, stress management, and social support could increase telomere length by approximately 10% over five years [20].
Adopt a plant-rich diet, such as the Mediterranean diet, which includes whole grains, nuts, seeds, green tea, legumes, fresh fruits (berries), vegetables (leafy greens), omega-3 fatty acids from sources like flaxseed and fish oil or fatty fish and foods rich in folate. This diet is rich in antioxidants and anti-inflammatory properties that help maintain telomere length [21]. 5. Fasting Fasting, especially intermittent fasting, has attracted interest for its potential impact on health, including telomere preservation. Multiple studies have shown that intermittent fasting (IF) and other fasting regimens can reduce markers of oxidative stress and inflammation. Research on animals has demonstrated that caloric restriction and intermittent fasting can boost telomerase activity and enhance telomere maintenance in specific tissues. A human study by Cheng et al. (2019) found a correlation between intermittent fasting and longer telomeres, by reducing PKA activity and IGF1 levels, which are crucial for regulating telomerase function. A study showed that 36 hours of fasting induced changes in DNA methylation and another one histone modifications, hence fasting has the potential to induce epigenetic changes. Important note: Be careful with a time-restricted eating schedule (often seen as a form of intermittent fasting, where you eat all meals within an 8 hour time-frame), especially women in menopause or people with a pre-existing heart condition. The American Heart Association presented data indicating that people with a pre-existing heart condition have a 91% higher risk of of death of a heart disease when following the time-restricted eating schedule with an 8 hour window, compared to those who eat within a 12-16 hours window. However, several experts have criticised the data, which aren´t published in a peer reviewed journal. When considering fasting, or a time-restricted eating schedule, especially for a longer period, talk to a qualified HCP first. 6. Exercise
EMERGING TECHNOLOGIES IN TELOMERE-TARGETING SKINCARE Small RNAs in skincare Small RNAs play a significant role in the effectiveness of telomere-targeting skincare by influencing skin regeneration and cellular processes. Recent research has highlighted their potential in enhancing wound healing and reducing scarring, which are critical aspects of maintaining healthy skin. Small RNAs, such as microRNAs, are involved in regulating gene expression related to skin aging and and show potential in telomere maintenance [29]. They can modulate the expression of genes that control cellular senescence, oxidative stress response, and inflammation, all of which are crucial for preserving telomere integrity and function [30].
RNAi technology in development RNAi-based skincare approaches could target genes involved in telomere maintenance or have effects on markers related to telomere biology:
RNA-based telomere extension is a method developed at Stanford University and uses modified RNA to extend telomeres in cultured human cells, allowing cells to divide more times than untreated cells [35]. IN OFFICE DERMATOLOGICAL TREATMENTS Aesthetic, regenerative treatments that support skin quality may indirectly support telomere preservation.
Telomere shortening questionable as stand-alone hallmark [36] Telomere length (TL) has long been considered one of the best biomarkers of aging. However, recent research indicates TL alone can only provide a rough estimate of aging rate and is not a strong predictor of age-related diseases and mortality. Other markers like immune parameters and epigenetic age may be better predictors of health status and disease risk. TL remains informative when used alongside other aging biomarkers like homeostatic dysregulation indices, frailty index, and epigenetic clocks. TL meets some criteria for an ideal aging biomarker (minimally invasive, repeatable, testable in animals and humans) but its predictive power for lifespan and disease is questionable. There is inconsistency in epidemiological studies on TL's association with aging processes and diseases. This has led to debate about TL's reliability as an aging biomarker. It's unclear if telomere shortening reflects a "mitotic clock" or is more a marker of cumulative stress exposure. TL is still widely used in aging research but there are ongoing questions about its usefulness as a standalone biomarker of biological age. As research in regenerative medicine advances, we're seeing promising developments in therapies targeting telomere biology for longevity, health and beauty. While telomere research is exciting, it's important to remember that it's just one part of a comprehensive approach to aging, and future treatments will likely combine multiple strategies to target preferably all 12 hallmarks for the best results. Always consult a qualified healthcare professional or dermatologist to determine what the most suitable approach is for you. . Take care! Anne-Marie
References
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[23] Hachmo Y, Hadanny A, Abu Hamed R, Daniel-Kotovsky M, Catalogna M, Fishlev G, Lang E, Polak N, Doenyas K, Friedman M, Zemel Y, Bechor Y, Efrati S. Hyperbaric oxygen therapy increases telomere length and decreases immunosenescence in isolated blood cells: a prospective trial. Aging (Albany NY). 2020 Nov 18;12(22):22445-22456 [24] Gutlapalli SD, Kondapaneni V, Toulassi IA, Poudel S, Zeb M, Choudhari J, Cancarevic I. The Effects of Resveratrol on Telomeres and Post Myocardial Infarction Remodeling. Cureus. 2020 Nov 14;12(11):e11482. [25] Widgerow AD, Ziegler ME, Garruto JA, Bell M. Effects of a Topical Anti-aging Formulation on Skin Aging Biomarkers. J Clin Aesthet Dermatol. 2022 Aug;15(8):E53-E60. PMID: 36061477; PMCID: PMC9436220. [26] Alt, C.; Tsapekos, M.; Perez, D.; Klode, J.; Stoffels, I. An Open-Label Clinical Trial Analyzing the Efficacy of a Novel Telomere-Protecting Antiaging Face Cream. Cosmetics 2022, 9, 95. [27] Cosmetics & Toiletries Telomere protection: Act on the origin of youth, June 3th 2015 Sederma [28] Yu Y, Zhou L, Yang Y, Liu Y. Cycloastragenol: An exciting novel candidate for age-associated diseases. Exp Ther Med. 2018 Sep;16(3):2175-2182. [29] Gerasymchuk M, Cherkasova V, Kovalchuk O, Kovalchuk I. The Role of microRNAs in Organismal and Skin Aging. Int J Mol Sci. 2020 Jul 25;21(15):5281. [30] Jacczak B, Rubiś B, Totoń E. Potential of Naturally Derived Compounds in Telomerase and Telomere Modulation in Skin Senescence and Aging. International Journal of Molecular Sciences. 