Facial blushing is fairly common and an involuntary reddening of the face oftentimes triggered by embarrassment or stress [1][2]. It can be a distressing experience, disrupting social interactions and impacting self-confidence. While you're engaged in a pleasant conversation, an unexpected surge of warmth floods your face, causing visible redness that feels impossible to control. It can lead to embarrassment and a desire to find effective ways to manage or prevent such episodes.
 
Excessive facial flushing is more than just a cosmetic concern; significantly affecting one's quality of life and social interactions. While surgical intervention exist and effective, they often come with high costs and potential risks. Fortunately, there is a range of less invasive approaches to manage this condition.
 
SYMPTOMS
Severe facial blushing is often associated with social anxiety disorder (SAD), can manifest through various physiological and psychological symptoms:
 
1. Intense reddening of the face, neck, and chest [3][4]
2. Sensation of heat or warmth in the affected areas [4]
3. Increased blood flow to facial blood vessels [3][5]
4. Elevated skin temperature in the face [3]
5. Perspiration, particularly in the face and palms [6]
6. Increased heart rate and blood pressure [6]
7. Feelings of embarrassment or self-consciousness [3][4]
8. Avoidance of social situations or eye contact [4][7]
9. Heightened awareness of one's own blushing [3][8]
10. Persistent worry about blushing in social situations [7][8]
 
UNDERSTANDING FACIAL FLUSHING
The face has more capillary loops per unit area and generally more vessels per unit volume than other skin areas. Blood vessels in the cheeks are wider in diameter and closer to the surface.
 
There are several factors contributing to blushing or flushing:
1. Neurovascular dysregulation: Research suggests that individuals prone to facial flushing may have heightened sensitivity in the neural pathways controlling blood flow to the face [9].
2. Genetic predisposition: A study published in Nature Genetics (2015) [10] identified genetic variants associated with rosacea, a condition often characterized by facial flushing.
3. Environmental triggers: Factors such as temperature changes, spicy foods, alcohol, emotional stress and exercise can exacerbate flushing [11].
4. Underlying medical conditions: In some cases, facial flushing may be a symptom of conditions like rosacea, menopause, carcinoid syndrome or hyperthyroidism [12].
5. Certain medications for diabetes, bloodpressure or cholesterol can excercabate flushing.
 
The blushing response is primarily mediated by the sympathetic nervous system. When triggered by social stimuli or self-conscious emotions, facial blood vessels dilate (expand), increasing blood flow to the skin [3][5]. This process is regulated by beta-adrenergic sympathetic nerves, which are responsible for the dilation of blood vessels in the face [6].

​MENOPAUSE
Facial flushing is a common symptom experienced by women during menopause, often associated with hot flashes. This is primarily attributed to hormonal changes, particularly the decline in estrogen levels.
 
1. Prevalence: Approximately 75% of perimenopausal and menopausal women experience flushing [13].
2. Mechanism: Flushing occurs due to vasodilation of dermal and subcutaneous blood vessels, likely caused by the loss of peripheral vascular control associated with estrogen deficiency [13].
3. Duration: Hot flashes, including facial flushing, can persist for years after menopause. Among women 5-9 years postmenopausal, over 20% still report clinically significant hot flashes [14].
4. Associated symptoms: Flushing is often accompanied by sensations of heat, sweating, anxiety, and chills [15].
5. Impact on skin: Menopausal hormonal changes affect the skin barrier, making it more sensitive and vulnerable to irritation [16].
6. Treatment: Estrogen therapy is generally effective in managing menopausal flushing [13]. However, for women who cannot use estrogen, alternative treatments are necessary [17].
7. Persistence: In a study of women with significant hot flashes at baseline, 50% reported unchanged or worsened symptoms after 3 years [14].
8. Risk factors: Women who are more recently menopausal, have previously used estrogen, or have undergone hysterectomy are more likely to experience persistent hot flashes [14].
 
