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
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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.
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[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
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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:
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[5] Ichimiya T et al. Autophagy and Autophagy-Related Diseases: A Review. Int J Mol Sci. 2020
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[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
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Blue light, is also known as high-energy visible (HEV) light and is the most energetic part of the visible light spectrum (380 - 700 nm) with wavelengths ranging from indigo or ultramarine light 420-440 nanometers, blue light 450-495 nanometers to cyan light 480 - 520 nanometers. Blue light has lower energy than ultraviolet (UV) radiation (280–400 nm) and can reach further into the dermis, up to the depth of 1 mm. [1] Sunlight is the primary natural source of blue light. Up to 50% of the damaging oxidative stress in human skin is generated in the VIS spectrum and the other 50% by UV light [2], contributing to premature ageing, ox-inflammageing and hyperpigmentation like age spots.
 
Blue light from electronic devices
The use of electronic devices has led to increased exposure to artificial blue light sources, however the amount of blue light emitted during the conventional use of electronic devices is by far not enough to trigger harmful skin effects. If you sit in front of a monitor uninterrupted for a week at a distance from the screen of approximately 30 cm, this would be the same as the blue light intensity of spending one minute outside on a sunny day in Hamburg Germany at around midday at midsummer. If you hold a smartphone right next to the skin, the intensity does increase, but it would still take approximately 10 hours of uninterrupted use to match the effect on the skin of just one minute of sunlight. The emissions from electronic devices are barely noticeable in comparison to natural blue light directly from the sun and are, thus negligible. However, blue light or HEV light from sunlight can be harmful for skin. Dr Ludger Kolbe Chief Scientist for Photobiology and his team at Beiersdorf AG did pioneering research regarding the harmful effects of HEVIS. [3-4]

I would also like to take the opportunity to debunk an important myth at the start of this article as infrared or near infrared light does not induce damaging free radicals (even in high amounts), there is no such thing "infra-ageing" as a result or IR and in fact red light photobiomodulation supports skin rejuvenation. Read more

Direct effects of blue light and HEV Light on skin
Blue light and HEV light can have both beneficial and detrimental effects on the skin. The most significant direct effects are mediated through their interaction with chromophores, such as flavins, porphyrins, and opsins, which can trigger the overproduction of reactive oxygen species (ROS), reactive nitrogen species (RNS). and hyperpigmentation. Reactive oxygen and nitrogen species cause DNA damage and modulate the immune response. [1]

This oxidative stress can lead to:
Photo-ageing: Exposure to blue light and HEV light can induce premature skin aging, causing wrinkles, fine lines, and loss of elasticity.
Hyperpigmentation: Blue light and HEV light can stimulate melanin production, leading to uneven skin tone and the development of age spots or other forms of hyperpigmentation.
DNA damage: The ROS and RNS generated by blue light and HEV light can cause DNA damage, plus potentially increase the risk of skin cancer.
Inflammation: The oxidative stress triggered by blue light and HEV light can cause an inflammatory response in the skin, exacerbating conditions like acne, eczema, and psoriasis.

Molecular and physiological mechanisms of direct blue light effects on the skin [1]

1. ROS generation 
2. Carotenoid degradation. Carotenoids are one of the key antioxidants protecting from ROS damage. Most of the carotenoids found in the skin absorb radiation in the blue section of the spectrum. The highest concentration of carotenoids in the skin is found in the stratum corneum, the outermost skin layer that serves as permeability barrier, thus preventing transepidermal water loss. 
3. Flavin degradation (the main chromophores responsible for blue light-induced ROS overproduction and abundant in mitochondria)
4. DNA damage (keratinocytes + melanocytes) both oxidative and cyclobutane-pyrimidine-dimer (CPD) DNA lesions
5. Whole genome DNA methylation (epigenetic modification)  
6. Decreased proliferation of fibroblasts and keratinocytes, however to the contrary also stimulation of proliferation and differentiation keratinocytes 
7. Decreased expression TP73  the gene involved in proliferation, in primary human keratinocytes and melanocytes
8. Decreased cell viability 
9. Apoptosis 
10. Decreased ATP synthesis Read more 
11. Decreased expression of genes regulating mitochondrial function  & blue light-induced ROS generation damages mitochondrial DNA and disrupts respiration
12. Increased EGFR phosphorylation and reduced EGFR expression (keratinocytes)
13. Downregulation of TGF-β signaling fibroblasts 
14. Increased pro-inflammatory cytokines 
15. Increased COX-2 levels 
16. Delayed recovery of epidermal permeability barrier
17. MMP1-release (collagenase 1) responsible for collagen type I and III degradation
18. Decreased procollagen 1 content (fibroblasts) 
19. Decreased collagen lattice contractility
20. Increased protein carbonylation (one of the most harmful irreversible oxidative protein modifications and considered a major hallmark of oxidative damage)
21. Hyperpigmentation and age spots (compared with UV, blue light produced darker hyperpigmentation that lasted longer in phototypes IV-VI).  While both UV and blue light cause hyperpigmentation via ROS generation, only blue light causes hyperpigmentation via opsin stimulation.  Opsins are a class of photosensitive G protein-coupled receptors, which regulate various signaling cascades found in retina and skin, hence this is why both glasses (although according to some studies blue light glasses don't do their job properly [14] and topical products protecting from damaging blue light make sense. Blue light irradiation over 5 consecutive days results in increased perinuclear vacuolization in keratinocytes and an increased number of melan-A-positive cells. Blue light irradiation increased melanin production, oxygen saturation, and hemoglobin content in female volunteers. When exposed to blue light, OPN3 initiated a signaling cascade that leads to increases in the enzymes tyrosinase and dopachrome tautomerase (DCT) that are responsible for melanogenesis. Blue light-induced hyperpigmentation is more pronounced and persistent in people with darker skin (Fitzpatrick types III–VI), likely because they have higher levels of tyrosinase–DCT complexes than people with lighter skin (Fitzpatrick types I and II). 
22. Erythema (redness) most pronounced in individuals with lighter skin types (Fitzpatrick skin types I-III) - 17% compared to UV
23. Photolytic release of NO from nitrosated proteins (can cause significant local vasodilation and possibly even to reduce systemic blood flow)
24. Decreased expression of antimicrobial peptides (AMPs eliminate pathogenic micro-organisms, including bacteria, fungi, and viruses)
25. Blue light has a greater contribution to ROS generation from carbonylated proteins located in the stratum corneum than UV. CPs are detected in a higher frequency at sun-exposed sites of the skin in elderly subjects. 
26. At wavelengths of 412–426 nm and high fluences, blue light is cytotoxic to human keratinocytes and skin-derived endothelial cells.

The severity of these effects can vary depending on skin type, duration and intensity of exposure.

Indirect effects of blue light and HEV Light on skin
Blue light and HEV light can also have indirect effects on the skin by disrupting the body's circadian rhythms. This occurs via both the central mechanism, which involves stimulation of light-sensing receptors located in the retina, and via the peripheral mechanism, which involves direct interaction with skin cells. By disrupting the normal circadian rhythm, blue light can negatively affect the skin's natural overnight repair and regeneration processes. [1] 

The circadian rhythm has been shown to affect multiple cellular and physiological processes occurring in the skin:

• Normal keratinocyte proliferation peaks at night. 
• The rate of blood flow, permeability to both hydrophilic and lipophilic compounds and transepidermal water loss are all higher in the evening and at night than during the day.
• Sebaceous gland activity is highest during the day and decreases in the evening and at night.
• Repair of sunlight-induced DNA damage also mostly occurs at night. 

Topical dermatological skin care products containing bio-active ingredients supporting skin's repair and regeneration mechanisms are thus more effective when used later in the day.

Molecular mechanisms of indirect effects of blue light on the skin [1]

1. Decreases plasma melatonin
2. Delayed melatonin onset
3. Decreased melatonin duration
4. Decreased melatonin exposure
5. Decreased subjective sleepiness
6. Decreased proximal skin temperature
7. Increased cortisol level
8. Decreased per 1 transcription
9. Alteration of ECTO-NOX oscillatory pattern
10. Decreased keratin-1 & keratin-10
11. Elastic fiber network disruption

A new study by researchers from the University of Basel, published in Nature Human Behavior 2024 however suggests that blue light might not impact our "internal clock". 

Ideal daytime & nighttime skin care regimen
When considering cosmetic interventions, a strategy of daytime protection plus defense and night-time repair may be optimal. The skin's own repair mechanisms, such as base excision repair and nucleotide excision repair, attempt to mitigate blue light induced DNA damage. [12]

Daytime protection plus defense
Of course prevention and/or reduction of blue light exposure from sunlight is key. Reduce the time spent on electronic devices, especially before bedtime, can help minimize the disruption of circadian rhythms and the indirect effects of blue light and HEV light on the skin.
Against premature ageing and hyperpigmentation an evidence based effective approach could be the daily use of tinted broad-spectrum sunscreen preferably containing Licochalcone A (the most effective anti-oxidant reducing damaging free radical activity from both UV and blue light and moreover protects against collagenase MMP-1 expression) strengthening skin's biological defense [4-5-6-7], while iron oxides in colour pigments provide physical protection against blue light. Against hyperpigmentation there are (tinted) sunscreens which on top contain the most potent human tyrosinase inhibitor found in dermatological skin care called Thiamidol® [8-9] and one of the 3 ingredients in the "new Kligman Trio" (NT)  [18] and Glycyrrhetinic Acid which supports skin's DNA repair and skin pigmentation [10] and inhibits hyaluronidase activity (HYAL1). Most regular sun filters used in sunscreen don't offer any protection against blue light, however according to the website of BASF the chemical UV filters Tinosorb® A2B and Tinosorb® M can reduce the exposure to blue light. [11] Ectoin or ectoine has shown positive effects against high-energy visible light by decreasing the levels of OPN3 or Opsin-3, a photoreceptor involved in light perception, after HEVL exposure, suggesting role in mitigating light-induced stress on skin cells. Although ectoin does not act as an anti-oxidant or provide a physical barrier, it effectively preserves cellular integrity and function under HEVL stress conditions. [19] However, 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. [20] More data would be needed.
​
Scattering and absorption of blue light [5]
The penetration depth of visible light is influenced by the reflection, scattering, and absorption mediated not only by the skin’s physical barrier but also by the VL chromophores in the skin and Fitzpatrick skin or photo-type (FST). The primary VL-scatter and absorption molecules in the skin include hemoglobin, melanin, bilirubin, carotene, lipids, and other structures, including cell nuclei and filamentous proteins like keratin and collagen. Melanin and keratins are the primary VL absorbers and scatterers in the epidermis, while hemoglobin is the dominant absorber, and collagen is the major VL scatter in the dermis. Melanin's absorption spectrum ranges from 200 to 900 nm, with the peak absorption varying based on melanin moiety. This means that individuals with darker skin types, which have higher melanin content, are more prone to hyperpigmentation from blue light or VIS due to the greater absorption and scattering of VIS in their skin on top of the previously mentioned higher levels of tyrosinase–DCT complexes leading to increased melanogenesis, leading to both transient and long-lasting pigmentation [13],  dependent upon the total dose and exacerbation of melasma especially in individuals with FSTs III to VI. 

Blue light tanning
Recent data demonstrate synergistic effects between VL and UV-A on erythema and pigmentation. VL-induced pigmentation is more potent and more sustained than UVA1-induced pigmentation in darker skin tones.Typically, three mechanisms are involved in the responsive reaction of melanocytes to VL, with increased melanin content: immediate pigment darkening (IPD), persistent pigment darkening (PPD), and delayed tanning (DT). [15] Read more. VL can also exacerbate post inflammatory hyperpigmentation (study with FST IV and V). [16] 

Blue light therapy
While the detrimental effects of blue light and HEV light on the skin have been well-documented, these wavelengths have also shown promise in the treatment of certain skin conditions. In controlled clinical settings, blue light has been used to:
Treat Acne: Blue light can reduce the growth of Propionibacterium acnes, the bacteria responsible for acne, and has an anti-inflammatory effect.
Manage Psoriasis and Atopic Dermatitis: Blue light has been found to have an anti-inflammatory and antiproliferative effect, making it potentially beneficial for the treatment of these chronic inflammatory skin diseases.
Reduce Itch: Some studies have suggested that blue light may help alleviate the severity of itching in certain skin conditions.
Vitiligo:  Blue light therapy via LEDs can stimulate repigmentation in patients with vitiligo with minimal adverse events, however larger studies are needed. [17] 
The optimal protocols for blue light therapy are still being developed, and the long-term safety of this treatment modality requires further investigation and should not be initiated without HCP recommendation and monitoring.

Overall, the research suggests that prolonged or excessive exposure to high-energy blue light, can have negative long-term effects on skin structure, function, and appearance in all phototypes. As our understanding of the individual variations in skin's response to blue light exposure deepens, the development of personalised or tailored effective solutions become increasingly more tangible. Always consult a qualified healthcare professional or dermatologist to determine what the most suitable approach is for your particular skin condition and rejuvenation goals. 

Take care!
​Anne-Marie

References

1. Skin Pharmacol Physiol. Direct and Indirect Effects of Blue Light Exposure on Skin: A Review of Published Literature Orawan Suitthimeathegorn et al. 2022
2. Methods, Effects on detection of radical formation in skin due to solar irradiation measured by EPR spectroscopy
   Stephanie Albrecht et al. 2016
3. EADV Congress, Paris, France 2018, Poster No. P1672. Assessment of hazard potential of high-energy visible light from electronic devices for the skin. Batzer J, Eggers K, Kolbe L, Weise J. 
4. High-energy visible light at ambient doses and intensities induces oxidative stress of skin—Protective effects of the antioxidant and Nrf2 inducer Licochalcone A in vitro and in vivo Tobias Mann et al. 2019
5. Journal of the American Academy of Dermatology Impact of visible light on skin health: The role of antioxidants and free radical quenchers in skin protection. Henry W. Lim MD et al. 2022
6. EADV Poster 2018 Licochalcone A protects from reactive oxygen species and matrix metalloproteinase-1 expression induced bz high-energy visible light irradiation in vitro Ladewig S. et al.
7. Experimental Dermatology, Licochalcone A activates Nrf2 in vitro and contributes to licorice extract-induced lowered cutaneous oxidative stress in vivo Jochen Kühn et al. 2014
8. J Invest Dermatol. Next Time, Save Mushrooms for the Pizza! Thomas J Hornyak 2018
9. J Invest Dermatol. Inhibition of Human Tyrosinase Requires Molecular Motifs Distinctively Different from Mushroom Tyrosinase
   Tobias Mann et. al 2018
10. Journal of Investigative Dermatology Conference-paper: 39th Annual European Society for Dermatological Research: Glycyrrhetinic Acid: A Novel Modulator of Human Skin Pigmentation and DNA-Repair M. Hong et a. 2009
11. BASF all about sun blue light exposed 
12. Photodermatol Photoimmunol Photomed Blue light induces DNA damage in normal human skin keratinocytes Cécile Chamayou-Robert et al. 2022
13. Pigment Cell Melanoma Res. Differences in visible light-induced pigmentation according to wavelengths: a clinical and histological study in comparison with UVB exposure Luc Duteil et a. 2014
14. Cochrane Database of Systematic Reviews Review - Intervention Blue‐light filtering spectacle lenses for visual performance, sleep, and macular health in adults Sumeer Singh et al. 2023
15. J Clin Med. The Emerging Role of Visible Light in Melanocyte Biology and Skin Pigmentary Disorders: Friend or Foe? Xuanxuan He et al. 2023
16. Journal of the American Academy of Dermatology Cutaneous interaction with visible light: What do we know? Cohen MD et al 2023 
17. Review Photodermatol Photoimmunol Photomed A focused review of visible light therapies for vitiligo Mitchell J Winkie 2024
18. J Eur Acad Dermatol Venereol. Efficacy and safety of a novel triple combination cream compared to Kligman's trio for melasma: A 24-week double-blind prospective randomized controlled trial Clémence Bertold et al. 2023
19. Bicard-Benhamou, Valérie A global and powerful approach to circumvent harmful effects of blue light and IR-A irradiations on the skin EMD Group
    
20. Sci Rep 7, 15272 (2017). Schröter, M.A., Meyer, S., Hahn, M.B. et al. Ectoine protects DNA from damage by ionizing radiation.