2021; 22(12):6381. [31] Roig-Genoves, J.V., García-Giménez, J.L. & Mena-Molla, S. A miRNA-based epigenetic molecular clock for biological skin-age prediction. Arch Dermatol Res 316, 326 (2024). [32] Eline Desmet, Stefanie Bracke, Katrien Forier, Lien Taevernier, Marc C.A. Stuart, Bart De Spiegeleer, Koen Raemdonck, Mireille Van Gele, Jo Lambert, An elastic liposomal formulation for RNAi-based topical treatment of skin disorders: Proof-of-concept in the treatment of psoriasis, International Journal of Pharmaceutics, Volume 500, Issues 1–2, 2016, Pages 268-274, ISSN 0378-5173 [33] Oger E, Mur L, Lebleu A, Bergeron L, Gondran C, Cucumel K. Plant Small RNAs: A New Technology for Skin Care. J Cosmet Sci. 2019 May/Jun;70(3):115-126. PMID: 31398100. [34] Vimisha Dharamdasani, Abhirup Mandal, Qin M. Qi, Isabella Suzuki, Maria Vitória Lopes Badra Bentley, Samir Mitragotri, Topical delivery of siRNA into skin using ionic liquids, Journal of Controlled Release, Volume 323, 2020, Pages 475-482, ISSN 0168-3659 [35] Krista Conger January 2015 Stanford Medicine News Center Telomere extension turns back aging clock in cultured human cells, study finds [36] Alexander Vaiserman, Dmytro Krasnienkov Telemore length as marker of biological age: state-of-the-art, open issues and future perspectives Front. [37] Martínez P, Blasco MA. Telomere-driven diseases and telomere-targeting therapies. J Cell Biol. 2017 Apr 3;216(4):875-887 
Hair is a powerful factor in how we're perceived by others and even how we see ourselves. It plays a significant role in the perception of youth and attractiveness. Studies have shown that hair style, color, and quality can significantly affect how old we look and how attractive we're considered [1]. Research suggests that hair is one of the most defining characteristics of our appearance, with the potential to make us look years younger or older [1]. From an evolutionary perspective, lustrous hair has long been associated with youth, health, and fertility [1]. Culturally, hair has been a symbol of beauty and status across societies for centuries [2].
HAIR GENETICS BEYOND MATERNAL INHERITANCE We have approximately 5 million hair follicles distributed across our bodies, with only about 100,000 located on the scalp [3][4]. Contrary to popular belief, hair characteristics are not solely inherited from one's mother. Human genetic makeup consists of 23 pairs of chromosomes, including the sex-determining X and Y chromosomes [5]. Females typically have two X chromosomes (with one usually inactivated through a process called X-chromosome inactivation), while males have one X and one Y chromosome [6]. Our hair's characteristics, including texture, color, and growth patterns, are determined by about 600 genes [7]. Interestingly, only 11% of these genes are located on the X chromosome [8]. The majority of genes influencing hair traits are found on autosomes (non-sex chromosomes), contributing to the inheritance patterns observed in families [9]. For instance, genes like EDAR and FGFR2 have been associated with hair thickness in Asian populations, while TCHH has been linked to hair texture in individuals of Northern European ancestry [10]. Research has identified several genes on the X chromosome that play a role in male pattern baldness, including the androgen receptor (AR) gene. Telomere length in hair follicle stem cells correlates with hair growth capacity and may be a biomarker for hair follicle aging. The complexity of hair genetics extends beyond sex chromosomes, involving multiple autosomal genes, environmental factors, hence epigenetics, and this is great news as changes in epigenetic patterns are partially reversible! Epigenetics Epigenetics refers to heritable changes in gene expression that occur without alterations in the DNA sequence itself [11]. Environmental factors, diet, lifestyle, chronic stress, sleep, circadian rhythms, physical activity, aging and even social interactions can influence gene expression through four main epigenetic mechanisms:
These epigenetic mechanisms can significantly impact hair biology
Example of change in epigenetic pattern Ever wondered why hair starts growing in odd places as we age? It is a good example of epigenetic changes. As we get older, changes in our epigenome can cause regions of our DNA that are normally silent (due to histone modifications) to become readable. In essence, we're becoming more like our ancient ancestors! This is why some people start growing more hair in places like ears and noses as they age. Epigenetic changes can thus silence or activate hair growth-related genes, potentially contributing to hair loss or promoting regeneration. Thus, the future of our hair health is literally (at least partially) in our hands today!. Lifestyle changes and hair regrowth Lifestyle modifications have demonstrated impacts on hair regrowth, particularly in early stages of hair loss and for prevention. 1. Nutrition: A balanced diet rich in proteins, vitamins (especially biotin, vitamins A, C, and D), and minerals (iron, zinc) has been associated with improved hair growth [20]. Supplementation with these nutrients has shown benefits in treating telogen effluvium and other hair loss conditions [21]. 2. Stress Management: Chronic stress can lead to telomere shortening and premature hair follicle aging. Stress reduction techniques like meditation and yoga have been linked to increased telomerase activity, potentially benefiting hair growth. 3. Exercise: Regular physical activity improves blood circulation to the scalp, potentially enhancing nutrient delivery to hair follicles. A study found that moderate exercise was associated with increased expression of hair growth-related genes. 4. Sleep: Adequate sleep is crucial for maintaining healthy hair growth cycles. Sleep deprivation has been linked to increased oxidative stress and inflammation, which can negatively impact hair follicles. Studies have shown promising results in targeting epigenetic mechanisms for hair loss treatment
