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

Collagen banking is a proactive skincare strategy falling under the category prejuvenation aimed at preserving and stimulating collagen production to maintain youthful, firm and excellent skin quality over time. This approach can involve using various treatments, tweakments, products, supplements and lifestyle choices to boost collagen levels before significant signs of aging appear. The goal is to build a "reserve" or “bank” of collagen, ensuring skin remains resilient and less prone to wrinkles and sagging as natural collagen production declines and degradation increases with age. To start banking collagen as early as in your twenties makes sense, as the producing cell called the dermal fibroblast is still very healthy and active. Moreover as the loss is not yet so great (just a few percent loss), thus less invasive methods work well to maintain a youthful status quo. I´s never too late to start “banking” collagen, although when you are more mature, the word rejuvenation might be more suitable. 
 
There is no direct scientific evidence that collagen stimulation is more effective in your twenties than in your sixties.
However, starting collagen stimulation earlier may be beneficial:
▌Collagen production begins to decline around age 25-30, decreasing by about 1% per year.
▌By the 50s and beyond, the collagen loss is greater >30%, becomes more noticeable and it´s always harder to get back what you lost than to maintain what you have.
▌Peak collagen levels occur at twenty years of age, thus maintaining what you have the highest achievable level.
▌Starting collagen stimulation treatments earlier may help prevent further collagen loss and require less invasive and number of treatments.
 
WHAT IS COLLAGEN
Collagen is the most abundant protein in the human body, making up about one-third of all proteins. 
1. Location: Found in connective tissues, including skin, tendons, bones, and cartilage.
2. Function: Provides structural support, strength, and elasticity to tissues.
3. Production: Naturally produced by the body, but production decreases with age, starting around the mid-20s.
Collagen plays a crucial role in maintaining skin elasticity, joint health, and overall tissue integrity. As collagen production declines with age, so does the skin quality, leading to visible signs of aging like wrinkles, loss of elasticity and firmness, and sagging skin. Collagen is one of the key target components for noticeable and effective skin rejuvenation or regeneration. 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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

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

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

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:

1. Proteins are tagged with ubiquitin molecules by enzymes called ubiquitin ligases [8].
2. The proteasome recognizes these ubiquitin tags [9].
3. The regulatory particles unfold the protein and feed it into the core [10].
4. The core particle's β subunits break down the protein into short peptides [11].​

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:

1. Compensatory activation: Inhibition of the proteasome can lead to increased autophagic activity as a compensatory response [15].
2. Shared signaling pathways: Both systems are regulated by common signaling molecules, such as mTOR and AMPK [16].
3. Reciprocal degradation: Components of each system can be degraded by the other, helping to maintain balance [17].

This ensures efficient protein quality control and cellular homeostasis [18].
 
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:

1. Structural components: Proteins form the structural framework of cells and tissues, including skin, muscles, and organs.
2. Enzymatic functions: Most biochemical reactions in the body are catalyzed by protein enzymes.
3. Signaling molecules: Many hormones and neurotransmitters are proteins or peptides.
4. Transport: Proteins like hemoglobin transport vital molecules throughout the body.
5. Immune defence: Antibodies, which are proteins, play a crucial role in the immune system.
6. Cellular regulation: Proteins control gene expression and cellular processes.
7. Energy source: When necessary, proteins can be broken down for energy.

Important proteins in skin and the human body based on their overall impact and prevalence:

1. Collagen: Most abundant protein in the human body. Provides structure and strength to skin, bones, and connective tissues.
2. Hemoglobin: Essential for oxygen transport in blood. Critical for cellular respiration and energy production.
3. Albumin: Most abundant protein in blood plasma. Maintains osmotic pressure and transports various molecules.
4. Insulin: Regulates blood glucose levels. Crucial for metabolism and energy utilisation.
5. Actin: Key component of the cytoskeleton. Essential for cell structure, division, and movement.
6. Keratin: Major structural protein in skin, hair, and nails. Provides protection and waterproofing.
7. Elastin: Provides elasticity  to skin and blood vessels. Crucial for tissue flexibility and resilience.
8. Fibronectin: Important for cell adhesion, wound healing and is the "organiser" of the ECM. Plays a role in tissue repair and embryonic development.
9. Filaggrin: Essential for skin barrier function. Helps maintain skin hydration and pH balance.

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:

• Psoriasis: Altered proteasome function may contribute to the excessive proliferation of skin cells.
• Atopic dermatitis: Impaired proteasome activity may lead to increased inflammation and compromised skin barrier function.
• Skin cancer: Proteasome inhibitors have shown promise as potential treatments for certain types of skin cancer.

PROTEASOME AND CELLULAR SENESCENCE
The proteasome plays a crucial role in preventing cellular senescence, a state of permanent cell cycle arrest associated with aging:

1. Oxidative stress management: The proteasome degrades oxidized proteins, preventing their accumulation and subsequent cellular damage.
2. Cell cycle regulation: By controlling the levels of cell cycle regulators, the proteasome influences cellular senescence and proliferation.
3. Telomere maintenance: Proteasomal activity is involved in the regulation of telomere-associated proteins, impacting cellular lifespan.

PROTEASOME AND IMMUNE FUNCTION
The proteasome is integral to immune system function:

1. Antigen processing: A specialized form of the proteasome, the immunoproteasome, is crucial for generating peptides for MHC class I antigen presentation.
2. Inflammation regulation: The proteasome controls the levels of pro-inflammatory factors, helping to modulate immune responses.
3. T-cell activation: Proteasomal activity is essential for proper T-cell activation and differentiation.

 The proteasome is thus important in maintaining immune homeostasis and combating infections.

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:
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[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
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[28=42] Mao, Y. Structure and Function of the 26S Proteasome. In: Harris, J.R., Marles-Wright, J. Macromolecular Protein Complexes III. Springer, 2021.
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[30=44] Lifespan.io. Loss of Proteostasis. Lifespan.io Topics. Accessed 2024.

Autophagy was initially classified under "altered proteostasis" as part of the hallmarks of aging. However as autophagy is involved in various other aspects of aging, such as DNA repair and metabolism,  it's now seen as an "integrative hallmark". Autophagy is the cell´s way of cleaning up and recycling it´s own parts to maintain health and efficiency [1] by breaking down various parts of the cell, such as proteins, fats, and small structures called organelles. This breakdown happens in special compartments within the cell called lysosomes, which contain enzymes that can digest these cellular components. Impaired autophagy is a cause of aging and not just a consequence. When the efficiency of autophagy declines, it contributes to the accumulation of damaged cellular components, affecting other hallmarks of aging and the progression of health and beauty (skin health) problems [1][2]. 

SIMPLIFIED HOW AUTOPHAGY WORKS
▌Initiation: The process begins when a cell is under stress, such as during nutrient deprivation or oxidative stress.
▌Formation of the autophagosome: A double-membrane structure called a phagophore forms and expands to engulf damaged or unnecessary cellular components.
▌Encapsulation: The phagophore completely surrounds the targeted cellular material, forming a sealed vesicle called an autophagosome.
▌Fusion with lysosome: The autophagosome travels through the cell and fuses with a lysosome, forming an autophagolysosome - see picture below
▌Breakdown and recycling: Inside the autophagolysosome, lysosomal enzymes break down the captured cellular material into basic building blocks like amino acids, fatty acids, and nucleotides.
▌Reuse of materials: The broken-down components are released back into the cell's cytoplasm, where they can be reused to build new cellular structures or generate energy.

THREE MAIN TYPES OF AUTOPHAGY (illustration)
A. Macroautophagy: The most common form, involving the formation of autophagosomes that engulf cellular components and fuse with lysosomes for degradation.
B. Chaperone-mediated autophagy: Selective degradation of specific proteins with the help of chaperone proteins.
D. Microautophagy: Direct engulfment of cytoplasmic material by lysosomes.

Various impairments in these autophagy mechanisms can occur:
▌Autophagosome formation
▌Decreased lysosomal function
▌Impaired fusion of autophagosomes with lysosomes
▌Accumulation of non-degradable material in lysosomes  
These impairments lead to the accumulation of damaged cellular components, contributing to the aging process.

CONSEQUENCES DECLINE AUTOPHAGIC ACTIVITY 

1. Accumulation of damaged proteins and organelles: Impaired autophagy leads to the buildup of dysfunctional cellular components, which can interfere with normal cellular processes [1]. Malfunctioning autophagy disrupts proteostasis and cellular quality control [3]. 
2. Mitochondrial dysfunction: Autophagy is crucial for mitochondrial quality control. Its decline contributes to the accumulation of damaged mitochondria, leading to reduced energy production and increased oxidative stress [1][2].
3. Increased susceptibility to age-related diseases: Impaired autophagy is associated with various age-related pathologies, including neurodegenerative diseases, cardiovascular disorders, and cancer [1][2].
4. Stem cell exhaustion: Autophagy is essential for maintaining stem cell function. Its decline contributes to reduced tissue regeneration capacity [1].
5. Cellular senescence: Impaired autophagy promotes the accumulation of senescent cells, which can contribute to chronic inflammation and tissue dysfunction [1][2].
6. Proteostasis network: Autophagy is part of the proteostasis network, essential for cellular quality control. Malfunctioning autophagy disrupts proteostasis, contributing to the aging process [3].
7. Metabolic Stress: Conditions like sarcopenic obesity, insulin resistance, and type 2 diabetes mellitus (T2DM) are characterized by metabolic derangements and intracellular stresses, which are aggravated by impaired autophagy [4].​​

GENERAL CAUSES IMPAIRED AUTOPHAGY - HEALTH
Disruption of key regulatory pathways
Autophagy is tightly regulated by several molecular pathways, and disruption of these can impair the process:
▌Nutrient sensing pathways: Inhibition of AMPK and SIRT1 or activation of mTOR can suppress autophagy initiation [1][5]. 
▌Mutations affecting proteins like ULK1, Atg13, or other autophagy-related genes can disrupt autophagosome formation [5].
▌Dysregulation of transcription factor TFEB, which controls expression of autophagy and lysosomal genes, can impair the process [1][5].
Defects in autophagosome formation or maturation
Problems with the machinery involved in forming or maturing autophagosomes can impair autophagy:
▌Disruption of membrane sources like the ER or mitochondria can affect autophagosome formation [6].
▌Mutations affecting proteins involved in autophagosome-lysosome fusion, like Dynein, can block completion of autophagy [6].
Lysosomal dysfunction
Since lysosomes are crucial for the degradation step of autophagy, lysosomal defects can severely impair the process:
▌Lysosomal storage disorders, like Pompe disease, directly impair the degradative capacity of lysosomes [1].
▌Accumulation of undegraded material in lysosomes can overwhelm their function over time [1].
Cellular stress and damage
Various cellular stressors can both induce and potentially overwhelm autophagy:
▌Oxidative stress and mitochondrial dysfunction can both trigger and potentially impair autophagy if severe [7][8].
▌Accumulation of protein aggregates, as seen in neurodegenerative diseases, can overwhelm autophagic capacity [6][7].
Metabolic imbalances
Disruptions in cellular metabolism can impair autophagy:
▌Chronic exposure to excess nutrients, like in obesity or alcoholic liver disease, can suppress autophagy through mTOR activation [1][5].
▌Energy deficits can potentially impair autophagy if severe enough to disrupt basic cellular functions [5]. 
In many cases, impaired autophagy results from a combination of these factors, often creating a vicious cycle where initial dysfunction leads to further cellular stress and damage, progressively worsening autophagic impairment over time [1][7][8]. This is particularly evident in age-related and neurodegenerative diseases, where multiple factors converge to disrupt cellular homeostasis and autophagic function.

SKIN AGING
Autophagy impairment contributes significantly to skin aging through multiple mechanisms: [9]
▌Reduced collagen and elastin production by fibroblasts
▌Accumulation of damaged ECM components
▌Altered keratinocyte differentiation and reduced barrier function (thinning)
▌Reduced stem cell function and altered cellular metabolism
▌Accumulation of cellular damage and reduced stress resistance 
Impaired autophagy in fibroblasts and keratinocytes leads to wrinkles and reduced skin elasticity [10][11] and more visible signs of aging skin.