Mitochondria are the "powerhouses" or "lungs" of our cells and bioenergetic semi-autonomous organelles with their own genomes and genetic systems. [1] They are responsible for generating the energy that fuels a wide range of cellular processes in the skin, including cell signaling, pigmentation, wound healing, barrier integrity [2], metabolism and quality control.  [3] Mitochondria exist in each cell of the body and are generally inherited exclusively from the mother. Their primary role is cellular respiration; a process converting the energy in nutrients (like glucose) into a usable form of energy called ATP or Adenosine Triphosphate. Mitochondria are particularly abundant in the skin, reflecting the skin's high metabolic demand. When the functionality of mitochondria is impaired or declines, it impacts skin's vitality, health and beauty. Mitochondrial dysfunction is 1 of the 12 hallmarks of skin ageing. 

The skin is particularly susceptible to mitochondrial stress due to its constant exposure to environmental insults, such as UV radiation, pollution, and other oxidative stressors. These factors can damage mitochondrial DNA, leading to increased production of reactive oxygen species (ROS) and disrupting the delicate balance of cellular processes. [4] In aged post-mitotic cells, heavily lipofuscin-loaded lysosomes perform poorly, resulting in the enhanced accumulation of defective mitochondria, which in turn produce more reactive oxygen species causing additional damage (the mitochondrial-lysosomal axis theory). [5]

Optimal mitochondrial function is indispensable for sustaining the specialized functions of each cell type, like keratinocyte differentiation, fibroblast ECM production, melanocytes melanin production and distribution, immune cell surveillance, sebocytes and adipocytes. [6] Mitochondrial dysfunction is both directly and indirectly linked to chronological ageing and photo-ageing. [7] As mitochondrial function declines, the skin's ability to regenerate and repair itself is decreased. [2] This results in visible signs of aging, such as wrinkles, loss of elasticity, dryness, uneven pigmentation, melasma, age spots, lipomas, impaired wound healing. [2-4-5-8-9] Mitochondrial dysfunction also has been implicated in skin conditions like acne, eczema, lupus, psoriasis, vitiligo, atopic dermatitis and even skin cancer. [10]

Ageing is associated with changes in mitochondrial morphology, including [6] 
▌Hyperfusion or increased fragmentation
▌Loss of mitochondrial connectivity [11-7]
▌Decline in the efficiency of oxidative phosphorylation, leading to reduced ATP production
▌Decline mitochondrial membrane potential (ΔΨM)
▌Compromised cellular energy metabolism
▌Reduced mitochondrial turnover (downregulated biogenesis)
▌Impaired mitochondrial quality control such as mitophagy (removal of damaged mitochondria through autophagy) [6]

These alterations are related to the increased production of ROS exhibited by mitochondria during ageing, the accumulation of which causes oxidative damage to mitochondrial and cell components contributing to cellular senescence. [12] 

Good mitochondrial function or metabolism: [7]
▌Redox homeostasis: (the way of reducing oxidative stress) - mitochondrial respiration and ROS production are essential for keratinocyte differentiation
▌ATP production: Adenosine Triphosphate provides energy to drive and support many processes in living cells (and GTP)
▌Respiration: mitochondrial respiration is the most important generator of cellular energy
▌Biogenesis: allows cells to meet increased energy demands, to replace degraded mitochondria and is essential for the adaptation of cells to stress [6]
▌Calcium homeostasis
▌Cellular growth
▌Programmed cell death (apoptosis) reducing cell senescence [13]
▌Mitochondrial protein synthesis: mitochondria typically produce 13 proteins encoded by mitochondrial DNA (mtDNA)

Dysfunctional Mitochondria: [7]
▌Oxidative stress
▌Decreased ATP levels
▌Dysfunctional OXPHOS: Oxidative phosphorylation, a metabolic pathway in which enzymes oxidize nutrients to release stored chemical energy in the form of ATP
▌Altered mitochondrial biogenesis 
▌Calcium imbalance
▌Cell death

Mitochondrial proteins
Mitochondria contain >1,100 different proteins (MitoCoP) that often assemble into complexes and supercomplexes such as respiratory complexes and preprotein translocases. The chaperones Heat Shock Proteins HSP60-HSP10 are the most abundant mitochondrial proteins. [3] Small heat shock proteins form a chaperone system that operates in the mitochondrial intermembrane space. Depletion of small heat shock proteins leads to mitochondrial swelling and reduced respiration. [14]

Mitochondrial hyperpigmentation
Emerging research has shed light on the intricate relationship between mitochondrial dysfunction and the development of hyperpigmentation, a condition characterized by the overproduction and uneven distribution of melanin in the skin. One of the key mechanisms underlying this connection is the role of mitochondria in the regulation of melanogenesis, the process by which melanin is synthesized. Mitochondria are involved in the production of various cofactors and signaling molecules that are essential for the activity of tyrosinase, the rate-limiting enzyme in melanin synthesis. [15] When mitochondrial function is impaired, it can lead to an imbalance in the production and distribution of these cofactors and signaling molecules, ultimately resulting in the overproduction and uneven deposition of melanin in the skin. [15] This can manifest itself as age spots, melasma, and other forms of hyperpigmentation. The link between mitochondrial dysfunction and hyperpigmentation has been further supported by studies on genetic disorders that involve mitochondrial dysfunction, such as mitochondrial DNA depletion syndrome. In these conditions, patients often exhibit a range of pigmentary skin changes, including patchy hyper- and hypopigmentation, as well as reticular pigmentation. [16]

Mitochondrial crosstalk and exosomes
Mitochondria can crosstalk and move beyond cell boundaries. [17] Mitochondria-derived material might be transferred to neighboring cells in the form of cell-free mitochondria or included in extracellular vesicles [18-19]. This process supports cellular repair and contributes to vital mitochondrial functions. Besides restoring stressed cells and damaged tissues due to mitochondrial dysfunction, intercellular mitochondrial transfer also occurs under physiological and pathological conditions. [20] The transfer of active mitochondria from mesenchymal stem cells (MSCs) has been identified as a repair mechanism for rejuvenating damaged skin fibroblasts. [21] 

MITOCHONDRIAL SUPPORT
Move
According Martin Picard phD being physically active is a protective factor against almost everything health related. Exercise stimulates the production of mitochondria as more energy is required. 

Be hungry sometimes
If there is too much supply of energy acquired via food leads to mass shrinking of mitochondria or fragmentation. Don´t over-eat, be calorie neutral and sometimes being calorie deficient is good for mitochondria. Maintain a healthy weight, preferably with a mediterranean diet containing phenolic and polyphenolic compounds (increase mitochondrial function and number) nitrate rich vegetables, soybeans and cacao beans. 

​Mitohormesis
In model organisms, lifespan can be improved by compromising mitochondrial function, which induces a  hormetic response (“mitohormesis”), provided that this inhibition is partial and occurs early during development.

Feel good
Feeling good (positivity), especially at night, has a scientifically proven positive effect on mitochondrial health index, it is even a predictive factor. 

​Q10 or Coenzyme Q10 (CoQ10)
Q10 is part of the mitochondrial respiration chain and essential for cellular energy production. About 95% of our cellular energy is generated with support of Q10, which is produced by the human body itself. During skin ageing, both the cellular energy production and levels of Q10 are declined. Q10 is a powerful anti-oxidant [22], thus protecting cells from oxidative stress and damage and has proven to be able to "rescue" senescent cells by decreasing elevated senescent markers like p21 levels and β-Galactosidases positive cell numbers (in-vitro). Q10 is bio-active, increasing collagen type I and elastin production. [23] Q10 can be supplemented via nutrition, however also via topical application and is considered an evidence based active ingredient in skin care products.  Ubiquinol (reduced form) shows higher bioavailability compared to ubiquinone (oxidized form). [23] 

Pyrroloquinoline quinone (PQQ)
Q10 improves the energy in the mitochondria, however PQQ has shown to increase the number of mitochondria and a redox maestro. I´ve written a full post about this compound, which can be found as skincare ingredient and supplement. Read more about PQQ

Glutathione
Glutathione is formed in cell's cytoplasm from glutamic acid, cysteine and glycine. It is present in 2 forms: reduced (GSH) and oxidized (GSSG). Reduced GSH is an active anti-oxidant, while the presence of inactive GSSG is increased under oxidative stress. The ratio between GSH and GSSH is considered a measure of oxidative stress. Glutathione participates in redox reactions, acts as co-factor of many anti-oxidant enzymes and is the most important non-enzymatic anti-oxidant, essential for synthesis of proteins and DNA. Low Glutathione results in accelerated ageing and inflammatory skin diseases. Mitochondrial glutathione (mGSH) is the main line of defense for the maintenance of the appropriate mitochondrial redox environment to avoid or repair oxidative modifications leading to mitochondrial dysfunction and cell death. [24] Glutathione can be increased via supplementation via precursors cysteine or N-acetylcysteine (not recommended for pregnant women), a combination of Glycine and NAC (called GlyNAC) part of the popular "power of three" supplementation, or the reduced form of Glutathione itself, or increased via topical active ingredients like Licochalcone A. [25] 
I´ve written about GlyNAC in my post on autophagy.

Nicotinamide
NR nicotinamide ribosome which is the precursor of NMN nicotinamide mononucleotide which is the precursor of NAD+ nicotinamide adenine dinucleotide all could have a protective effect on mitochondria. Nicotinamide adenine dinucleotide is present in living organisms as ions NAD+ and NADP+ and in reduced forms NADH and NADPH. NADH is a cofactor of processes inside mitochondria:
▌ATP production
▌Activation of "youth proteins" sirtuins
▌Activation of PARP Poly (ADP-ribose) polymerase, a family of proteins involved in many cellular processes such as DNA repair, genomic stability and programmed cell death
▌Reduction of ROS (free radicals)
NAD levels as lowered during ageing. [26] One of the fans of NMN supplementation is Harvard Professor David Sinclair, best known for his work on understanding why we age and how to slow its effects and also featured in my article about hormesis. There are about 14 studies done to date with NMN supplementation in humans, one of which was done by Professor Sinclair. NMN supplementation does raise NAD levels, however there aren't substantial proven health benefits, unless you are unhealthy.

Resveratrol
Although systemically Resveratrol promotes mitochondrial biogenesis. [27] Other data shows that UVA (14 J/cm(2)) along with resveratrol causes massive oxidative stress in mitochondria. As a consequence of oxidative stress, the mitochondrial membrane potential decreases which results in opening of the mitochondrial pores ultimately leading to apoptosis in human keratinocytes. [28]

Magnesium
Magnesium supplementation has been shown to improve mitochondrial function by increasing ATP production, decreasing mitochondrial ROS and calcium overload, and repolarizing mitochondrial membrane potential. There are many forms of Magnesium, however Citrate, Malate and Orotate are particularly good for energy. 

L-Carnitine
Placebo-controlled trials have shown positive effects of L-Carnitine supplementation on both pre-frail subjects and elderly men. The effect is possibly mediated by counteracting age-related declining L-carnitine levels which may limit fatty acid oxidation by mitochondria. 

NEW Ergothioneine (EGT) 
Ergothioneine (EGT) is a sulfur-containing amino acid derivative known for its antioxidant properties, particularly in mitochondria. It is transported into cells and mitochondria via the OCTN1 transporter, where it helps reduce reactive oxygen species (ROS) and maintain cellular homeostasis [29]. EGT binds to and activates 3-mercaptopyruvate sulfurtransferase (MPST), enhancing mitochondrial respiration and exercise performance [30]. It also protects against oxidative stress and inflammation, potentially benefiting conditions like neurodegenerative diseases [31]. 

Melatonin
Not much talked about when it comes to mitochondria, however should not be ignored as mitochondria can benefit significantly from melatonin supplementation. 
1. Antioxidant protection: Melatonin acts as a powerful antioxidant within mitochondria, scavenging free radicals and reducing oxidative damage to mitochondrial DNA and proteins [32][34].
2. Regulation of mitochondrial homeostasis: Melatonin helps maintain electron flow, efficiency of oxidative phosphorylation, ATP production, and overall bioenergetic function of mitochondria [32][34].
3. Preservation of respiratory complex activities: Melatonin helps maintain the activities of mitochondrial respiratory complexes, which are crucial for energy production [32][34].
4. Modulation of calcium influx: Melatonin regulates calcium influx into mitochondria, helping prevent calcium overload which can be damaging [32][34].
5. Protection of mitochondrial permeability transition: Melatonin helps regulate the opening of the mitochondrial permeability transition pore, which is important for maintaining mitochondrial integrity [32][34].
6. Enhancement of mitochondrial fusion: Melatonin promotes mitochondrial fusion, which is part of the quality control process for maintaining healthy mitochondria [33].
7. Promotion of mitophagy: Melatonin enhances the removal of damaged mitochondria through mitophagy, helping maintain a healthy mitochondrial population [33].
8. Reduction of nitric oxide generation: Melatonin decreases nitric oxide production within mitochondria, which can be damaging in excess [32][34].
9. Selective uptake by mitochondria: Melatonin is selectively taken up by mitochondrial membranes, allowing it to exert its protective effects directly within these organelles [34].
10. Support of mitochondrial biogenesis: Some studies suggest melatonin may promote the formation of new mitochondria [33].

The key antioxidants used by mitochondria are Glutathione (GSH), Glutathione peroxidase (GPx), Coenzyme Q10 (CoQ10), Superoxide dismutase (SOD), Melatonin, Vitamin C (ascorbate) and Vitamin E (α-tocopherol).