In office therapies 1. Low-Level Laser Therapy (LLLT): LLLT works by decreasing nitric oxide enzyme activity, leading to a beneficial "micro-stress" in mitochondria. This hormetic effect increases energy production, allowing stem cells to stay young and rejuvenate. Clinical studies have demonstrated improved hair density and thickness with LLLT in androgenetic alopecia patients. 2. Platelet-Rich Plasma (PRP) and exosomes: These regenerative therapies deliver growth factors and signaling molecules to hair follicles, potentially reversing miniaturization and promoting the anagen phase. PRP has shown promising results in multiple clinical trials for androgenetic alopecia. 3. HydraFacial Keravive scalp treatment: A 3-step process involving cleansing, exfoliating, and nourishing the scalp to improve hair follicle health. 4. Hair Transplantation: Includes techniques like Follicular Unit Extraction (FUE) and strip harvesting to transplant hair from donor areas to balding areas. 5. Scalp micropigmentation: A cosmetic tattooing procedure that creates the appearance of a fuller head of hair. 6. Corticosteroid Injections: Used primarily for treating alopecia areata by injecting steroids directly into affected areas of the scalp. 7. Microneedling: Uses small needles to create micro-injuries in the scalp, potentially stimulating hair growth when combined with topical treatments. 8. Scalp Reduction: A surgical procedure that removes bald areas of the scalp and stretches hair-bearing skin. 9. Mesotherapy: Involves injecting vitamins, minerals, and other nutrients directly into the scalp to nourish hair follicles. BALD AINT BAD (for men)
Always consult a qualified healthcare professional or dermatologist to determine what the most suitable approach is for your particular skin or hair condition. Take care! Anne-Marie
The picture I used for this post is from my lovely daughter, who is blessed with fabulous hair.
References
3/3/2024 Comments The vitamin D dilemma
Balancing Health, Beauty, and vitamin D
Like many who promote skin health and beauty, I often find myself navigating the delicate balance between the benefits and risks of sun exposure. Moderate exposure to sunlight is essential for vitamin D production, triggers beneficial stress responses and DNA repair mechanisms in our bodies through hormesis, promoting overall health and well-being. However, excessive sun exposure can overwhelm these protective systems, leading to harmful effects such as skin damage and increased cancer risk. Vitamin D is a crucial prohormone that plays a vital role in numerous functions, including: 1. Bone health and calcium absorption [1] 2. Immune system modulation [1] 3. Regulation of up to 2,000 genes involved in various biological processes [1] – more details below 4. Potential cancer prevention [1] THE SUNLIGHT PARADOX: HEALTH BENEFITS VS. RISKS Benefits of sunlight exposure 1. Vitamin D production (80-90%) [1] 2. Regulation of circadian rhythms and improved sleep quality [1] 3. Mood enhancement and potential alleviation of depressive symptoms [1] 4. Lowering of blood pressure through nitric oxide production in the skin [1] Risks of excessive sun exposure 1. DNA damage, including the formation of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) [2] 2. Oxidative stress and generation of reactive oxygen species (ROS) [2] 3. Premature skin aging and hyperpigmentation [2] 4. Increased risk of skin cancers, including melanoma [2] Health benefits of vitamin D 1. Bone health: Promotes calcium absorption and bone mineralization, preventing conditions like rickets and osteoporosis [3] 2. Muscle strength and function: Helps maintain muscle strength and reduce the risk of falls, especially in older adults [4] 3. Immune system support: Modulates immune responses and may reduce the risk of autoimmune diseases [5] 4. Heart health: Low vitamin D levels have been linked to increased risk of heart diseases, though the exact relationship is unclear [6] 5. Reduced risk of severe illnesses: May make severe flu and COVID-19 infections less likely [7] 6. Mood regulation: May play a role in regulating mood and decreasing the risk of depression [8] 7. Weight management: There is a relationship between (low) vitamin D levels and (over)weight, though the exact nature is not fully understood [9] 8. Reduced risk of multiple sclerosis (MS): Low levels of vitamin D are linked with an increased risk of MS [10] 9. Brain health: Supports brain cell activity and may have neuroprotective properties 10. Anti-inflammatory effects: Has anti-inflammatory properties that support overall health Skin health and beauty benefits of Vitamin D 1. Skin barrier function: Regulates the generation of keratinocytes, which are critical for maintaining the skin barrier [11] 2. Skin immunity: Indispensable for the activation of immune cells in the skin, supporting its protective function [12] 3. Antimicrobial effects: Has direct antimicrobial effects in the skin, helping to fight off pathogens [13] 4. Regulation of sebaceous glands: Important for growth regulation and optimum functioning of sebaceous glands [14] 5. Photoprotective effects: Topical application may offer some protection against UV-induced skin damage [15] 6. Wound healing: Promotes repair of damaged tissue and restoration of the skin's barrier mechanism [16] 7. Anti-aging effects: May have antiaging effects on the skin, though more research is needed in this area [17] 8. Skin cell differentiation and growth: Plays a role in the proliferation and differentiation of skin cells [18] 9. Melanin regulation: Protects the epidermal melanin unit and restores melanocyte integrity [19] 10. Potential role in skin conditions: May play a role in managing conditions like psoriasis, atopic dermatitis, and vitiligo [20] 11. Skin hydration: Topical application of vitamin D improves skin hydration and symptoms of dry skin [21] VITAMIN D AND PARP A study published in the International Journal of Molecular Medicine demonstrated that the active form of vitamin D inhibits poly(adenosine diphosphate-ribose) polymerase (PARP). PARP is an enzyme that plays a crucial role in DNA repair. PARP acts like a cellular "first responder" for DNA damage, initiating the repair process to keep our genetic material intact.