DIFFERENCE BETWEEN BLUSHING AND FLUSHING
While the terms 'blushing' and 'flushing' are sometimes used interchangeably, they can be distinguished based on their triggers. Blushing is typically associated with emotional responses, while flushing may have various physiological causes. Severe cases of facial blushing are known as idiopathic cranio-facial erythema [18][19].
 
Two types of blushing have been identified:
1. Wet blushing is associated with increased perspiration. This type is believed to result from an overactive sympathetic nervous system [20], which regulates various bodily functions, including the dilation of facial blood vessels. In some people, these nerves exhibit heightened sensitivity to emotional stress [21]. 
The blushing response is primarily mediated by the sympathetic nervous system. When triggered by social stimuli or self-conscious emotions, facial blood vessels dilate, increasing blood flow to the skin [3][5], resulting in visible reddening [22][23].  This reaction can extend to the ears, neck, and chest.
 
Mellander et al. discovered that facial veins possess unique characteristics, including beta-adrenoceptors or beta-adrenergic sympathetic nerves, responsible for the dilation of blood vessels in the face, in addition to alpha-adrenoceptors, which may contribute to emotional blushing [6][24].
 
2. Dry flushing is a form of flushing caused by circulating vasodilating mediators in the bloodstream and does not involve increased perspiration [19][20]. These mediators can be either exogenous (from ingested substances) or endogenous (associated with systemic disorders). This type of flushing is also referred to as "vasodilator-mediated flushing" and is distinct from autonomic neural-mediated flushing, which typically involves sweating [20].
 
PSYCHOLOGICAL IMPACT
Blushing may serve a regulatory role in social interactions, potentially mitigating incidents that could spark social conflicts. It signals awareness of social transgressions and may elicit more sympathetic responses from others [25][26].
 
Severe blushing can significantly impact an individual's quality of life [23], even lead to social anxiety and avoidance behaviours [7][8]. The fear of blushing itself known as erythrophobia can exacerbate the condition, creating a cycle of anxiety and increased blushing propensity [4][8].
 
Severe facial blushing is a common symptom of social anxiety disorder (formerly known as social phobia), characterized by intense fear of social situations and negative evaluation [23]. People with this disorder often experience heightened self-conscious emotional reactivity, with blushing being a core physiological symptom [3].
 
MEASUREMENT AND ASSESSMENT

Blushing can be assessed through various methods:

▌Self-report measures, such as the Blushing Propensity Scale [4][8]
Blushing Propensity Scale (Leary & Meadows, 1991) 
Indicate how often you feel yourself blush in each of the following situations using the scale below: 
 
1 = I NEVER feel myself blush in this situation.
2 = I RARELY feel myself blush in this situation.
3 = I OCCASIONALLY feel myself blush in this situation. 
4 = I OFTEN feel myself blush in this situation.
5 = I ALWAYS feel myself blush in this situation. 
 
____  1. When a teacher calls on me in class
____  2. When talking to someone about a personal topic
____  3. When I'm embarrassed
____  4. When I'm introduced to someone I don't know
____  5. When I've been caught doing something improper or shameful
____  6. When I'm the center of attention
____  7. When a group of people sings "Happy Birthday" to me
____  8. When I'm around someone I want to impress
____  9. When talking to a teacher or boss
____  10. When speaking in front of a group of people
____  11. When someone looks me right in the eye
____  12. When someone pays me a compliment
____  13. When I've looked stupid or incompetent in front of others
____  14. When I'm talking to a member of the other sex
 
The total score is obtained by summing the ratings across all items. 
For example:
Low blushing propensity scores ranged from 3-17, with a mean of 11.4
High blushing propensity scores ranged from 40-63, with a mean of 51.3
 
▌ Physiological measurements of blood flow and skin temperature [3][5]
▌ Observational assessments by trained raters [8]
 
Research has shown that the relationship between blushing and social anxiety is strong for self-perceived blushing, small for physiological blushing, and medium for observed blushing [8].
 
MANAGEMENT STRATEGIES 
It´s important to understand why this is happening to you and address contributing factors or triggers. Persistent or severe facial flushing should be evaluated by a dermatologist, as it may be a symptom of underlying conditions like for example rosacea [27], especially when accompanied by other symptoms. 
 