SKIN SPECIFIC CAUSES IMPAIRED AUTOPHAGY - BEAUTY
Autophagy decline was observed in both intrinsic and extrinsic skin aging [12].
Oxidative stress and environmental factors
Skin cells are constantly exposed to environmental stressors that can impair autophagy:
▌Ultraviolet (UV) radiation is a major factor that can disrupt autophagy in skin cells, particularly keratinocytes and melanocytes [13][14].
▌Reactive oxygen species (ROS) generated from various environmental factors can deactivate key autophagy regulators like Akt and mTORC1, leading to impaired autophagy initiation [15].
Aging and senescence
As skin cells age, their autophagic capacity tends to decline:
▌Premature skin aging is associated with decreased autophagy in various skin cell types [13].
▌Senescence of mesenchymal cells in the dermis is linked to impaired autophagy and contributes to skin aging [14].
Dysregulation of autophagy pathways
Several molecular pathways can become dysregulated, leading to impaired autophagy:
▌Mutations or alterations in autophagy-related genes (ATGs) can disrupt the formation of autophagosomes and impair the process [15][16].
▌Dysfunction of the mTORC1 signaling pathway, a key regulator of autophagy, can lead to autophagy impairment [17].
Cellular energy imbalances
Disruptions in cellular metabolism can impair autophagy in skin cells:
▌Low cellular energy levels (high AMP/ATP ratio) can abnormally trigger AMPK activation, disrupting normal autophagy regulation [17].
▌Nutrient imbalances can affect mTORC1 activity, which is crucial for proper autophagy function [17].
Inflammatory processes
Chronic inflammation in the skin can interfere with normal autophagy:
▌Inflammatory skin conditions like psoriasis and atopic dermatitis are associated with impaired autophagy in various skin cell types [16][17].
Lysosomal dysfunction
Since lysosomes are crucial for the final stages of autophagy, their dysfunction can severely impair the process:
▌Accumulation of undegraded material in lysosomes, which can occur with aging or in certain skin conditions, can overwhelm lysosomal function and impair autophagy completion [15][14].

ROLE OF UV AND BLUE LIGHT IN AUTOPHAGY IMPAIRMENT
IMPLICATIONS FOR SKIN HEALTH AND PHOTOAGING

UV Radiation and autophagy:
UV exposure has a complex effect on autophagy in skin cells. Acute UV exposure activates autophagy as a protective mechanism. This process helps degrade oxidized lipids and metabolic wastes, potentially slowing photoaging. However, chronic UV exposure leads to autophagy impairment and accelerated skin aging [13]. 
UV radiation modulates several signaling pathways involved in regulating autophagy: [14] [18]
1. mTOR (mechanistic target of rapamycin): A negative regulator of autophagy
2. AMPK (AMP-activated protein kinase): Promotes autophagy
3. PI3K/Akt pathway: Influences autophagy regulation
4. p53: Plays a role in UV-induced autophagy response
UV exposure also affects the expression and activity of autophagy-related genes like Atg5, Atg7, and LC3 [14]. The UV-induced DNA damage and oxidative stress contribute significantly to autophagy dysfunction over time.
Blue light and autophagy:
▌Blue light induces approximately 50% of the oxidative stress in skin cells compared to UV.
▌It penetrates deeper into the skin, affecting both epidermal keratinocytes and dermal fibroblasts.
▌Prolonged exposure may lead to autophagy impairment, contributing to premature skin aging and pigmentation issues.
Molecular mechanisms and key players: [14]
Several molecular mechanisms and key players are involved in the UV-autophagy relationship:

1. Sirtuins, especially SIRT1, regulate both autophagy and aging processes.
2. FoxO transcription factors are involved in autophagy regulation and are affected by UV exposure.
3. PPARδ activation can induce autophagy markers and protect against photoaging.
4. Heat shock proteins like HSP70 are involved in chaperone-mediated autophagy and are affected by UV exposure.
5. Nrf2, an important regulator of antioxidant responses and autophagy, is modulated by UV radiation.
6. The heme oxygenase (HO) system, especially HO-1, is induced by UV radiation and linked to autophagy regulation.
7. NF-κB activation by UV radiation plays a role in photoaging and is connected to autophagy processes.

AUTOPHAGY AND DNA REPAIR 
Autophagy plays a crucial role in maintaining cellular homeostasis and genomic stability, particularly in skin health and DNA repair [19]. When UVB radiation hits our skin, it activates AMPK, which in turn boosts the autophagy process in our cells [18]. This mechanism is essential for repairing various types of DNA damage, including broken DNA strands, small structural changes, and errors that occur during DNA replication [20]. Autophagy positively regulates the recognition of DNA damage by nucleotide excision repair (NER) and enhances the repair of UV-induced lesions, particularly through the removal of oxidized proteins and lipids [21]. By responding to various DNA lesions and regulating multiple aspects of the DNA damage response (DDR), autophagy helps maintain the integrity of our genetic material and promotes overall skin health.

IMPACT ON SKIN CELLS
The skin, being the largest organ, is significantly affected by impaired autophagy, which impacts various skin cells differently, leading to visible signs of aging such as wrinkles, reduced skin thickness, and pigmentation changes. Ethnic differences in autophagy capacity may influence susceptibility to skin damage [12]. 
Autophagy has different effects in three categories of skin cells: [13] 
▌stem cells: autophagy supports self-renewal and quiescence. Declining autophagy can lead to stem cell loss over time.
▌short-lived differentiating cells: like keratinocytes, autophagy contributes to differentiation processes like cornification but is less impacted by aging.
▌long-lived differentiated cells (hair follicles and sweat glands): autophagy maintains cell survival and function. Decreased autophagy leads to accumulation of damaged components.
The roles of autophagy in skin aging are complex and cell type-specific [13].

Keratinocytes
Keratinocytes, the primary cell type in the epidermis, rely heavily on autophagy for differentiation and barrier function [16]. Different autophagy proteins showed distinct localization patterns in the epidermis [12]. LC3 and ATG9L1 were enriched in granular layers, while ATG5-ATG12 and ATG16L1 were in basal/spinous layers [12]. Autophagy plays a critical role in keratinocyte cornification, the process by which these cells form the outermost layer of the skin. Autophagy protects keratinocytes against UV-induced DNA damage and inflammation, potentially slowing photoaging [13]. 
Impaired autophagy in keratinocytes can lead to:
▌Reduced barrier function
▌Increased susceptibility to environmental stressors [14] 
▌Altered epidermal differentiation
▌Accumulation of damaged proteins and organelles 
▌Increased DNA damage, senescence, and aberrant lipid composition after oxidative stress [14][22].
mTOR inhibition directly promoted keratinocyte differentiation [12].

Fibroblasts
Dermal fibroblasts are responsible for producing extracellular matrix (ECM) components, including collagen and elastin. Fibroblast autophagy helps clear lipofuscin (age pigment) and damaged proteins that accumulate with age. 
Autophagy impairment in fibroblasts can result in:
▌Reduced proteostasis and ECM production (collagen and elastin production) [13]
▌Accumulation of senescent cells and DNA damage [13]
▌Increased matrix metalloproteinase (MMP) activity, leading to ECM degradation
▌Altered cellular metabolism and energy production
▌Accumulation of autophagosomes, resulting in the deterioration of dermal integrity and skin fragility [10][11]
​These changes contribute to the formation of wrinkles and loss of skin elasticity [14].

Melanocytes
Melanocytes, responsible for skin pigmentation, are particularly sensitive to autophagy impairment [13]. Autophagy defects disturb melanosome biogenesis and transport, leading to pigmentation disorders. Autophagy-deficient melanocytes display a senescence-associated secretory phenotype (SASP), contributing to inflammation and pigmentation changes [23]. Declining melanocyte autophagy may contribute to age-related pigmentation changes and hair graying.
The consequences of impaired autophagy:
▌Accumulation of damaged melanosomes
▌Altered melanin production and distribution
▌Increased susceptibility to oxidative stress, inflammation and senescence
▌Pigmentation disorders like vitiligo and hyperpigmentation

Stem cells
Skin stem cells, including those in hair follicles and the interfollicular epidermis, rely on autophagy for maintenance and function.
Impaired autophagy in stem cells can lead to:
▌Reduced self-renewal capacity
▌Altered differentiation potential
▌Accumulation of damaged cellular components
▌Premature stem cell exhaustion
These effects contribute to reduced skin regeneration and repair capacity with age [14].

Sweat glands and sebaceous glands 
Autophagy is essential for normal sebum production in sebaceous glands (long-lived cells) and in sweat glands suppresses accumulation of lipofuscin ("age pigment") during aging and maintains gland function [13]. Autophagy plays a crucial role in the function of sweat glands and sebaceous glands.
Impairment can result in:
▌Reduced sweat production, affecting thermoregulation
▌Altered sebum composition and production - can affect skin barrier function and contribute to conditions like acne [24] 
​▌Increased susceptibility to infections and skin disorders

Merkel cells
Autophagy regulates serotonin signaling in Merkel cells and may impact age-related changes in touch sensation [13]. 

Hair follicles
In hair follicles, (long lived cells) autophagy promotes hair growth [14] and may counteract age-related hair loss when pharmacologically activated [13]. 

PIGMENTATION
Dysregulation of autophagy in melanocytes affects melanin synthesis and transfer, leading to pigmentation disorders [23]. Autophagy activity correlates with skin lightness measurements and plays a role in  melanosome degradation in keratinocytes . autophagy proteins like LC3, p62, ATG9L1, ATG5-ATG12 and ATG16L1 were decreased in hyperpigmented skin, while mTORC1 activity was increased in hyperpigmented elbow skin [12]. 
Autophagy impairment can lead to various pigmentation disorders: [12]
▌Hyperpigmentation: Accumulation of damaged melanosomes and altered melanin distribution
▌Hypopigmentation: Potential link to vitiligo through increased melanocyte sensitivity to oxidative stress
▌Uneven skin tone: Dysregulation of melanin production and transfer to keratinocytes
Restoring autophagy (inhibiting mTORC1 with Torin 1) improved both pigmentation (maintaining skin color uniformity) and epidermal differentiation (barrier function) [12] and could be a therapeutic approach for photoaging and hyperpigmentation.

PIGMENTATION ISSUES 
1. Senile Lentigo (Age Spots):
Studies have shown that autophagy declines in hyperpigmented skin areas such as senile lentigocompared to even-toned skin [12]. This decline in autophagy is associated with increased melanin deposition and melanocyte proliferation in the epidermis [13]. The impaired autophagy in these areas also correlates with reduced levels of late epidermal differentiation markers like filaggrin and loricrin [13].
2. Photoaging:
Ultraviolet (UV) radiation, a major cause of photoaging, affects autophagy in skin cells. While UV exposure initially increases autophagy as a protective mechanism, chronic exposure leads to impaired autophagic function. This impairment contributes to the accumulation of damaged cellular components and oxidized proteins, accelerating the photoaging process [14][12].
3. Xerotic hyperpigmentation:
In areas of skin with severe xerosis (dry skin) and hyperpigmentation, an exacerbated decline in autophagy has been observed. This decline is accompanied by severe dehydration and barrier defects, showing correlations with deteriorating skin physiological conditions [13]. The impaired autophagy in these areas contributes to both pigmentation abnormalities and compromised epidermal differentiation.
 
These examples demonstrate that impaired autophagy is associated with various aspects of skin aging, including pigmentation changes, barrier function decline, and altered epidermal differentiation. The decline in autophagic activity appears to be both a result of aging processes and a contributing factor to the progression of skin aging symptoms [12][13][14].
 
SOLAR ELASTOSIS
Solar elastosis is characterized by the accumulation of abnormal elastotic material (broken elastin fibres due to sun damage) in the dermis.
While not directly linked to impaired autophagy, the loss of autophagy and/or it's housekeeping partner proteasome could be a contributing factor.
1. Autophagy is crucial for cellular homeostasis: Autophagy is described as "an essential cellular process that maintains balanced cell life" and is responsible for "clearing surplus or damaged cell components notably lipids and proteins" [12].
2. Impaired autophagy in photoaging: Loss of autophagy leads to both photodamage and the initiation of photoaging in UV exposed skin [12][18].
3. UV radiation affects autophagy: UV exposure can both stimulate and impair autophagy, depending on the circumstances. For example, repeated UVA radiation negatively affects the autophagy process in fibroblasts due to modifications in lysosomal functioning [25].
4. Accumulation of damaged components: When autophagy is impaired, there's a reduced ability to clear damaged cellular components. This could  include broken down elastin fibres. The proteasome and autophagy work closely together in cleaning up and recycling proteins like elastin. 
5. Chronic inflammation: Photoaging is characterized by a chronic inflammatory response, which can be exacerbated by defects in autophagy. In turn, defects in autophagy have also been shown to cause severe inflammatory reaction in the skin [12].