VITAMIN D SYNTHESIS IN THE SKIN
When UVB rays from sunlight hit the skin, they trigger the production of vitamin D [22]: 1. UVB radiation converts 7-dehydrocholesterol in the skin to previtamin D3 2. Previtamin D3 then isomerizes to vitamin D3 3. Vitamin D3 is transported to the liver and converted to 25-hydroxyvitamin D [25(OH)D] 4. Finally, 25(OH)D is converted to the active form, 1,25-dihydroxyvitamin D (calcitriol), in the kidneys FACTORS INFLUENCING VITAMIN D PRODUCTION 1. Latitude: Higher latitudes receive less UVB radiation, especially during winter months [23] 2. Time of day: UVB rays are strongest at solar noon [23] 3. Season: Vitamin D production is lower in winter due to reduced UVB radiation [23] 4. Skin pigmentation: Darker skin requires longer sun exposure to produce the same amount of vitamin D as lighter skin [24] 5. Age: Older adults produce less vitamin D from sun exposure [23] 6. Sunscreen use: High SPF sunscreens can significantly reduce vitamin D production [25] 7. Air pollution: Reducing UVB radiation reaching the earth's surface EPIGENETICS Vitamin D regulates up to 2000 genes, involving both direct genomic effects and epigenetic mechanisms. 1. Vitamin D receptor (VDR) binding The active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], binds to the vitamin D receptor (VDR). This liganded VDR then forms a heterodimer with the retinoid X receptor (RXR) [26][27]. 2. Direct gene regulation The VDR/RXR complex binds to specific DNA sequences called vitamin D response elements (VDREs). These VDREs can be located in promoter regions, introns, or even far from the transcription start sites of target genes [26][27][28]. 3. Epigenetic mechanisms
VDR interacts with numerous coregulatory proteins that can either activate or repress gene transcription [26][28]. 5. Genome-wide effects Genome-wide studies have shown that VDR can bind to hundreds of genomic loci, regulating gene activity at various locations, including many kilobases upstream or downstream of transcription start sites [26][28]. 6. Primary and secondary target genes Vitamin D regulates both primary target genes (directly controlled by VDR) and secondary target genes (controlled by transcriptional regulators encoded by primary targets) [26][30]. 7. Cell-specific regulation The effects of vitamin D on gene expression are highly cell-specific, depending on the epigenetic landscape of each cell type [26][31]. 8. Dose-dependent effects Higher doses of vitamin D supplementation have been shown to affect the expression of more genes in a dose-dependent manner [32]. RECOMMENDATIONS FOR SUN EXPOSURE Factors such as latitude, season, cloud cover, and individual skin type can all affect vitamin D synthesis [33][34]. Additionally, morning and evening sun contains less UVB radiation, which is necessary for vitamin D production, so longer exposure times may be needed [34]. Health experts often recommend midday sun exposure for optimal vitamin D production, while dermatologists typically advise against it due to increased UV intensity. Considerations 1. Midday sun (higher UVB) is more efficient for vitamin D production, requiring shorter exposure times [35] 2. Shorter exposure times may reduce overall UV damage risk [35] 3. Individual factors, such as skin type and location, should be considered when making recommendations [35] Impact of skin type Darker skin requires longer exposure times due to higher melanin content [1][36]
Type VI: 25.25 minutes [37]
Recommendation fair skin (Fitzpatrick Types I-III)
Recommendation darker skin (Fitzpatrick Types IV-VI) 1. Longer sun exposure times are needed, typically 15-30 minutes 3-5 times per week [40] 2. Consider exposing larger body surface areas when possible [40] 3. Sun exposure during midday hours may be more effective for vitamin D production [35] Variations based on location and season
Sunscreen and vitamin D production Sunscreen can decrease vitamin D3 formation in the skin. The effect varies based on coverage, thickness, and SPF. [36] Nevertheless, I would highly recommend the always use sunscreen on face, neck and décolletage as and expose skin surface areas to sunlight in the shortest amount possible to minimise DNA damage and the risk of sunburn and skin cancer. [1][36] ALTERNATIVE STRATEGIES FOR VITAMIN D SUFFICIENCY For many people, especially those living at higher latitudes, with darker skin, or those unable to obtain adequate sun exposure, or at high risk for skin damage, vitamin D supplementation may be necessary to maintain optimal levels, particularly during winter months [33][42]. However, excessive vitamin D3 levels can have negative health effects. 