1. Topical treatments: 
▌Brimonidine gel (Mirvaso®) has shown efficacy in reducing facial erythema in rosacea patients [28] and might help to reduce redness from facial flushing.
▌Oxymetazoline cream (Rhofade®) is another FDA-approved topical treatment for persistent facial erythema [29].
 
2. Oral medications:
▌Low-dose oral beta-blockers, such as propranolol, have demonstrated effectiveness in reducing blushing and flushing [30].
▌Clonidine (antihypertensive), is a centrally acting alpha-adrenergic agonist, has shown mixed results in treating some types of flushing, with positive results in menopausal women. However it failed to reduce flushing provoked by red wine, chocolate, and hot weather in rosacea studies or in rosacea patients. [31].
 
3. Laser and light therapies:
▌Pulsed dye laser and intense pulsed light treatments can help reduce visible blood vessels and overall redness [32].
 
4. Cognitive Behavioral Therapy (CBT):
▌CBT has shown promise in helping individuals manage the psychological aspects of blushing and reduce its frequency [33].
 
5. Skincare routine and lifestyle modifications:
▌By simplifying your routine, use gentle, non-irritating skincare products, daily (tinted) broadspectrum sunscreen and avoid known triggers can help manage symptoms [34]. 
▌Regular exercise and stress-reduction techniques like meditation may help regulate the body's response to flushing triggers [35].
 
6. Dietary adjustments:
▌Reducing intake of spicy foods, alcohol, and hot beverages may help [11].
 
7. Botulinum Toxin injections:
▌Small doses of botulinum toxin have shown potential in reducing facial flushing in some studies [36].
 
8. Vasoconstriction can help against facial flushing, and there are several methods to achieve this effect using topical ingredients and cooling techniques:
▌Topical vasoconstrictors:
Oxymetazoline, an alpha-adrenergic agonist, has shown effectiveness in reducing facial redness and flushing associated with rosacea by constricting blood vessels when applied topically [37]. This ingredient is available in some countries as a prescription cream under the brand name Rhofade.
The active compound in Visine eye drops, tetrahydrozoline hydrochloride, is a vasoconstrictor that constricts blood vessels to reduce redness [38]. While primarily used for eye redness, it may potentially help with facial flushing due to its vasoconstrictive properties. Visine is not approved, specifically researched or recommended for use on facial skin [38], however might give a very temporary positive effect. Be aware that prolonged use of vasoconstrictors like tetrahydrozoline can lead to rebound dilation of blood vessels, potentially worsening redness over time [38].
▌Cooling therapies:
Localized cooling can induce vasoconstriction and reduce skin blood flow. A study using cryotherapy demonstrated that skin cooling produced a significant reduction in cutaneous vascular conductance (CVC) that persisted even after the active cooling period [39]. This suggests that cooling therapies, such as using ice packs or cooling pads, could be effective in managing facial flushing.
▌Thermoelectric cooling devices:
An on-site thermoelectric cooling device was tested for its efficacy in regulating skin blood perfusion. The study showed that when active cooling was applied, there was a significant drop in skin temperature and perfusion, indicating vasoconstriction [40].
▌Skincare ingredients:
Caffeine is found in many creams and serums, has anti-inflammatory properties and constricts microcapillaries (bloodvessels). This might eliviate the redness temporarily, however can cause irritation in higher concentrations, especially in sensitive skin.
 
While not directly causing vasoconstriction, certain skincare ingredients can help manage facial redness:
 
Silymarin, a compound derived from milk thistle has demonstrated potential benefits. A double-blind, placebo-controlled study found that a topical treatment combining silymarin and methylsulfonylmethane was particularly effective for rosacea subtype 1, which is characterized by facial flushing and persistent redness [41]. Silymarin's has anti-inflammatory and antioxidant properties, which help modulate cytokines and angiokines involved in skin redness [42]. A systematic review of polyphenols (including silymarin) in rosacea treatment found evidence that these compounds may be beneficial, especially in reducing facial erythema [42], confirmed by in vivo by studies I´ve done myself on patients with couperose and ageing related facial redness [43]. We´ve proven Silymarin´s effect on improving skin´s microcirculation and microcapillaries including strenghtening of microcapillary walls.
 
