The widespread belief that the epidermis renews itself every 28 days is inaccurate. Epidermal turnover primarily involves keratinocytes, the predominant cell type in the epidermis with 90%. These cells originate in the basal layer (stratum germinativum) and progressively move upward through the epidermal layers, undergoing various changes before being shed from the skin's surface as dead, flaky cells - a process known as desquamation [1].

The keratinocyte journey has several stages:

1. 1. Formation in the basal layer
2. 2. Migration through epidermal layers
3. 3. Maturation and differentiation
4. 4. Transformation into corneocytes (fully differentiated keratinocytes without nuclei or organelles)
5. 5. Shedding from the stratum corneum (outermost epidermal layer) [1]

This continuous cycle of cell production, maturation, and shedding is called epidermal turnover [1]
 
Epidermal turnover rates vary significantly with age:
▌In young adults: approximately 28-40 days [2]
▌In more mature adults: 60+ days [2]
This age-related slowdown is attributed to decreased cell proliferation [3]

KERATINOCYTE LIFESPAN 
The keratinocyte lifecycle can be divided into two main phases:
1. Active life: Approximately 8 to 10 days from mitosis (in the basal layer) to arrival in the stratum corneum [1].
2. Stratum corneum transit: The period spent in the outermost layer as corneocytes (dead keratinocytes) before shedding [1].

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 broadband 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] Additionally, its protective mechanisms include stabilising cell membranes and reducing inflammatory responses triggered by light exposure. [20]
​
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.

Many people associate a tan with health, beauty and an active lifestyle. Although a moderate dose of solar radiation is indispensable for our health, unfortunately, there is no such thing as a real "healthy tan" or "healthy sun-kissed glow" as it is always a visible sign of skin damage. Tanning is a response by the skin to exposure to ultraviolet (UV) radiation (and HEV or Blue Light), either from natural sunlight or artificial sources like tanning beds which leads to photo-ageing, pigmentary disorders (like age spots or hyperpigmentation) and immunosuppression, hence skin cancer. When skin is exposed to sunlight: UV rays and high energy visible light (HEV) or also called Blue Light (the most energetic region of HEV), it produces more melanin, a pigment that darkens the skin as a (partial) protective mechanism to prevent further damage. The amount of artificial blue light emitted during the conventional use of electronic devices is not enough to trigger harmful skin effects. (Click here to read more)

MELANIN
Melanin is only produced by cells called melanocytes, mostly distributed in the epidermal-dermal junction. Melanocytes contain specialized organelles called melanosomes to store and produce melanin. Melanosomes are transferred from the melanocytes to the neighboring keratinocytes, which are the most abundant cells in the epidermis. One melanin-forming melanocyte surrounded by 36 keratinocytes and a Langerhans cell is called the melano-epidermal unit. [1.2]  Melanocytes use the amino acid tyrosine to produce melanin and protect epidermal keratinocytes and dermal fibroblasts from the damaging effects of solar radiation.. [13]

The are two melanin pigment classes:

1. Eumelanin, which has a black or brown hue and has photoprotective qualities via its ability to absorb and scatter ultraviolet radiation and scavenge reactive oxygen species.
2. Pheomelanin, which has a yellow to red hue, is photosensitizing by stimulating lipid-peroxidation and leads to the production of reactive oxygen species. Pheomelanin is predominant in lighter phototypes. [1]

​
Differences in skin pigmentation do not result from differences in the number of melanocytes in the skin, as one might assume, but from differences in the melanogenic activity (melano-competence), the type of melanin produced in melanosomes (the ratio between eumelanin and pheomelanin differs per Fitzpatrick phototype) and the size, number and packaging of melanosomes, with melanin content of melanosomes ranging from 17.9% to 72.3%. [7] The amount of melanin is never enough for adequate photoprotection, and a "base tan" does not prevent sunburn. Particularly darker phototypes are more sensitive for the damaging effects of Blue Light. Both eumelanin and pheomelanin production are promoted by UV radiation and Blue Light and therefore sunscreens offering a combination of both UV (A + B) protection and Blue Light defense are recommended for all phototypes.

TANNING PROCESS 
The skin's tanning process occurs in four distinct phases: [3]

1. The first phase includes immediate pigment darkening (IPD) within minutes and can remain for several hours (or days depending on the exposure duration) of UV exposure and is caused by the immediate photo-oxidation oxidation and redistribution of pre-existing melanin or melanin precursors in the skin and therefor is most pronounced in skin with significant pre-existing pigmentation (melano-competent skin). IPD does not involve the production of new melanin [2] and is gray/black in color. [5 6]
2. The second phase involves an intermediate step, called persistent pigment darkening (PPD) to brown color, which occurs within hours and remains for days is by some thought to result from newly synthesized melanin in the epidermis [5], or as a result from the oxidation of melanin (similar to IPD) [7], thus not necessarily involves melanogenesis processes. [6] PPD is elicited more strongly by UVA than UVB and therefore is also used as testmethod to measure UVA protection (UVA-PF) of sunscreens. [7] 
3. The third phase of neo-melanogenesis or delayed tanning (DT) which develops in days and remains for max 10 days to 3-4 weeks (depending on dose and skin color) [7], results from prolonged increases in melanin content. [5] Delayed tanning is induced mainly by UVB radiation, but both (larger doses in comparison to IPD) of UVA, UVB and Blue Light can contribute. UVB-induced DT is slightly photoprotective (SPF3), while DT induced by UVA isn't. [7]
4. The fourth phase is a distinct pigmentation response called long-lasting pigmentation  (LLP) which remains >9 months after initial UV exposure and results from prolonged activation of the pigmentary system [5]  or retarded desquamation of the epidermis. Darker phototypes have the highest tendency to be LLP positive and advanced age may also facilitate the LLP response. [8] >2 MED (minimal erythema doses) showed an LLP frequency of 40–70%. [8]

ROLE OF UVA, UVB AND BLUE LIGHT
One of the most important acute effects of UVR is DNA damage. UVA and UVB show different properties regarding their biological effects on the skin. [7] Shorter wavelengths (nm) correspond to higher energy. Infrared does not induce oxidative stress. Read more

UVA radiation (320-400 nm) penetrates deeper into the skin and can induce indirect DNA damage by the generation of reactive oxygen species (ROS), leading to premature skin aging. UVA, in contrast to UVB is not filtered by window glass, is able to penetrate deeper into the skin and reach the dermis. They are present constantly, with relatively equal intensity, during all daylight hours throughout the year. It has been estimated that 50% of exposure to UVA occurs in the shade. UVA rays are less intense than UVB, but there are 30 to 50 times more of them. To produce the same erythemal response, approximately 1000 times more UVA dose is needed compared with UVB. [7] The bulbs used in tanning beds emit mostly UVA. 