AUTOPHAGY FAT CELLS
Autophagy in fat cells, or adipocytes, plays a significant role in regulating adipose tissue biology and metabolism. 
1. Role in adipose tissue biology: Autophagy is crucial for maintaining cellular homeostasis in adipose tissue by degrading and recycling cellular components. It influences adipogenic differentiation and affects the size and function of adipose tissue depots [26].
2. Influence of obesity: In obesity, autophagy is often altered. Adipocytes in obese individuals show increased autophagic activity, which is associated with enhanced lipid mobilization and metabolic activity [27]. This process can be influenced by proinflammatory cytokines, leading to selective degradation of lipid droplet proteins like Perilipin 1 [27].
3. Adipocyte browning: Autophagy is involved in the browning of white adipose tissue, which is associated with increased energy expenditure and protection against obesity [28]. Suppression of autophagy can block adipogenesis and lipid accumulation, indicating its role in fat storage and metabolism [28].
4. Response to fasting: During fasting, autophagy is upregulated in adipose tissue to promote fat breakdown and support metabolic processes like ketogenesis [29]. This response involves the regulation of genes that influence autophagic activity.
5. Regulation by mTOR: The mTOR signaling pathway is a major regulator of autophagy in adipocytes. Under conditions of nutrient deprivation or stress, mTOR activity is inhibited, leading to the activation of autophagy [17].
 
AUTOPHAGY AND INSULIN RESISTANCE
​Activation of autophagy is beneficial for improving insulin sensitivity without compromising insulin production [30][31].
Impaired autophagy as a cause of insulin resistance
1. Accumulation of cellular debris: When autophagy is impaired, damaged organelles and proteins accumulate in cells, leading to cellular stress and inflammation that can contribute to insulin resistance [32].
2. ER stress: Autophagy inhibition can cause severe endoplasmic reticulum stress in adipocytes, which can suppress insulin receptor signaling and contribute to peripheral insulin resistance [33].
3. Mitochondrial dysfunction: Impaired autophagy can lead to accumulation of damaged mitochondria, which can disrupt cellular metabolism and contribute to insulin resistance [32].
4. Reduced insulin signaling: Knockdown of autophagy genes like Atg7 in adipocytes can reduce insulin-stimulated phosphorylation of insulin receptor subunits and IRS-1, directly impairing insulin signaling [33].
Insulin resistance as a cause of impaired autophagy
1. Hyperinsulinemia: Chronic exposure to high insulin levels, as seen in insulin-resistant states, can suppress autophagy through activation of mTORC1 and inhibition of FoxO1 [30].
2. Nutrient excess: The excess nutrients associated with obesity and insulin resistance can inhibit autophagy through mTORC1 activation [32][33].
3. Altered gene expression: Insulin resistance can downregulate the expression of genes encoding major autophagy components, further impairing autophagic function [34]. 

Bidirectional relationship
The relationship between insulin resistance and impaired autophagy often creates a vicious cycle:
1. Initial insulin resistance can lead to suppression of autophagy.
2. Impaired autophagy then exacerbates cellular stress and dysfunction.
3. This cellular dysfunction further worsens insulin resistance.
4. The cycle continues, progressively worsening both conditions [32][33].

Tissue-specific effects
The relationship between autophagy and insulin sensitivity can vary depending on the tissue:
1. In insulin-responsive tissues like muscle, liver, and adipose tissue, moderate activation of autophagy can improve insulin sensitivity by reducing cellular stress and inflammation [30][32].
2. In pancreatic β-cells, however, excessive autophagy can reduce insulin storage and secretion, potentially worsening glucose intolerance despite improved peripheral insulin sensitivity [30]. 
​
PREVENTION AND TREATMENT OPTIONS
Targeting nutrient-sensing pathways (mTORC1, AMPK, SIRT1) can enhance autophagic activity and mitigate age-related cellular damage [4][35][36]      
The most efficient and evidence-based methods to improve autophagy are:

1. Intermittent fasting (IF):
▌The 16/8 method (16 hours fasting, 8 hours eating window) is commonly recommended [37][38].
▌Alternate-day fasting and the 5:2 diet (5 days normal eating, 2 days restricted calories) are also effective [38][39].
▌Fasting periods of 18-72 hours show increasing benefits for autophagy [37].
Fasting a lot is not recommended for women in their reproductive age, the use of geroprotectors (a few mentioned under point 6) are more suitable.

2. Calorie restriction (CR): [4]
▌Reducing daily calorie intake by 10-40% can trigger autophagy [38].
▌Long-term calorie restriction increases the expression of autophagy-related genes [40].

3. Exercise: [4]
▌Both aerobic exercise and resistance training stimulate autophagy [37][41].
▌Aerobic exercise (lower intensity, longer duration) may be more effective for autophagy than high-intensity exercise [37].

4. Ketogenic diet:
▌A high-fat, low-carb diet can mimic fasting effects and trigger autophagy [41]. 

5. Sleep:
▌Good quality sleep supports autophagy, as it follows the sleep-wake cycle [41].

6. Specific nutrients and supplements:
▌Spermidine (naturally occurring in our body and food) has been shown to enhance autophagy [40][42] and is on top of the list.
▌Resveratrol, found in red wine and grapes, may induce autophagy [40] (in very high doses), however there are contradicting study outcomes.
▌Curcumin (from turmeric) has shown potential in animal studies [41].
▌Green tea contains compounds that may support autophagy [40].
▌GlyNAC - more information below

7. Stress management:
▌Chronic stress can interfere with autophagy, so stress reduction techniques like meditation or yoga may be beneficial [38].

8. Pharmacological Interventions: 
▌Several antidiabetic medicines and other pharmacological agents are being explored to modulate autophagy and slow aging [3][4]. 
▌Genetic approaches to upregulate autophagy-related genes (e.g., ATG7, BECN1) are being investigated as potential therapeutic strategies for neurodegenerative diseases [35][43].    

9. Hormetic stress activates autophagy:
Hormesis influences and activates autophagy through various mechanisms, contributing to cellular stress resistance and potential health benefits.
▌Hormesis appears to be executed by a variety of physiological cellular processes, including autophagy that cooperatively interact and converge  [44].
▌Hormetic heat shock activates autophagy in human RPE cells [45]. Heat shock factor 1 (HSF1) plays a role in hormetic autophagy activation [46=73]. HHS enhances the expression of fundamental autophagy-associated genes in ARPE-19 cells through the activation of HSF1 [45]. 
▌Inhibition of mTOR (mechanistic target of rapamycin) is a key pathway for hormetic autophagy activation. Inhibition of mTOR (specifically dephosphorylation of mTOR complex 1) triggers augmented autophagy [44]. 
▌Hormetic autophagy contributes to stress resistance, longevity, and improved proteostasis [46].

10. Sunscreen: 
I promote the use of sunscreens, particularly ones with the natural compounds Licochalcone A (powerful anti-oxidant, Nrf2 activator, Glutathione stimulator and MMP1 inhibitor) [47][48][49][50] and Glycerrhetinic Acid (supports DNA repair) [51]. The regular use of sunscreen can decrease the risk of impaired autophagy in skin:
▌Reduction of oxidative stress: By blocking UV rays, sunscreen helps prevent the generation of excessive ROS, which can impair autophagy [18].
▌Prevention of DNA damage: Sunscreen protects skin cells from UV-induced DNA damage, which can interfere with autophagy-related gene expression [18][21].
▌Maintenance of cellular homeostasis: By reducing overall UV-induced stress on skin cells, sunscreen helps maintain the balance necessary for proper autophagy function [21].
Several studies have demonstrated the link between UV protection and autophagy preservation. A study published in the Journal of Investigative Dermatology showed that UV radiation can dysregulate autophagy in skin cells, and that protecting against UV exposure can help maintain normal autophagy function [21]. Research published in the International Journal of Molecular Sciences highlighted that sunscreen use can prevent UV-induced damage to autophagy-related proteins and pathways in skin cells [18]. A review in Frontiers in Pharmacology discussed how sunscreen, as part of a comprehensive photoprotection strategy, can help preserve autophagy function in skin by reducing overall UV-induced cellular stress [21].
By using sunscreen regularly, individuals can significantly reduce their risk of impaired autophagy in skin cells, contributing to overall skin health and  slowing the photoaging process.

11. Red light therapy:
Red light therapy, particularly at a wavelength of 660 nm, has been shown to promote autophagy, the cellular process of cleaning out damaged cells and regenerating healthier ones. Studies indicate that this therapy can enhance autophagy in various contexts, such skin health [57]. Additionally, red light therapy is often used in combination with fasting to further boost cellular repair processes associated with autophagy. Red light activates autophagy in retinal cells: Studies have shown that red light exposure can activate multiple steps of the autophagy process in retinal pigment epithelium (RPE) cells. It increases autophagy-related proteins and promotes the formation of autophagosomes [58].

12. Polynucleotides:
1. DNA damage response: DNA damage can trigger autophagy as a protective mechanism. Polynucleotides, particularly damaged DNA, can activate autophagy pathways [59].
2. RNA-mediated regulation: Certain RNA molecules, such as microRNAs and long non-coding RNAs, can modulate autophagy-related gene expression and signaling pathways [59].

13. Exosomes:
Exosomes have a complex relationship with autophagy:
1. Autophagy regulation: Exosomes can carry proteins and RNAs that influence autophagy in recipient cells. For example, some exosomal microRNAs can target autophagy-related genes [59].
2. Protein content alteration: Autophagy modulators can significantly alter the protein content of phosphatidylserine-positive extracellular vesicles (PS-EVs), including exosomes, produced by cancer cells [59].
3. Signaling molecules: Exosomes can contain important signaling molecules like SQSTM1 and TGFβ1 pro-protein, which are involved in autophagy regulation [59].
4. Intercellular communication: Exosomes derived from cells treated with autophagy modulators can influence the metabolism and phenotype of recipient cells [59].
5. Autophagy-related protein transport: Exosomes can carry autophagy-related proteins like LC3-II, potentially transferring autophagic capabilities between cells [59].
The relationship between exosomes and autophagy is bidirectional. Autophagy can also influence exosome production and content. The specific effects may vary depending on the cell type, physiological context, and the particular polynucleotides or exosomes involved.

GLYNAC AND AUTOPHAGY
GlyNAC, a combination of glycine and N-acetylcysteine, has shown promising effects on various aspects of cellular health, including autophagy. 

Glutathione synthesis and oxidative stress
GlyNAC supplementation has been shown to improve glutathione (GSH = body's master antioxidant) synthesis and reduce oxidative stress [52][53][54]. GSH is a crucial antioxidant that plays a role in regulating autophagy and DNA repair. By improving GSH levels, GlyNAC may indirectly support autophagic processes [52][53].
Aging hallmarks
GlyNAC supplementation has been shown to improve multiple hallmarks of aging, including mitochondrial dysfunction, oxidative stress, and inflammation [52][53][54].[55].These improvements may indirectly support autophagic processes, as these hallmarks are interconnected with autophagy regulation [1][2].
Direct evidence on autophagy
While direct evidence of GlyNAC's effect on autophagy is limited, some studies provide insights:
1. In a study on HIV patients, GlyNAC supplementation improved mitophagy markers, suggesting a potential role in enhancing selective autophagy of mitochondria [53].
2. N-acetylcysteine, a component of GlyNAC, has been shown to induce autophagy in various cellular models, potentially through its antioxidant properties and effects on mTOR signaling [56].
Potential mechanisms
The potential mechanisms by which GlyNAC might influence autophagy include:
1. Reduction of oxidative stress, which can promote autophagy induction [52][53][54].
2. Improvement of mitochondrial function, which is closely linked to mitophagy regulation [7][8][52][53].
3. Modulation of nutrient-sensing pathways, such as mTOR, which are key regulators of autophagy [53][56].
Future directions
While the evidence suggests that GlyNAC supplementation may have beneficial effects on cellular processes related to autophagy, more direct research is needed to fully elucidate its impact on autophagic flux and regulation.


