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

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

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

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

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

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

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

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

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
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[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. 
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[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
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[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

One of the people I follow ever since I started to work on skin epigenetics back in 2017 and longevity is Harvard professor David Sinclair. He is best known for his (sometimes controversial) work on understanding why we age and how to slow its effects. He was talking about hormesis, a phenomenon where exposure to low doses of stressors induces beneficial effects. A hormetic (cellular defense) response can modulate ageing processes by activating genes related to maintenance and repair pathways through mild stress exposure in our body and skin, leading to enhanced longevity (thus anti-ageing) and health. [1 - 2] 

Originating from the early 2000s, the concept of hormesis has evolved to evidenced based dermatological applications. [3] Various factors, including environmental stressors, lifestyle choices, and genetic predispositions, can influence the hormetic responses in skin cells. Understanding these influences is essential for optimizing skin health and beauty through hormetic pathways. Many terms are used for hormetic responses in the scientific literature, including the Arndt-Schulz Law, biphasic dose response, U-shaped dose response, preconditioning/adaptive response, overcompensation responses, rebound effect, repeat bout effect, steeling effect, among others. [4]

Ageing is an emergent, epigenetic and a meta-phenomenon, not controlled by a single mechanism. 
Cellular damage has three primary sources: [3]

1. Reactive oxygen species (ROS) and free radicals (FR) generated by external factors like UV radiation and metabolic processes involving oxygen, metals, and other molecules
2. Nutritional components like glucose and its metabolites, which interact with FR
3. Spontaneous errors in biochemical processes, including DNA replication, gene expression, and protein modifications

Despite the constant occurrence of damaging events within cells, a variety of repair mechanisms at the molecular, cellular, and physiological levels work to counteract these events and ensure survival.

Effective homeodynamic space or buffering capacity (body's ability to maintain stability or balance in changing conditions) is characterized by:

1. Stress response (SR)
2. Damage prevention, repair, and removal
3. Continuous remodeling and adaptation

Ageing can be conceptualized as gradual reduction of the body's ability to maintain stability or balance in changing conditions, hence loss of buffering capacity.

Stress response is a reaction to physical, chemical, or biological factors (stressors) aimed at counteracting, adapting, and surviving, is a critical component of the homeodynamic space.
There are seven main cellular stress response pathways:

1. Heat Shock Response (HSR) -  read more about Heat Shock Proteins
2. Unfolded Protein Response (UPR)
3. Autophagy
4. Antioxidant response
5. Inflammatory response
6. DNA repair response
7. Sirtuin response

Each SR pathway is specific to the type of damage induced by the stressor and the downstream effectors involved, with some overlap but generally distinct responses. [3]

Hormetins can be categorized into three types:

1. Physical (e.g., exercise, hypergravity, heat, radiation)
2. Biological
3. Nutritional (e.g., infections, micronutrients, spices, natural and synthetic compounds), and psychological (e.g., mental challenges, meditation)

Numerous studies and articles have explored the effects of potential anti-ageing hormetins or hormetic treatments, including heat shock, radiation, hypergravity, curcumin, kinetin, rosmarinic acid, ferulic acid, an extract containing 95% saponins, food / calorie restriction [1.2.3], alcohol (ethanol) [4], other xenophormetic compounds like resveratrol, catechins, lignans [5], pro-oxidants [6] and epigenetics. [7]  

Hallmarks of aging benefiting from hormesis
1. Loss of proteostasis
Hormetic stress can upregulate heat shock proteins (HSPs) and other molecular chaperones, improving protein folding and maintenance. [9] This directly supports proteostasis, which is crucial for cellular (skin) health and longevity.
2. Mitochondrial dysfunction
Mild stress can stimulate mitochondrial biogenesis and improve mitochondrial function, potentially counteracting age-related mitochondrial decline.[9]
3. Cellular senescence
Hormetic interventions may help clear senescent cells or prevent their accumulation, though this effect is less direct and requires further research. [8]
4. Deregulated nutrient sensing
Hormetic stressors like caloric restriction or intermittent fasting can improve nutrient sensing pathways, particularly involving sirtuins and AMPK. [9]
5. Epigenetic alterations
Some hormetic stressors can influence epigenetic markers, potentially reversing age-related epigenetic changes. [8]
6. Stem cell exhaustion
Mild stress may stimulate stem cell activity and regeneration, though this effect varies depending on the type and intensity of the stressor. [9]
7. Altered intercellular communication
Hormesis can modulate inflammatory responses and improve intercellular signaling, potentially addressing the "inflammaging" phenomenon. [8][9]