​Red light therapy
By incorporating red light therapy into your skin care routine, you can help to counteract the damaging effects of mitochondrial dysfunction and support the skin's natural renewal processes.

As we continue to explore the 12 hallmarks of ageing, I am confident that we will gain even more valuable insights and develop breakthrough innovations that will improve skin quality, health, beauty and vitality. Always consult a qualified healthcare professional or dermatologist to determine what the most suitable approach is for your particular skin condition and rejuvenation goals. 

Take care!
Anne-Marie

References

1. Biological Sciences Why chloroplasts and mitochondria retain their own genomes and genetic systems: Colocation for redox regulation of gene expression John F. Allen et al. 2015
2. Experimental Dermatology Mitochondrial dysfunction: a neglected component of skin diseases René G. Feichtinger et al. 2014
3. Cell Metab. Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context Marcel Morgenstern et al. 2021
4. Br J Dermatol Oxidative stress and ageing M A Birch-Machin et al. 2016
5. Antioxid Redox Signal Oxidative stress, accumulation of biological 'garbage', and aging Alexei Terman et al. 2006
6. Front. Physiol., Mitochondrial dynamics and metabolism across skin cells: implications for skin homeostasis and aging
   Ines Martic et al. 2023
7. Cell Death Dis. Mitochondria in skin health, aging, and disease Annapoorna Sreedhar et al. 2020
8. Journal of Dermatological Treatment. The skin aging exposome Krutmann, J. et al. 2017 
9. Experimental Dermatology Regulation of melanogenesis--controversies and new concepts. Schallreuter, K. U. et al. 2008
10. Int J Mol Sci. Dermatologic Manifestations of Mitochondrial Dysfunction: A Review of the Literature Nicole Natarelli et al. 2024
11. Review Cell Metab Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure
    Marc Liesa et al. 2013
12. Stem Cell Reviews and Reports Telomeres and Mitochondrial Metabolism: Implications for Cellular Senescence and Age-related Diseases Xingyu Gao et al. 2022
13. Experimental & Molecular Medicine Mitochondria-associated programmed cell death as a therapeutic target for age-related disease
    Thanh T. Nguyen et al. 2023
14. Nature Cell Biology Small heat shock proteins operate as molecular chaperones in the mitochondrial intermembrane space
    Elias Adriaenssens et al. 2023
15. Review Exp Dermatol Regulation of melanogenesis--controversies and new concepts Karin U Schallreuter et al. 2008
16. Pigment Cell Melanoma Res. Mitochondrial DNA-depleter mouse as a model to study human pigmentary skin disorders Kyrene M. Villavicencio et al. 2021
17. J. Cell Biol. Mitochondria on the move: horizontal mitochondrial transfer in disease and health. Dong L.-F. 2023
18. Review Int J Mol Sci. Mitochondria Can Cross Cell Boundaries: An Overview of the Biological Relevance, Pathophysiological Implications and Therapeutic Perspectives of Intercellular Mitochondrial Transfer Daniela Valenti et al. 2021
19. Int J Mol Sci. Do Extracellular Vesicles Derived from Mesenchymal Stem Cells Contain Functional Mitochondria? Ljubava D. Zorova 2022
20. Review Signal Transduct Target Ther. Intercellular mitochondrial transfer as a means of tissue revitalization Delin Liu et al. 2021
21. Front. Physiol. Mesenchymal stem cells shift mitochondrial dynamics and enhance oxidative phosphorylation in recipient cells Newell C. et al. 2018
22. BioFactors Topical treatment with coenzyme Q10-containing formulas improves skin's Q10 level and provides antioxidative effects
    Anja Knott et al. 2015
23. Free Radical Biology and Medicine Anti-ageing effects of ubiquinone and ubiquinol in a senescence model of human dermal fibroblasts
    Fabio Marcheggiani et al. 2021
24. Antioxid Redox Signal. Mitochondrial Glutathione, a Key Survival Antioxidant Montserrat Marí et al. 2009
25. Exp Dermatol Licochalcone A activates Nrf2 in vitro and contributes to licorice extract-induced lowered cutaneous oxidative stress in vivo
    Jochen Kühnl et al. 2015
26. PLoS One Age-associated changes in oxidative stress and NAD+ metabolism in human tissue Hassina Massudi et al. 2012
27. Exerc Sport Sci Rev. Mitochondrial Protection by Resveratrol Zoltan Ungvari et al. 2011
28. J Photochem Photobiol B Resveratrol-sensitized UVA induced apoptosis in human keratinocytes through mitochondrial oxidative stress and pore opening Jean Z Boyer et al. 2012
29. Liu HM, Tang W, Wang XY, Jiang JJ, Zhang W, Wang W. Safe and Effective Antioxidant: The Biological Mechanism and Potential Pathways of Ergothioneine in the Skin. Molecules. 2023
30. Sprenger HG et al. Ergothioneine boosts mitochondrial respiration and exercise performance via direct activation of MPST. bioRxiv [Preprint]. 2024 
31. Leow, D.M.-K.; Cheah, I.K.-M.; Fong, Z.W.-J.; Halliwell, B.; Ong, W.-Y. Protective Effect of Ergothioneine against 7-Ketocholesterol-Induced Mitochondrial Damage in hCMEC/D3 Human Brain Endothelial Cells. Int. J. Mol. Sci. 2023, 24, 5498. 
32. Daniel P. Cardinali et al. Publicado en Hormones and Behavior, 2012, Melatonin and mitochondrial dysfunction in the Central Nervous System
33. Lei Xudan et al. The potential influence of melatonin on mitochondrial quality control: a review Frontiers in Pharmacology 2024
34. Srinivasan V. et al. Int. J. Alzheimers Dis. Melatonin in mitochondrial dysfunction and related disorders (2011)

​Our DNA is as like precious book of life filled with information and instructions, with telomeres acting like the protective covers. Just as book covers get worn over time, our telomeres naturally shorten as we age. This shortening is like a biological clock, ticking away with each cell division.
 
Telomere shortening is considered one of the twelve key hallmarks of aging. Those hallmarks all play an important role in longevity, health-span, and skin quality, thus both health and beauty. Telomeres are the protective end-caps of chromosomes, similar to the plastic caps at the end  of shoelaces. They maintain genomic stability and prevent chromosomal damage.

Telomeres become slightly shorter each time a cell divides, and over time they become so short that the cell is no longer able to successfully divide. They shorten more rapidly in dermal fibroblasts compared to epidermal keratinocytes, hence there are significant differences amongst our cells. Telomeres in skin cells may be particularly susceptible to accelerated shortening because of both proliferation and DNA-damaging agents such as reactive oxygen species and sun exposure. [16]​​.

When a cell is no longer able to divide due to telomere shortening, this can lead to

1. Replicative senescence: The cell enters a state of permanent cell cycle arrest and stops dividing, also known as cellular senescence [1-8]. 
2. Activation of DNA damage response: The critically short telomeres are recognized as DNA double-strand breaks, triggering a DNA damage response [8].
3. Changes in gene expression: Senescent cells undergo changes in gene expression, including upregulation of cell cycle inhibitors like p16 and p21 [2].
4. Development of senescence-associated secretory phenotype (SASP): Senescent cells secrete various inflammatory factors, growth factors, and proteases that can affect surrounding cells and tissues [2][7]. 
5. Accumulation of senescent cells in tissues: As more cells reach replicative senescence, they accumulate in tissues over time, potentially contributing to age-related decline in tissue function [7][8]. 
6. Potential for apoptosis: In some cases, cells with critically short telomeres may undergo programmed cell death (apoptosis) instead of senescence [8].
7. Increased genomic instability: Very short telomeres can lead to chromosome fusions and genomic instability if cell cycle checkpoints are compromised [9].
8. Impaired tissue regeneration: The inability of cells to divide can impair the regenerative capacity of tissues [7].
9. Contribution to aging and age-related diseases: The accumulation of senescent cells is thought to be a major contributor to the aging process and various age-related pathologies [7][8].​

This consequently affects both health and beauty 

• Increased risk of cardiovascular diseases
• Higher susceptibility to certain cancers
• Accelerated cognitive decline
• Premature skin aging and reduced skin quality [10]​

FACTORS INFLUENCING TELOMERE SHORTENING
Sleep quality
Poor sleep quality significantly impacts telomere length:

• Obstructive sleep apnea is linked to shortened telomeres
• Shorter sleep duration, longer sleep latency, and lower sleep efficiency are associated with faster telomere shortening
• Sleep loss may activate DNA damage responses and cellular senescence pathways

Other Factors

• Chronic stress
• Poor diet: can lead to oxidative stress and inflammaging, hence ox-inflammaging. 
• Obesity is linked to accelerated telomere shortening
• Sedentary lifestyle: lack of physical activity may contribute to faster telomere shortening, especially in middle-aged and older adults
• Environmental pollutants and smoking
• Oxidative stress and inflammation [11]

INTERVENTIONS FOR TELOMERE PRESERVATION 
1. Possible strategies to preserve telomere length

• Use sunscreen to avoid oxidative stress, inflammation and of course DNA damage
• Telomerase activation (associated with cancer development!)
• Antioxidant protection
• DNA repair and protection
• Gene regulation (e.g., Klotho and FOXO3)
• Gene therapy (EXG-001, a gene therapy using a Sendai virus vector encoding ZSCAN4, has shown success in elongating telomeres in patients with telomere biology disorders) [12] and AAV9-TERT​[37]
• Senolytic therapie
• Epigenetic reprogramming: Reversing age-related changes in gene expression [13]
• NAD+ boosters
• In-office dermatological treatments (e.g., microneedling with growth factors, PRP therapy)
• Telomere shelterin protein, specifically the telomeric repeat binding factor 2 (TRF2), which safeguards telomeres from DNA damage. Given that TRF2 inhibition can expedite telomere shortening and DNA damage, restoring the compromised telomeric shelterin machinery could provide a potential approach to mitigate telomere attrition [14]
• Targeting the reverse transcriptase telomerase enzyme, which is responsible for creating new telomeric DNA from an RNA template [14]

Telomerase [15] 
Telomerase is an enzyme that plays a crucial role in maintaining the length of telomeres and skin cell function. Telomerase is a ribonucleoprotein enzyme, meaning it contains both protein (TERT plus dyskerin) and RNA components (TER or TERC). Its primary function is to add repetitive DNA sequences (telomeres) to the ends of chromosomes, preventing them from shortening during cell division. Telomerase is active in embryonic stem cells, some adult stem cells, cancer cells, certain skin cells, specifically:

• keratinocytes in the basal layer of the epidermis
• epidermal stem cells
• epidermal melanocytes derived from dermal stem cells
• epidermal stem cells and dermal stem cells
• almost undetectable in the dermis, specifically in dermal fibroblasts [16] this is probably why their telomeres shorten faster than in keratinocytes 

2. Sleep Optimization
Poor sleep quality is associated with shorter telomere length. Studies have found significant associations between shortened telomere length and poor sleep quality and quantity, including obstructive sleep apnea [17]. Not feeling well rested in the morning was significantly associated with shorter telomere length in older adults [18]. Sleep loss and poor sleep quality may activate DNA damage responses and cellular senescence pathways [17]. Poor sleep can increase oxidative stress and inflammation, which may accelerate telomere shortening [17]. Disruption of circadian rhythms due to poor sleep may negatively impact telomere maintenance [17].
Improving sleep quality through lifestyle changes and sleep hygiene practices may help preserve telomere length. [19]

•  Maintain a consistent sleep schedule
•  Create a relaxing bedtime routine
•  Optimize sleep environment
•  Limit screen time before bed

3. Stress Management
A study showed that diet, exercise, stress management, and social support could increase telomere length by approximately 10% over five years [20].

•  Practice meditation, yoga, and breathing exercises, regular breaks, optimise work-life balance [19]

4. Nutrition
Adopt a plant-rich diet, such as the Mediterranean diet, which includes whole grains, nuts, seeds, green tea, legumes, fresh fruits (berries), vegetables (leafy greens), omega-3 fatty acids from sources like flaxseed and fish oil or fatty fish and foods rich in folate. This diet is rich in antioxidants and anti-inflammatory properties that help maintain telomere length​ [21]. 
5. Fasting 
Fasting, especially intermittent fasting, has attracted interest for its potential impact on health, including telomere preservation. Multiple studies have shown that intermittent fasting (IF) and other fasting regimens can reduce markers of oxidative stress and inflammation. Research on animals has demonstrated that caloric restriction and intermittent fasting can boost telomerase activity and enhance telomere maintenance in specific tissues. A human study by Cheng et al. (2019) found a correlation between intermittent fasting and longer telomeres, by reducing PKA activity and IGF1 levels, which are crucial for regulating telomerase function. A study showed that 36 hours of fasting induced changes in DNA methylation and another one histone modifications, hence fasting has the potential to induce epigenetic changes. Important note: Be careful with a time-restricted eating schedule (often seen as a form of intermittent fasting, where you eat all meals within an 8 hour time-frame), especially women in menopause or people with a pre-existing heart condition. The American Heart Association presented data indicating that people with a pre-existing heart condition have a 91% higher risk of of death of a heart disease when following the time-restricted eating schedule with an 8 hour window, compared to those who eat within a 12-16 hours window. However, several experts have criticised the data, which aren´t published in a peer reviewed journal. When considering fasting, or a time-restricted eating schedule, especially for a longer period, talk to a qualified HCP first.
6. Exercise

• Regular physical activity, particularly high-intensity interval training (HIIT) [22]

7. Oxygen therapy

• Intermittent Hypoxic Training (IHT) involves brief exposure to low oxygen levels, simulating high-altitude conditions, and has been explored for its effects on longevity, epigenetics, and telomeres, among other health aspects. IHT can induce changes in gene expression through hypoxia-inducible factors (HIFs), ​
• Hyperbaric Oxygen Therapy (HBOT) involves breathing pure oxygen in a pressurised environment, typically at 2-3 times normal atmospheric pressure, which can stimulate regenerative processes typically activated during hypoxia [23]. While traditionally used to treat decompression sickness and certain wound healing disorders, recent research has explored HBOT's potential effects on aging, longevity and telomeres. A groundbreaking 2020 study found that HBOT increased telomere length by over 20% in healthy aging adults following 60 daily sessions. The therapy also reduced the number of senescent cells, which are associated with aging ​[23]. 