1. Dietary sources: Fatty fish, egg yolks, and fortified foods 2. Vitamin D3 supplements: The recommended dose is 1000 units per 25 pounds bodyweight (>4000 IU or 100 micrograms only under medical supervision) and taken alongside vitamin K2 and magnesium for a synergistic effect. Best is to take it in the morning in line with circadian rhythms. Consult with a healthcare provider for appropriate dosage and monitor your levels. 3. UVB lamps: Under medical supervision, these can be used for controlled vitamin D production. For the average adult a range of 30-50 ng/mL (75-125 nmol/L) is seen as optimal, 50 ng/mL (125 nmol/L) may be too high and below 20 ng/mL (50 nmol/L) are generally considered deficient. Achieving optimal vitamin D levels while protecting skin health requires a personalised approach. I hope that the information provided will help you to navigate the delicate balance between sun exposure benefits, risks and the use of sunscreens. Always consult a healthcare professional, especially if you have a history of skin cancer or are at risk for vitamin D deficiency. Take care Anne-Marie References [1] Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr. 2004 [2] Cadet J, Douki T. Formation of UV-induced DNA damage contributing to skin cancer development. Photochem Photobiol Sci. 2018 [3] Holick MF. Vitamin D deficiency. N Engl J Med. 2007 [4] Bischoff-Ferrari HA et al. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Archives of Internal Medicine. 2009 [5] Prietl B et al. Vitamin D and immune function. Nutrients. 2013 [6] Wang TJ et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation. 2008 [7] Martineau AR et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017 [8] Anglin RE et al. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. British Journal of Psychiatry. 2013 [9] Vimaleswaran KS et al. Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Medicine. 2013 [10] Munger KL et al. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006 [11] Bikle DD. Vitamin D metabolism and function in the skin. Molecular and Cellular Endocrinology. 2011 [12] Schauber J. et al. Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D–dependent mechanism. Journal of Clinical Investigation. 2007 [13] Liu PT et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006 [14] Krämer C et al. Characterization of the vitamin D endocrine system in human sebocytes in vitro. Journal of Steroid Biochemistry and Molecular Biology. 2009 [15] Dixon KM, Deo SS, Wong G, Slater M, Norman AW, Bishop JE, Posner GH, Ishizuka S, Halliday GM, Reeve VE, Mason RS. Skin cancer prevention: a possible role of 1,25dihydroxyvitamin D3 and its analogs. Journal of Steroid Biochemistry and Molecular Biology. 2005 [16] Oda Y, Uchida Y, Moradian S, Crumrine D, Elias PM, Bikle DD. Vitamin D receptor and coactivators SRC2 and 3 regulate epidermis-specific sphingolipid production and permeability barrier formation. Journal of Investigative Dermatology. 2009 [17] Rinnerthaler M, Bischof J, Streubel MK, Trost A, Richter K. Oxidative stress in aging human skin. Biomolecules. 2015 [18] Bikle DD. Vitamin D regulated keratinocyte differentiation. Journal of Cellular Biochemistry. 2004 [19] Ranson M, Posen S, Mason RS. Human melanocytes as a target tissue for hormones: in vitro studies with 1α-25, dihydroxyvitamin D3, α-melanocyte stimulating hormone, and beta-estradiol. Journal of Investigative Dermatology. 1988 [20] Mostafa WZ, Hegazy RA. Vitamin D and the skin: Focus on a complex relationship: A review. Journal of Advanced Research. 2015 [21] Russell M. Assessing the relationship between vitamin D3 and stratum corneum hydration for the treatment of xerotic skin. Nutrients. 2012 [22] Wacker M, Holick MF. Vitamin D - effects on skeletal and extraskeletal health and the need for supplementation. Nutrients. 2013 [23] Webb AR, Engelsen O. Calculated ultraviolet exposure levels for a healthy vitamin D status. Photochem Photobiol. 2006 [24] Farrar MD, et al. Efficacy of a dose range of simulated sunlight exposures in raising vitamin D status in South Asian adults: implications for targeted guidance on sun exposure. Am J Clin Nutr. 2013 [25] Matsuoka LY, et al. Sunscreens suppress cutaneous vitamin D3 synthesis. J Clin Endocrinol Metab. 1987 [26] Fetahu IS, Höbaus J, Kállay E. Vitamin D and the epigenome. Front Physiol. 2014 [27] Carlberg C. Vitamin D and Its Target Genes. Nutrients. 2022 [28] Christakos S et al. Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects. Physiol Rev. 2016 [29] Voltan G et al. Vitamin D: An Overview of Gene Regulation, Ranging from Metabolism to Genomic Effects. Genes (Basel). 