UVB radiation (280-320 nm) is less prevalent than UVA, primarily affects the outermost layers of the skin, causing direct DNA damage (more potent than UVA) and triggers inflammatory responses that lead to increased melanin production. UVB radiation fluctuates throughout the day, are at their strongest at noon. and are more cytotoxic and mutagenic than UVA. The action spectrum for UV-induced tanning and erythema are almost identical, but UVA is more efficient in inducing tanning whereas UVB is more efficient in inducing erythema (redness). Dark skin is twice as effective compared to light skin in inhibiting UVB radiation penetration. [7] UVB helps the skin to produce Vitamin D.

Blue light (400-500 nm) visible light accounts for 50% of sunlight [11] and can contribute to immediate, delayed, continuous and long-lasting pigmentation by activating melanocyte-specific photoreceptors and increasing melanin synthesis, particularly in individuals with darker (melano-competent) skin types [9], cause DNA damage [10] and generate damaging reactive oxygen species in both the epidermis and the dermis. [12] The effects may last longer than those induced by UVA and UVB radiation. Blue Light can penetrate even deeper than UVA and reach the hypodermis. Blue light therapy is used to target acne causing bacteria and inflammation, however the risks might outweigh the benefits especially in darker phototypes and it might worsen acne marks.

EPIDERMIS AND DERMIS
Both dermal fibroblasts and epidermal keratinocytes play a crucial role in regulating skin pigmentation and tanning response. [13 15]  In comparison to epidermal tanning, dermal tanning is less visible, however more immediate.

Dermal fibroblasts secrete various paracrine factors that regulate melanocyte function, survival, and melanin production. Factors like hepatocyte growth factor (HGF), nerve growth factor (NGF), stem cell factor (SCF), and basic fibroblast growth factor (bFGF) stimulate melanogenesis and pigmentation [14 15] Fibroblast senescence and altered secretory profiles in conditions like melasma contribute to abnormal pigmentation by stimulating melanogenesis. [15]

Epidermal keratinocytes produce factors like α-melanocyte stimulating hormone (α-MSH) and Wnt1 that activate melanogenic pathways in melanocytes, leading to increased melanin synthesis and transfer to keratinocytes. [15 16]. Keratinocyte-derived exosomes can enhance melanin production by melanocytes. [16]  Differences in autophagic activity between various keratinocytes also influences pigmentation. [15]

MicroRNAs
MicroRNAs are small, non-coding RNA molecules that regulate gene expression by binding to messenger RNA (mRNA) and typically suppressing protein production, for example collagen. They are classified as epigenetic modulators. Several miRNAs have been identified as differentially expressed in aged skin compared to young skin, including:
   - miR-383, miR-145, miR-34a (upregulated in sun-exposed aged skin)
   - miR-6879, miR-3648, miR-663b (downregulated in sun-exposed aged skin) [17]

Enjoy the sun, however protect your (and your children's) skin from a photo-damaging tan to remain skin health and beauty. Sunless self-tanning products containing dihydroxyacetone (DHA) or Erythrulose provide a safe alternative to achieve a "sun-kissed" glow. You can use after-sun skin care which helps to rehydrate, reduce damage of "sun-stressed" skin and support it's repair. 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. Molecules. Photoprotection and Skin Pigmentation: Melanin-Related Molecules and Some Other New Agents Obtained from Natural Sources
   Francisco Solano 2020
2. Exp Dermatol. Skin Pigmentation and its Control: From Ultraviolet Radiation to Stem Cells
   Joseph Michael Yardman-Frank et al. 2021
3. Photodermatol Photoimmunol Photomed The dynamics of pigment reactions of human skin to ultraviolet A radiation Indermeet Kohli et al 2019 
4. Review J Int Med Res The effects of ultraviolet exposure on skin melanin pigmentation J P Ortonne et al. 1990
5. J Investig Dermatol Symp Proc. Short- and Long-Term Effects of Ultraviolet Radiation on the Pigmentation of Human Skin
   Sergio G. Coelho 2009
6. Int J Cosmet Sci. Pigmentation effects of blue light irradiation on skin and how to protect against them R. Campiche et al 2020
7. Photochem Photobiol. The Protective Role of Melanin Against UV Damage in Human Skin Michaela Brenner et al 2008
8. Pigment Cell Melanoma Res. Long-Lasting Pigmentation (LLP) of Human Skin, a New Look at an Overlooked Response to UV
   Sergio G. Coelho et al 2009
9. J Invest Dermatol. Melanocytes Sense Blue Light and Regulate Pigmentation through Opsin-3 Claire Regazzetti et al 2018
10. Photodermatol Photoimmunol Photomed. Blue light induces DNA damage in normal human skin keratinocytes
    Cécile Chamayou-Robert et al 2022
11. Front. Med., Damaging effects of UVA, blue light, and infrared radiation: in vitro assessment on a reconstructed full-thickness human skin
    Paula Montero et al 2023
12. Journal of Photochemistry and Photobiology B: Biology The potential role of UV and blue light from the sun, artificial lighting, and electronic devices in melanogenesis and oxidative stress Enrique Navarrete de Gálvez et al 2022
13. Pigment Cell Melanoma Res. Participation of keratinocyte- and fibroblast-derived factors in melanocyte homeostasis, the response to UV, and pigmentary disorders Parth R. Upadhyay et al 2021
14. PLoS One. Key Regulatory Role of Dermal Fibroblasts in Pigmentation as Demonstrated Using a Reconstructed Skin Model: Impact of Photo-Aging Christine Duval et al 2014
15. Dermatology and Therapy Update on Melasma—Part I: Pathogenesis Ana Cláudia C. Espósito et al 2022
16. Nature Exosomes released by keratinocytes modulate melanocyte pigmentation Alessandra Lo Cicero et al 2015
17. Nature Identification of chronological and photoageing-associated microRNAs in human skin Srivastava, A., Karlsson, M., Marionnet, C. et al. 2018

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

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

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

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

This consequently affects both health and beauty 

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

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

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

Other Factors

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

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

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

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

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

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

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

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

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

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

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

7. Oxygen therapy

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

​​8. Supplements

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

9. Skincare ingredients

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Mechanisms of skin cell senescence:

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

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

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

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

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

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

STRATEGIES TO COMBAT CELL SENESCENCE

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

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

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

Skin care ingredients: [18]

• Aquatide™ (Heptasodium hexacarboxymethyl dipeptide-12): Known to protect the skin from pollution and sun radiation, activating SIRT-1 to decrease cellular senescence
• Crepidiastrum Denticulatum Extract: This ingredient has shown potential in reducing senescent cells and rejuvenating the skin
• Exosomes: Found in products like Plated SkinScience Intense Serum, exosomes have been linked to a reduction in the number of senescent cells after use. Read more about exosomes
• Melatonin: Known for its anti-inflammatory properties, melatonin can help prevent senescent cells in the skin
• Pollux CD™ (Crepidiastrum Denticulatum Extract): Another ingredient that may aid in reducing senescent cells and promoting skin rejuvenation
• Saururus Chinensis: This ingredient has shown promise in addressing cellular senescence and supporting skin health
• Ulmus Davidiana: Known for its potential to reduce cellular senescence and improve skin condition
• Natural polyphenols have shown anti-senescent effects on skin cells [19]
• OS-01 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 
   

Hair is a powerful factor in how we're perceived by others and even how we see ourselves. It plays a significant role in the perception of youth and attractiveness. Studies have shown that hair style, color, and quality can significantly affect how old we look and how attractive we're considered [1]. Research suggests that hair is one of the most defining characteristics of our appearance, with the potential to make us look years younger or older [1]. From an evolutionary perspective, lustrous hair has long been associated with youth, health, and fertility [1]. Culturally, hair has been a symbol of beauty and status across societies for centuries [2].

HAIR GENETICS BEYOND MATERNAL INHERITANCE
We have approximately 5 million hair follicles distributed across our bodies, with only about 100,000 located on the scalp [3][4]. Contrary to popular belief, hair characteristics are not solely inherited from one's mother. Human genetic makeup consists of 23 pairs of chromosomes, including the sex-determining X and Y chromosomes [5]. Females typically have two X chromosomes (with one usually inactivated through a process called X-chromosome inactivation), while males have one X and one Y chromosome [6]. Our hair's characteristics, including texture, color, and growth patterns, are determined by about 600 genes [7]. Interestingly, only 11% of these genes are located on the X chromosome [8]. The majority of genes influencing hair traits are found on autosomes (non-sex chromosomes), contributing to the inheritance patterns observed in families [9]. For instance, genes like EDAR and FGFR2 have been associated with hair thickness in Asian populations, while TCHH has been linked to hair texture in individuals of Northern European ancestry [10]. Research has identified several genes on the X chromosome that play a role in male pattern baldness, including the androgen receptor (AR) gene. Telomere length in hair follicle stem cells correlates with hair growth capacity and may be a biomarker for hair follicle aging. The complexity of hair genetics extends beyond sex chromosomes, involving multiple autosomal genes, environmental factors, hence epigenetics, and this is great news as changes in epigenetic patterns are partially reversible!

Epigenetics
Epigenetics refers to heritable changes in gene expression that occur without alterations in the DNA sequence itself [11]. Environmental factors, diet, lifestyle, chronic stress, sleep, circadian rhythms, physical activity, aging and even social interactions can influence gene expression through four main epigenetic mechanisms:

1. DNA methylation: This involves the addition of methyl groups to DNA, typically at CpG sites, which can lead to gene silencing [12].
2. Histone modifications: These include various chemical changes to histone proteins, such as acetylation, methylation, and phosphorylation, which can alter chromatin structure and gene accessibility [13].
3. Chromatin remodeling: This process involves the restructuring of nucleosomes, affecting DNA accessibility and gene expression [14].
4. Non-coding RNAs: These include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and small interfering RNAs (siRNAs), which can regulate gene expression at both transcriptional and post-transcriptional levels [15].

These epigenetic mechanisms can significantly impact hair biology

• Silencing or activation of hair growth-related genes: Epigenetic modifications can alter the expression of genes crucial for hair follicle cycling, potentially contributing to hair loss or promoting regeneration [16].
• Regulation of hair follicle stem cells: Epigenetic mechanisms play a vital role in maintaining hair follicle stem cell function and identity [17].
• Response to environmental stressors: Factors such as oxidative stress, pollution, and diet can induce epigenetic changes that affect hair growth patterns [18].
• Aging-related hair changes: The accumulation of epigenetic alterations over time may contribute to age-related hair loss and graying [19].

Example of change in epigenetic pattern
Ever wondered why hair starts growing in odd places as we age? It is a good example of epigenetic changes. As we get older, changes in our epigenome can cause regions of our DNA that are normally silent (due to histone modifications) to become readable. In essence, we're becoming more like our ancient ancestors! This is why some people start growing more hair in places like ears and noses as they age. Epigenetic changes can thus silence or activate hair growth-related genes, potentially contributing to hair loss or promoting regeneration. Thus, the future of our hair health is literally (at least partially) in our hands today!. 

Lifestyle changes and hair regrowth
Lifestyle modifications have demonstrated impacts on hair regrowth, particularly in early stages of hair loss and for prevention.
1. Nutrition: A balanced diet rich in proteins, vitamins (especially biotin, vitamins A, C, and D), and minerals (iron, zinc) has been associated with improved hair growth [20]. Supplementation with these nutrients has shown benefits in treating telogen effluvium and other hair loss conditions [21].
2. Stress Management: Chronic stress can lead to telomere shortening and premature hair follicle aging. Stress reduction techniques like meditation and yoga have been linked to increased telomerase activity, potentially benefiting hair growth.
3. Exercise: Regular physical activity improves blood circulation to the scalp, potentially enhancing nutrient delivery to hair follicles. A study found that moderate exercise was associated with increased expression of hair growth-related genes.
4. Sleep: Adequate sleep is crucial for maintaining healthy hair growth cycles. Sleep deprivation has been linked to increased oxidative stress and inflammation, which can negatively impact hair follicles.