​​8. Supplements

• Omega-3 fatty acids
• Vitamin D
• Resveratrol
• Astragalus root extract (TA-65) - also available as skincare ingredient
• N-acetylcysteine (NAC)
• Q10

9. Skincare ingredients

• Antioxidants: Vitamins C and E help reduce oxidative stress, a major factor in telomere shortening [10]
• Resveratrol or Polyphenols: Boosts telomerase activity, which can help preserve and extend telomeres [24]
• TriHex™ Technology: Reduces telomere shortening and upregulates anti-aging genes like Klotho and FOXO3 [25]
• Astragalus root extract (TA-65): protects telomeres [26]
• Juvinity: Protects telomeres effectively [27]
• Cycloastragenol (CAG), possibly more potent in comparison to Astragalus root extract [28]
• Photolyase from Anacystis nidulans and endonuclease from Micrococcus luteus are xenogenic DNA repair enzymes which elicited a significant reduction in the rate of telomere shortening compared to a negative control [14] (not availailable yet)

​
EMERGING TECHNOLOGIES IN TELOMERE-TARGETING SKINCARE
Small RNAs in skincare
Small RNAs play a significant role in the effectiveness of telomere-targeting skincare by influencing skin regeneration and cellular processes. Recent research has highlighted their potential in enhancing wound healing and reducing scarring, which are critical aspects of maintaining healthy skin. Small RNAs, such as microRNAs, are involved in regulating gene expression related to skin aging and and show potential in telomere maintenance [29]. They can modulate the expression of genes that control cellular senescence, oxidative stress response, and inflammation, all of which are crucial for preserving telomere integrity and function [30]. 

• miR-29: Associated with decreased elastin and collagen levels
• miRNA-19b: Biomarker of cellular aging, enhances collagen expression
• miR-34a: affects telomere maintenance and cellular senescence pathways in skin cells 

An epigenetic molecular clock based on miRNA expression profiles has been developed to predict biological skin age, suggesting miRNAs play a key role in skin aging processes [31].  Most biological skin age tests are based on DNA-methylation. Despite promising findings, the delivery of small RNAs into the skin remains challenging due to their negative charge and susceptibility to degradation by nucleases. 
RNAi technology in development
RNAi-based skincare approaches could target genes involved in telomere maintenance or have effects on markers related to telomere biology:

• SECosomes and DDC642 Liposomes for enhanced delivery of RNAi molecules [32]
• Plant Small RNA (PSR) Technology using baobab seedcake extract [33]
• Ionic Liquids for siRNA delivery ​[34]

One of the main hurdles is the delivery of RNAi molecules into the skin. Similar to miRNA molecules, they have a negative charge and moreover are relatively large, making it difficult for them to penetrate the skin barrier. Research is focused on developing effective delivery systems, such as modified liposomes, to overcome these challenges. Multiple patents have been filed for RNAi-based skincare solutions, indicating strong interest and potential for future products. However, as of now, these products have not yet reached the commercial market. 

RNA-based telomere extension is a method developed at Stanford University and uses modified RNA to extend telomeres in cultured human cells, allowing cells to divide more times than untreated cells [35].​

IN OFFICE DERMATOLOGICAL TREATMENTS
Aesthetic, regenerative treatments that support skin quality may indirectly support telomere preservation.

1. Anti-inflammatory or anti-oxidant approaches, including IV or red light therapy
2. Oxygen therapy or facials
3. Microneedling with growth factors
4. Exosomes
5. Polynucleotides 
6. Platelet-rich plasma (PRP) therapy

It's important to note that while these treatments show beneficial outcomes in various aspects of skin rejuvenation, their direct effects on telomeres in human skin cells are not yet established through clinical trials.  ​

Telomere shortening questionable as stand-alone hallmark [36]
Telomere length (TL) has long been considered one of the best biomarkers of aging. However, recent research indicates TL alone can only provide a rough estimate of aging rate and is not a strong predictor of age-related diseases and mortality. Other markers like immune parameters and epigenetic age may be better predictors of health status and disease risk. TL remains informative when used alongside other aging biomarkers like homeostatic dysregulation indices, frailty index, and epigenetic clocks. TL meets some criteria for an ideal aging biomarker (minimally invasive, repeatable, testable in animals and humans) but its predictive power for lifespan and disease is questionable. There is inconsistency in epidemiological studies on TL's association with aging processes and diseases. This has led to debate about TL's reliability as an aging biomarker. It's unclear if telomere shortening reflects a "mitotic clock" or is more a marker of cumulative stress exposure. TL is still widely used in aging research but there are ongoing questions about its usefulness as a standalone biomarker of biological age.

As research in regenerative medicine advances, we're seeing promising developments in therapies targeting telomere biology for longevity, health and beauty. While telomere research is exciting, it's important to remember that it's just one part of a comprehensive approach to aging, and future treatments will likely combine multiple strategies to target preferably all 12 hallmarks for the best results. Always consult a qualified healthcare professional or dermatologist to determine what the most suitable approach is for you.
​.
Take care!
Anne-Marie 

References
[1] Martin, H., Doumic, M., Teixeira, M.T. et al. Telomere shortening causes distinct cell division regimes during replicative senescence in Saccharomyces cerevisiae. Cell Biosci11, 180 (2021)
[2]  M. Borghesan, W.M.H. Hoogaars, M. Varela-Eirin, N. Talma, M. Demaria, A Senescence-Centric View of Aging: Implications for Longevity and Disease, Trends in Cell Biology, Volume 30, Issue 10, 2020, Pages 777-791, ISSN 0962-8924,
[3] McHugh D, Gil J. Senescence and aging: Causes, consequences, and therapeutic avenues. J Cell Biol. 2018 Jan 2;217(1):65-77. 
[4] Oeseburg, H., de Boer, R.A., van Gilst, W.H. et al. Telomere biology in healthy aging and disease. Pflugers Arch - Eur J Physiol 459, 259–268 (2010)
[5] Catarina M Henriques, Miguel Godinho Ferreira, Consequences of telomere shortening during lifespan, Current Opinion in Cell Biology, Volume 24, Issue 6, 2012
[6] Henriques CM, Ferreira MG. Consequences of telomere shortening during lifespan. Curr Opin Cell Biol. 2012
[7] Chaib, S., Tchkonia, T. & Kirkland, J.L. Cellular senescence and senolytics: the path to the clinic. Nat Med 28, 1556–1568 (2022)
[8] Lei Zhang et al. Cellular senescence: a key therapeutic target in aging and diseases JCI The Journal of Clinical Investigation 2022
[9] Muraki K, Nyhan K, Han L, Murnane JP. Mechanisms of telomere loss and their consequences for chromosome instability. Front Oncol. 2012 Oct 4;2:135. 
[10] Marlies Schellnegger et al. Aging, 25 January 2024 Sec. Healthy Longevity Volume 5 - 2024 Unlocking longevity: the role of telomeres and it´s targeting interventions 
[11] Bär C, Blasco MA. Telomeres and telomerase as therapeutic targets to prevent and treat age-related diseases. F1000Res. 2016 Jan 20;5:F1000 Faculty Rev-89. 
[12] Kasiani C. Myers et al.  Blood (2022) 140 (Supplement 1): 1895–1896. Gene therapies November 15 2022 Successful Ex Vivo Telomere Elongation with EXG-001 in a patients with Dyskeratosis Congenital Kasiani C. Myers et al.  
[13] Falckenhayn C, Winnefeld M, Lyko F, Grönniger E. et al. Identification of dihydromyricetin as a natural DNA methylation inhibitor with rejuvenating activity in human skin. Front Aging. 2024 Mar 4;4:1258184
[14] Minoretti P, Emanuele E. Clinically Actionable Topical Strategies for Addressing the Hallmarks of Skin Aging: A Primer for Aesthetic Medicine Practitioners. Cureus. 2024 Jan 19;16(1):e52548
[15] Guterres, A.N., Villanueva, J. Targeting telomerase for cancer therapy. Oncogene 39, 5811–5824 (2020). 
[16] Buckingham EM, Klingelhutz AJ. The role of telomeres in the ageing of human skin. Exp Dermatol. 2011 Apr;20(4):297-302.
[17] Debbie Sabot, Rhianna Lovegrove, Peta Stapleton, The association between sleep quality and telomere length: A systematic literature review, Brain, Behavior, & Immunity - Health, Volume 28, 2023, 100577, ISSN 2666-3546
[18] Iloabuchi, Chibuzo et al. Association of sleep quality with telomere length, a marker of cellular aging: A retrospective cohort study of older adults in the United States Sleep Health: Journal of the National Sleep Foundation, Volume 6, Issue 4, 513 – 521
[19] Rossiello, F., Jurk, D., Passos, J.F. et al. Telomere dysfunction in ageing and age-related diseases. Nat Cell Biol 24, 135–147 (2022)
[20] Elisabeth Fernandez Research September 16 2013 Lifestyle changes may lengthen telomeres, A measure of cell aging. Diet, Meditation, Exercise can improve key element of Immune cell aging, UCSF Scientist report 
[21] Martínez P, Blasco MA. Telomere-driven diseases and telomere-targeting therapies. J Cell Biol. 2017 Apr 3;216(4):875-887.​
[22] Guo, J., Huang, X., Dou, L. et al. Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Sig Transduct Target Ther 7, 391 (2022). 
[23] Hachmo Y, Hadanny A, Abu Hamed R, Daniel-Kotovsky M, Catalogna M, Fishlev G, Lang E, Polak N, Doenyas K, Friedman M, Zemel Y, Bechor Y, Efrati S. Hyperbaric oxygen therapy increases telomere length and decreases immunosenescence in isolated blood cells: a prospective trial. Aging (Albany NY). 2020 Nov 18;12(22):22445-22456
[24] Gutlapalli SD, Kondapaneni V, Toulassi IA, Poudel S, Zeb M, Choudhari J, Cancarevic I. The Effects of Resveratrol on Telomeres and Post Myocardial Infarction Remodeling. Cureus. 2020 Nov 14;12(11):e11482. 
[25] Widgerow AD, Ziegler ME, Garruto JA, Bell M. Effects of a Topical Anti-aging Formulation on Skin Aging Biomarkers. J Clin Aesthet Dermatol. 2022 Aug;15(8):E53-E60. PMID: 36061477; PMCID: PMC9436220.
[26] Alt, C.; Tsapekos, M.; Perez, D.; Klode, J.; Stoffels, I. An Open-Label Clinical Trial Analyzing the Efficacy of a Novel Telomere-Protecting Antiaging Face Cream. Cosmetics 2022, 9, 95. 
[27] Cosmetics & Toiletries Telomere protection: Act on the origin of youth, June 3th 2015 Sederma
[28] Yu Y, Zhou L, Yang Y, Liu Y. Cycloastragenol: An exciting novel candidate for age-associated diseases. Exp Ther Med. 2018 Sep;16(3):2175-2182. 
[29] Gerasymchuk M, Cherkasova V, Kovalchuk O, Kovalchuk I. The Role of microRNAs in Organismal and Skin Aging. Int J Mol Sci. 2020 Jul 25;21(15):5281.
[30] Jacczak B, Rubiś B, Totoń E. Potential of Naturally Derived Compounds in Telomerase and Telomere Modulation in Skin Senescence and Aging. International Journal of Molecular Sciences. 2021; 22(12):6381. 
[31] Roig-Genoves, J.V., García-Giménez, J.L. & Mena-Molla, S. A miRNA-based epigenetic molecular clock for biological skin-age prediction. Arch Dermatol Res 316, 326 (2024). 
[32] Eline Desmet, Stefanie Bracke, Katrien Forier, Lien Taevernier, Marc C.A. Stuart, Bart De Spiegeleer, Koen Raemdonck, Mireille Van Gele, Jo Lambert,
An elastic liposomal formulation for RNAi-based topical treatment of skin disorders: Proof-of-concept in the treatment of psoriasis, International Journal of Pharmaceutics, Volume 500, Issues 1–2, 2016, Pages 268-274, ISSN 0378-5173
​[33]  Oger E, Mur L, Lebleu A, Bergeron L, Gondran C, Cucumel K. Plant Small RNAs: A New Technology for Skin Care. J Cosmet Sci. 2019 May/Jun;70(3):115-126. PMID: 31398100.
​[34] Vimisha Dharamdasani, Abhirup Mandal, Qin M. Qi, Isabella Suzuki, Maria Vitória Lopes Badra Bentley, Samir Mitragotri, Topical delivery of siRNA into skin using ionic liquids, Journal of Controlled Release, Volume 323, 2020, Pages 475-482, ISSN 0168-3659​
​[35] Krista Conger January 2015 Stanford Medicine  News Center  Telomere extension turns back aging clock in cultured human cells, study finds
[36] Alexander Vaiserman, Dmytro Krasnienkov Telemore length as marker of biological age: state-of-the-art, open issues and future perspectives Front. 
[37] Martínez P, Blasco MA. Telomere-driven diseases and telomere-targeting therapies. J Cell Biol. 2017 Apr 3;216(4):875-887

​​In skin biology, senescence is a process by which a cell ages and permanently stops dividing but does not die. This is why they are also referred to as "zombie cells". Age-related accumulation of senescent cells is caused by of increased levels of senescence-inducing stressors and/or reduced elimination of senescent cells. Under normal physiological conditions, senescent cells play an important role maintaining cellular homeostasis and inhibiting proliferation of abnormal cells. However, over time, large numbers of zombie cells can build up in the skin and contribute to the overall reduction in skin's regenerative properties, impacting both its beauty and health.

​There are 2 forms of cell senescence:
Acute senescence: Senescent cells are produced in response to acute stressors to facilitate for example tissue repair, wound healing. They are cleared by our immune system.
Chronic senescence: A not programmed process as response to prolonged stress or damage and these senescent cells are not cleared by our immune system, leading to the accumulation of zombie cells impacting our skin health and beauty.