Being aware of the phenomenon of hormesis can result in discovering the usefulness of new compounds, or synergistic effects of combining hormetic treatments which otherwise may have been rejected due to their effects of stress induction. What is bad for us in excess, can be beneficial in moderation, or (quote): "What doesn't kill you makes you stronger". [6]. The future of hormesis in dermatology holds great promise for innovative  interventions, advanced hormetic technologies or personalized skin care regimens. 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

Read more:
The impact of senescent zombie cells on skin ageing
The role of heat shock proteins in skin rejuvenation
Neurocosmetics, the skin-brain connection & neuro-ageing
The role of the lymphatic system in ageing skin
The power of light and photo-biomodulation
Bio-stimulators
Skin glycation
Exosomes

References

1. Sage Journal Hormetic Modulation of Aging and Longevity by Mild Heat Stress Suresh I. S. Rattan 2005
2. Dose Response. Hormesis as a Pro-Healthy Aging Intervention in Human Beings? Francine Z. Marques 2010
3. Dose Response. Hormesis-based anti-aging products: a case study of a novel cosmetic. Rattan SI et al. 2012
4. Nature npj Aging and Mechanisms of Disease How does hormesis impact biology, toxicology, and medicine?
   Edward J. Calabrese & Mark P. Mattson 2017 - updated 2023
5. Explor Res Hypothesis Med. Xenohormesis: Applying Evolutionary Principles to Contemporary Health Issues. Suter S et al. 2017
6. Gac Med Mex. Hormesis: What doesn't kill you makes you stronger Norma Edith López-Diazguerrero et al 2013 
7. Ageing Res Rev. Hormesis and epigenetics: is there a link? Alexander M Vaiserman et al. 2011
8. New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary Tomas Schmauck-Medina - Aging
9. Hormesis in aging. Ageing Res Rev. Rattan SI. 2008 
   

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

While factors like genetics and lifestyle (including sun exposure) play significant roles in skin ageing, the role of the lymphatic system in skin ageing is an  overlooked however interesting strategy to improve skin's youthful functional (health) and physical attributes (beauty).

The lymphatic system, a vital part of the immune system, is responsible for draining excess fluid, toxins, and waste products from tissues. In the skin, lymphatic vessels collect waste and transport it to lymph nodes for filtration. The lymphatic vessels work with tiny, reflexive muscular contractions constantly pumping cleansing (toxins and debris) lymph fluid through their channels. Interestingly it explains why injections with the muscle relaxant botulinum toxin can cause oedema. 

The function of the lymphatic system

1. Collecting excess fluid from your tissues and returning it to your bloodstream, thus less puffiness and more sculpted.
2. It filters out waste products and abnormal cells from this fluid, thus reducing damage on healthy skin cells and skin components.
3. Protect against invaders like viruses, bacteria, and fungi, hence reducing inflammation.

If you combine all these functions, it's pretty much protecting against accelerated skin ageing.

As we age the lymphatic function and density is decreasing 1:

• Decrease in initial lymphatic vessel density and lymphatic endothelial cell numbers 1.2
• Decrease in collecting lymphatic vessel density and collecting LEC numbers and alters their phenotype
• Decrease in dendritic cell migration and lymphatic pumping and increased leakiness in lymphatic vessels 
• Decrease LEC VEGFR3 signaling and increased senescence and apoptosis 
• Increased immune cell infiltration and nitrosative stress surrounding lymphatics 
• Decreased chemokine and altered junctional protein expression by LECs 
• Downregulation of lymphatic-specific genes like PROX1 (master gene lymphatic system)
• Downregulation of VEGF-C (mediator of lymphangiogenesis and reduction inflammation)

This in turn will contribute to accelerated skin ageing.

Effects of lymphatic system decline on skin:

1. Fluid accumulation: Reduced lymphatic function results in fluid buildup, causing puffiness, especially around the eyes and cheeks.
2. Toxin buildup: Accumulation of toxins in the skin due to poor lymphatic drainage can contribute to inflammation and skin conditions.
3. Decreased nutrient delivery: Impaired lymphatic circulation hinders the supply of essential nutrients to skin cells.
4. Slower healing: A compromised lymphatic system slows down the skin's ability to repair itself, making it more prone to damage and wrinkles.