Studies have shown promising results in targeting epigenetic mechanisms for hair loss treatment

• Histone Deacetylase (HDAC) inhibitors have shown potential in promoting hair growth in preclinical models [22].
• miRNAs have been identified as regulators of hair follicle cycling and potential therapeutic targets [23].
• lncRNAs have been implicated in hair follicle development and cycling [24].
• DNA Methyltransferase (DNMT) Inhibitors: 5-azacytidine, a DNMT inhibitor, has been shown to promote hair follicle neogenesis in wound healing models by modulating Wnt signaling [25]. This suggests potential applications in treating hair loss disorders.
• Epigenetic Modulation of Wnt Signaling: Enhancing Wnt signaling through epigenetic mechanisms has emerged as a promising approach. For example, inhibition of SFRP1, an epigenetically regulated Wnt inhibitor, has been shown to promote hair growth in preclinical models [26].

​
In office therapies
1. Low-Level Laser Therapy (LLLT): LLLT works by decreasing nitric oxide enzyme activity, leading to a beneficial "micro-stress" in mitochondria. This hormetic effect increases energy production, allowing stem cells to stay young and rejuvenate. Clinical studies have demonstrated improved hair density and thickness with LLLT in androgenetic alopecia patients.
2. Platelet-Rich Plasma (PRP) and exosomes: These regenerative therapies deliver growth factors and signaling molecules to hair follicles, potentially reversing miniaturization and promoting the anagen phase. PRP has shown promising results in multiple clinical trials for androgenetic alopecia.
3. HydraFacial Keravive scalp treatment: A 3-step process involving cleansing, exfoliating, and nourishing the scalp to improve hair follicle health.
4. Hair Transplantation: Includes techniques like Follicular Unit Extraction (FUE) and strip harvesting to transplant hair from donor areas to balding areas.
5. Scalp micropigmentation: A cosmetic tattooing procedure that creates the appearance of a fuller head of hair.
6. Corticosteroid Injections: Used primarily for treating alopecia areata by injecting steroids directly into affected areas of the scalp.
7. Microneedling: Uses small needles to create micro-injuries in the scalp, potentially stimulating hair growth when combined with topical treatments.
8. Scalp Reduction: A surgical procedure that removes bald areas of the scalp and stretches hair-bearing skin.
9. Mesotherapy: Involves injecting vitamins, minerals, and other nutrients directly into the scalp to nourish hair follicles.

BALD AINT BAD (for men)

• Perceived dominance and strength. A study from the University of Pennsylvania found that bald men were rated as more dominant, taller, and stronger than men with full heads of hair [27].
• Attractiveness and confidence. Bald men are often perceived as more attractive and confident [28][29].
• Intelligence and success. Men with receding hairlines were 17% more likely to be considered successful and 13% more likely to be viewed as intelligent compared to men with full heads of hair [30].
• Leadership potential. The perception of dominance in bald men could increase their potential for leadership roles [27].
• Masculinity. Baldness is often associated with higher levels of masculinity, which can be beneficial in various social contexts [31].
• Age and maturity. Bald men are often perceived as more mature and experienced, which can be advantageous in professional settings [32].
• Cultural shift. There's been a cultural shift in recent years, with baldness becoming more accepted and even celebrated, as evidenced by the popularity of bald celebrities and public figures [33].

Always consult a qualified healthcare professional or dermatologist to determine what the most suitable approach is for your particular skin or hair condition.

Take care!
Anne-Marie

The picture I used for this post is from my lovely daughter, who is blessed with fabulous hair.

References

1. Fink, B., Hufschmidt, C., Hirn, T., Will, S., McKelvey, G., & Lankhof, J. (2016). Age, Health and Attractiveness Perception of Virtual Human Hair. Frontiers in Psychology, 7, 1893. 
2. The AutoEthnographer. (n.d.). Is Beauty Truly in the Eye of the Beholder? Hair and Societal Standards. ​
3. Buffoli B, et al. The human hair: from anatomy to physiology. International Journal of Dermatology. 2014;53(3):331-341.
4. Martel JL, et al. Anatomy, Hair Follicle. In StatPearls. StatPearls Publishing; 2022.
5. Genetics Home Reference. What are the different ways in which a genetic condition can be inherited? 2020.
6. Lyon MF. Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature. 1961;190:372-373.
7. Heilmann-Heimbach S, et al. Hunting the genes in male-pattern alopecia: how important are they, how close are we and what will they tell us? Experimental Dermatology. 2016;25(4):251-257.
8. Hagenaars SP, et al. Genetic prediction of male pattern baldness. PLoS Genetics. 2017;13(2):e1006594.
9. Medland SE, et al. Common variants in the trichohyalin gene are associated with straight hair in Europeans. American Journal of Human Genetics. 2009;85(5):750-755.
10. Fujimoto A, et al. A scan for genetic determinants of human hair morphology: EDAR is associated with Asian hair thickness. Human Molecular Genetics. 2008;17(6):835-843.
11. Panhard S, Lozano I, Loussouarn G. Greying of the human hair: a worldwide survey, revisiting the '50' rule of thumb. Br J Dermatol. 2012;167(4):865-73.
12. Jones PA, Takai D. The role of DNA methylation in mammalian epigenetics. Science. 2001;293(5532):1068-70.
13. Kouzarides T. Chromatin modifications and their function. Cell. 2007;128(4):693-705.
14. Clapier CR, Cairns BR. The biology of chromatin remodeling complexes. Annu Rev Biochem. 2009;78:273-304.
15. Mercer TR, et al. Long non-coding RNAs: insights into functions. Nat Rev Genet. 2009;10(3):155-9.
16. Botchkareva NV. The molecular revolution in cutaneous biology: chromosomal territories, higher-order chromatin remodeling, and the control of gene expression in the epidermis and hair follicle. J Invest Dermatol. 2017;137(5):e93-e99.
17. Lien WH, et al. In vivo transcriptional governance of hair follicle stem cells by canonical Wnt regulators. Nat Cell Biol. 2014;16(2):179-90.
18. Trueb RM. Oxidative stress in ageing of hair. Int J Trichology. 2009;1(1):6-14.
19. Panhard S, Lozano I, Loussouarn G. Greying of the human hair: a worldwide survey, revisiting the '50' rule of thumb. Br J Dermatol. 2012;167(4):865-73.
20. Guo, E. L., & Katta, R. (2017). Dermatology Practical & Conceptual, 7(1), 1-10.
21. Almohanna, H. M., et al. (2019). Dermatology and Therapy, 9(1), 51-70.
22. Lee WS, et al. Valproic acid induces hair regeneration in murine model and activates alkaline phosphatase activity in human dermal papilla cells. PLoS One. 2012;7(4):e34152.
23. Andl T, et al. The miRNA-processing enzyme dicer is essential for the morphogenesis and maintenance of hair follicles. Curr Biol. 2006;16(10):1041-9.
24. Wan DC, Wang KC. Long noncoding RNA: significance and potential in skin biology. Cold Spring Harb Perspect Med. 2014;4(5):a015404.
25. Yang, C. C., et al. (2015). Journal of Investigative Dermatology, 135(9), 2289-2298.
26. Rishikaysh, P., et al. (2014). International Journal of Molecular Sciences, 15(1), 1647-1670.
27. Mannes, A. E. (2013). Shorn scalps and perceptions of male dominance. Social Psychological and Personality Science, 4(2), 198-205.
28. Muscarella, F., & Cunningham, M. R. (1996). The evolutionary significance and social perception of male pattern baldness and facial hair. Ethology and Sociobiology, 17(2), 99-117.
29. Henss, R. (2001). Social perceptions of male pattern baldness: A review. Dermatology and Psychosomatics, 2(2), 63-71.
30. Innerbody Research. (2021). Perception of Chrome Domes in the US. Retrieved from https://www.innerbody.com/perception-of-chrome-domes-in-the-us 
31. Kranz, D. (2011). Young men's coping with androgenetic alopecia: Acceptance counts when hair gets thinner. Body Image, 8(4), 343-348.
32. Cash, T. F. (1999). The psychosocial consequences of androgenetic alopecia: A review of the research literature. British Journal of Dermatology, 141(3), 398-405. 
33. Ricciardelli, R. (2011). Masculinity, consumerism, and appearance: A look at men's hair. Canadian Review of Sociology, 48(2), 181-201.