It has been suggested that inflammageing is mainly related to senescent cells and their associated SASP (Senescence Associated Secretory Phenotype) which increase in the body with age and contribute to inflammageing. Senescent cells cause inflammageing and inflammageing causes cell senescence. [1]

Senescence can be triggered by a number of stress signals to the cell [1]:

• DNA damage (main cause) - including ROS-induced
• Telomere shortening or dysfunction
• Oncogene activation or loss of tumor suppressor functions
• Mitochondrial dysfunction
• Nutrient deprivation
• Epigenetic changes
• Inflammageing - including tabacco induced [7]

Mechanisms of skin cell senescence:

1. Cell Cycle Arrest: Senescent cells lose proliferative capacity and enter irreversible growth arrest. [20 - 21]
2. Senescence-Associated Secretory Phenotype (SASP): Secretion of inflammatory factors by senescent cells. [20 - 21]
3. Chromatin Alterations: Changes in chromatin structure and gene expression.  [22]

The presence of senescent cells accelerates the ageing process due to their communication with nearby cells through various molecules: [18]

• Matrix metalloproteinases (MMPs)
• Growth factors
• Cytokines
• Chemokines
• Matrix-modeling enzymes
• Lipids
• Extracellular vesicles (EVs)

Fibroblast senescence could be the main driver of the skin ageing. [3] The increased number of senescent fibroblasts results in the production of SASPs rich in pro-inflammatory cytokines, including interleukin (IL)-1, IL-6, IL-8, IL-18, matrix metalloproteinases (MMPs), and a variety of other inflammatory chemokines [2] resulting in the breakdown of collagen, loss of elasticity and wrinkle formation. [3]
Autophagy in dermal fibroblasts is essential for maintaining skin balance and managing the ageing process, particularly in response to external stressors like UV radiation and particulate matter (PM), by repairing cellular machineries. [4] Insufficient autophagy leads to an exaggerated skin inflammation triggered by inflammasome activation, resulting in accelerated ageing characteristics. When exposed to UVB (in vitro), skin cell types like fibroblasts and keratinocytes show DNA damage and increased senescence markers, such as increased SASPs. [3] Dermal fibroblasts also release insulin-like growth factor (IGF)-1, essential for epidermal cell proliferation and differentiation. [5] IGF-1 signalling in senescent fibroblasts is significantly decreased [6]. Inhibition of the IGF-1 pathway decreases collagen production in the dermis, causing epidermal thinning. Additionally, mitochondrial dysfunction and increased levels of superoxide anions prompt fibroblast ageing, thereby speeding up the skin ageing process. [5] Fibroblasts isolated from photo-aged skin produce a greater amount of pro-melanogenic growth factors. [14] Ageing-associated pigmentation has also been reported to be driven by (UVA-induced) fibroblast senescence. [15-16] 

Keratinocyte senescence 
The epidermis shows less impact of senescent keratinocytes due to their quicker turnover in comparison to fibroblasts. Senescent keratinocytes experience reduced ECM production and cell adhesions [8], along with elevated MMP expression in UV-induced senescence [9], and increased SASP levels, including pro-inflammatory cytokines. [10] Airborn particulate matter (PM2.5) can penetrate a disrupted skin barrier. PM2.5-induced ROS leads to epigenetic modification: reduced DNA methyltransferase, elevated DNA demethylase expression, p16INK4a promotor hypomethylation and therewith accelerated keratinocyte senescence. [11] Keratinocytes are the main type of cells that signal the need for melanogenesis. [12] UVR-induced DNA damage in keratinocytes activates melanogenesis. [13] 

Melanocyte senescence
Senescent melanocytes express markers of inflammageing and dysfunctional telomeres. Senescent melanocyte SASPs induce telomere dysfunction  and limit the proliferation of the surrounding cells, hence, senescent melanocytes affect and impair basal keratinocyte proliferation and contribute to epidermal atrophy. [17] 

STRATEGIES TO COMBAT CELL SENESCENCE

PREVENTION
Sunscreen: Protection against UV radiation combined with blue light defense (Licochalcone A: powerful anti-oxidant, Nrf2-Activator & increasing Glutathione + Colour pigments) and prevention + repair DNA damage (Glycyrrhetinic Acid)

INTERVENTION
Senotherapeutics can be classified into three development strategies: [25] 

1. ​Senolytics, which eliminate senescent cells from tissues  [23], hyperbaric oxygen therapy (HBOT) shows promising results
2. Senomorphics (SASP inhibitors) induce senescent cells to obtain the functions and morphology of young cells or delay the progression of young cells to senescent cells
3. Senescence-targeting immunotherapeutics mediate the clearance of senescent cells

Skin care ingredients: [18]

• Aquatide™ (Heptasodium hexacarboxymethyl dipeptide-12): Known to protect the skin from pollution and sun radiation, activating SIRT-1 to decrease cellular senescence
• Crepidiastrum Denticulatum Extract: This ingredient has shown potential in reducing senescent cells and rejuvenating the skin
• Exosomes: Found in products like Plated SkinScience Intense Serum, exosomes have been linked to a reduction in the number of senescent cells after use. Read more about exosomes
• Melatonin: Known for its anti-inflammatory properties, melatonin can help prevent senescent cells in the skin
• Pollux CD™ (Crepidiastrum Denticulatum Extract): Another ingredient that may aid in reducing senescent cells and promoting skin rejuvenation
• Saururus Chinensis: This ingredient has shown promise in addressing cellular senescence and supporting skin health
• Ulmus Davidiana: Known for its potential to reduce cellular senescence and improve skin condition
• Natural polyphenols have shown anti-senescent effects on skin cells [19]
• OS-1 peptide protects skin cells from UVB-induced cellular senescence [24]
• Anti-oxidants like Vitamin C combined with anti-inflammatory ingredients help to reduce ox-inflammageing
• Cleansing + toners: Gently removing debris (incl. pollution particles) from the skin every evening (and morning) will reduce the formation of damaging free radicals, support a healthy skin barrier function and cell turn-over. Read more

​Life-style modifications
Of course a healthy life-style and diet (consider also intermittent fasting) will support both your body & skin longevity and beauty

Prevention and intervention of skin cell senescence offers a promising approach to improve skin health and beauty. Always consult a qualified healthcare professional or dermatologist to determine the most suitable approach for your particular skin condition and rejuvenation goals. 

Take care!
Anne-Marie

References

1. Immunity & Ageing. Aging and chronic inflammation: highlights from a multidisciplinary workshop Danay Saavedra et al. 2023
2. Proc. Natl. Acad. Sci. USA. Biomarker that identifies senescent human cells in culture and in aging skin in vivo Dimri G.P., et al. 1995
3. Int J Mol Sci. Cellular Senescence and Inflammaging in the Skin Microenvironment Young In Lee et al. 2021
4. J. Investig. Dermatol. The role of autophagy in skin fibroblasts, keratinocytes, melanocytes, and epidermal stem cells. Jeong D. et al. 2020
5. J. Investig. Dermatol. Connective tissue and fibroblast senescence in skin aging. Wlaschek M. et al. 2021
6. EMBO Mol. Superoxide anion radicals induce igf-1 resistance through concomitant activation of ptp1b and pten. Med.Singh K. et al. 2015
7. Front. Genet. Biomarkers of cellular senescence and skin aging. Wang A.S. et al. 2018
8. Mol. Cell Proteom. Consistency of the proteome in primary human keratinocytes with respect to gender, age, and skin localization. Sprenger A., et al. 2013
9. J. Investig. Dermatol. Elevated matrix metalloproteinases and collagen fragmentation in photodamaged human skin: Impact of altered extracellular matrix microenvironment on dermal fibroblast function. Quan T. et al. 2013
10. J. Investig. Dermatol. Cellular senescence and the senescence-associated secretory phenotype as drivers of skin photoaging. Fitsiou E. et al. 2020
11. Exp. Mol. Med. Particulate matter-induced senescence of skin keratinocytes involves oxidative stress-dependent epigenetic modifications. Ryu Y.S. et al. 
12. J. Investig. Dermatol. Cellular senescence and the senescence-associated secretory phenotype as drivers of skin photoaging. Fitsiou E., et al. 2020
13. Int. J. Mol. Sci. Elucidation of melanogenesis cascade for identifying pathophysiology and therapeutic approach of pigmentary disorders and melanoma. Hida T., et al. 2020
14. Ageing Res. Rev. Premature cell senescence in human skin: Dual face in chronic acquired pigmentary disorders. Bellei B. et al. 2020
15. Theranostics. Senescent fibroblasts drive ageing pigmentation: A potential therapeutic target for senile lentigo. Yoon J.E. et al. 2018
16. J. Investig. Dermatol. Senescent fibroblast-derived gdf15 induces skin pigmentation. Kim Y. et al. 2020
17. EMBO J. Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction. Victorelli S. et al. 2019
18. Blog Targeting Cellular Senescence and Skin Aging with Skin Care. Dr Leslie Baumann 2022
19. Int J Mol Sci. Skin Aging, Cellular Senescence and Natural Polyphenols Erika Csekes et al. 2021
20. Antioxidants 2023 Hallmarks and Biomarkers of Skin Senescence: An Updated Review of Skin Senotherapeutics
    by Darya Bulbiankova et al. 2023
21. Nature npj aging  Blocking negative effects of senescence in human skin fibroblasts with a plant extract Ingo Lämmermann et al. 2018
22. Ageing Research Reviews How good is the evidence that cellular senescence causes skin ageing? Evon Low et al. 2021
23. Nature medicine  Cellular senescence and senolytics: the path to the clinic Selim Chaib et al 2022
24. UV Damage Increases Cellular Senescence. Here's How to Stop It. Oneskin
25. Biomol Ther (Seoul). Senotherapeutics and Their Molecular Mechanism for Improving Aging Jooho Park et al. 2022

Many of the skin regenerating or rejuvenating treatments, like energy based devices in the doctors-office are based on the principle to cause controlled damage and therewith provocation of a skin rejuvenating repair response. One of the fascinating mechanisms behind laser "damage" is the heat shock response leading to increased production of regenerating heat shock proteins (HSPs). Heat shock proteins respond to heat stress, are crucial cellular defence mechanisms against stress (environmental and physiological), act as chaperones, aiding in protein folding, prevention of protein damage, cellular protection and repair, with other words HSPs play a crucial role in proteostasis. [1] 

HEAT SHOCK PROTEINS AND OX-INFLAMMAGEING
UV radiation and blue light cause oxidative stress and inflammation, and can overwhelm skin's own capacity to counteract the increased formation of reactive oxygen species (ROS) and inflammatory mediators. Chronic oxidative stress state and chronic low grade of inflammation are hallmarks of skin ageing and their combination can be called ox-inflammageing. Oxidative stress and inflammation alter cellular signal transduction pathways and thereby the expression of the ECM genes as well as the structure of the ECM proteins like collagen, fibronectin and elastin. Their reduced expression and increased degradation manifests eventually at the skin surface as wrinkles, loss of firmness, and elasticity. Heat shock proteins are chaperone proteins that facilitate the formation of the ECM and prevention of molecular oxidative damage or degradation and are classified based on their molecular weights.

• HSP-27 increases cellular antioxidant score by increasing cellular reduced glutathione, and reducing oxidized proteins. [2]
• HSP-70 is reduced with cellular ageing, provides anti-inflammatory, skin protective properties incl. chaperone-mediated autophagy [3,4].
• HSP-47 is a collagen specific chaperone protein, is co-stimulated with fibrillar collagen by ECM strengthening agents, such as copper, in dermal fibroblasts [5]. UVA radiation inhibited the expression HSP-47 in dermal fibroblasts. [6]
• HSP-90 facilitates the migration of dermal fibroblasts, and the maturation of the ECM, imperative to wound healing. [7]

The process of skin ageing is connected down-regulation of regulator heat shock proteins in the skin. [8] Higher levels of HSPA1 were present in keratinocytes isolated from young (17–35 years) in comparison to more mature (65–90 years) individuals. [1] It seems that also in keratinocytes, the stress response can be modulated by some age-related factors. [9] 

HEAT SHOCK PROTEINS AND PROTEOME
Proteostasis, or protein homeostasis, refers to the balance between protein synthesis (like collagen, fibronectin and elastin), folding, and degradation. As we age, this balance is disrupted, leading to the accumulation of misfolded and aggregated proteins [10]. Loss of proteostasis is another hallmark of aging and HSPs play a crucial role in maintaining proteostasis through several mechanisms:
1. Protein folding: HSPs assist in the proper folding of newly synthesised proteins and refolding of misfolded proteins [10][11].
2. Protein degradation: HSPs collaborate with the ubiquitin-proteasome system and autophagy to target misfolded proteins for degradation [10][12].
3. Stress response: Under stress conditions, HSPs are upregulated to protect cells from protein damage and maintain cellular functions [13][14].
HSP-70 and HSP-90 are particularly important in protein folding and refolding, while small HSPs are involved in preventing protein aggregation [11][14]. Several studies have provided evidence supporting the potential of HSPs as an intervention to improve proteostasis: lifespan extension: [15], neuroprotection (HSP70), stress resistance and cellular survival [13][14], protein aggregation prevention (small HSPs) [11][14], autophagy regulation and particularly HSP70 is crucial for cellular protein quality control [16].
  
STIMULATION OF REJUVENATING HEAT SHOCK PROTEINS
Heat shock protein synthesis can be initiated not only by heat but also by many chemical and physical stimuli, such as heavy metals, amino acid analogues, oxidative stress, viral infection and UV and ionizing irradiation. [17]

Exercise and hormesis:
Mild stress induced by exercise or other hormetic interventions has been shown to upregulate HSPs and improve proteostasis.

Laser
Laser treatments have been shown to induce a heat shock response in the skin from epithelial cells to deeper connective tissues, leading to the production of heat shock proteins. This response is characterized by the temporary changes in cellular metabolism, release of growth factors, and increased cell proliferation and thus contribute to tissue regeneration and rejuvenation. [17]

CBD
It has been proven that a large number of genes belonging to the heat shock protein super-family were up-regulated following cannabidiol (CBD) treatment. [18]

UV radiation
Ultraviolet radiation (UV)‐induced cell death and sunburn cell formation can be inhibited by previous heat shock exposure and UV itself can induce HSP expression. However, levels of HSP-27 have been found to be elevated in sun‐protected aged skin indicating a link between HSP-27 expression and age‐dependent epidermal alterations. [19] I would recommend daily protection from UV radiation and blue light (or high energy visible light).

Ultrasound
Ultrasound exposure at different frequencies, intensities, and exposure times can induce HSP-72 expression. Higher ultrasound frequencies, such as 10 MHz, have been found to significantly increase HSP-72 levels. Additionally, increasing the temperature during ultrasound exposure has shown to enhance HSP-72 expression. Interestingly, ultrasound at 1 MHz was unable to induce HSP-72 significantly, while 10 MHz ultrasound induced HSP-72 after 5 minutes of exposure. [16] 

Radiofrequency
​Radiofrequency has been shown to increase HSP-70 and decrease melanin synthesis and tyrosinase activity. [20] RF-US treatment significantly increased levels of HSP47 proteins. [21]

Red & near infra red light
Although I've not seen much peer reviewed published evidence, red light and near infra red light therapy may release the HSPs in the skin if tissue reaches >42 - 45 degrees (even for 8 - 10 seconds).

Nicotinamide
​Nicotinamide and its derivatives have been found to stimulate the expression of heat shock proteins, including HSP-27, HSP-47, HSP-70, and HSP-90 in the skin. These proteins play as mentioned before an essential role in collagen production, skin protection, skin health and rejuvenation. [6] NAD as nutrient interestingly has proven to tweak the epigenome by modulating DNMT1 enzymatic DNA methylation and cell differentiation. [22] In topical applications an ingredient called Dihydromyricetin also called Epicelline® has been successful in inhibiting DNMT1 enzyme activity biochemical assays. [23]

Stimulation of heat shock proteins offers a promising and novel invasive, non invasive and topical approach for skin regeneration, rejuvenation,  reduction of ox-inflammageing and prevention of loss of proteostasis. Always consult a qualified healthcare professional or dermatologist to determine the most suitable approach for your particular skin condition and rejuvenation goals. 