By improving autophagy, we're not just investing in our appearance, but in the fundamental processes that keep our body healthy. 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] Aman, Y., et al. (2021). Autophagy in healthy aging and disease. Nature Aging, 1(8), 634-650.
[2] Rubinsztein, D. C., et al. (2011). Autophagy and aging. Cell, 146(5), 682-695.
[3] Kaushik, S. et al. (2021). Autophagy and the hallmarks of aging. Ageing Research Reviews, 72.
[4] Kitada, M., & Koya, D. (2021). Autophagy in metabolic disease and ageing. Nature Reviews Endocrinology, 17, 647 - 661.
[5] Ichimiya T et al. Autophagy and Autophagy-Related Diseases: A Review. Int J Mol Sci. 2020
[6] Budini M. et al. Front. Mol. Neurosci. Autophagy and Its Impact on Neurodegenerative Diseases: New Roles for TDP-43 and C9orf72 (2017).
[7] Niture S. et al. Int. J. Hepatol. Emerging Roles of Impaired Autophagy in Fatty Liver Disease and Hepatocellular Carcinoma (2021)
[8] Edens B.M. et al. Front. Cell. Neurosci. Impaired Autophagy and Defective Mitochondrial Function in Motor Neuron Degeneration (2016)
[9] Jeong D et al. The Role of Autophagy in Skin Fibroblasts, Keratinocytes, Melanocytes, and Epidermal Stem Cells. J Invest Dermatol. 2020
[10] Kim H et al. (2018). Autophagy in Human Skin Fibroblasts: Impact of Age. International Journal of Molecular Sciences, 19
[11] Tashiro K. et al. Biochem. Biophys. Res. Commun. Age-related disruption of autophagy in dermal fibroblasts modulates ECM  (2014)
[12] Wang M et al. Autophagy: Multiple Mechanisms to Protect Skin from Ultraviolet Radiation-Driven Photoaging. Oxid Med Cell Longev. 2019
[13] Murase D. et al. Int. J. Mol. Sci. Autophagy Declines with Premature Skin Aging Altering Skin Pigmentation and Epidermal Diff. (2020).
[14] Eckhart Leopold, Tschachler Erwin , Gruber Florian  Autophagic Control of Skin Aging Frontiers in Cell and Developmental Biology 2019
[15] Lin Y. et al. Front. Immunol. The multifaceted role of autophagy in skin autoimmune disorders (2024).
[16] Kim HJ, Park J, Kim SK, Park H, Kim JE, Lee S. Autophagy: Guardian of Skin Barrier. Biomedicines. 2022
[17] Klapan K, Simon D, Karaulov A, Gomzikova M, Rizvanov A, Yousefi S, Simon HU. Autophagy and Skin Diseases. Front Pharmacol. 2022
[18]  Ma J et al. Autophagy plays an essential role in ultraviolet radiation-driven skin photoaging. Front Pharmacol. 2022 
​[19] Gomes LR, Menck CFM, Leandro GS. Autophagy Roles in the Modulation of DNA Repair Pathways. Int J Mol Sci. 2017
[20] Umar S.A. et al. RSC Adv. Integrating DNA damage response and autophagy in UV-B induced skin photo-damage (2020).
[21] Zhong X. et al. Medicine. Role of autophagy in skin photoaging: A narrative review (2024).
[22] Song X. et al. Redox Biol. Autophagy deficient keratinocytes show increased DNA damage and senescence after oxidative stress (2016).
[23] Ni C. et al. Int. J. Biochem. Cell Biol. Autophagy deficient melanocytes display SASP with oxidized lipid mediators (2016).
[24] Rossiter H. et al. Exp. Dermatol. Inactivation of autophagy changes sebaceous gland morphology and function (2018).
[25] Gromkowska-Kępka K.J. et al. J. Cosmet. Dermatol. The impact of ultraviolet radiation on skin photoaging: in vitro studies review (2021).
[26] Romero M, Zorzano A. Role of autophagy in the regulation of adipose tissue biology. Cell Cycle. 2019 
​[27] Ju L. et al. Cell Death Dis. Obesity-associated inflammation triggers autophagy-lysosomal response in adipocytes (2019)
​[28] Seung-Hyun Ro et al. Front. Physiol., 28 January 2019 Autophagy in Adipocyte Browning: Emerging Drug Target for Intervention in Obesity
[29] Furthering fat loss in the fasting response - EurekAlert! Peer reviewed publication Osaka University 2022
[30] Yamamoto S et al. Autophagy Differentially Regulates Insulin Production and Insulin Sensitivity. Cell Rep. 2018
[31] Ning Wang et al. Autophagy: Playing an important role in diabetes and its complications, Medicine in Drug Discovery 2024
[32] Frendo-Cumbo S. et al. Front. Cell Dev. Biol. Communication Between Autophagy and Insulin Action (2021).
[33] Budi Y.P. et al. PeerJ. Autophagy's role in high-fat diet-induced insulin resistance in mouse adipose tissues (2022).
[34] Kezhong Zhang; “NO” to Autophagy: Fat Does the Trick for Diabetes. Diabetes 1 February 2018
[35] Uddin M. et al. Front. Aging Neurosci. Autophagy and Alzheimer's Disease: Mechanisms to Therapeutic Implications (2018).
​[36] Cheon S. et al. Exp. Neurobiol. Autophagy, Cellular Aging and Age-related Human Diseases (2019)
[37] Al-Bari M. et al. Int. J. Mol. Sci. Targeting Autophagy with Natural Products for Cancer Therapy (2021) - dr Erik Berg Youtube 2023
[38] InsideTracker. Autophagy Fasting: What You Should Know Before Starting Your Fast (2024)
[39] Life MD Autophagy Fasting: What You Need to Know Before Starting Jeffrey Vacek, DNP, FNP-C 2023
[40] DECODE AGE Autophagy: Definition, Process, causes & Supplements Dec 20, 2023 By Madhulatha Kesam Reddy Naga
[41]. MedicineNet How Do You Trigger Autophagy? Medical Author: Dr. Jasmine Shaikh, MD Medical Reviewer: Pallavi Suyog Uttekar, MD
[42] Hofer, S.J.et al. Spermidine is essential for fasting-mediated autophagy and longevity. Nat Cell Biol 26, 1571–1584 (2024)
[43] Tan C. et al. Neurobiol. Aging. Autophagy in aging and neurodegenerative diseases (2014)
[44] Moore MN. Lysosomes, Autophagy, and Hormesis in Cell Physiology, Pathology, and Age-Related Disease. Dose Response. 2020 
[45] Amirkavei M et al. Hormetic Heat Shock Enhances Autophagy through HSF1 in Retinal Pigment Epithelium Cells. Cells. 2022
[46] Kumsta C. et al. Nat. Commun. Hormetic heat stress and HSF-1 induce autophagy in C. elegans (2017)
[47] Mann T. et al. Photodermatol. Photoimmunol. Photomed. HEVIS induces skin oxidative stress: Protective effects of Licochalcone A (2019)
[48] Lim H.W. et al. J. Am. Acad. Dermatol. Impact of visible light on skin health: Antioxidants in skin protection (2022)
[49] Ladewig S. et al. EADV Poster. Licochalcone A protects against HEV light-induced ROS and MMP-1 expression in vitro (2018)
[50] Kühn J. et al. Exp. Dermatol. Licochalcone A activates Nrf2 and reduces cutaneous oxidative stress in vivo (2014)
[51] Hong M. et al. J. Invest. Dermatol. Glycyrrhetinic Acid: Modulator of Skin Pigmentation and DNA-Repair (2009)
[52] Kumar P. et al. Clin. Transl. Med. GlyNAC supplementation improves multiple aging-related deficits in older adults (2021)
[53] Kumar P. et al. Clin. Transl. Sci. GlyNAC supplementation improves multiple aging-related deficits in older adults (2020)
[54] Kumar P. et al. Antioxidants. GlyNAC improves mitochondrial function and insulin resistance in type 2 diabetes (2022)
[55].Kumar P. et al. Nutrients. GlyNAC supplementation increases lifespan and corrects aging-related defects in mice (2021)
[56] Sun Y. et al. CNS Neurosci. Ther. N-acetylcysteine induces mitochondria-dependent apoptosis in glioma cells (2016)
[57] Yang KL et al. In vitro anti-breast cancer studies of LED red light therapy through autophagy. Breast Cancer. 2021 
[58] Pinelli R. et al. Antioxidants. Light pulses and phytochemicals promote autophagy to counter oxidative stress in AMD (2023)
[59] Hanelova K. et al. Cell Commun. Signal. Autophagy modulators affect signaling molecules in PS+ extracellular vesicles (2023)

Circadian rhythms are biological processes linked to the cycles of the day. Many bodily functions vary according to these rhythms, including the following:
▌Body temperature
▌Pulse rate and blood pressure
▌Reaction time and performance
▌The production of melatonin, serotonin and cortisol
▌Intestinal activity
Travellers who make frequent long-distance flights often have direct experience in the importance of getting acclimated to a new time zone. One’s inability to adjust can lead to sleeping problems and disturbances in cognitive functions. People who do shift work, or work under bright lights, can face similar issues. Problems arise whenever the daily rhythm is disturbed. Human beings have an internal clock that lasts about 25 hours and resets itself daily when it is exposed to daylight. Blind people can thus have sleeping problems, and yet, even without the ability to see sunlight, their bodies function mostly just fine. Light clearly has a central role in the regulation of our daily lives, and can be used to reset our circadian rhythms. 

SKIN & CIRCADIAN RHYTHMS
Our skin follows a natural daily cycle, known as the circadian rhythm, which influences its functions at different times of the day. This rhythm helps the skin protect itself during the day and repair itself at night.

Daytime: protection and vigilance
During the day, your skin protects you from various environmental threats, such as harmful UV rays and pathogens. Thanks to the circadian rhythm, your skin's barrier becomes stronger, and its immune defences are on high alert. This means your skin is busy producing protective proteins and ramping up immune responses to keep everything in balance and prevent damage. Activities like cell growth and movement are more pronounced during the day, helping to maintain and repair your skin.

Nighttime: repair, regeneration, and weaker barrier
As night your skin switches to repair mode, focusing on fixing any damage it endured during the day, such as UV-induced DNA damage. The skin cells, particularly keratinocytes, follow a natural rhythm that boosts nighttime repair activities, including increased cell growth and improved barrier recovery. Clock genes like BMAL1 and PER play a vital role in timing these repair processes. During this repair phase, the skin's barrier becomes weaker:
Slower barrier recovery: The skin takes longer to recover from any daytime damage or stress, leaving it more vulnerable.
Higher permeability: While this allows skincare products to penetrate more deeply, it also means the skin is less effective at keeping out harmful substances and Transepidermal Water Loss (TEWL) is increased, meaning the skin is prone to lose more moisture and become dehydrated. 
Disruptions to this rhythm can impair skin function and accelerate aging, highlighting the importance of using the right nighttime skincare products to support the skin's barrier and hydration.
 
The effects of blue light on circadian rhythms: A controversial topic
Blue light, particularly in the 460-480 nm range, has long been considered a potent modulator of circadian rhythms. This short-wavelength light is abundant in sunlight and is also emitted in a very low dose by many electronic devices. The traditional view holds that exposure to blue light, especially in the evening, can disrupt circadian rhythms and negatively impact sleep quality.
Traditional perspective
Research has shown that blue light is particularly effective at suppressing melatonin production, a hormone crucial for regulating sleep-wake cycles [1]. Studies have demonstrated that exposure to blue light can phase-shift the human circadian clock more effectively than other wavelengths [2]. This has led to recommendations to limit blue light exposure from electronic devices before bedtime.
Challenging the consensus
However, recent research has challenged this established view. A study by researchers at the University of Basel suggests that the color of light may not significantly affect circadian rhythms [3]. Instead, they propose that the overall brightness of light plays a more significant role in influencing the internal clock.

Sunscreen and skin circadian rhythms 
There is no direct information about the impact of sunscreen on circadian rhythms. UV radiation, which sunscreen blocks, can affect circadian rhythms. A study on keratinocytes showed that UVB radiation can suppress several genes involved in circadian rhythm regulation for up to 24 hours [4]. The skin has its own peripheral circadian clock [4]. While sunscreen protects against UV (and some sunscreens defend against blue light) damage, it's unclear if it directly affects this skin-specific circadian rhythm. I would consider a significant impact very unlikely, however am curious to see this backed up by scientific research. 

It's clear that light exposure, particularly its timing and intensity, plays a crucial role in regulating circadian rhythms and that circadian rhythms impact our skin and highly recommend daily use of sunscreen with UV protection and blue light defence.

Take care!
Anne-Marie

References:
[1] Ksendzovsky, A. et al. (2017). Clinical implications of the melanopsin-based non-image-forming visual system. Neurology, 88(13), 1282-1290
[2] Tosini, G. et al. (2016). Effects of blue light on the circadian system and eye physiology. Molecular Vision, 22, 61-72.
[3] Spitschan, M. et al. (2023). Effects of calibrated blue–yellow changes in light on the human circadian system. Nature Human Behaviour
[4] Hettwer, S. et al. (2020). Influence of cosmetic formulations on the skin's circadian clock. International Journal of Cosmetic Science
[5] Desotelle, J. A. et al. (2012). The circadian control of skin and cutaneous photodamage. Photochemistry and Photobiology, 88(5), 1037-1047.