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

​​We all know the fairy tail sleeping beauty, however there is actual scientific evidence supporting that good sleep does make you more attractive.

Chronic poor sleep quality is associated with increased signs of intrinsic ageing, diminished skin barrier function, lower satisfaction with appearance (1). 

A variety of studies in the literature have shown that sleep plays a role in restoring immune system function and that changes in the immune response may affect collagen production. (2)

Before going into the science supporting that sleep makes you more beautiful, some tips for better sleep and less wrinkles:

• Have a routine. Go to bed at a similar time each night and get up at the same time each morning, including on the weekends. It helps to have a skin care routine! Read more
• Make sure your bedroom is quiet, dark, relaxing, and at a comfortable temperature
• Remove electronic devices, such as TVs, computers, and smart phones, from the bedroom
• Avoid large meals, caffeine, and alcohol before bedtime
• Get some exercise. Being physically active during the day can help you fall asleep more easily at night.
• Sleep on your back. Side sleeping causes "compression wrinkles" in face and décolletage. When you are young, they disappear, but when you are more mature, they become more permanent.
• If you sleep in the side, sleep on a silk pillow cover. Silk’s slippery surface reduces friction on the skin (and hair), and thus reduces the risk of facial wrinkles and morning creases that other fabrics might cause when you sleep on your side or face. 

A study was conducted with 60 healthy caucasian women, who were categorised as poor quality sleepers [Pittsburg Sleep Quality Index (PSQI) > 5, sleep duration ≤ 5 h] or good quality sleepers (PSQI ≤ 5, sleep duration 7-9 h. Good sleepers had significantly lower intrinsic skin ageing scores by SCINEXA(TM) . At baseline, poor sleepers had significantly higher levels of TEWL (trans-epidermal water loss). At 72 h after tape stripping, good sleepers had 30% greater barrier recovery compared with poor sleepers. At 24 h after exposure to ultraviolet light, good sleepers had significantly better recovery from erythema (redness). Good sleepers also reported a significantly better perception of their appearance and physical attractiveness compared with poor sleepers. (1)

Sleep loss could also impact sexual behaviour and collaboration, because sleep is connected with attractiveness, which has an important impact in many social contexts (2). The notion of beauty sleep is actually very important, because sleep deprived people are perceived as more fatigued, less attractive, and even less healthy than when they are rested (3). Sleep deprivation is associated with increased signs of intrinsic skin ageing (fine lines, uneven pigmentation, reduced elasticity) (4), with much slower recovery rates after skin barrier disruption and lower satisfaction with appearance. If we compare people with a normal night sleep with the same persons but sleep deprived, the sleep deprived ones look more fatigued, with hanging eyelids, redder eyes, more swollen eyes, darker circles under the eyes, paler skin, more wrinkles and fine lines around the eyes, the corners of the mouth as being more droopy and more sad (5). 

In conclusion, the sleep is not connected only with good health (6,7), but is also a link between attractiveness and health. (2,8)


Take care and sleep well

1. Does poor sleep quality affect skin ageing? P Ovetakin-White, A Suggs, B Koo, M S Matsul, D Yarosh, K D Cooper, E D Baron, 2015.
2. Medical Hypotheses Volume 75, Issue 6, December 2010, Pages 535-537 Can poor sleep affect skin integrity? V. Kahan et al.
3. Rhodes G. - The evolutionary psychology of facial beauty. Annu Rev Psychol. 2006;57:199–226. 
4. Axelsson J, Sundelin T, Ingre M, Van Someren EJ, Olsson A, Lekander M. - Beauty sleep: experimental study on the perceived health and att ractiveness of sleep deprived people. BMJ. 2010;341:c6614. 
5. Oyetakin-White P, Koo B, Matsui M, Yarosh D, Fthenakis C, Cooper K, Baron E. - Effects of Sleep Quality on Skin Aging and Function. J Invest Dermatol. 2013; :S126–S126. 
6. Sundelin T, Lekander M, Kecklund G, Van Someren EJW, Olsson A, Axelsson J. - Cues of fatigue: eff ects of sleep deprivation on facial appearance. SLEEP. 2013;9:1355–1360. 
7. Bryant PA, Trinder J, Curtis N. - Sick and tired: does sleep have a vital role in the immune system. Nat Rev Immunol. 2004;4:457–467. 
8. Horne J. - Why we sleep—the functions of sleep in humans and other mammals. Oxford University Press. 1988;23:15–17. 
9. Maedica (Bucur). 2017 Sep; 12(3): 191–201. Perceived Age and Life Style. The Specific Contributions of Seven Factors Involved in Health and Beauty, Victor Gabriel CLATICI et al.

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.

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

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

REGENERATIVE AESTHETICS

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

POLYNUCLEOTIDES IN REGENERATIVE AESTHETICS

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

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

THE FUTURE OF POLYNUCLEOTIDES

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

Take care.