Licochalcone A works as a powerful anti-oxidant has anti-ínflammatory properties and proven to significantly improve redness, including in patients with rosacea and couperose [43].
 
Menthoxypropanediol (MPD) is a synthetic derivative of menthol that can be beneficial for reducing skin redness. MPD provides a cooling sensation when applied to the skin, which can help soothe irritated and red skin, however particurlarly effective I relieve from itch associated with atopic dermatitis [44].
 
There are more “anti-redness” ingredients available in skincare products, usually tested and suitable for rosacea or couperose prone skin, thus unfortunately not specifically intended to improve blushing or flushing.
 
9. Color cosmetics and skincare: Foundation or skincare products containing colour pigments unify the skin tone and can help to cancel out some of the redness.
 
10. Surgery: Endoscopic thoracic sympathectomy (ETS) is an operation to treat severe facial blushing, performed under general anesthesia as a last resort when other treatments have failed. 
 
The cure rate for facial blushing with ETS is high, but varies across studies. A case series of 831 patients reported a mean symptom improvement score decrease from 9 to 3 (on a 10-point scale) at 29 months follow-up, which was statistically significant (p<0.0001) [45]. Another study found that 85% of 244 patients with facial blushing reported being "totally satisfied" at a mean follow-up of 8 months [45].
 
While initial results are often positive, long-term outcomes may vary. A study with a median follow-up of 19.6 months found that complete resolution of blushing was achieved in 48% of patients, with significant differences based on the type of blushing (emotional: 55%, thermoregulatory: 28%, constant: 15%, P = .03)[46]. The most common side effect is compensatory sweating, reported in up to 90% of patients [47]. In a long-term follow-up study, 6.3% of patients who had ETS for hyperhidrosis regretted having the operation [48]. Thus, while ETS can be effective for many patients with severe facial blushing, it's crucial to carefully consider the potential risks and long-term outcomes before proceeding with this invasive treatment.
 
11. Hormone replacement therapy
HRT can effectively reduce facial flushing in menopausal women. HRT is highly effective in alleviating hot flushes and night sweats, which are common vasomotor symptoms experienced during menopause [52][53]. These symptoms often manifest as facial flushing.
▌HRT significantly reduces the frequency of hot flushes compared to placebo, with a 77% reduction in frequency observed in clinical trials [52].
▌The severity of vasomotor symptoms, including facial flushing, is also significantly reduced with HRT compared to placebo [2]. The benefits of HRT in reducing vasomotor symptoms are often seen within a few weeks of starting treatment [54].
▌Estrogen, a key component of HRT, helps regulate vascular function. During menopause, the decline in estrogen levels can lead to increased blood flow and dilated blood vessels, potentially worsening flushing. HRT can help stabilize these hormone levels.
 
It's important to note that while HRT is effective, it does come with potential risks and benefits that should be discussed with a healthcare provider to determine if it's the right treatment option for an individual.
 
PREVALENCE
In a study of patients undergoing anesthesia, 47% of women and 33% of men reported blushing easily[49]. Blushing is (more) common in young people and women [49]. In a surgical study for facial blushing treatment, 82% of patients had emotional blushing, 58% had thermoregulatory blushing, and 32% had constant blushing [50]. While these figures don't provide a definitive prevalence for the general population, they suggest that facial blushing and flushing are relatively common, especially among those with social anxiety disorders where blushing is reported to affect up to 50% of patients [51].
 
Always consult a qualified professional for a proper diagnose, guidance and support.
 