2023 [30] Veijo Nurminen et al. Front. Physiol., 05 March 2019 Sec. Integrative Physiology Primary Vitamin D Target Genes of Human Monocytes [31] Vassil Dimitrov et al. Vitamin D-regulated Gene Expression Profiles: Species-specificity and Cell-specific Effects on Metabolism and Immunity, Endocrinology, Volume 162, Issue 2, February 2021 [32] GrassrootsmHealth Nutrient Research Institute. Vitamin D Supplementation Amount Influences Change in Genetic Expression. [Internet]. 2018 [33] Wacker M, Holick MF. Sunlight and Vitamin D: A global perspective for health. Dermatoendocrinol. 2013 [34] Nagaria TD et al. The Sunlight-Vitamin D Connection: Implications for Patient Outcomes in the Surgical Intensive Care Unit. Cureus. 2023 [35] Rhodes LE, et al. Recommended summer sunlight exposure levels can produce sufficient (≥20 ng ml(-1)) but not the proposed optimal (≥32 ng ml(-1)) 25(OH)D levels at UK latitudes. J Invest Dermatol. 2010 [36] Ashley, R. (n.d.). Ask the Doctors - How much sunshine do I need for enough vitamin D? UCLA Health. [37] Yilmaz, B., & Karakas, M. (2024). UV index-based model for predicting synthesis of (pre-)vitamin D3 in human skin. Scientific Reports, 14(1), 3188. [38] Mead MN. Benefits of sunlight: a bright spot for human health. Environ Health Perspect. 2008 [39] American Academy of Dermatology. Sunscreen FAQs. [40] Farrar MD, et al. Efficacy of a dose range of simulated sunlight exposures in raising vitamin D status in South Asian adults: implications for targeted guidance on sun exposure. Am J Clin Nutr. 2013 [41] Miyauchi, M., & Nakajima, H. (2016). The solar exposure time required for vitamin D3 synthesis in the human body estimated by numerical simulation and observation in Japan. Journal of nutritional science and vitaminology, 62(5), 379-385. [42] Healthline How to Safely Get Vitamin D From Sunlight Ryan Raman, MS, RD — Updated on April 4, 2023 
Pyrroloquinoline quinone (PQQ), by some called "the fourteenth vitamin", also known as methoxatin deserves a full blog post due to its health & beauty benefits. PQQ, discovered in 1979, is an aromatic tricyclic o-quinone, a small quinone molecule, naturally found in various foods (Kumazawa et al., 1995; Mitchell et al., 1999), and plays a crucial role in various biological processes, particularly in cellular energy production and antioxidant defence [1].
Chemical structure and properties PQQ is water-soluble and it´s molecular formula is C14H6N2O8 - see picture. It is structurally similar to other quinones, like for example Coenzyme Q10, however possesses unique redox (oxidation reduction) properties that contribute to its biological activities [1]. PQQ is highly stable and efficient in redox cycling, can undergo multiple redox cycles, allowing it to participate in numerous biochemical reactions with various compounds. It does not easily self-oxidize or condense into inactive forms [2]. When compared on a molar basis, PQQ can be 100 to 1000 times more efficient in redox cycling assays than other enediols, such as ascorbic acid (vitamin C) and menadione, as well as many isoflavonoids, phytoalexins and polyphenolic compounds [2]. The reduced form of PQQ (PQQH2) can act as an aroxyl radical scavenger, even more effectively than α-tocopherol against peroxyl radicals [2]. Peroxyl radicals (ROO•) are involved in lipid peroxidation and contribute oxidative stress in biological systems, potentially damaging DNA, proteins, and lipids. 
PQQ is thus an exceptionally potent antioxidant: [3]
▌Direct scavenging of reactive oxygen species (ROS) ▌Regeneration of other antioxidants like vitamin E ▌Induction of antioxidant enzymes such as superoxide dismutase and catalase [4] Mitochondrial function and biogenesis One of the most significant roles of PQQ is its impact on mitochondrial function and biogenesis. Mitochondria are the powerhouses of cells, responsible for producing the majority of cellular energy in the form of ATP (adenosine triphosphate) [5]. PQQ has been show to
Anti-inflammatory effects PQQ exhibits anti-inflammatory properties, which may contribute to its potential in managing chronic inflammatory conditions: Reduction of inflammatory markers: PQQ has been shown to decrease levels of pro-inflammatory cytokines such as TNF-α and IL-6 [10] Modulation of NF-κB signaling: PQQ can inhibit the activation of NF-κB, a key transcription factor involved in inflammatory responses [11] Neuroprotection PQQ has demonstrated significant neuroprotective effects in various studies, particularly in the areas of cognitive function, protection against neurotoxins, and nerve growth factor (NGF) production.