Our DNA faces a staggering number of damaging events each day. Estimates suggest that each cell in our body endures approximately 70,000 DNA lesions [1] up to 100.000 per day [2][3]. While this number includes all types of DNA damage, sunlight remains a major culprit, especially for skin cells, which may experience even higher rates of DNA damage. Oxidative stress, another significant contributor, is estimated to cause about 10,000 DNA lesions per cell per day [1][3]. 
 
Frequency types of DNA damage: [3]
▌Oxidative damage: 10,000 to 11,500 incidents per cell per day in humans 
▌Depurinations: 2,000 to 10,000 per cell per day in mammalian cells 
▌Single-strand breaks: About 55,200 per cell per day in mammalian cells 
▌Double-strand breaks: 10 to 50 per cell cycle in human cells   

Factors influencing DNA damage and rates: [4]
▌Environmental factors: UV-radiation, pollution and lifestyle choices (e.g., smoking) can increase oxidative stress 
▌Frequency of exposure: repeated UV exposure can overwhelm repair mechanisms 
▌Age: DNA repair efficiency declines with age
▌Skin phototype: individuals with fair skin are more susceptible to UV-induced damage 
▌Cell type and location in the body
▌Individual factors: like genetics and epigenetics  

SUNLIGHT INDUCED DNA DAMAGE
UVA, UVB, and High Energy Visible Light (HEVIS) harm our genetic material in different ways. UVA makes up the majority of UV radiation reaching the Earth's surface, and both UVA and blue light are used in artificial UV exposure settings [5][6]. 50% of the damaging oxidative stress in human skin is generated in the VIS spectrum and the other 50% by UV light [7].
 
UVB-Induced DNA damage
UVB (280-315 nm) is generally considered the most harmful due to its higher energy content and efficient absorption by DNA [6], and is known to directly interact with DNA, primarily causing the formation of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) [8]. These lesions can distort the DNA helix, potentially leading to mutations if left unrepaired.
▌Direct formation of cyclobutane pyrimidine dimers (CPDs): Most abundant UVB-induced lesion, formed between adjacent pyrimidines [6][5]
▌Formation of 6-4 photoproducts (6-4PPs): Second most common UVB-induced lesion [6][5]
▌Generation of Dewar valence isomers: Derived from 6-4PPs upon further UVB exposure [6]
▌Oxidative DNA damage: Through generation of reactive oxygen species (ROS), though less prominent than with UVA [9][10]
▌DNA-protein crosslinks: Formed between DNA and nearby proteins [6]
▌Single-strand breaks: Can occur as a result of UVB exposure [11]
▌Pyrimidine hydrates: Minor UVB-induced lesions [12]
▌Oxidative DNA-lesions,  such as 8-oxodeoxyguanosine, when they are in proximity or on opposite DNA-strands, may generate double-strand breaks [5] 

​UVB radiation is considered more genotoxic than UVA due to its direct absorption by DNA and efficient formation of mutagenic CPDs and 6-4PPs. However, both UVA and UVB contribute to solar UV-induced DNA damage and mutagenesis.
 
UVA-Induced DNA damage
UVA-induced (315-400 nm) DNA damage occurs through various mechanisms, primarily involving indirect effects but also some direct damage. 
▌Photosensitization: Interaction with endogenous photosensitizers like riboflavin and porphyrins, leading to reactive oxygen species (ROS) generation [13]
▌Oxidative stress: ROS-induced oxidative DNA damage, with 8-oxo-7,8-dihydroguanine (8-oxoG) as a primary lesion [13][6][5]
▌Indirect cyclobutane pyrimidine dimer (CPD) formation: Through photosensitized triplet energy transfer, less efficient than UVB [13]
▌Direct DNA damage: Formation of CPDs, particularly at TT sequences [5][6]
▌Genomic instability [6]
▌Single-strand and double-strand DNA breaks [6][14] UVA-induced DNA double-strand breaks result from the repair of clustered oxidative DNA damages [6]. This means UVA doesn't directly cause DSBs, but rather creates oxidative damage that can lead to DSBs during the repair process. While UVA was originally not expected to induce DSBs due to its relatively low photonic energy, several studies have shown that UVA can induce DSBs in a replication-independent manner [6]. Oxidative DNA-lesions, such as 8-oxodeoxyguanosine, when they are in proximity or on opposite DNA-strands, may generate double-strand breaks [5]. 

Blue Light (HEViS)-induced DNA damage
Blue light or high-energy visible light (HEVIS)-induced (400-700 nm) DNA damage occurs through mechanisms similar to UVA, primarily involving indirect effects mediated by reactive oxygen species (ROS). 
▌Photosensitization: Interaction with endogenous photosensitizers like riboflavin and porphyrins, leading to ROS generation [15]
▌Oxidative stress: ROS-induced oxidative DNA damage, with 8-oxo-7,8-dihydroguanine (8-oxoG) as a primary lesion [5][16][17]
▌Mitochondrial DNA damage: Blue light can penetrate into cells and damage mitochondrial DNA, leading to mitochondrial dysfunction [6]
▌Indirect formation of cyclobutane pyrimidine dimers (CPDs): Through photosensitized triplet energy transfer, though less efficient than UVA or UVB [5][18]
▌Single-strand DNA breaks: Caused by ROS-induced oxidative damage [19]
▌Lipid peroxidation: ROS-induced damage to cellular membranes, indirectly affecting DNA integrity [20]
▌Protein oxidation: Damage to DNA repair enzymes and other proteins involved in maintaining genomic stability [21]
▌Chromosome aberrations (clastogenic/aneugenic effects) [5]
▌DNA double-strand breaks (DSBs), through indirect mechanisms   

Double-Strand Breaks (DSBs)
While DSBs are less common than other types of UV-induced DNA damage, they are particularly dangerous because they affect both strands of the DNA helix and can lead to genomic instability if not properly repaired [14][22].
▌UVA-induced DSBs: These often result from the repair of clustered oxidative DNA lesions. When repair enzymes attempt to fix closely spaced lesions on opposite strands simultaneously, it can lead to DSBs [6]. Some studies have found that UVA radiation can induce DSBs, particularly through oxidative stress mechanisms [6][23]. Other research suggests that UVA alone may not directly cause significant DSB formation or activate certain DNA damage response pathways associated with DSBs [24]
▌UVB-induced DSBs: UVB can cause DNA double-strand breaks. These can occur directly or as a result of replication fork collapse at sites of unrepaired lesions [22][25]
▌ROS-induced DSBs: UVA, UVB and Blue Light can generate reactive oxygen species (ROS), which can cause various types of DNA damage, including DSBs [5][6][14][23]  

The dose and wavelength of UV radiation can influence the types and extent of DNA damage, including DSB formation [25][26].
 
Cellular specificity of DNA damage
Different skin cell types exhibit varying susceptibilities to DNA damage:
1. Keratinocytes: Most numerous and most exposed, they bear the brunt of UV-induced CPDs [6]. Blue light has been shown to cause DNA damage in human keratinocytes, potentially contributing to premature skin aging [5]
2. Melanocytes: Particularly vulnerable to oxidative damage due to melanin production [27]
3. Fibroblasts: While less directly exposed, they can accumulate damage over time, contributing to photoaging [27]
Mitochondria, the powerhouses of the cell, have their own DNA and are particularly susceptible to DNA damage due to their proximity to reactive oxygen species (ROS) production. While oxidative stress in mitochondria can lead to damage, a certain level of ROS is actually necessary for proper cellular signaling and adaptation.

Other types of DNA damage
Beyond UV-induced damage, our DNA faces threats from various sources:
1. Hydrolytic Damage: Spontaneous hydrolysis can lead to depurination and depyrimidination [1]
2. Alkylation: Endogenous and exogenous alkylating agents can modify DNA bases [1]
3. Mismatch Errors: During DNA replication, incorrect nucleotides may be incorporated [1]
 
MECHANISMS OF DNA REPAIR
Cells have sophisticated DNA repair mechanisms, however, some damage may escape repair, potentially leading to mutations or cellular dysfunction over time.
 
1. Nucleotide Excision Repair (NER):
▌Primary mechanism for repairing UV-induced DNA damage, particularly cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs)[25][28][29]
▌Involves recognition of DNA distortion, excision of the damaged segment, and synthesis of new DNA to fill the gap [30].  
2. Base Excision Repair (BER):
▌Repairs oxidative DNA damage caused by UVA and HEViS-induced reactive oxygen species (ROS) [30][31]
▌Involves removal of damaged bases (including oxidative lesions like 8-oxoG [29], creation of an apurinic/apyrimidinic (AP) site, and DNA synthesis to fill the gap [29][30]
3. Homologous Recombination Repair (HRR):
▌Repairs double-strand breaks that can result from UV exposure, particularly during DNA replication [32]
▌Uses an undamaged DNA template (usually a sister chromatid) to accurately repair the break [32]
4. Mismatch Repair (MMR):
▌Corrects errors in DNA replication that result in mismatched base pairs and small insertion/deletion loops [29][30][33]
▌Important for maintaining genomic stability and preventing mutations [30] 
5. Double-Strand Break Repair: Includes homologous recombination and non-homologous end joining [29]
6. Non-Homologous End Joining (NHEJ): [32]
▌An alternative mechanism for repairing double-strand breaks 
▌Directly ligates broken DNA ends without the need for a homologous template   

NER is particularly crucial for UV-induced damage, while the repair of oxidative lesions through BER can be challenging due to the persistent nature of oxidative stress. Additionally, research has highlighted the role of the AMPK pathway in promoting UVB-induced DNA repair by increasing the expression of XPC, a key protein in the NER pathway [28].
 
OTHER DNA REPAIR MECHANISMS
In addition to the mechanisms primarily responsible for repairing sunlight-induced damage, our bodies have several other DNA repair pathways:
 
1. Direct Reversal Repair:
▌Includes mechanisms like O6-methylguanine-DNA methyltransferase (MGMT), which directly removes alkyl groups from guanine bases [25]  
2. Translesion Synthesis (TLS):
▌Not a repair mechanism per se, but allows DNA replication to bypass damaged sites [30]
▌Can be error-prone but prevents replication fork collapse and more severe DNA damage [30]  
3. Interstrand Crosslink Repair: 
▌Repairs covalent links between DNA strands that can block replication and transcription [30]
▌Involves a complex interplay of multiple repair pathways, including NER and homologous recombination [30]  
4. Single-Strand Break Repair:
▌Repairs breaks in one strand of the DNA double helix [30]
▌Often involves components of the BER pathway [30] 
These repair mechanisms often work in concert, and there can be significant overlap and interaction between different pathways. The choice of repair mechanism depends on factors such as the type of damage, the cell cycle stage, and the availability of repair proteins [28][30].
 
CONSEQUENCES OF UNREPAIRED DNA DAMAGE
When DNA repair mechanisms fail or are overwhelmed, several outcomes can occur:
1. Skin Aging: Accumulation of damage in epidermal keratinocytes and dermal fibroblasts leads to reduced collagen production and elastin degradation [34]
2. Hyperpigmentation: DNA damage in melanocytes can trigger increased melanin production [34]
3. Skin Cancer: Mutations in key genes like p53 can lead to uncontrolled cell growth [34]
 
CORRELATION INCREASE DAMAGE, INCREASED RISK OF PREMATURE AGING & CANCER
While a large amount of DNA damage does increase the workload on repair mechanisms and can potentially lead to more errors, it's not a simple direct relationship. The body has multiple layers of protection, including cell death pathways for severely damaged cells. The balance between efficient repair, controlled cell death, and mutation accumulation is crucial in determining outcomes related to cancer and aging. Both cancer and aging are complex, multifactorial processes influenced by many factors beyond DNA damage and repair.
 