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

AGEs cause changes in the skin through 3 processes:

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

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

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

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

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

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

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

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

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

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

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

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

Take care
Anne-Marie

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

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

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

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

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

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

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



​Take care

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

Skin flooding is the latest TikTok trend to counteract dry or dehydrated skin. It is basically layering hydrating mists, serums or creams to boost hydration in the skin. The idea is to start with a humectant-rich, lightweight products first and then add a thicker emollient to seal in the moisture on the skin. This is a trend which is suitable for all genders at all ages if products are chosen wisely.

DRY OR DEHYDRATED SKIN
There is a difference between dry and dehydrated skin. Dehydrated skin is water-lacking skin, considered a skin condition and can be temporary, while dry skin is lipid-lacking skin and seen as a skin-type. All skin types (yes including oily skin) can be dehydrated. Picture yourself in an environment like airplane without any humidity. Our skin will react to this "dehydration condition" by either (over)production of oils and lipids to "protect" itself fro drying out or get very dehydrated. When the skin is producing a fierce amount of oils and lipids as compensation, you do not have lipid-lacking or dry skin, however your skin might be dehydrated. Lipid-lacking or dry skin has less ability to produce those oils or lipids and often has an impaired skin barrier. Lipids are the "mortar" between the bricks and when they are lacking, more water will evaporate from the skin and thus it loses hydration.

FLOODING
Therefore "flooding" without "suffocating" the skin, can be a good approach for dehydrated skin and all skin types at all ages. If you want to start your flooding regimen on damp skin, you start immediately after cleansing and toning or use a light mist containing hyaluronic acid and glycerin. Both ingredients are powerful humectants and attract and bind water to the skin surface. Afterwards you might want to first apply a hyaluronic acid containing serum and then a cream to "seal the deal". The difference between flooding and slugging is that flooding is focusing on maximising skin hydration or moisture, while slugging is focusing on prevention of trans-epidermal water loss by (semi)occlusion. Read more about slugging.

HYALURONIC ACID 
Be aware not all hyaluronans are the same. There are different sizes. A macro-hyaluron (about 2000 kDa or larger) will lay on the surface of the skin and bind water there where the skin is losing the most water. A biologicaly active size hyaluron is the 52 kDa micro-hyaluron. This particular size molecule has proven to penetrate into the metabolic active layer of the epidermis, where is actually stimulates the keratinocytes (a certain skin cell) to produce +209% more hyaluron. This can be enough when you are young as the decline of hyaluron in the skin starts first in the epidermis.

Be aware it is NOT recommended to use a hyalruon size below 30 kDa in skin care. Hyaluronic acid has the ability to bind and attract water up to 10.000 times is molecular weight, are great to plump up the skin, however the smaller sizes have a different function and can actually harm the skin by for example causing inflammation. 

LINES AND WRINKLES
If you get a bit older, also the dermis will lose it's most important filling substance (hyaluron). There is another skin cell type which can be stimulated to produce more called the fibroblast. This cell is a key cell in the junction of the epidermis and dermis and the dermis, so deeper layer. The powerful anti-oxidant and bio-active Glycine Saponin or abbreviated Saponin can bio-stimulate this cell to produce +256% more skin's own hyaluron, +49% more collagen and +19% more elastin. Moreover, there are products on the market which contain all of the above PLUS Enoxolone. Enoxolone has the ability to inhibit the activity of an enzyme called HYAL1 >50%. HYAL1 is one of 6 different hyaluronidase enzymes which degrate skin's own hyaluron, hence eliminate it from our skin. These enzymes get more active in sun-exposed or mature skin and are partially responsible why our skin will lose hyaluron as we age. Together with the anti-oxidant Saponin, Enoxolone can slow down the elimination of skin's own hyaluron via 2 complimentary pathways: physical and enzymatic degradation. With other words, products containing 2 different sizes of hyaluron, Glycine Saponin and Enoxolone will fill, stimulate and defend skin's own hyaluron in both the epidermis (top layer) and the dermis (middle layer) of the skin. Great for dehydrated and early or visible signs of ageing, like fine lines and (even deepest) wrinkles.

DAY AND NIGHT
For daytime I would highly recommend a cream with protective SPF and for nighttime a product containing regenerative and barrier repairing Dexpanthenol or Pro-Vitamin B5. Anti-oxidants are good in every day and night time routine. If you want to use a refreshing hydrating mist, there is only one product with hyaluronic acid I recommend and it is Eucerin Hyaluron-Filler Mist Spray. The reason for this is that it has a skin friendly pH unlike (thermal) water. Water has a pH of 7-8 which is like a slight "insult" to the skin's healthy pH every time you spray. With the Hyaluron-Filler Mist Spray, you rebalance the skin's healthy pH level and use it as much as you like. pH to me is the foundation of good skin health. I have written a few pH related blog-posts and if you are interested simply click on the "read more" button below.

Take care

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

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

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

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

Take care
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*in vitro

We all learned that sleeping in make-up is the ultimate skincare sin. What is bad about it is when you go 24 hours without washing your face and end up going to bed leaving your day-time make-up on. Over the course of the day, our skin accumulates pollutants, dirt and dead skin-cells.

If dirt and pollutants are left on the skin, they may cause micro-inflammation and contribute to premature ageing skin via a process called inflamm-aging and free-radical damage which is a major contributor to skin-ageing. The combination of both micro-inflammation and free-radical damage is called ox-inflammation. We should aim to reduce or preferably avoid it. Pollution, dirt and sebum (oils) can impact the skin's healthy pH balance and thus lead to a weakening of the skin barrier function, more sensitive skin, dehydration, slowed down skin-cell renewal process and thus ageing. Not removing dead skin cells together with dirt increases the risk of clogged pores. 

Make-up itself usually doesn’t contain harming ingredients. Coloured micro-pigments actually provide additional sun-protection. Make-up or foundation itself is thus not the problem, however the fact that we don’t cleanse our skin after a busy day and/or evening is what could make us age faster. Not doing your PM cleanse and care routine is anyway a missed opportunity to support your skin’s night-time recovery with beneficial active ingredients.

If you go out in the evening, take the opportunity to cleanse before getting ready and get rid of debris which was accumulated during day-time.

Don’t worry about falling asleep in your make-up once or twice. Just don’t make it a habit. I would always aim to remove eye make-up. Sleeping in full eye make-up (mascara, liner, eyeshadow) increases the risk of an eye-inflammation, redness and corneal abrasions. Waking up with “panda-eyes” filled with black rheum or goop isn’t pretty either.