To sum it up, the ageing lymphatic system can lead to skin dullness, dryness, decreases regeneration, more wrinkles, unevenness and puffiness especially around the eyes. Therewith rejuvenation and activation of the lymphatic system can lead to overall improvement of skin health and beauty.

Rejuvenating the lymphatic system for youthful sculpted skin:

1. Healthy Diet: Consume a diet rich in fruits, vegetables, and antioxidants supports lymphatic function and reduce inflammation.
2. Hydration: Stay adequately hydrated helps maintain the fluid balance in the body and supports lymphatic circulation.
3. Exercise: Regular physical activity, especially movements that promote lymph flow like (facial) yoga or rebounding, can improve lymphatic drainage.
4. Massage: Gentle lymphatic drainage massage, Gua Sha or pressure, tapping techniques can stimulate lymphatic vessels, improving fluid circulation and detoxification.
5. Skin Care: As photo (sun) damage is a primary cause of accelerated skin ageing (80% up to 90%) including lymphatic vessels(2), start with prevention by using sunscreen on a daily base. Moreover, some active ingredients incorporated in skincare, like Mulberry White Bark extract, fermented Ginseng and others (3.4) have proven to rejuvenate or reactivate the skin's lymphatic system.

Wrongful injected fillers in the tear trough or malar (eye socket - cheek area) septum can lead to worsening of malar oedema (fluid retention) or malar bags. 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. Structural and Functional Changes in Aged Skin Lymphatic Vessels R. Kataru et al. Front. Aging, 2022 
2. Reduction of lymphatic vessels in photodamaged human skin Kentaro Kajiya, Rainer Kunstfeld, Michael Detmar, Jin Ho Chung J Dermatol Sci. 2007 
3. Patent Cosmetic preparations comprising natural activators
4. Patent Cosmetic preparations comprising daphne extracts

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, reduce inflammation, 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

It was always believed that the moment we are born, is the moment we are exposed to environmental influences. The truth is that there is ample evidence that already during pregnancy the mothers behaviour: smoking or food has a significant impact on how well we age. We know that all skin needs to be protected against UV and HEVIS by using sunscreen, especially in sun exposed areas from birth onwards.

Although you can not start too early taking care of your skin, the right age to start with a well-ageing skin care routine is actually just post-adolescence for 3 reasons.

1. During adolescence most start with their first cleansing and care routines to remove access of sebum, debris and reduce plus prevent break-outs or comedones. Boys may already shave facial hair. So teenagers or young adults are used to a morning- and evening skin care routine which benefits the overall sense of well-being.
2. Most commonly growth stops when puberty ends and this is the moment the degenerative biological process starts, even though there are no visible signs yet.
3. Prevention of pre-mature ageing skin is the most effective and efficient strategy. 

SKIN NEEDS CARE
There is a movement stating that normal unproblematic skin doesn't need care. I strongly disagree. The choice of products at this age depends of course on the skin type, skin condition, skin health, and environment (like weather conditions, pollution), however the morning care should always focus on protecting every skin type, using suncreen (UV + HEVIS protection) and ideally complimented by anti-oxidants to reduce damaging free radical activity, while the evening routine should at least include proper cleansing (to remove dirt and pollutants), which may be followed by product catering to specific needs, like for example sebum regulating, barrier repairing or hydrating ingredients. I would not make a differentiation between darker or lighter skin in terms of photoprotection, as dark skin only has a natural SPF of 13.3 and light skin of 3.4, hence both not enough to prevent sun damage. However, dark skin has a lower amount of ceramides in the statum corneum and is therefore more prone to trans-epidermal water loss. 

LAZY SKIN?
If you are afraid of spoiling your skin and making it "lazy" using skin care for a long time, know that all effects from a dermo-cosmetic product are 100% reversible, thus temporary. This is regulated by law and to enjoy the benefits from skin care, you need to keep using the products. When you stop, your skin will bounce back to it's original state at least after a full regeneration cycle of about 28 days. A few things to avoid are: sun-damage, especially burns, over-exfoliation (damaged skin barrier) and slugging of oily or acne-prone skin (breakouts). 

Take care.