Metabolic health ▌Glucose metabolism: Some studies suggest that PQQ can enhance insulin sensitivity and glucose tolerance. ▌Lipid metabolism: PQQ has been shown to activate AMPK (AMP-activated protein kinase), a key regulator of energy metabolism and linked to cellular increases in the NAD+/NADH ratio and increased sirtuins expression [16]. Both NAD+ and sirtuins were key topics of David Sinclair´s longevity research. Sirtuins are a family of proteins known to be involved in epigenetic regulation through their deacetylase activity. Sleep quality & quantity Sleep quality and quantity are crucial for overall health and beauty, with experts generally recommending 7-9 hours of sleep daily for adults. Recent research has shown that Pyrroloquinoline quinone (PQQ) can significantly improve sleep quality, offering a promising avenue for those struggling with sleep issues. A clinical trial involving 17 adults who took 20 mg of PQQ daily for eight weeks demonstrated notable improvements in sleep onset, maintenance, and duration. These improvements were measured using two well-established sleep assessment tools: the Oguri-Shirakawa-Azumi Sleep Inventory and the Pittsburgh Sleep Quality Index [9][17]. The study also found a correlation between these improvements and changes in the cortisol awakening response, providing biomarker-supported evidence of enhanced sleep quality. The mechanisms behind PQQ's sleep-enhancing effects are multifaceted:
PQQ is naturally present in various foods, including: ▌Fermented soybeans (natto) ▌Green peppers ▌Kiwi ▌Parsley ▌Tea ▌Papaya ▌Spinach ▌Celery [1] ▌Dark chocolate PQQ can be present in human body, even in breast milk due to diet, because only bacteria can synthesise PQQ. SKIN HEALTH AND BEAUTY Clinical Studies on PQQ in Skincare A clinical study conducted by Dr. Zoe Diana Draelos and colleagues investigated the effects of a topical formulation containing a modified form of PQQ called topical allyl pyrroloquinoline quinone (TAP) on skin aging. on 40 subjects over a 12 week period. The study findings included: ▌Improved skin texture and dullness: Significant improvements were observed in skin texture and dullness after 4 weeks of twice-daily application (both p<0.0001) ▌Reduced appearance of lines and wrinkles: The study reported improvements in the appearance of fine lines and wrinkles (p=0.01) ▌Histological improvements: Histologic evaluation demonstrated reductions in solar elastosis from baseline at 6 weeks (33%, p=0.01) and 12 weeks (60%, p=0.002). ▌Improvements were also noted in skin tone at week 4 (p=0.01). ▌Significantly increased expression of DNA methyltransferase (DNMT3A, DNMT3B), cytochrome oxidase assembly factor-10 (COX10), and tumor protein-53 (TP53) genes (all p<0.05), indicating enhanced support of epidermal homeostasis, renewal, and repair. Increasing or decreasing DNA methyltransferase is considered an epigenetic modification:
▌Increased expression of heat shock protein 60 (HSPD1) and thioredoxin reductase (TXNRD1) occurred in tissues treated with TAP versus control (p<0.05), indicating enhanced antioxidative response and adaptation. Cell senescence PQQ protected human dermal fibroblasts (HDFs) from UVA-induced senescence [22]. This is supported by the study showing that PQQ treatment reduced the percentage of senescent cells stained by X-gal following UVA irradiation compared to the UVA-only group [22]. PQQ has demonstrated significant anti-senescence properties in various studies. In a study using Bmi-1 deficient mice, which exhibit accelerated aging, PQQ supplementation was found to reduce cell senescence markers in the skin [23]. The researchers observed that PQQ intake decreased levels of matrix metalloproteinases (MMPs), which are associated with cellular senescence and tissue degradation. PQQ supplementation was shown to rescue cellular senescence parameters in articular cartilage [24]. The researchers found that PQQ inhibited the development of the senescence-associated secretory phenotype (SASP), which is characterized by increased secretion of inflammatory cytokines and contributes to tissue degeneration. DNA damage In the skin aging study (mice), PQQ supplementation was found to significantly reduce oxidative stress and DNA damage [23]. This protective effect was attributed to PQQ's ability to maintain redox balance and inhibit the DNA damage response pathway. Furthermore, in the osteoarthritis study, PQQ treatment was observed to mitigate DNA damage in chondrocytes [24]. Skin barrier & collagen PQQ has been shown to have positive effects on the skin barrier (mice). The study revealed that PQQ supplementation improved skin thickness and collagen structure, which are important components of the skin's barrier function [23]. Recommended dosage for supplementation The optimal dosage of PQQ for supplementation can vary depending on the intended use and individual factors. However, based on available research and expert recommendations: 1. General health benefits: Typical doses range from 10 to 20 mg per day [1]. 2. Cognitive function: Studies have used doses of 20 mg per day for cognitive benefits. 3. Skin health: For skin benefits, doses of 10 to 20 mg per day have been suggested, although more research is needed to establish optimal dosages for dermatological applications. It is important to consult with a healthcare provider before starting any new supplement regimen, as dosage requirements may vary based on individual health status and needs. PQQ in skincare products PQQ is an interesting bioactive ingredient to be incorporated into skincare products due to its potential benefits for skin health, beauty and regeneration. When looking for PQQ in skincare products, it may be listed under various names, including: ▌Pyrroloquinoline quinone ▌Methoxatin ▌BioPQQ (a patented form of PQQ) The efficacy and safety in skincare products depends on the concentration of PQQ, overall formulation and other ingredients in the formula. Safety and tolerability PQQ has generally been found to be safe and well-tolerated in both animal and human studies. However, as with any supplement or new skincare ingredient, there are some considerations: 1. Oral supplementation: Studies using oral PQQ supplements at doses up to 20 mg per day have reported no significant adverse effects in short-term use. 2. Topical application: The Draelos study on topical PQQ application reported that the product was highly tolerable, with no significant adverse reactions. 