Take care
Anne-Marie
 
References:
[1] Ioannou S, et al. Front Hum Neurosci. 2017;11:525.
[2] Thorstenson CA, et al. Cognition and Emotion. 2019;34(3):413-426.
[3] Nikolić M, et al. J Child Psychol Psychiatry. 2020;61(12):1339-1348.
[4] Su D, Drummond PD. Clin Psychol Psychother. 2011;19(6):488-495.
[5] Ishikawa N, et al. Front Psychol. 2023;14:1259928.
[6] Jadresic E. Medwave. 2016;16(6):e6490.
[7] Kristian S, Christer D. Thorac Surg Clin. 2016;26(4):459-463.
[8] Nikolić M, et al. Clin Psychol Sci Pract. 2015;22(2):177-193.
[9] Mikkelsen CS, et al. J Clin Exp Dermatol Res. 2016;7(2). 
[10] Nature Genetics. (2015). 47(12), 1449-1452.
[11] Weinkle, A. P., et al. (2015). Journal of Clinical & Aesthetic Dermatology, 8(8), 37–42.
[12] Huynh, T. T. (2013). American Family Physician, 87(9), 638-644.
[13] Kamp E, et al. Clin Exp Dermatol. 2022;47(12):2117-2122.
[14] Huang AJ, et al. Arch Intern Med. 2008;168(8):840-846.
[15] Bansal R, Aggarwal N. J Midlife Health. 2019;10(1):6-13.
[16] Rajab F. Dermatology Times. 2023;44(02).
[17] Sassarini J, Anderson RA. Lancet. 2017;389(10081):1775-1777.
[18] Wilkin JK. J Am Acad Dermatol. 1988;19(2 Pt 1):309-131. 
[19] Wilkin JK. Clin Dermatol. 1993;11(2):211-231.
[20] Rastogi V, et al. Clin Med Res. 2018;16(1-2):16-28.
[21] Cutlip WD, Leary MR. Behav Neurol. 1993;6(4):181-5.
[22] Gerlach AL, et al. J Abnorm Psychol. 2001;110(2):247-58. 
[23] Social Anxiety Alliance UK. (n.d.). Blushing and Social Anxiety. 
[24] Mellander S, et al. Acta Physiol Scand. 1982;114(3):393-399.
[25] Anthroinpractice. Anthropology in Practice. 2011.
[26] Thorstenson CA, et al. Cognition and Emotion. 2019;34(3):1-14.
[27] Better Health Channel. (n.d.). Blushing and flushing. 
[28] Fowler, J., et al. (2013). Journal of Drugs in Dermatology, 12(6), 650-656.
[29] Baumann, L., et al. (2018). Journal of Drugs in Dermatology, 17(1), 97-105.
[30] Drott, C., et al. (2002). Annals of Surgery, 236(2), 155-162.
[31] Wilkin JK. Arch Dermatol. 1983;119(3):211-214.
[32] Wat, H., et al. (2014). Journal of Cutaneous and Aesthetic Surgery, 7(2), 73–80.
[33] Zou, J. B., et al. (2016). Behaviour Research and Therapy, 77, 86-97.
[34] Del Rosso, J. Q., et al. (2017). Journal of Clinical and Aesthetic Dermatology, 10(6), 37-46.
[35] Egeberg, A., et al. (2017). British Journal of Dermatology, 176(3), 591-600.
[36] Park, K. Y., et al. (2013). Dermatologic Surgery, 39(3pt1), 419-424.
[37] Skin Plus Pharmacy. (n.d.). Topical Oxymetazoline for Rosacea.
[38] Wikipedia contributors. (n.d.). Visine. Wikipedia.
[39] Khoshnevis S, et al. J Biomech Eng. 2016;138(3):4032126.
[39] Mejia N, et al. J Med Device. 2015;9(4):0445021-445026.
[40] Draelos, Z. D. (n.d.). Rosacea and skin care. 
[41] Berardesca E, et al. J Cosmet Dermatol. 2008;7(1):8-14.
[42] Saric S, et al. J Altern Complement Med. 2017;23(12):920-929.
[43] Van Geloven A, et al. EADV 2016 P2194.
[44] Weber TM, et al. J Cosmet Dermatol. 2006;5(3):227-32.
[45] NICE. (2014). Endoscopic thoracic sympathectomy for primary facial blushing. Interventional procedures guidance [IPG480]. 
[46] Park JK, et al. Medicine. 2022;101(27):e29808.
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Lipid peroxidation is a chemical process involving the oxidative degradation of lipids, particularly polyunsaturated fatty acids (PUFAs) such as arachidonic acid. It´s initiated when free radicals, especially reactive oxidative species, "steal" electrons from lipids, resulting in the formation of lipid radicals and cell damage.