1. DNA damage accumulation and cancer/aging risk
▌DNA damage does accumulate over time in cells, with estimates of 10,000 to 100,000 DNA lesions per cell per day [3]
▌This accumulated damage, if not properly repaired, ca n lead to mutations that contribute to both cancer development and aging [35][36] 
2. DNA repair and mutation risk
▌While DNA repair mechanisms are generally beneficial, they are not perfect and can occasionally introduce errors [30]
▌High levels of DNA damage can overwhelm repair systems, potentially leading to more errors during the repair process [37]  
3. Connection to cancer and premature aging
▌Defects in DNA repair pathways are associated with increased cancer risk and premature aging syndromes [37][38]
▌Some inherited mutations in DNA repair genes (like POLE/POLD1) can lead to higher mutation rates and increased cancer risk, though not necessarily premature aging in all aspects [36] 
4. Balance between repair and consequences
▌There's a delicate balance between DNA repair, cell death, and mutation accumulation [38]
▌Excessive DNA damage can lead to increased cell death and stem cell exhaustion, potentially promoting premature aging [38]
▌However, if mutations accumulate without triggering cell death, this can increase cancer risk [38]  
5. Stem cell considerations
▌Stem cells have special mechanisms to maintain low mutation rates, but when mutations do occur, clonal expansion can contribute to both aging and cancer risk [38]  

PREVENTION AND SUPPORT OF DNA REPAIR
1. Sun Protection: Broad-spectrum sunscreens (preferably including blue light protection), protective clothing, and avoiding peak UV hours remain the most effective strategies [39].
2. Antioxidants: Both topical and oral antioxidants can help combat oxidative stress, though their efficacy in preventing DNA damage is still debated [40].
3. Glycyrrhetinic Acid (GA): has protective effects against DNA damage and enhances DNA repair mechanisms both topical or as supplement.
4. DNA repair enzymes: Topical applications of enzymes like T4 endonuclease V have shown promise in enhancing repair [39].
6. Ectoine exhibits a complex effect on DNA damage, protecting against some forms of radiation-induced damage while potentially enhancing structural changes in DNA under certain conditions [64]. It significantly reduces ionizing radiation-induced DNA strand breaks [64], but may increase transitions from supercoiled to open circular DNA conformations at non-physiological pH levels [63].
7. Lifestyle factors: Adequate sleep, a balanced diet, and stress management can support overall cellular health and DNA repair processes.
8. Supplements:
▌Vitamin C: Dose: 500 mg [41]. .Vitamin C has been shown to potentially induce nucleotide excision repair (most important for sun damage) through anti-oxidant properties, however in high concentrations may be acting as pro-oxidant.
▌Folic Acid and Vitamin B12: Dose 15 mg folic acid and 1 mg vitamin B12 thrice weekly [42] Folic acid has show promise in markers for genomic instability, but does not significantly affect DNA strand breakage and excess may even increase DNA mutations and affect DNA repair gene expression. Vitamin B12 plays a role in DNA synthesis and methylation, which are important for genomic stability. 
▌Selenium (as selenomethionine): Dose: 100 μg/day [43] promising, not conclusive.
▌Zinc: Dose: 22 mg/day Molecular Nutrition & Food Research. A small increase in dietary zinc can reduce oxidative stress and DNA damage as shown by reduced leukocyte DNA strand breaks, however more comprehensive human studies are necessary to be conclusive.
▌Coenzyme Q10: Dose: 100 mg/day Associated with reduced baseline DNA damage [44]. Ubiquinol-10 may enhance DNA resistance to oxidative damage and reducing strand breaks in vitro. Further research is needed to be conclusive.
▌Taurine: Taurine supplementation has been shown to reduce DNA damage in several studies [45][46][47]. In one study, taurine (20 mM) reduced formation of DNA base adducts like 5-OH-uracil, 8-OH adenine, and 8-OH guanine by 21-49% [45]. Taurine (2 g three times daily) decreased DNA damage associated with exercise [49][50]. Taurine suppresses DNA damage and improves survival of mice after oxidative DNA damage [52]. Most studies used doses between 1-6 g per day [51]. A proposed safe level of taurine consumption is 3 g/day [49]. Doses as high as 10 g/day for 6 months have been tested [51]. For exercise benefits, 2 g three times daily was effective [49][50]. Taurine acts as an antioxidant and can protect against oxidative DNA damage [45][46]. It may activate DNA repair pathways involving p53 [48][53]. Taurine deficiency is associated with increased DNA damage and cellular senescence [52]. 
▌ Magnesium:  Plays a crucial role in DNA repair and recommended dose varies by gender and age. Magnesium Malate and Citrate or Orotate are good for energy, while Glycinate and Threonate have an additional bonus as both support sleep quality, DNA repair processes are influenced by circadian rhythms and more active overnight. Sleep enhances the repair over double-strand breaks. Dark chocolate and deep green vegetables contain Magnesium. 
The studies cited come mostly from reputable peer-reviewed journals. Supplements have shown benefits in specific studies, their effects may vary depending on individual factors, correct dose and overall health status. Always consult with a healthcare professional before starting any new supplement regimen.

PARP (Poly ADP-ribose polymerase) plays a crucial role in DNA repair, particularly in the base excision repair (BER) pathway. PARP acts like a cellular "first responder" for DNA damage, initiating the repair process to keep our genetic material intact.
1. DNA damage sensing: PARP1, the most abundant PARP enzyme, acts as a DNA damage sensor, quickly binding to single-strand breaks (SSBs) in DNA [54][55].
2. Recruitment of repair factors: Once bound to damaged DNA, PARP1 catalyzes the synthesis of poly(ADP-ribose) (PAR) chains on various proteins, including itself. This PARylation helps recruit other DNA repair factors to the site of damage [54][56].
3. Base Excision Repair (BER): PARP is a key component of the BER complex, which also includes DNA ligase III, DNA polymerase beta, and the XRCC1 protein [55].
4. Chromatin relaxation: PARylation of histones by PARP leads to chromatin relaxation, allowing better access for repair enzymes to the damaged DNA [55][56]. This is moreover an epigenetic mechanism.
5. Regulation of other repair pathways: PARP is also involved in other DNA repair pathways, including nucleotide excision repair (NER) and double-strand break repair [55][56].

Boosting PARP activity for enhanced DNA repair:
1. Raising NAD+ levels: PARP activation will decrease NAD+ levels. Increasing NAD+ levels through precursors like nicotinamide riboside or nicotinamide mononucleotide might support PARP activity [57], especially in response to oxidative stress and DNA damage [58][59]. .Although NMN supplementation does raise NAD+ levels and it´s health benefits are hyped by longevity experts, some scientists are skeptical as they find the data in humans not very convincing to date, with minor benefits for unhealthy and older volunteers in 14 publications. Fact is that NAD+ levels decrease as we age as a result of declining levels or activity of the NAD+ recycling enzyme NAMPT in the biosynthetic salvage pathway and other NAD+ consuming enzymes like CD38 and as mentioned before PARPs.
1. Lifestyle factors: Regular exercise and calorie restriction have been shown to increase NAD+ levels, which could indirectly support PARP function [57]. Both aerobic and resistance exercise have been shown to increase NMAPT levels, reversing age related declines [66][61]. 
2. Avoiding PARP inhibitors: Certain medications and supplements (interestingly these include polyphenols like resveratrol, favonoids and Vitamin D) can inhibit PARP activity [62]. Avoiding these could help maintain normal PARP function, although PARP inhibition can also have significant therapeutic benefits too.
3. Managing oxidative stress: Reducing oxidative stress through antioxidant-rich diets and lifestyle modifications may help preserve PARP function, as excessive oxidative damage can lead to PARP overactivation and subsequent depletion [56].
 
VITAMIN D
The biggest benefit of sunlight for humans, next to enhancing our mood, is that sunlight is the primary source of vitamin D3 synthesis for most people. UVB radiation (290-315 nm) converts 7-dehydrocholesterol in the skin to previtamin D3, which then isomerizes to vitamin D3 [1]. Click here to read more about Vitamin D. A study published in the International Journal of Molecular Medicine demonstrated that the active form of vitamin D inhibits PARP. 
 ​ 
The most effective protection against UV-induced DNA damage is avoiding excessive sun exposure and using protective clothing. Sunscreens help, however their efficacy depends on the formula, applied amount, distribution evenness and reapplication. Some research is exploring the topical delivery of repair enzymes [39], while the efficacy of Glycyrrhetinic Acid to enhance DNA repair is well established. 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
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[3] Wikipedia, DNA repair Journal (peer reviewed
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[5] Cécile Chamayou-robert, Olivier Brack, Olivier Doucet, Carole Di Giorgio. Blue light induces DNA damage in normal human skin keratinocytes. Photodermatology, Photoimmunology & Photomedicine, 2022
[6] Greinert R, Volkmer B, Henning S, Breitbart EW, Greulich KO, Cardoso MC, Rapp A. UVA-induced DNA double-strand breaks result from the repair of clustered oxidative DNA damages. Nucleic Acids Res. 2012
[7] Exp Dermatol. Skin Pigmentation and its Control: From Ultraviolet Radiation to Stem Cells Joseph Michael Yardman-Frank et al. 2021
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[9] Rajeshwar P. Sinhaa Photochemical & Photobiological Sciences UV-induced DNA damage and repair: a review 2002
[10] André Passaglia Schuch, Natália Cestari Moreno, Natielen Jacques Schuch, Carlos Frederico Martins Menck, Camila Carrião Machado Garcia, Sunlight damage to cellular DNA: Focus on oxidatively generated lesions, Free Radical Biology and Medicine, 2017
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UVB-induced DNA and photosystem II damage in two intertidal green macroalgae: Distinct survival strategies in UV-screening and non-screening Chlorophyta, Journal of Photochemistry and Photobiology B: Biology, Volume 132, 2014
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[22] Rolfsmeier ML, Laughery MF, Haseltine CA. Repair of DNA double-strand breaks following UV damage in three Sulfolobus solfataricus strains. J Bacteriol. 2010 
[23] Zhivagui, M., Hoda, A., Valenzuela, N. et al. DNA damage and somatic mutations in mammalian cells after irradiation with a nail polish dryer. Nat Commun 14, 276 (2023). 
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No Formation of DNA Double-Strand Breaks and No Activation of Recombination Repair with UVA, Journal of Investigative Dermatology, Volume 131, Issue 5, 2011
[25] Kciuk M, Marciniak B, Mojzych M, Kontek R. Focus on UV-Induced DNA Damage and Repair-Disease Relevance and Protective Strategies. Int J Mol Sci. 2020 Oct 1;21(19):7264. doi: 10.3390/ijms21197264. PMID: 33019598; PMCID: PMC7582305.
[26] M O Bradley and V I Taylor PNAS DNA double-strand breaks induced in normal human cells during the repair of ultraviolet light damage June 15, 1981
[27] Debacq-Chainiaux F, et al. UV, stress and aging. Dermatoendocrinol. 2012;4(3):236-240.
[28] Shah P, He YY. Molecular regulation of UV-induced DNA repair. Photochem Photobiol. 2015 
[29] Marteijn JA, et al. Understanding nucleotide excision repair and its roles in cancer and ageing. Nat Rev Mol Cell Biol. 2014;15(7):465-481.
[30] Chatterjee N, Walker GC. Mechanisms of DNA damage, repair, and mutagenesis. Environ Mol Mutagen. 2017 
[31] Karran P, Brem R. Protein oxidation, UVA and human DNA repair. DNA Repair (Amst). 2016 
[32] Clancy, S. (2008) DNA damage & repair: mechanisms for maintaining DNA integrity. Nature Education 
[33] Chen, J.; Potlapalli, R.; Quan, H.; Chen, L.; Xie, Y.; Pouriyeh, S.; Sakib, N.; Liu, L.; Xie, Y. Exploring DNA Damage and Repair Mechanisms: A Review with Computational Insights. BioTech 2024, 13, 3. 
[34] Rittié L, Fisher GJ. Natural and sun-induced aging of human skin. Cold Spring Harb Perspect Med. 2015;5(1):a015370.
[35] Wu HC, Kehm R, Santella RM, Brenner DJ, Terry MB. DNA repair phenotype and cancer risk: a systematic review and meta-analysis of 55 case-control studies. Sci Rep. 2022 
[36] Robinson, P.S., Coorens, T.H.H., Palles, C. et al. Increased somatic mutation burdens in normal human cells due to defective DNA polymerases. Nat Genet 53, 1434–1442 (2021)
[37] Hakem R. DNA-damage repair; the good, the bad, and the ugly. EMBO J. 2008 
[38] Stead ER, Bjedov I. Balancing DNA repair to prevent ageing and cancer. Exp Cell Res. 2021
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[41] Elizabeth D. Kantor et al. Specialty Supplement Use and Biologic Measures of Oxidative Stress and DNA Damage Cancer Epidemiol Biomarkers Prev (2013) 
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[43] Tobias Dansen et al. UMC Utrecht Assumption about cause DNA damage debunked 2024
[44] Dr Kara Fitzgerald 12 biological haalmarks of aging functional medicine longevity
[45]  Messina SA, Dawson R Jr. Attenuation of oxidative damage to DNA by taurine and taurine analogs. Adv Exp Med Biol. 2000
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[47] Mir Kaisar Ahmad, Aijaz Ahmed Khan, Shaikh Nisar Ali, Riaz Mahmood PLOS ONE Chemoprotective Effect of Taurine on Potassium Bromate-Induced DNA Damage, DNA-Protein Cross-Linking and Oxidative Stress in Rat Intestine March 6, 2015
[48] Lai L, Wang Y, Peng S, Guo W, Li F, Xu S. P53 and taurine upregulated gene 1 promotes the repair of the DeoxyriboNucleic Acid damage induced by bupivacaine in murine primary sensory neurons. Bioengineered. 2022 
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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

1. Stimulate mitochondrial biogenesis: PQQ activates PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), a key regulator of mitochondrial biogenesis [6].
2. Enhance mitochondrial efficiency: By improving electron transport chain function, PQQ helps increase ATP production [7].
3. Protect mitochondria from oxidative damage:  As a potent antioxidant, PQQ shields mitochondria from harmful free radicals [8].