Take care!
Anne-Marie 
​
References

1. Cell Stress Chaperones. Heat shock proteins in the physiology and pathophysiology of epidermal keratinocytes Dorota Scieglinska et al 2019 
2. Antioxid. Redox Signal. Hsp27 consolidates intracellular redox homeostasis by upholding glutathione in its reduced form and by decreasing iron intracellular levels. Arrigo, A.P. et al. 2005
3. J. Biol. Chem. Prevention of UVB radiation-induced epidermal damage by expression of heat shock protein 70. Matsuda, M. et al. 2010
4. Exp. Cell Res. The expression of heat shock protein 70 decreases with cellular senescence in vitro and in cells derived from young and old human subjects Gutsmann-Conrad, A. 1998
5. Connect. Tissue Res. Beneficial regulation of fibrillar collagens, heat shock protein-47, elastin fiber components, transforming growth factor-β1 vascular endothelial growth factor and oxidative stress effects by copper in dermal fibroblasts Philips, N. et al. 2012, 
6. Cosmetics Stimulation of the Fibrillar Collagen and Heat Shock Proteins by Nicotinamide or Its Derivatives in Non-Irradiated or UVA Radiated Fibroblasts, and Direct Anti-Oxidant Activity of Nicotinamide Derivatives Neena Philips et al. 2015
7. EMBO Extracellular heat shock protein-90α: Linking hypoxia to skin cell motility and wound healing. J. Li, W. et al. 2007
8. Journal of Cosmetics Dermatological Sciences and Applications - Facial Skin Rejuvenation with High Frequency Ultrasound: Multicentre Study of Dual-Frequency Ultrasound Dirk Meyer-Rogge et al. 2012
9. Cells Tissues Organs. HSP70 and EndoG modulate cell death by heat in human skin keratinocytes in vitro Sathivel Chinnathambi 2008
10. Alagar Boopathy LR, Jacob-Tomas S, Alecki C, Vera M. Mechanisms tailoring the expression of heat shock proteins to proteostasis challenges. J Biol Chem. 2022 
11. Hu C, Yang J, Qi Z, Wu H, Wang B, Zou F, Mei H, Liu J, Wang W, Liu Q. Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities. MedComm (2020).
12. Sojka, D.R., Abramowicz, A., Adamiec-Organiściok, M. et al. Heat shock protein A2 is a novel extracellular vesicle-associated protein. Sci Rep 13, 4734 (2023). 
13. Lang, B.J., Guerrero, M.E., Prince, T.L. et al. The functions and regulation of heat shock proteins; key orchestrators of proteostasis and the heat shock response. Arch Toxicol 95, 1943–1970 (2021)
14. Belenichev Igor F. , Aliyeva Olena G. , Popazova Olena O. , Bukhtiyarova Nina V. Involvement of heat shock proteins HSP70 in the mechanisms of endogenous neuroprotection: the prospect of using HSP70 modulators Frontiers in Cellular Neuroscience 2023
15. Tartiere Antonio G. , Freije José M. P. , López-Otín Carlos The hallmarks of aging as a conceptual framework for health and longevity research Frontiers in Aging 2024
16. Ultrasound in Medicine & Biology Expression of Heat Shock Proteins after Ultrasound Exposure in HL-60 Cells
    Werner Sontag et al. 2009 
17. Lasers in Medical Science  Article Variable heat shock response model for medical laser procedures Matjaž Lukač et al. 2019
18. Anticancer Inhibiting Heat Shock Proteins Can Potentiate the Cytotoxic Effect of Cannabidiol in Human Glioma Cells
    Katherine A Scott et al. 2015
19. International Journal of Cosmetic Science Heat shock proteins in the skin Constanze Jonak et al. 2006
20. Molecules. Attenuation Effect of Radiofrequency Irradiation on UV-B-Induced Skin Pigmentation by Decreasing Melanin Synthesis and through Upregulation of Heat Shock Protein 70 Hyoung Moon Kim et al. 2021
21. Biochem Biophys Res Commun. Effects of radiofrequency and ultrasound on the turnover rate of skin aging components (skin extracellular matrix and epidermis) via HSP47-induced stimulation Fiona Louis et al. 2020
22. Cells. NAD Modulates DNA Methylation and Cell Differentiation Simone Ummarino et al. 2021
23. Front Aging Identification of dihydromyricetin as a natural DNA methylation inhibitor with rejuvenating activity in human skin
    Cassandra Falckenhayn et al. 2024 

Like epigenetics and exosomes, neurocosmetics represent a revolutionary approach for skin care incorporating neuroscience principles, leveraging the skin-brain connection to improve skin health and beauty. The term itself is a fusion of the words neuroscience and cosmetics. It differs from psychodermatology which like neurocosmetics connects the interaction between mind and skin, but in a different way. Some describe it as how simple sensory stimulation can improve our overall wellbeing and call it "mood beauty", however this doesn't do it justice as neurocosmetics go beyond mood boosting skincare. 
​
DEFINITION NEUROCOSMETICS 
Dermatologist Professor Laurent Misery back in 2002 described that neurocosmetics are products which are supposed to modulate the neuro-immuno-cutaneous-system (NICS) function at an epidermal level. Skin cells can produce neuromediators, which are mediators for transmission of information between skin, immune and the nervous system. All skin cells express specific receptors for neuromediators and by binding of the neuromediator to its receptor, modulation of cell properties and skin functions are induced like cell differentiation and proliferation (renewal), pigmentation, etc. Hence, keratinocytes, Langerhans cells, melanocytes, endothelial cells, fibroblasts and the other cells of the skin are modulated and controlled by the nerves and in return skin is able to modulate neuronal activity and growth. [1] 

SKIN-BRAIN CONNECTION
In an article from the International Journal of Novel Research and Developments, the skin-brain connection was described as a psychobiological concept that highlights how emotions, stress, and neurotransmitters impact skin health. Indicating that the skin acts as a neuroimmunoendocrine organ, emphasizing its sensitivity to neural signals and stress responses. [4]

CUTANEOUS NERVOUS SYSTEM
The skin a sophisticated sensory organ that allows you to interact with your environment through touch and feel. It contains a complex network of nerves that send information about sensations like pressure, pain, itch and temperature from the skin through the spinal cord to the brain [9]. The dynamic interactions between the skin and the nervous system is influenced by factors like stress and inflammation, which can impact skin health and ageing. [7] 
Nerves in the skin: These nerves are like tiny messengers that tell your brain about what your skin is feeling: pressure, heat or pain.
Types of nerve fibers: Some are thick and wrapped in a protective coating, which helps them send messages quickly. Others are thin and slow but are very good at sending messages about pain or temperature changes. [3]
Sensory receptors: These receptors can tell if something is touching the skin lightly or if there's a lot of pressure. They can also sense if something is hot, cold, or causing pain. [3]
Autonomic nervous system: Part of the cutaneous nervous system helps control things that happen in the skin automatically, like sweating to regulate body temperature. [8]
Nerve cells: There are about 20 different types of neurons in our skin. [10]

The contribution of epidermal keratinocytes to NICS [3]

• They play a crucial role in the skin-brain connection.
• They express receptors found in the central nervous system, influencing functions like epidermal proliferation and barrier maintenance.
• They release oxytocin (in small amounts), impacting pain relief, behavior and social bonding.
• They house sensory systems and secrete bioactive molecules able to influence neural functioning.
• They produce cytokines and chemokines (signals) guiding immune cells to the site of injury and are thus are active participants in the immune response during wound healing. [12]
• They produce antimicrobial peptides that can directly kill the invading pathogens. [12]

CUTANEOUS NEURO-AGEING
Neuro-ageing is defined as the changes in the nervous system which cause continuous neurodegeneration due to oxidative stress, neuroinflammation or impaired neuromodulation. As skin ages, Aβ-toxin (increased by oxidative stress) accumulates at the nerve endings innervating the tissue, causing disrupted cellular communication, particularly affecting fibroblasts’ ability to produce collagen and extracellular matrix. On top there is a decrease of nerve growth factor (NGF) production,  important for the development and maintenance of nerve cells. Different factors can lead to a drop in NGF production, resulting in malfunctioning keratinocytes and reduced lipolytic activity of adipocytes, visibly impacting skin hydration and firmness. [6]

Skin nerve fibres are significantly reduced in number following UV irradiation and in ageing skin [5] and therefore neuro-protectors or targetting neurodegeneration can reduce stress manifestations and promote healthy cellular communication for optimal skin function. [3] Although not much is known regarding skin specific or topical neuroprotectors (most research was focussed on the brain), probably potent anti-oxidants, by significantly reducing oxidative stress from UV and blue light and anti-inflammatory ingredients may inhibit skin neuro-ageing and can be neuroprotective especially when combined with sunscreen and strengthening of the skin barrier. 

NEUROCOSMETIC VARIETY OF ACTIONS

• Neurocosmetics can be dermo(cosmetic) products with 1 or more bio-active ingredients which can inhibit or stimulate certain skin functions to enhance skin function (health) and appearance (beauty) and on top our well-being.
• They can make use of sensations like cooling and heat, make use of "neuro-relaxing" anti-aging ingredients or utilize neurocosmetic strategies to combat inflammatory responses related to skin stress. [2] 
• Neurocosmetics can target nerve clusters to improve skin conditions and prevent neuro-ageing. [3] 
• Neurocosmetics can address unwelcome sensations like itch or as a result from sensitive or hypersensitive skin and may include bio-mimicking peptides. [4] 

THE FUTURE OF NEUROCOSMETICS
The neurocosmetics market is booming, with a projected value of USD 2.69 billion by 2030. [11] The future of neurocosmetics holds promise for innovative ingredients and concepts that harness new neuroscientific insights to revolutionize skin care and sunscreen formulations, to cater to both physical and emotional aspects of skin health and beauty. 

Take care!
Anne-Marie

References 

1. International Journal of Cosmetic Science Les nerfs à fleur de peau L. Misery 2002
2. Neurocosmetics in Skincare - The Fascinating World of Skin–Brain Connection: A Review to Explore Ingredients, Commercial Products for Skin Aging, and Cosmetic Regulation Vito Rizzi et al Cosmetics 2021, 8(3), 66
3. Ectodermal origins of the skin-brain axis: a novel model for the developing brain, inflammation, and neurodevelopmental conditions
   C. Jameson et al Mol Psychiatry. 2023; 28(1): 108–117.
4. JNRD - Neurocosmetics: A Review to the Skin-Brain Connection Anuja V. Pathade et al 2022
5. Natural and Sun-Induced Aging of Human Skin Laure Rittié and Gary J. Fisher Cold Spring Harb Perspect Med. 2015
6. Emotion an Erasmus Mundus Student Project, Neurocosmetics: Fighting against skin neuro-ageing Nicola Garzon 2023 
7. Inflamm Allergy Drug Targets. Brain-skin connection: stress, inflammation and skin aging Ying Chen et al 2014
8. The Skin: An Extension of Our Heart - BrainFacts 2024
9. Frontiers in Neurol. Architecture of the Cutaneous Autonomic Nervous System Patrick Glatte et al 2019
10. Harvard Medical School How neurons grow comfortable in their own skin. Christy Brownlee 2023
11. GlobeNewswire 1 March 2023 
12. International Journal of Molecular Sciences. The Immune Functions of Keratinocytes in Skin Wound Healing Minna Piipponen et al 2020

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. 

If you've scrolled through Instagram, you may have caught a glimpse of dermatologists raving about LED masks emitting red light, the secret, evidenced based weapon behind skin rejuvenation known as photo biomodulation. It uses low-powered light within the red to near-infrared range (wavelengths from 632 to 1064 nm) to induce a biological reaction aka stimulate cellular processes. The wonders of red light, also known as LLLT (low-level laser therapy), PBM (red light photo-biomodulation), or PBMT (photo-biomodulating therapy), extend far beyond non-invasive skin rejuvenation. I am not a fan of devices for home use, mostly because of lacking safety and/or efficacy, PBM definitely earned it's prominent spot in my skincare routine. 

A summary of the benefts of red light with and without near infrared light for skin
Numerous studies have demonstrated the effectiveness of red and infrared light therapy for skin rejuvenation. A combination of red light and near IR light has proven to stimulate the production of collagen (I & III) plus elastin production (Li WH et al Int J Cosmet Sci 2021), enhance mitochondrial ATP production, cell signaling, growth factor synthesis, rebalance ROS (reactive oxidative species) and reduce inflammation. Stem cells can be activated allowing tissue repair and healing. Wrinkle and scar reduction was observed and it can reduce UV damage both as treatment and prophylactic measure. In pigmentary disorders such as vitiligo, it can increase pigmentation by melanocyte proliferation and reduce depigmentation by inhibiting autoimmunity (Pinar Avci et al. Semin Cutan Med Surg. 2013 & Mitchell J Winkie et al. Review Photodermatol Photoimmunol Photomed A focused review of visible light therapies for vitiligo 2024). It has the potential to activate both keratinocytes (epidermis) and fibroblasts (epidermal junction and dermis). With consistent use, you can expect a reduction of lines and wrinkles, improvement of skin tone and texture. PBMT (when done effective and safe) will compliment both your skin rejuvenating and regenerating at home skincare regimen and in-office procedures or even post-surgical skin recovery.

ATP
ATP (adenosine triphosphate) is the primary source of energy for cellular processes and plays a crucial role in various biological functions. When red light with specific wavelengths (630 nm to 638 nm and 810 nm) is absorbed by the skin cells, it stimulates the mitochondria, which are the powerhouses of the cells responsible for ATP synthesis. This increase in ATP production is providing cells with more energy to carry out their functions effectively and has several beneficial effects on the skin like boosting cellular metabolism, promoting more efficient nutrient uptake and waste removal. The increased ATP levels facilitate collagen synthesis by fibroblasts, a vital component for skin structure, elasticity and firmness and reduction of lines and wrinkles.. ATP aids in the repair and regeneration of damaged skin cells. It accelerates the healing process, making it beneficial for wound healing, post-surgical recovery, and addressing skin issues such as acne scars.

​ROS (Reactive Oxidative Species)
By modulating ROS levels, red light therapy helps reduce oxidative stress and its detrimental effects on the skin. ROS are highly reactive molecules that are naturally produced by cells as byproducts of metabolic processes. While low levels of ROS play important roles in cellular signaling and immune responses, excessive ROS can lead to oxidative stress and damage to cells and tissues. Restoring the balance of ROS result in improved skin health, reduced inflammation, and enhanced skin rejuvenation. Red light therapy has been shown to modulate reactive oxidative species (ROS) levels in the skin by promoting antioxidant defense mechanisms and reducing oxidative stress:

• Antioxidant Enzyme Activation: Stimulation of antioxidant enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase. These enzymes play a crucial role in neutralizing and detoxifying ROS, preventing their accumulation and harmful effects.
• Mitochondrial Function Enhancement: By enhancing mitochondrial respiration and reducing electron leakage, red light therapy helps maintain the balance between ROS production and elimination.
• Nitric Oxide Regulation: Nitric oxide can interact with ROS, leading to the formation of peroxynitrite, a highly reactive molecule. By regulating NO levels, red light therapy helps prevent the excessive formation of peroxynitrite and subsequent oxidative damage.
• Redox Signaling: Activation of redox-sensitive signaling pathways like Nrf2 enhances the expression of antioxidant genes, leading to increased ROS scavenging capacity.