3. Long-term safety: While short-term studies have shown good safety profiles, more research is needed to establish the long-term safety of PQQ supplementation and topical use. 4. Potential interactions: As with any supplement, PQQ may interact with certain medications or other supplements. Individuals taking medications or with pre-existing health conditions should consult a healthcare provider before using PQQ supplements. 5. Pregnancy and breastfeeding: Due to limited research, pregnant and breastfeeding women are generally advised to avoid PQQ supplementation unless directed by a healthcare provider [1]. PQQ could be a game-changer for (skin) health and beauty. While the science looks promising, we're still in the early stages of understanding all that PQQ can do. As with any supplement or skincare ingredient, always consult a qualified healthcare professional to determine what the most suitable approach is for your health and beauty goals. Take care Anne-Marie References: [1] Harris, C. B., et al. (2013). Dietary pyrroloquinoline quinone (PQQ) alters indicators of inflammation and mitochondrial-related metabolism in human subjects. J Nutr Biochem, 24(12), 2076-2084. [2] Akagawa M, et al. Recent progress in studies on the health benefits of pyrroloquinoline quinone. Bioscience, Biotechnology, and Biochemistry. 2016;80(1):13-22 [3] Misra, H. S., et al. (2012). Pyrroloquinoline-quinone: a reactive oxygen species scavenger in bacteria. FEBS Lett, 586(22), 3825-3830. [4] Qiu, X. L., et al. (2009). Protective effects of pyrroloquinoline quinone against Abeta-induced neurotoxicity in human neuroblastoma SH-SY5Y cells. Neurosci Lett, 464(3), 165-169. [5] Chowanadisai, W., et al. (2010). Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1alpha expression. J Biol Chem, 285(1), 142-152. [6] Stites, T., et al. (2006). Pyrroloquinoline quinone modulates mitochondrial quantity and function in mice. J Nutr, 136(2), 390-396. [7] Bauerly, K., et al. (2011). Altering pyrroloquinoline quinone nutritional status modulates mitochondrial, lipid, and energy metabolism in rats. PLoS One, 6(7), e21779. [8] Zhang, Y., et al. (2009). Neuroprotective effects of pyrroloquinoline quinone against rotenone injury in primary cultured midbrain neurons. Neurosci Lett, 455(3), 174-179. [9] Nakano, M., et al. Effects of oral supplementation with pyrroloquinoline quinone on stress, fatigue, and sleep. Funct Foods Health 2012 [10] Liu, Y., Jiang, Y., Zhang, M., Tang, Z., He, M., Bu, P., & Li, J. (2020). Pyrroloquinoline quinone ameliorates skeletal muscle atrophy, mitophagy and fiber type transition induced by denervation via inhibition of the inflammatory signaling pathways. Annals of Translational Medicine, 8(5), 207. [11] Wen, J., Shen, J., Zhou, Y., Zhao, X., Dai, Z., & Jin, Y. (2020). Pyrroloquinoline quinone attenuates isoproterenol hydrochloride-induced cardiac hypertrophy in AC16 cells by inhibiting the NF-κB signaling pathway. International Journal of Molecular Medicine, 45(3), 873-885. [12] Tamakoshi, M., Suzuki, T., Nishihara, E., Nakamura, S., & Ikemoto, K. (2023). Pyrroloquinoline quinone disodium salt improves brain function in both younger and older adults. Food & Function, 14(6), 3201-3211. [13] Zhang, Q., Zhang, J., Jiang, C., Qin, J., Ke, K., & Ding, F. (2014). Involvement of ERK1/2 pathway in neuroprotective effects of pyrroloquinoline quinine against rotenone-induced SH-SY5Y cell injury. Neuroscience, 270, 183-191. [14] Zhang, Q., Shen, M., Ding, M., Shen, D., & Ding, F. (2011). The neuroprotective effect of pyrroloquinoline quinone on traumatic brain injury. Journal of Neurotrauma, 28(3), 359-366. [15] Yamaguchi, K., Sasano, A., Urakami, T., Tsuji, T., & Kondo, K. (1993). Stimulation of nerve growth factor production by pyrroloquinoline quinone and its derivatives in vitro and in vivo. Bioscience, Biotechnology, and Biochemistry, 57(7), 1231-1233. [16] Mohamad Ishak NS, Ikemoto K. Pyrroloquinoline-quinone to reduce fat accumulation and ameliorate obesity progression. Front Mol Biosci. 2023 [17] Mitsugu Akagawa et al. Bioscience, Biotechnology, and Biochemistry Recent progress in studies on the health benefits of pyrroloquinoline quinone 2015 [18] Kazuto Ikemoto et al. The effects of pyrroloquinoline quinone disodium salt on brain function and physiological processes The Journal of Medical Investigation 2024 [19] Kowalczyk P, Sulejczak D, Kleczkowska P, Bukowska-Ośko I, Kucia M, Popiel M, Wietrak E, Kramkowski K, Wrzosek K, Kaczyńska K. Mitochondrial Oxidative Stress-A Causative Factor and Therapeutic Target in Many Diseases. Int J Mol Sci. 2021 [20] Guo C, Sun L, Chen X, Zhang D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res. 2013 [21] Jonscher KR, Chowanadisai W, Rucker RB. Pyrroloquinoline-Quinone Is More Than an Antioxidant: A Vitamin-like Accessory Factor Important in Health and Disease Prevention. Biomolecules. 2021 [22] Zhang C, Wen C, Lin J, Shen G. Protective effect of pyrroloquinoline quinine on ultraviolet A irradiation-induced human dermal fibroblast senescence in vitro proceeds via the anti-apoptotic sirtuin 1/nuclear factor-derived erythroid 2-related factor 2/heme oxygenase 1 pathway. Mol Med Rep. 2015 [23] Li J, Liu M, Liang S, Yu Y, Gu M. Repression of the Antioxidant Pyrroloquinoline Quinone in Skin Aging Induced by Bmi-1 Deficiency. Biomed Res Int. 2022 [24] Qin R, Sun J, Wu J, Chen L. Pyrroloquinoline quinone prevents knee osteoarthritis by inhibiting oxidative stress and chondrocyte senescence. American Journal of Translational Research. 2019 [25] Lee, J.-J.; Ng, S.-C.; Hsu, J.-Y.; Liu, H.; Chen, C.-J.; Huang, C.-Y.; Kuo, W.-W. Galangin Reverses H2O2-Induced Dermal Fibroblast Senescence via SIRT1-PGC-1α/Nrf2 Signaling. Int. J. Mol. Sci. 2022, 23, 1387. |
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