A study in humans demonstrated that dietary PQQ supplementation increased mitochondrial function in healthy adults. After 8 weeks of supplementation with 20 mg PQQ daily, participants showed significant improvements in mitochondrial-related functions [9].

​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.

1. Cognitive Function: PQQ supplementation has been associated with improved cognitive performance in humans, particularly in areas of attention and working memory. A clinical study involving adults aged 20-65 years found that 20 mg/day of PQQ for 12 weeks improved composite memory and verbal memory scores [12]. In younger adults (20-40 years), PQQ improved cognitive flexibility, processing speed, and execution speed after 8 weeks of supplementation [12].
2. Neuroprotection against toxins: PQQ has shown protective effects against neurotoxins in animal models, suggesting potential applications in neurodegenerative diseases. In a study using D-galactose-induced cognitive impairment in mice, PQQ treatment ameliorated memory deficits and neurotoxicity by reducing oxidative stress and modulating the Akt/GSK-3β pathway [13]. PQQ also demonstrated neuroprotective effects against traumatic brain injury in rodent studies [14].
3. Nerve Growth Factor (NGF) production: PQQ stimulates the production of NGF, which is crucial for the growth, maintenance, and survival of neurons. Research has shown that PQQ enhances NGF production and increases the expression of NGF receptors, contributing to its neuroprotective effects [15]. This mechanism may play a role in PQQ's potential to improve cognitive function and protect against neurodegenerative disorders.

These findings suggest that PQQ has promising effects on cognitive function and neuroprotection, though more research is needed to fully understand its mechanisms and potential therapeutic applications in humans.

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:  

1. Mitochondrial support: PQQ increases the number and efficiency of mitochondria, improving cellular energy production and metabolic function. This supports better regulation of sleep-related processes, including neurotransmitter production and stress response [17][18].
2. Antioxidant properties: PQQ's powerful antioxidant capabilities help reduce oxidative stress, which is associated with sleep disturbances. 
3. Anti-inflammatory effects: By reducing inflammation, PQQ may help alleviate factors that can interfere with quality sleep [17][21]. 

Mitochondrial dysfunction and increased oxidative stress are associated with sleep disturbances [19][20], and by targeting these issues, 

​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:

• ▌DNMT1 is primarily responsible for maintaining existing methylation patterns during DNA replication. Publication DNMT1 inhibition
  ▌DNMT3A and DNMT3B are involved in de novo methylation, establishing new methylation patterns.

▌Significantly increased expression of sirtuin-1 (SIRT1) and sequestosome-1/p62 (SQSTM1) were demonstrated in tissues treated with TAP, compared to control (p<0.05), suggesting enhanced oxidative response, protection of collagen from degradation, and autophagy effects. SIRT1 is widely recognized as a crucial epigenetic regulator involved in many biological processes, including metabolism, genomic stability maintenance and aging.
▌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. 

Have you ever wondered what those SPF numbers really mean, or how they're determined? From cutting-edge measurement techniques to the truth about water resistance, UV-filters, the world of sunscreen is far more interesting than you might think. Whether you're a beach enthusiast, interested in your skin`s health and beautyspan, or just curious about the science behind your daily skincare routine, this post will shed new light on the powerful protective shield between you and the sun's rays including some useful tips.

SPF
​SPF means Sun Protection Factor. The labelled SPF is not indicating the amount of time you can stay in the sun safely, like for example with SPF 50, it would be 50 minutes, however it indicates how much longer it takes for you to get a sunburn (primarily but not exclusively caused by UVB). Thus with SPF 50, it would take 50 times longer.
This is very specific for you and depends on factors like 
▌Your phototype 
▌UV index, cloudy day or not 
▌Season & climate
▌Time of day
▌Latitude & altitude
▌How much product you applied: amount
▌How well you distributed the product: coverage
▌Rubbing off: clothes or touching towelling
▌Sweating
▌Activities like swimming, sauna, etc

MEASUREMENT SPF
SPF (Sun Protection Factor) measurement involves several methods, each with its own advantages and pitfalls.

In vivo method (ISO 24444)
ISO 24444 is the international standard for the in vivo determination of the Sun Protection Factor (SPF) of sunscreen products. This standard specifies a method for evaluating how well a sunscreen protects human skin against erythema, which is the reddening of the skin caused by UV radiation exposure.

▌In vivo testing: The SPF is determined by testing on human subjects. A controlled amount of sunscreen is applied to the skin, and the test involves measuring the Minimal Erythema Dose (MED) with and without sunscreen. The SPF is calculated as the ratio of these doses.
▌Procedure: The test involves exposing treated and untreated skin areas to UV radiation using a solar simulator. The MED is determined by observing the point at which slight but visible reddening occurs on the skin after exposure.
▌SPF Calculation: The SPF value is calculated as an arithmetic mean of all valid individual SPF values obtained from all test subjects.
▌Global Adoption: ISO 24444 has been widely adopted in nearly 60 countries, including those in Europe, Australia, New Zealand, Japan, and several others, ensuring a harmonized approach to SPF testing across different regions.
▌Advantages: Provides real-world data on sunscreen performance.
▌Disadvantages: Requires exposure of human subjects to UV radiation and sunburn (unethical). Can be time-consuming and expensive. Results may vary due to individual skin differences.
 
In Vitro Spectrophotometric Method
▌Process: Uses a spectrophotometer to measure UV transmission through a thin film of sunscreen applied to a substrate.
▌Measurement: Calculates SPF based on the absorption spectrum.
▌Advantages: Rapid, cost-effective, and doesn't require human subjects.
▌Disadvantages: May not accurately represent real-world conditions. Results can be affected by the substrate used and application technique.  

Double Plate Method (DPM), also known as the Cosmetics Europe In vitro method
Is a technique under development as ISO 23675. The Double Plate Method offers a promising alternative for sunscreen testing by eliminating the need for human subjects and providing a more standardized approach to measuring SPF. It is expected to be officially published as an international standard in early 2025.
▌Dual plate system: Utilizes two types of PMMA plates—moulded and sandblasted—to simulate the skin's surface. The combination of these plates helps overcome limitations related to the affinity of different sunscreen formulations for a single type of plate.
▌Automated spreading: The sunscreen is applied to the plates using a robot, ensuring consistent application that mimics human application but with improved reproducibility.
▌UV exposure: The plates are exposed to UV radiation with a spectrum similar to that used in the in vivo ISO 24444 method, allowing for assessment of the sunscreen's photostability and effectiveness.
▌Measurement: Initial absorbance is measured before UV exposure, and final absorbance is measured post-exposure. These measurements are used to calculate the in vitro SPF.
▌Validation and standardization: The method is currently in the validation process by ISO experts and aims to provide accurate, repeatable, and reproducible SPF predictions.
 
Hybrid Diffuse Reflectance Spectroscopy (HDRS)
Hybrid Diffuse Reflectance Spectroscopy (HDRS) is newer technique and associated with the ISO 23698 standard. This method is being developed as a non-invasive alternative to traditional SPF measurement methods like ISO 24444, which involves in vivo testing on human skin using UV radiation to provoke an erythemal response.
▌Non-Invasive: HDRS does not require UV exposure that causes erythema (skin reddening), thus addressing ethical concerns associated with traditional SPF testing methods.
▌Hybrid approach: Combines in vivo diffuse reflectance spectroscopy on the skin with in vitro transmission measurements of sunscreen products. This allows for comprehensive assessment without causing physical harm to test subjects[5].
▌Comprehensive assessment: Provides a hybrid spectrum that evaluates both UVB and UVA protection, correlating closely with traditional in vivo SPF and in vitro UVA protection factor (UPF) test results[3].
▌Ethical and safe: Eliminates the need for UV-induced skin reactions, making it a more ethical testing method.
▌Efficient: Reduces the time required for testing compared to traditional methods.
▌Reliable: Demonstrated good correlation with established standards like ISO 24444 and ISO 24443, making it a viable alternative for sunscreen testing.
The HDRS method is currently at the Final Draft International Standard (FDIS) stage, indicating it is close to becoming an official ISO standard, expected to be published in early 2025. 
Researchers and regulatory bodies continue to work on improving these methods to ensure more accurate and reliable SPF measurements across different sunscreen formulations.
 
UVA PROTECTION
A higher SPF value generally correlate with higher UVA protection, especially in regions requiring the 1:3 UVAPF-to-SPF ratio for broad-spectrum labeling. It is called the UVA-COLIPA ratio as defined in ISO 24443 or Critical Optical Radiation Absorption (CORA). CORA is a measure used to assess the UVA protection of sunscreen products. According to European regulations, the UVA protection factor of a sunscreen must be at least one-third of its labeled SPF value. This ensures that sunscreen products provide a minimal and balanced level of protection against both UVA and UVB radiation. 
 
UVA protection in sunscreens is sometimes not listed but disclosed on the product by a black circle with UVA in it, or listed and measured using different systems across various continents:
 
Europe
The UVAPF is not per se disclosed on the product.Look for the black circle with UVA written in it.
▌PPD (Persistent Pigment Darkening): Measures UVA protection directly.
▌UVAPF (UVA Protection Factor): Must be at least 1/3 of the labeled SPF value.
▌Critical Wavelength: At least 370 nm for broad-spectrum protection. 

Asia (particularly Japan and Korea)
PA System: Derived from PPD measurements.
▌PA+ (PPD 2-4)
▌PA++ (PPD 4-8)
​▌PA+++ (PPD 8-16)
▌PA++++ (PPD 16 or higher) 

United States
▌Broad Spectrum: Indicates UVA protection, but no specific rating system.
▌Critical wavelength of at least 370 nm required for broad-spectrum labeling.

Australia
▌Broad Spectrum: Similar to US, requires UVA protection to be at least 1/3 of the labeled SPF like in Europe

Measurement methods
▌In vivo PPD Test: Measures skin darkening after UVA exposure.
▌Critical Wavelength: Determines the wavelength below which 90% of UV absorption occurs.
▌In vitro PMMA Plate Method: Used for measuring UVAPF-to-SPF ratio in Europe. 

HOW SUN-FILTERS WORK
UVA FILTER 
▌absorption maximum between 320 and 400 nm 
UVB FILTER
▌absorption maximum between 290 and 320 nm 
BROADSPECTRUM FILTER 
▌absorption throughout the UV spectrum from 290 to 400 nm
 
MINERAL VS CHEMICAL
The terms "mineral" and "chemical" filters in sunscreens are often considered inaccurate because they do not accurately reflect the chemical nature of the ingredients used. Instead, the terms "organic" and "inorganic" are more precise:
 
Why the terms matter
1. Chemical nature: The term "chemical" suggests synthetic or artificial, which can be misleading since both organic and inorganic filters involve chemical processes. "Organic" refers to carbon-containing compounds, while "inorganic" refers to mineral-based compounds without carbon.
2. Mechanism of action: The terms "physical" and "chemical" imply different mechanisms of action (reflection vs. absorption), but both types of filters can absorb UV radiation.
3. Consumer perception: Using accurate terminology helps consumers make informed choices based on their preferences for natural or synthetic ingredients and their environmental impact.
 