The difference between LLLT and PBM
LLLT refers specifically to the use of lasers, which produce coherent, focussed and an intense beam of monochromatic light, while PBM has a broader range of light sources, may include laser as well as light-emitting diodes (LEDs) and other non-laser devices. LEDs are often used in PBM because they are cost effective, versatile and have the ability to cover large treatment areas. LLT uses higher power densities with more energy and has a shorter treatment duration in comparison to PBM to achieve desired therapeutic effects. While there are similarities in terms of mode of action", there is a difference of light source, treatment application and parameters. Based on consensus, PBM and PBMT are considered the correct way to describe this photonic specialty for therapeutic applications. In this post I will focus on PBM and specifically LEDs. A home device claiming to use cold near infrared laser light or Low-Level Laser Therapy is called LYMA laser. It is sold for several thousand euro´s.

LED masks and LED panels
LED masks specifically produced by the brand Omnilux (FDA cleared) are currently very popular for very good reasons; they are safe and effective when the LEDs emit the right wavelengths and used in the recommended frequency. Omnilux combines 2 therapeutically effective and complimentary wavelengths: 633nm and near-infrared 830 nm. Both wavelengths (more precise 630nm + 850nm) I would recommend to minimally look for in any red LED device, which will disqualify most LED masks and panels in the market! I've include some (not affiliated) links to devices below. Both masks and panels can be effective, however most panels are stronger in comparison to masks 60 mW/cm² vs mW/cm²), hence have the benefit of a shorter treatment time to get a similar result. Intensity and power of red light therapy devices are typically measured in terms of irradiance (measured in milliwatts per square centimeter, mW/cm²) and radiant flux (measured in watts, W), which quantify the amount of light energy emitted by the device. Wearing a mask during a hot summer or in a warmer climate will make you sweat and depending on the materials of the mask and straps, they may be very uncomfortable to wear. Panels have the benefit that they give a more even distribution of emitted light as masks are worn on the face and thus the LED bulbs are pushed on a small skin surface area, panels can cover a larger area (depending on their size) and are more versatile in use, as area's like neck, décolletage, or knees are easier to treat with a panel. With a mask you may be more mobile, although I would not recommend walking around while using the mask. My personal preference would be a panel for the reasons mentioned before and panels are more suitable (more hygienic) for family sharing. My son can use it after an intense workout to speed up his recovery and I like to use it for purposes beyond photo-biomodulation or skin rejuvenation, for example to improve my sleep. With a panel I get more "bang for my buck".

Red light and NIR (Near Infra Red light) have the ability to penetrate varying depths of the skin, resulting in distinct benefits, thus combinations of wavelengths will provide complementary effects.

630 nm Wavelength
This wavelength is often used for its skin rejuvenation benefits. It has a relatively shallow penetration depth and is absorbed closer to the surface of the skin primarily affecting the epidermis. 630nm light is associated with increased circulation, reduced inflammation, reduced sebum production, improved skin tone & texture, aiding in the delivery of nutrients and oxygen to skin cells, and stimulating the production of collagen, leading to improved skin elasticity and a reduction of the appearance of fine lines & wrinkles. 
660 nm Wavelength
At 660nm, red light can penetrate a little deeper into the skin, reaching the dermis. It is known for its ability to stimulate collagen production, enhance cellular metabolism, and promote anti-inflammatory effects, helping to reduce redness and inflammageing. It also promotes wound healing, making it beneficial for post-surgical or post-trauma skin recovery.
810 nm Wavelength
Improve healing & recovery & accelerate wound healing.
830 nm Wavelength
Accelerate healing, reduce infection, improve aesthetic outcome following plastic surgery, increase endorfines (mood-enhancing), improve bone repair and growth.
850 nm Wavelength
Improve general inflammation body, enhance muscle recovery, improve wound healing, reduced fine lines, wrinkles and hyperpigmentation.

Always consult a qualified healthcare professional or dermatologist to determine if and what the most suitable red light therapy approach is for your particular skin condition and rejuvenation goals. 

Take care!

References:
Hamblin, Michael R. "Mechanisms and applications of the anti-inflammatory effects of photobiomodulation." AIMS biophysics 4.3 (2017): 337-361.
Barolet, Daniel. Regulation of Skin Collagen Metabolism In Vitro Using a Pulsed 660 nm LED Light Source: Clinical Correlation with a Single-Blinded August 2009Journal of Investigative Dermatology 129(12):2751-9
Wunsch A, Matuschka K. (2014). A controlled trial to determine the efficacy of red and near-infrared light treatment in patient satisfaction, reduction of fine lines, wrinkles, skin roughness, and intradermal collagen density increase. Journal of Cosmetic and Laser Therapy, 16(5), 232-237.
Avci P, et al. (2013). Low-level laser (light) therapy (LLLT) in skin: stimulating, healing, restoring. Seminars in Cutaneous Medicine and Surgery, 32(1), 41-52.
​​
Links to some devices which combine 630 nm and 850 nm:
FDA-approved devices ensure safety and regulatory compliance, however the panels are more powerful:
Omnilux(tm) Mask (FDA clearance)
Very affordable panel (no FDA clearance)
Affordable panel (no FDA clearance)

Skin ageing is a biological degenerative process, marked by loss. The number of patients seeking nonsurgical rejuvenation of the face and the body is continuing to increase due to a growing ageing population concerned with physical appearance. Women wish to maintain a youthful appearance and attractiveness represent 92% of all cosmetic procedures.(1) Men are keen to maintain physical characteristics associated with virility.(2) Millennials are also increasingly concerned with preserving their beauty and youth.(3) Among the various treatment approaches, different minimally invasive techniques have been developed and dermal fillers currently come second after botulinum toxin type A (BTA).(3) Their use is increasing worldwide. 

"The fear of looking done is the number 1 reason why patients don't seek treatment"*

​The range of fillers available for soft-tissue augmentation is constantly expanding. The latest advances in filler technology include bio-stimulators that exert their aesthetic effect by promoting predominantly collagenesis or biological stimulation of new collagen and sometimes also elastin production. Therewith they provide a biological answer to the skin ageing degeneration process, with gradual and often very natural results. Over the course of last years the knowledge on injectable bio-stimulators has grown, and therewith their safety and popularity as they provide subtle longer lasting results.

Facial fillers can be broken into 3 main groups:

1. classic dermal fillers (mainly hyaluronic acid-based) 
2. biostimulating fillers
3. bioremodelers (Profhilo) or skin boosters (mainly hyaluronic acid based) improving overall skin quality and hydration

There is evidence that classic dermal fillers stimulate collagen I and III and elastin production by stretching of the dermal fibroblasts near the injection side (4). Although classic hyaluron based fillers are still the most popular treatment for soft tissue augmentation, I will focus on bio-stimulators.

Bio-stimulating fillers promote the body’s natural production of some ECM components (mostly collagen) over a period of several months. 
Their differences are characterized by their property of inducing natural collagen production.

SYNTHETIC BIOSTIMULATORS

1. Ceramics, Calcium Hydroxylapatite (CaHA) Radiesse 30% microspheres Merz  or Crystalys Luminera 55.7% microspheres Allergan
2. NEW Mix of Hyaluron filler = CaHa HArmonyCa: Calcium hydroxyapatite microspheres 25-45 microns in diameter (55.7%) cross-linked sodium hyaluronate gel (20 mg/ml), phosphate buffer. Lidocaine hydrochloride (3 mg/ml) Allergan or NEAUVIA stimulate 26 mg/ml Ha crosslinked with PEG = 1% CaHa
3. Poly-L-lactic acid (PLLA) Sculptra 150 mg/vial Galderma or Lanluma V [210 mg /vial] and Lanluma X [630 mg/vial] Sinclair Pharmaceuticals
4. Polymers, polycaprolactone (PCL) Ellansé, 30% microspheres Sinclair ​or GOURI
5. Polydioxanone (PDO) a resorbable, synthetic biocompatible polymer, a material we know from PDO threads - brand Ultra-COL
6. Polymethyl methacrylate (PMMA), Bellafill 20% microspheres in bovine collagen, Suneva Medical - permanent polymer (not recommended)

Besides their different compositions, formulations, product preparations and injection modalities, their main differences consist of their degradation kinetics, level of efficacy and duration of action. The aliphatic polyesters, PCL and PLLA, degrade slowly by hydrolysis of the ester bonds and have a long duration with PCL having the longest. CaHA degrades more rapidly by a different mechanism. 

Calcium Hydroxylapatite
Calcium hydroxylapatite: Calcium hydroxylapatite is a type of mineral that is commonly found in human teeth and bones and in injectbales the calcium hydroxylapatite particles are suspended in a gel-like solution. The effects of this material last approximately 18 months with minimal inflammatory response. Radiesse is a biodegradable filler consisting of 30% synthetic CaHA microspheres (diameter of 25-45μm) suspended in a 70% aqueous carboxymethylcellulose gel carrier. The soluble carrier gel evenly distributes the Radiesse CaHA microspheres providing 1:1 correction and gradually dissipates leaving the microspheres at the injection site where they induce collagenesis (collagen type I and mostly collagen type III) by fibroblast activation. Animal studies have shown that this new collagen growth occurs as early as four weeks post-injection and continues for at least 12 months with an average duration of effect of 12 to 18 months, though some results have been noted 24 months post-injection. Radiesse provides both immediate (replacement volume) and long-lasting (collagen biostimulation) volume enhancement. (5)

Poly-L-lactic acid
PLLA is a biodegradable, bioresorbable biocompatible man-made polymer. This material has wide uses in absorbable stitches and bone screws. The effects of PLLA generally become increasingly apparent over time (over a period of several weeks) and its effects may last up to 2 years. There is an inflammatory response. PLLA is an alpha hydroxy acid polymer of the lactic acid L-enantiomeric structure that has been safely used in many applications and in medicine for more than 30 years. Its use has expanded worldwide, associated with good long-term aesthetic results thanks to its biostimulatory-collagen effect. PLLA-based fillers are supplied as a lyophilized powder to be reconstituted with sterile water. The collagen stimulatory properties were evidenced in human in subjects (n=14) who received PLLA injections (3 sessions, spaced 4 weeks apart) at the postauricular level by collagen histochemical determination on biopsies taken at different times. Increase of collagen type-I was shown at 3 and 6 months. This study opened the new class of collagen stimulators. The long duration of action was demonstrated in a first pivotal study comparing PLLA versus collagen (116/117 subjects, respectively); the long-term safety/efficacy was shown up to 25 months. The rationale for several sessions was first documented in a dedicated article; this modality allows the effect through collagen stimulation, a biological process to occur and avoids overcorrection. PLLA fillers are among the most clinically documented products. (6)

Polymers, polycaprolactone
The PCL-based collagen stimulator is composed of PCL microspheres suspended in a carboxymethyl-cellulose gel carrier providing immediate and sustained volumizing effects when injected; the morphology, the biocompatibility of the PCL microspheres embedded with the collagen fibers produced all contribute to the creation of a unique 3D scaffold for a sustained effect. Its safety has been investigated in clinical studies and vigilance surveys. It presents the advantage of a slower degradation than polylactic acid (PLLA) or polyglycolic acid (PGA), which both belong to the same chemical family.
Both the S and M products induced collagen production. In animal, the M product induced collagen type-III and type-I at early stage (measure at 9 months), and later predominantly collagen type-I, that deposits around the PCL microspheres (measure at 21 months). Many fibroblasts were found near the PCL microspheres. Interestingly, new elastin fibers were also formed, and neovascularization with new capillaries observed as well. (7)

NATURAL BIOSTIMULATORS

1. Platelet rich plasma
2. Platelet rich fibrin
3. Polynucleotides like Nucleofill or Nucleadyn
4. Exosomes
5. Alginate
6. Tropoelastin (precursor of elastin molecule)
​7. Poly-y-glutamic acid

Platelet-Rich Plasma (PRP): PRP treatments are produced by spinning a small volume of the patient’s own blood through a centrifuge. This separates and concentrates the blood’s components, including platelet-rich plasma and the “buffy coat,” a solution that contains immune cells. The provider combines these two components with a small amount of calcium chloride (which activates and keeps the PRP stable), then injects them into the treatment area. Over a period of months, PRP stimulates the body’s natural collagen production.

Platelet-Rich Fibrin (PRF): PRF is produced using a process similar to PRP concentration. The active material is a fibrin matrix rich in platelets, stem cells, and immune cells. Like PRP, PRF treatment stimulates collagen production and is also implicated in tissue regeneration, though there’s less data on the durability of its effects.

Because both treatments use material from the patient’s own body, so there’s no risk of rejection or similar complications. PRF and PRP effects are durable — typically lasting longer than 18 months.

Polynucleotides: Polynucleotides are most often natural, highly purified DNA molecules extracted for example from trout gonads and activate specialised cells called myofibroblasts and adipocytes. PN containing devices act as short time temporary fillers thanks to the viscoelasticity of the long DNA fragments and improve skin well‐being (cell growth) and steady self‐repair (tissue regeneration). Read more

Exosomes: The use of exosomes at the Aesthetic & Anti-Aging Medicine World Congress in Monaco was discussed during many session and some excellent results were presented. However their use is not yet approved and safety and long-term effect not yet established and largely depends on the source. Read more

BOTULINUM TOXIN 
There is evidence that the neuromodulator or musclerelaxer Botinumtoxin after injection upregulated the expression of type I collagen, decreases the production of some MMPs in fibroblasts, preventing collagen degradation and improves collagen organisation. (8.9.)

ENERGY BASED DEVICES
Intense Pulsed Light/BroadBand Light, Radiofrequency Microneedling, lasers, High-Frequency Ultrasound, Electromagnetic Tec. stimulate collagen production via a controlled damage and repair mechanism.

DERMO-COSMETICS WITH BIO-ACTIVES
There are innovative dermo-cosmetic products containing bio-stimulating ingredients, working more superficial in comparison to in-office treatments and they therefor are potentially an excellent choice as adjunctive care for biological rejuvenation and revitalization for younger looking and acting skin. They are safe to use easy to apply over face, neck and décolletage. Unlike in-office treatments their effects are temporary (fully reversible as regulated), hence they require daily or twice daily application.