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Our life expectance is increasing and the average age when menopause occurs didn't change much in the last decade. This is why more women will have to care for post menopause skin for a longer time. During and after menopause our skin will go through some changes and might even become problematic. In this blog post I will have a closer look into these changes.

Change
During the start of menopause, also called peri-menopause, women will notice some changes to their skin. This is because estrogen levels start to decline (-35% between age 35-50) and as estrogen level decline, androgen level proportionately become more dominant. As a result, the majority of women experience drier skin. Or when the hormone levels are differently balanced they may get a more oily skin or develop acne tarda (adult acne), because the oil gland activity is increased. Another problem is that the skin's pH level will increase, which will impact skin health, barrier and microflora or microbiome. A higher pH value may result in problematic skin.

Loss of biological activity 
Around this period the metabolic biological activity in the skin will decrease faster than in our 20s or 30s. The production of important components like hyaluronic acid (filling + hydration), collagen (strength + structure) and elastin (flexibility + stretch) by fibroblasts (a very important skin cell) isn't sufficient, while the speed of their degradation is inclining because the skin's natural resilience against damaging free radical activity is reduced and the activity of degradation enzymes, like hyaluronidase, collagenase and elastase is elevated. Therewith the presence of those important skin components is declining 30% in the first years. This leads to more advanced signs of ageing skin and an overall loss of skin quality: skin firmness, skin surface eveness, skin tone eveness and glow (Goldie, Clin Cosmet Invest Dermatol, 2021). 

Solution
Skin ageing is a multifaceted continuous biological degenerative process, with an impact on overall skin quality, self perceived attractiveness, confidence and comfort (Quality of Life). The optimal solution should improve all 4 emergent perceptual categories or EPG's of skin quality (an important component of human attractiveness) as mentioned above. This can be achieved by supporting skin's own resilience against the inclined loss by degradation (reduce free radical and enzymatic activity) and increase skin's own biological activity, hence skin's own production of hyaluron, collagen and elastin with bio-active ingredients or bio-stimulators and inhibit human tyrosinase activity (reduce age spots). I will explain the 4 key actions below:

1. Bio-stimulators
Some evidence based bio-actives we can find in skincare are:

• 52 kDa Micro-Hyaluron (stimulation of hyaluron production with 209%: hyaluron-filler)
• Creatine (stimulation of collagen I and IV by + 35%  and elastin with +36%)
• Glycine Saponin (stimulation of hyaluron production +256% collagen +49% elastin +19%) which is also a powerful anti-oxidant

There are very good in-office treatments for bio-stimulation.

2. Enzyme inhibitors
Some ingredients in skincare which inhibit enzymatic degradation are:

• Enoxolone (reduces hyaluronidase I activity by >50%)
• Arctiin (reduces HN-elastase activity by 79%) and is also an anti-oxidant

3. Anti-oxidants
Damaging free radical activity is increased in mature skin and ROS (Radical Oxidative Species) increase degradation of all components, enzymatic degradation and human tyrosinase activity, a powerful cocktail of anti-oxidants is a "must-have". The combination of fresh activated L-Ascorbic-Acid (primary defence with instant neutralisation of extra-cellular free radicals) and Licochalcone A (secondary defence with long-lasting intracellular stress protection is a valuable addition in any day or nighttime skincare regimen. Licochalcone A is moreover one of the most powerful anti-oxidants (if not the most powerful one) proven to reduce (deep) oxidative stress from High Energy Visible Light or HEVIS. As we know, free radicals from HEVIS damage the important skin-cell called the fibroblast and increase the risk of age spots. 

4. Human tyrosinase inhibition
A relatively new, effective and safe ingredient in skincare which was tested on inhibiting human tyrosinase is Thiamidol. Other ingredients in skincare were tested on mushrooms (Hornyak, Journal of Investigative Dermatology 2018 & Mann et al. 2018) and are not potent in reducing human tyrosinase activity. It took 10 years of pioneering research (dr Ludger Kolbe) and comparing 50.000 actives to patent and market it. In the mean time Thiamidol is loved and recommended globally by many dermatologists and evidence based with 35+ studies including >2000 participants with all Fitzpatrick phototypes. 

Every AM routine should at least have a skincare product with SPF of 15 or higher.
An improvement of skin quality leads to an improvement of quality of life (van Geloven et al. EADV 2022). 
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Hope this was helpful.
Take care

According to a survey with responses from 729 participants aged 18- 70+, with 65% of respondents coming from the United States and the majority of the remainder coming from Canada, the UK and Europe ‘lookism’ often trumps the performance of women when they are evaluated and often are pushed to the sidelines and/or pushed out to make room for younger workers. Once terminated, women find it much more challenging to get rehired at a time when may they lack funds for retirement. The pressure is especially high on single women and mothers 50+, which is a fast growing demographic. In many countries the retirement age is 67 years. It's not acceptable to be seen as less valuable or even irrelevant the last 17 years of your career, while having a lot of value to offer to jobs, companies and co-workers.

Ageing is a beautiful journey of collecting knowledge and experience. It is a privilege, however gendered ageism a growing and relevant problem. Physical ageing is a biological degenerative process, which can't be completely stopped, but can be positively influenced. For example, I work daily with a team on the creation of evidence based skincare products to significantly improve visible signs of ageing and quality of life. This requires that >80% of users agree that the product makes them feel more attractive, confident and comfortable in their skin. Unfortunately more needs to be done and age discrimination laws are less effective for mature women (McLaughin LABOUR 2020). Therefore gendered ageism should be addressed in diversity & inclusivity initiatives. When I turned 50, I joined an initiative in the company I work for called "New Generation 50+". It's a work-in-progress, however a start to reduce and hopefully together stop (gendered) ageism in the workplace and society. We should not accept the devaluation of mature women (or men). Many feel almost "invisible". If they don't "see you", make people listen to you and speak up if you feel you are not treated fairly. Many companies focus on recruiting "young talents". I would like to challenging them to hire, engage and retain 45+ talents. Being talented doesn't have an expiration date.

​Take care
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Vitamin C is a "must have" skin care ingredient our skin needs at any age.
 
One of the best researched skin care ingredients and proven to be very beneficial for skin is Vitamin C. Our skin uses Vitamin C as an anti-oxidant and the dermal fibroblasts need Vitamin C for the production of collagen. Two very good reasons to add this ingredients into your daily skincare routine whether you are twenty or eighty. Moreover, our skin depends on us for the needed supply, as our skin is not able to produce Vitamin C itself.
 