CHEMICAL OR ORGANIC FILTERS
▌Composition: These are carbon-based compounds designed to absorb UV radiation. They include aromatic compounds with carbonyl groups, such as cinnamates and benzophenones.
▌Mechanism: Organic filters absorb UV radiation and undergo a reaction, releasing the absorbed energy as heat or light of a lower-energy longer wavelength such as infrared radiation (i.e., heat).
▌Examples: Avobenzone, octocrylene, and oxybenzone and ecamsule are common organic filters.
▌Stability: Most newer organic filters are photostable, meaning they don´t stop working after absorbing too much UV light. However, avobenzone and octinoxate are photo-unstable and are therefore often combined with other filters. Butyl Methoxydibenzoylmethane, (avobenzone), provides excellent protection across the entire UVA range, including UVA1 (340-400 nm) and UVA2 (320-340 nm). This makes it the global gold standard for UVA protection.
▌Advantages: Chemical filters have a high “staying power”, meaning they don´t clump and stay in an even layer on the skin, often have lighter pleasant textures and offer high UVA protection.
▌Act to block ultraviolet radiation, which is light with wavelengths shorter than visible light
    ▌UVA1 (300-400) also called long UVA
    ▌UVA2 (315-340) 
    ▌UVB (290-315) radiation 
    ▌UVC (100-290) nm - not relevant  

.PHYSICAL OR INORGANIC FILTERS
▌Composition: These are mineral-based compounds, typically metal oxides like titanium dioxide (TiO2) and zinc oxide (ZnO).
▌Mechanism: Inorganic filters primarily reflect and scatter (actually also into the skin) UV radiation but can also absorb it due to their semiconducting properties. Act to block ultraviolet radiation which is light with wavelengths shorter than visible light.
▌Advantages: They offer broad-spectrum protection, are photostable, less likely to cause irritation.
▌Disadvantages: might leave a white cast, are sometimes cosmetically less elegant (greasy and thick) or less suitable for darker phototypes, and tend to clump together on your skin, even though you might not notice this. You need quite a large amount of zinc oxide to absorb a relatively small amount of UV and the risk is rather high that you don´t use enough.
▌Dermatologists in the US were recommending mineral sunscreens, because in the US the sunfilters approved by the FDA are restricted and to reach the UVA1 protection level, had to contain either avobenzone as organic filter or zinc oxide as inorganic filter. Although zinc oxide has lower UVA-PF, it was considered to have less irritation potential and was therefore preferred. Note: Avobenzone is an excellent filter found in sunscreens suitable and tested on sensitive skin, however it is always recommended to ask for a sample and try before you buy. 
▌Experimental studies have shown that when particle sizes are very small, as in micronized sunscreens, the mechanism of action is similar to that of chemical filters. Some say that only 5-10% of the mode of action is “reflection and scattering” and the rest is comparable to chemical filters.
 
WATERRESISTANT – WATERPROOF - SWEATPROOF
In Europe and other regions, the terms "water-resistant," "waterproof," and "sweatproof" on sunscreen labels have specific meanings and regulations.
The ISO standard for measuring water resistance in sunscreens is ISO 16217. This standard outlines the procedure for evaluating water resistance by comparing the Sun Protection Factor (SPF) before and after water immersion.
 
According to the guidelines:
1. A sunscreen can be labeled as "water-resistant" if it retains at least 50% of its SPF value after 40 minutes (2 x 20 minutes) of water immersion compared to the initial SPF value before immersion.
2. For "very water-resistant" claims, the product must maintain its effectiveness after 80 minutes (4 x 20 minutes) of water immersion.
▌Measurement method: The sunscreen is applied to the skin and immersed in water according to a strict ISO-protocol for the claimed duration. Afterwards, the SPF is measured to ensure it remains effective.
▌Disadvantages: 
    ▌Variability: Differences in application thickness and skin type can affect results.
   ▌Environmental factors: Chlorine, saltwater, and physical activity can impact sunscreen effectiveness, hence the testing method does not reflect real world.
 
While there are regional differences in how water resistance is labeled and regulated, no sunscreen can be truly waterproof or sweatproof. Consumers should look for "water-resistant" labels and reapply sunscreen regularly (every 2 hours) and preferably after swimming, sweating or toweling to maintain protection.
 
Europe
Water-resistant
▌Regulations: European regulations do not allow claims of "waterproof" or "sweatproof" due to the potential for misleading consumers.
 
United States
Water-resistant
▌Definition: Similar to Europe, U.S. regulations allow sunscreens to be labeled as "water-resistant" for either 40 or 80 minutes.
▌Regulations: The FDA prohibits the use of "waterproof" and "sweatproof" on labels since 2011, requiring clear indications of how long the product remains effective in wet conditions. 

Australia
Water-resistant
▌Definition: Australian regulations are strict, allowing water-resistant claims only if the sunscreen maintains its SPF after immersion in water for up to 4 hours.
▌Measurement method: Similar testing methods are used as in Europe and the U.S., with rigorous standards set by the Therapeutic Goods Administration (TGA).
 
SAFETY CONCERNS & MYTHS

Nanoparticles: Zinc oxide and titanium must be ground into tiny particles to avoid forming a “white cast”. This can be either micro-particles (100-250o nm) or even smaller than 100 nm (nanoparticles). Even these smallest particles don´t penetrate beyond the stratum corneum and are considered safe. They might penetrate deeper and cause reactions when applied on damaged skin, for example just after an aesthetic procedure like peeling, fractional laser etc. 

Endocrine disruption: Claims about hormone disruption are largely based on animal studies with unrealistically high doses. Human studies have not shown significant risks, which was confirmed after careful re-evaluation by regulatory bodies. The only filter to avoid is 4-Methylbenzylidene Camphor, also known as 4-MBC or Enzacamene, is a chemical sunscreen agent used primarily as a UVB filter. 4-MBC has been banned in the European Union due to concerns about its safety or lacking proper safety data.

Systemic absorption: While some sunscreen ingredients can be absorbed into the bloodstream, the levels are considered too low to cause harm. Larger companies and probably some smaller ones too, have serious safety departments who will make toxicology calculations taking lifetime exposure of the ingredient(s) and formula into consideration. They are in constant exchange with regulatory bodies and both exist to keep you safe. There is zero tolerance for systemic or side effect of skincare or sunscreens.

Free radical formation: Some filters in sunscreens react with UV and form free radicals, thus cause oxidative stress. Intelligent sunscreen formulations contain anti-oxidants to neutralize free radicals from UV, Blue Light and potentially UV-filters. My personal favorite is Licochalcone A, because it it is the most potent anti-oxidant to neutralize free radical activity from both UV and High Energy Visible Light. Moreover, it can work as both first line defence (extracellular) and second line defense (intracellular), backed up by science. 

DIY sunscreens: Crafting sunscreens at home can lead to uneven distribution of the filters if ingredients are not well mixed, too low concentrations of filters and thus inadequate protection. Serious sunscreen brands put their products through a long development process including SPF, UVA, microbiology, stability, safety and tolerability testing, product in use studies with hundreds of volunteers and clinical studies under supervision of a dermatologist. The potential skin damage from insufficient SPF far outweighs any cost savings, for both aesthetic and health reasons. 

Sunscreens cause skin cancer: They don´t and there is ample scientific evidence to support this. I do want to re-emphasise to apply sunscreen in the recommended amount and ensure adequate coverage to be well protected. Reapply every 2 hours, especially after swimming, perspiring or towelling.

Sunlight is inherently healthy: While some sun exposure is absolutely beneficial, excessive exposure is a known carcinogen and will make your skin age faster or cause hyperpigmentation. Do I need to remind you of famous pictures of a woman with leather-like looking very tanned wrinkled skin and the truck driver with severe solar elastosis on the side of his face exposed to sunlight? Sun is fun, however please be safe. Read more.

I must apply sunscreen every day: In case of skin cancer prevention I would consider Australia a reliable benchmark. The Cancer Council Australia and the Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) recommend using sunscreen on days when the UV Index forecast is 3 or higher. However, if you want to be safe and significantly decrease the risk of skin cancer, prevent premature aging and/or hyperpigmentation, daily use of sunscreen in face (or other unexposed areas) is highly recommended even with a lower UV Index, especially when using medication, skincare or undergo treatments making your skin more prone to sun-damage. Too much or too often is almost not possible when it comes to sunscreen use. 

TikTok trends and celebrity recommendations: Use common sense and what works well for them, might not work for you. "Scary sunscreen stories" seem to go viral at the moment and I wish the same people with huge following like Dr. Andrew David Huberman (associate professor of neurobiology and ophthalmology at Stanford University School of Medicine), or Gary Brecka (human biologist and biohacker) would instead of creating and spreading sunscreen myths focus on proper evidence based education on sunscreen use and skin cancer prevention. 

Ocean safe and sustainable formulas/products: The term "reef-safe" has become a buzzword in the sunscreen industry. Ocean or reef safe formula´s are usually formulated without microplastics (UNEP definition), with biodegradable polymers and improved filter-systems complying with regulations like the ones in Hawaii and Palau, are more sustainable formula´s in preferably in ditto packaging. Sustainability is extremely complicated, involving the whole supply-chain from ingredient sourcing, production, packaging (primary and secondary), transportation to recyclability and even marketing materials. I consider every step towards preserving our marine life and environment in general a significant one. 

TIPS
 
1. Select the right sunscreen: It's crucial to choose a sunscreen that suits your skin type, purpose and one you enjoy using. Opt for a higher SPF than you think you need, as you often apply less than the recommended amount to reach the labelled SPF on the product. The findings of this study suggest that at the start of the workday proper application of 2 mg/cm2 of SPF50+ (which is 60 or higher) sunscreen will degrade to an SPF level of less than 30 at 4 hours after application. Read more Take this into consideration when buying your sunscreen, you don’t reapply before your lunch break and go outside in the sun for a walk. Big disclaimer is that matters might be worse than reflected, as in some areas your sunscreen will have worn off completely and coverage is important for protection. A useful tip is to apply sunscreen twice; studies show that double application helps achieve the labeled SPF more reliably. Of course you can double up with a daycare containing SPF and a sunscreen.

2. Apply sunscreen properly: The most important of all tips. Take the time to apply sunscreen thoroughly about 15-20 minutes prior to going outside. Coverage and even distribution of the correct amount are key. The majority of sunscreens can be used after your daily moisturiser or serum and before (gently applied) make-up. Not all ingredients might go well together. Tinted products containing iron oxides offer additional protection against UV and High Energy Visible Light, however make-up with SFP is not sufficient as you will probably not apply enough of it to reach the listed SPF without looking cakey. 

3. Be aware of Blue Light: Although not mentioned in this post, blue light from sunlight can harm your skin. It's important to be informed about its effects, particularly darker phototypes. Read more.

4. Rethink tanning: There is no such thing as a healthy tan (except maybe a spray tan). A tan indicates skin damage. It's essential to recognize this and take protective measures. Read more.

5. Consider DNA damage: DNA damage from UV exposure is serious, though the skin can repair itself to an extent, there are ways to prevent damage (sunscreen) and support this repair process. Read more.

6. Prioritise SPF: Using (expensive) rejuvenating serums or creams is futile without daily sunscreen protection. Sunscreen is the foundation of any effective skincare routine. Moisturisers with a high SPF will offer the same UV protection as sunscreen, because SPF is regulated. The same amount as sunscreen is recommended to be applied and reapplied: 2mg per cm2. Calculate about 1 gram for face, 1 gram for the neck, 1 gram for décolletage, 1 gram for the back of 1 hand, 2 grams for your scalp and 2 grams per forearm. The precise amount depends on your skin surface.

7. Eye safety: Some filters may cause irritation when they migrate into the eye area. This is very annoying. You can avoid migration of the product by applying a little bit of translucent powder, a trick used by make-up artists to “set” foundation and concealer, however this works well for sunscreen too. Wear sunglasses for extra protection of the delicate eye area. Although some might recommend the use of mineral filters in the eye area, I am hesitant to make such a recommendation as mineral filters are more prone to migrate and clump than chemical filters. 
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8. Shiny greasy skin: Some sunscreens might make your skin look greasy or shiny. Moreover, skin´s sebum production is increased during daytime: circadian rhythms. There are special sunscreens for oily skin types with mattifying pigments and even sebum regulating technology. For example L-Carnitine has shown to reduce sebum production by 48%. Careful blotting, the use of a translucent or even better a powder with iron oxide containing colour pigments also help to mattify. 
 
Always consult a qualified healthcare professional to determine what the most suitable approach is for your skin health and beauty.
Sun is fun! Take care.

Anne-Marie
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Reference
 [1] van Bodegraven et. al. Redefine photoprotection: Sun protection beyond sunburn. Experimental Dermatology, 2024 ​​