Biostimulating active ingredients in skincare which have shown to particularly stimulate the fibroblast are for example:

• Creatine (bio-stimulation of collagen I and IV by + 35%  and elastin with +36%) (10)
• Glycine Saponin (bio-stimulation of hyaluron production +256% collagen +49% elastin +19%) which is also a powerful anti-oxidant (11.12)
• Arctiin (bio-stimulating collagen production + inhibiting of HN-Elastase responsible for collagen & elastin degradation) (10)

A 52 kDa Micro-Hyaluron molecule has proven to be the most potent to bio-stimulate the production of hyaluron by keratinocytes with 209%. (11) Read more about inhibiting hyaluron degradation

VITAMIN C IS NEEDED FOR COLLAGEN SYNTHESES! 
Our skin needs Vitamin C to produce collagen and is not able to produce it, thus relies on external resources for supply. Therefore I highly recommend to either get enough Vitamin C from your diet or use a high quality topical product pre & post biostimulators. Read more

BIOSTIMULATION FAT CELLS
Renuva is an allograft adipose matrix injectable that offers a non-surgical solution for volume restoration in various areas of the body, including the face, hands, and areas with contour irregularities. It stimulates the growth of own fat cells, potentially providing longer-lasting results. Renuva is FDA-regulated. In skincare the ingredient Magnolol or Magnolia Bark Extract has shown to increase the number and size of adipocites or fat cells to counteract volume-loss.

As the biological degeneration takes place in different layers of the skin and it's underlying structures, combining in-office treatments specifically targeting those layers in a series of treatments may provide longer lasting results and give higher patient satisfaction.(13) Safety and outcome rely on the qualification and experience of your cosmetic doctor, dermatologist or plastic surgeon. 


Take care


​Special thanks 
MD FAAD Hassan Galadari 
Jair Mauricio Cerón Bohórquez M.D.

References:
1. American Society Plastic Surgeons. 2020 national plastic surgery statistics; 2020. 
2. Wat H, Wu DC, Goldman MP. Noninvasive body contouring: a male perspective. Dermatol Clin. 2018;36(1):49–55. 
3. Wang JV, Akintilo L, Geronemus RG. Growth of cosmetic procedures in millennials: a 4.5-year clinical review. J Cosmet Dermatol. 2020;19(12):3210–3212. 
4. Evaluation of the biostimulatory effects and the level of neocollagenesis of dermal fillers: a review. Haddad S, Galadari H, Patil A, Goldust M, Al Salam S, Guida S International Journal of Dermatology, 29 Apr 2022
5. J Clin Aesthet Dermatol. 2015 Jan; 8(1): 38–49. Calcium Hydroxylapatite Over a Decade of Clinical Experience Jani Van Loghem, MD, Yana Alexandrovna Yutskovskaya, MD,b and WM. Philip Werschler, MDc
6. Clin Cosmet Investig Dermatol. 2022; 15: 997–1019. Collagen Stimulators in Body Applications: A Review Focused on Poly-L-Lactic Acid (PLLA)
Marie-Odile Christen Read more
7. Clin Cosmet Investig Dermatol. 2020; 13: 31–48. Polycaprolactone: How a Well-Known and Futuristic Polymer Has Become an Innovative Collagen-Stimulator in Esthetics Marie-Odile Christen and Franco Vercesi
8. Oh SH, Lee Y, Seo YJ, Lee JH, Yang JD, Chung HY, Cho BC. The potential effect of botulinum toxin type A on human dermal fibroblasts: an in vitro study. Dermatol Surg. 2012 Oct;38(10):1689-94. 
9. El-Domyati M, Attia SK, El-Sawy AE, Moftah NH, Nasif GA, Medhat W, Marwan B. The use of Botulinum toxin-a injection for facial wrinkles: a histological and immunohistochemical evaluation. J Cosmet Dermatol. 2015 Jun;14(2):140-4​
10 EADV 2022 Inhibition of extracellular matrix degrading enzymes and bio-stimulation of fibroblasts – A novel approach to mitigate the advanced degenerative process in skin aging Weise J, Vogelsang A, Sperling G, Welge V, Nölter A, Mielke H, Knott A, Harbig S, Stuhr A, Dunckel J, Warnke K, Geloven van A
11. EADV 2021 Multifaceted novel approach to increase skin’s own epidermal and dermal hyaluron content Bussmann T, Warnke K, Krüger A, Möller N, Harbig S, Stuhr A, Dunckel J, Geloven van A, Weise J | Beiersdorf AG, Hamburg, Germany
12. Photochemistry and Photobiology, 2005, 81: 581–587 Novel Aspects of Intrinsic and Extrinsic Aging of Human Skin: Beneficial Effects of Soy Extract Kirstin M. Su¨del et al
13. Combination Therapy in Midfacial Rejuvenation Humphrey et al. Dermatologic Surgery 42:p S83-S88, May 2016. 
*AMWC 2023 Tapan Patel

Polynucleotides (PNs) are a type of biomolecule that have recently gained traction in the field of skin care and aesthetic treatments. PNs are composed of multiple nucleotides, which are the building blocks of DNA and RNA. These biomolecules have shown promise in improving the appearance and health of the skin through their ability to stimulate cell growth (activate growth factors), tissue regeneration incl. collagen production, wound healing, fibroblast proliferation and have anti-inflammatory properties.

Polynucleotides (PN) are linear polymers composed of many nucleotide units and they play a key role in the storage and transmission of genetic information. There are two types of polynucleotides (aka nucleic acid) found in nature: ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). As mentioned, PN are composed of nucleotides, which consist of 3 parts: a nitrogenous base, a phosphate group. and a five-carbon sugar (2'-deoxyribose in DNA or ribose in RNA). The five base nucleotides are adenine, guanine, cytosine, thymine, and uracil. A DNA molecule consists of two long polynucleotide chains composed of four types of nucleotide subunits: adenine, thymine, guanine, and cytosine, while RNA uses adenine, guanine, cytosine and uracil. 

REGENERATIVE AESTHETICS

Regenerative aesthetics is an emerging branch of regenerative medicine with therapies or products aimed at recapturing youthful structure and function using the body's own systems. Examples of such treatments are platelet-rich plasma (PRP), the use of exosomes or polynucleotides.
Dr. Kate Goldie explained soft tissue regeneration fundamentals as following: 
1. Regeneration of tissue architecture (structure): tissue composition - component abundance, ratio's, position, density and biomechanics/integrity
2. Regeneration of tissue function: signaling, cell function, cellular components (incl. senescence), gene expression and molecular interaction.
The 3 treatment pillars of regenerative aesthetics are: cells, biocues and bio-stimulatory scaffolds. Key superficial soft quiescent cells are the fibroblasts and adipose derived stem cells. One of the big advantages of regenerative aesthetics is by using the body's own system, the results are natural and focused on "skin health" (function) and "skin quality" (appearance).

POLYNUCLEOTIDES IN REGENERATIVE AESTHETICS

Polynucleotides are most often natural, highly purified DNA molecules extracted for example from trout gonads and activate specialised cells called myofibroblasts and adipocytes. PN containing devices act as short time temporary fillers thanks to the viscoelasticity of the long DNA fragments and improve skin well‐being (cell growth) and steady self‐repair (tissue regeneration). Studies support their dermal reactivating properties or their efficacy as “bioreactivating primers” of skin. The final outcome is more natural and in‐depth tissue regeneration and a healthier look of the skin: a more radiant complexion, even skin tone, reduced appearance of fine lines, wrinkles and sagging, faster wound healing, improved pore size and skin thickness, elasticity and hydration. Furthermore, PNs are generally well-tolerated by the skin and have a low risk of adverse effects. Their effectiveness may vary depending on the individual's skin type, age, and overall health. The long-term effects of PNs on the skin are not yet fully understood, and more research is needed to determine their safety and efficacy. There are various brands available which use polynucleotides in their (meso-) injection gels. For example Mastelli Srl, Italy NEWEST® (Polynucleotide and Hyaluronic Acid) for bio-revitalization, BR Pharm HP Cell Vitaran Skin Healers, NUCLEADYN® or Nucleofill®.

One brand of (synthetic) polynucleotide-based skin care products is Yuva by Dr. Devgan Scientific Beauty. The Yuva line includes a range of products formulated with PNs, such as the Yuva Serum and the Yuva Enhancer. These products are marketed as being able to provide hydrating, anti-aging, and skin-rejuvenating benefits.

THE FUTURE OF POLYNUCLEOTIDES

While polynucleotides have many benefits, they also have some drawbacks. One of the primary limitations is their instability in certain environments. This instability can make it difficult to synthesize and manipulate polynucleotides in the lab. Moreover their are limitations, risks and ethical concerns harvesting or using (human identical) PN's, and long-term safety and efficacy data is not conclusive. However, PNs are a promising area of research in the field of skin care and aesthetic treatments and regeneration. We can expect to see further advancements in the development of PNs-based products and treatments. PNs are already used in combination with other biomolecules, such as hyaluronic acid, growth factors and anti-oxidants and used in combination with other treatments. For a personal recommendation on which aesthetic treatment is most suitable to aesthetically regenerate your skin, please consult an experienced board certified dermatologist, plastic surgeon or cosmetic doctor. 

Take care.

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

AGEs cause changes in the skin through 3 processes:

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

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

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

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

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

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

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

Take-aways from a study published in the International Journal of Cosmetic Science [2]:
1. NAHP significantly and dose-dependently inhibited the formation of advanced glycation end-products (AGEs) in a protein solution.
2. NAHP dose-dependently inhibited the formation of N-(carboxymethyl)lysine (CML), a specific AGE.
3. In fibroblast-populated collagen lattices, NAHP prevented the glycation-induced disturbance of fibroblast contractile capacity.
4. Ex vivo application of NAHP to skin explants decreased AGE fluorescence compared to glucose-treated samples.

​Anti-Oxidants
I would suggest to combine those ingredients with an ingredient like Licochalcone A. Numerous high ranked publications support that Licochalcone A protects cells from oxidative stress mediated by e.g. UV and HEVIS (blue light) induced reactive oxidative species (ROS). Due to the activation and nuclear translocation of the transcription factor NrF2, the expression of anti-inflammatory, antioxidant and detoxifying enzymes are induced. These enzymes protect the skin cells (like keratinocytes and fibroblasts) from ROS-induced damage, like lipid peroxidation and DNA as well as protein damage. If Licochalcone A is combined with L-Ascorbic Acid, (the most active form of Vitamin C), it supporting skin's own collagen production, provides superior biological cell protection amongst other relevant benefits. Vitamin C (and E) has shown to inhibit protein glycation [4].

SPRAY TAN
A study in Redox Biology indicates that sunless tanning with dihydroxyacetone (DHA) causes glycation and potential DNA damage in the epidermis [1].:
1. Glycation: DHA exposure led to the formation of advanced glycation end products (AGEs) in epidermal cells, confirmed by mass spectrometric detection of N-ε-(carboxyethyl)-l-lysine (CEL).
2. DNA damage: DHA induced a cellular stress response, including activation of stress-related genes and phosphoprotein signaling. While not directly measuring DNA damage, these responses are often associated with cellular stress that can lead to DNA damage.
3. Significance: The effects were observed at low millimolar concentrations of DHA, relevant to topical application. The stress response was rapid and pronounced, occurring within minutes of exposure.
4. Location: The effects were primarily observed in epidermal cells and reconstructs, with no mention of dermal effects.
This study suggests that sunless tanning with DHA may not be as safe as previously thought, warranting further investigation into its long-term effects on skin health [1], however no need to panic as this negative effect is only seen in the top layer of the skin.

DOUBLE TROUBLE: GLYCATION + UVB  [3]
The combination of GO-AGEs and UVB exposure has a more pronounced effect on skin inflammation and oxidative stress than either factor alone. This suggests a synergistic relationship between glycation and UV exposure in accelerating skin aging processes.
1. GO-AGEs combined with UVB irradiation significantly increased the secretion of pro-inflammatory cytokines (IL-1β, IL-6, IL-8) in skin cells compared to either GO-AGEs or UVB alone.
2. The GO-AGEs + UVB treatment group showed a more than three-fold increase in IL-6 and IL-8 mRNA levels compared to other groups.
3. GO-AGEs + UVB treatment induced significantly higher release of nitric oxide (NO) compared to other groups.
4. The combination of GO-AGEs and UVB enhanced reactive oxygen species (ROS) release, creating about 1.5 times more oxidative stress compared to control and other groups.
5. Cell viability was notably affected in the GO-AGEs, UVB, and GO-AGEs + UVB treatment groups compared to the control group.
These findings are significant as they demonstrate that the combination of GO-AGEs and UVB exposure has a more pronounced effect on skin inflammation and oxidative stress than either factor alone. This suggests a synergistic relationship between glycation and UV exposure in accelerating skin aging processes. Use sunscreen daily.
.
GLYCATION AND SKIN HEALTH
Acne
In addition to its role in ageing, glycation in the skin has also been linked to a range of skin health problems. One study published in the Journal of Cosmetic Dermatology found that the level of AGEs in the skin was significantly higher in individuals with acne than in those without acne. The study also showed that treating acne with a topical antibiotic significantly reduced the levels of AGEs in the skin.
Atopic Dermatitis
Another study published in the Journal of Investigative Dermatology found that individuals with atopic dermatitis had higher levels of AGEs in their skin than healthy individuals. This suggests that glycation may play a role in the development of inflammatory skin conditions.
Diabetes + Woundhealing
The correlation between high sugar levels and skin ageing can be seen in diabetic patients, where one-third of this population has skin complications. A prominent feature of ageing human skin is the fragmentation of collagen fibers, which severely damages the structural integrity and mechanical properties of the skin. Elevated levels of MMP-1 and MMP-2 and higher crosslinked collagen in the dermis of diabetic skin lead to the accumulation of fragmented and crosslinked collagen, thereby impairing the structural integrity and mechanical properties of dermal collagen in diabetes. Collagen crosslinking makes it impossible for them to easily repair, resulting in reduced skin elasticity and wrinkles. Keratinocytes and fibroblasts are the main cells involved in wound healing, but due to the high glucose (HG) microenvironment in diabetics, the functional state of these cells is impaired, thereby accelerating cellular senescence (programmed cell death).

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

Take care
Anne-Marie

References
[1] Perer J, Jandova J, Fimbres J, Jennings EQ, Galligan JJ, Hua A, Wondrak GT. The sunless tanning agent dihydroxyacetone induces stress response gene expression and signaling in cultured human keratinocytes and reconstructed epidermis. Redox Biol. 2020 Sep;36:101594.
[2] Knoblich C, et al. N‐acetyl‐L‐hydroxyproline – A potent skin anti‐ageing active preventing advanced glycation end‐product formation in vitro and ex vivo. Int J Cosmet Sci. 2023;1-10. doi:10.1111/ics.12930
[3] Sultana, R., Parveen, A., Kang, MC. et al. Glyoxal-derived advanced glycation end products (GO-AGEs) with UVB critically induce skin inflammaging: in vitro and in silico approaches. Sci Rep 14, 1843 (2024). https://doi.org/10.1038/s41598-024-52037-z
[3] Sadowska-Bartosz I, Bartosz G. Prevention of protein glycation by natural compounds. Molecules. 2015 Feb 16;20(2):3309-34. doi: 10.3390/molecules20023309. PMID: 25690291; PMCID: PMC6272653.

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

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

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

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

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

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



​Take care

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

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

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

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

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

Take care
​
*in vitro