We can either include enough Vitamin C in our diet or apply Vitamin C topically there where we need it the most. Usually this is the skin which is exposed to (sunlight) as this increases damaging free radical activity in our skin. An active form of vitamin C can reduce the free radical activity, which we call anti-oxidative effect. 
 
There are 4 things to consider when buying a skincare product containing Vitamin C:

1. Vitamin C needs to be used in an active form. Fresh reconstituted (mixed) L-Ascorbic Acid is the most active form of Vitamin C. A stabilized form of Vitamin C is not active anymore and therewith not as effective or not effective at all.
2. The formula has to have a low or very low pH value in order for the vitamin C to penetrate well into the skin.
3. The percentage of vitamin C needs to be above 8 and not over 20 to be optimal. For a good balance between great efficacy and tolerability, 10% fresh L-Ascorbic Acid is just right. Higher might not add much efficacy, but could create tolerability issues, especially for more sensitive skin.
4. The packaging and application form should protect the formula from light & air as much as possible. A dropper for example will expose the formula to air with every use.

 
Day or night?
Some recommend to use Vitamin C during the night, as the active form of Vitamin C will oxidize in daylight. Hence, your skin can benefit from the Vitamin C longer during the night. I would recommend Vitamin C to be used during daytime (thus added to your morning routine), as we need protection from damaging free radicals the most during daytime and the oxidization of Vitamin C is actually a sign that the ingredient is doing it’s job! It’s even better to add Vitamin C both to your day & night time skincare routine.
 
Is L-Ascorbid Acid enough?
Vitamin C is counteracting free radicals from UV light. However, UV is not the only damaging light form as there is also High Energy Visible Light or abbreviated HEVIS. This penetrates even deeper into the skin where also the dermal fibroblasts reside. The dermal fibroblasts are our collagen and hyaluronic acid producing cells and a key target in an effective anti-ageing skincare strategy. Lichochalcone A (Licorice-root extract) has proven to be the most potent anti-oxidant to protect the dermal fibroblasts and neutralize free radicals from HEVIS. Moreover, Lichocalcone A increases Glutathione, which is a skin’s own anti-oxidant. Licorice-root extract is an anti-ageing hero.

Summary
The combination of Vitamin C and Lichocalcone A will protect our skin and dermal fibroblasts from free radical damage by UV and HEVIS and will provide superior biological cell protection in comparison to Vitamin C only. For me this is a good reason to use a product containing both ingredients as a first step after my cleansing routine in the morning. If you have sensitive eyes, I recommend to use an eye care prior, which will form a barrier to help to prevent the low pH Vitamin C product to migrate into the eye area. Afterwards you can use the other products of your skincare routine. I would like to put emphasis on using a SPF of 30 or higher during the day. This will not only help to protect your skin, but also support the anti-oxidative benefits and make them last longer.
 
Hope this was helpful.
Take care!

Psoriasis occurs in many different forms and levels of severity. The first signs may appear between the age of 15 and 35 and 75% of patients are diagnosed before the age of 46 according to the World Health Organisation. As there is no cure for the disease, the highest prevalence is seen in a more mature age group age 50-69. Many of the treatments which are part of the standard treatment guidelines for psoriasis cause as a side effect premature ageing skin. For example PUVA, next to being an effective treatment, does cause (severe) photo-damage. Many patients will undergo such treatments on and off or continuously throughout their life.

Although the primary goal of dermatology is to improve the functional attributes of the skin (health) and lessen the tremendous burden psoriasis may cause, ultimately one aims to improve the skin's physical attributes (appearance).

Ageing skin is a biological degenerative process which influences the activity of collagen and hyaluronic acid producing cells (mainly fibroblasts) and leads to a decrease of skin components like collagen, hyaluron and functional elastin. Effective anti-aging skincare can support the protection of those cells and skin components (anti-oxidants and SPF) and thus slow down the fastened degenerative process. Some active ingredients (for example biologically active Glycine Saponin and Arctiin) have proven to effectively stimulate fibroblasts in the production of collagen and hyaluronic acid and thus replenish dermal components. Loss of those components and photo-damage eventually lead to visible signs of ageing.

Although ageing skin is natural, premature ageing skin isn't necessary. Most patients will probably already use a moisturising facial skincare product. It makes sense to recommend anti-ageing skincare instead to be used in conjunction with treatments which as a side effect cause premature ageing skin, particularly for exposed areas like the face. As psoriasis oftentimes doesn't occur in the face (except in the hairline), anti-ageing skincare will pose a low to no risk to aggravate facial skin and there are anti-ageing skincare products available which have proven to be suitable for psoriasis patients. 

Take care.

One of the frequently asked questions is, if it's necessary or if there is a benefit using a special eye care or cleansing products. Yes, there is!

As I mention in many of my previous posts, the right pH-level is very important for healthy skin. Skin usually prefers a pH of around 5. However there are some area's where the skin's natural pH balance is a little bit different. One of those area's is the area around the eyes. The preferred pH-level there is around 7, thus less acidic and more alkalic in comparison to your regular cleansing or care product for face or body.

This is one of the most important reasons why I would recommend to use a special eye make-up remover and eye care product, as they are adjusted to the pH level most suitable for use in the eye area. Furthermore, special eye products are tested and proven to be safe when used around the eyes, while it isn't always recommended or proven for a regular face product. 

Some care products have a tendency to "travel" or migrate into the eye area. Even when not directly applied around the eyes, they might end up there. A special eye care product can form a "barrier" and thus help to prevent that unwanted products move to the eye area and cause irritation. I would particularly recommend the use of an eye cream when using other products containing gold standard anti-ageing active ingredients like Vitamin A, C (or derivatives of both), Hydroxy Acids (Alpha, Beta or Poly), when you have experienced some sensitivity of the eyes or eye area in the past or have a more problematic skin type.

Eye care products preferably should not contain Vitamin C (L-Asorbic Acid or related) as it requires a low pH value of <4 to be active and do it's job properly. Eye care products with Vitamin C therewith are either too acidic to be used in the eye area or alternatively too alkalic for the Vitamin C to be effective. Safe to use in the eye area are products containing Hyaluronic Acid. Although  "Acid" is in the name, Hyaluronic Acid isn't acidic. One of it's key functions is attract and bind water, which usually has a pH of ~7.

Take care!