This process occurs through three stages: 

▌Initiation: A free radical (often hydroxyl radical) abstracts a hydrogen atom from a PUFA, creating a lipid radical. 
▌Propagation: The lipid radical reacts with molecular oxygen to form a lipid peroxyl radical, which can then abstract hydrogen  from another lipid, continuing a chain reaction and forming lipid hydroperoxides.
▌Termination: The chain ends when two radicals combine or antioxidants (like vitamin E) neutralise them, forming non-radical products.  [1][2] 

Uncontrolled  lipid peroxidation leads to membrane damage, cell dysfunction and death. While it occurs naturally during aging, external factors such as UV radiation, pollution, and cigarette smoke accelerate lipid peroxidation by generating reactive oxygen species (ROS). These ROS interact with PUFAs in cell membranes, initiating a cascading chain reaction that produces toxic aldehydes like malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE), which contribute to oxidative stress, cellular damage, and programmed cell death mechanisms like apoptosis and ferroptosis [1][2][3]. 

Sebum is primarily composed of saturated fatty acids (e.g., palmitic acid at ~31%) and monounsaturated fatty acids (e.g., sapienic acid at ~21%), but it also contains smaller quantities of PUFAs such as linoleic acid [4][5]. Despite their lower abundance, sebum PUFAs are highly susceptible to peroxidation due to their double-bond structure [1][3].  For example, in acne patients, reduced sebum PUFA levels correlate with inflammatory states, while increased saturated fatty acids exacerbate pro-inflammatory cytokine production [4]. This highlights the dual role of sebum lipids in maintaining skin barrier function and contributing to oxidative damage when peroxidation occurs [4][5].
​
Lipid peroxidation plays a role in various skin conditions, including acne and signs of photoaging [6][7], rosacea, psoriasis and eczema.

OILY SKIN AND LIPID PEROXIDATION

Oily skin is more susceptibility to lipid peroxidation due to increased sebum production and lipid accumulation at the skin surface [8]. The higher concentrations of sebum provides more substrate for oxidation, increasing the risk of barrier damage (membrane disruption), inflammation (triggering cytokine release), breakouts and cell death.

1. Altered sebum composition: UV radiation and pollution induce non-enzymatic oxidation of sebum lipids, generating comedogenic oxidation products that that spark acne-related inflammation [8][9]. The oxidation process particularly affects squalene and unsaturated fatty acids [10].
2. Squalene oxidation: As the most oxidation-prone sebum component, squalene generates pro-inflammatory peroxidation byproducts (e.g., squalene peroxides) when exposed to UV radiation [9][11]. These oxidized derivatives activate aryl hydrocarbon receptor pathways and promote inflammatory responses in keratinocytes [11]. 
3. Barrier integrity disruption: Lipid peroxidation products alter stratum corneum lipid organization, increasing trans-epidermal water loss and permeability. Reduced ceramides (especially Cer[NH] and Cer[AH]) worsen this barrier damage. [9].
4. Sebum viscosity changes: Oxidative modification increases sebum viscosity through formation of lipid peroxides and cross-linked polymers [8]. This thickened sebum causes pore blockage (follicular hyperkeratosis) and comedo formation, creating oxygen-free conditions where acne bacteria thrive [8].

​​ 
While lipid peroxidation is a natural byproduct of UV exposure, it is harmful at elevated levels. 
▌UV-mediated oxidation: UVA (320-400 nm) primarily drives non-enzymatic lipid oxidation (free radical pathways and non-radical pathways:oxygen oxidation, ozone reactions), while UVB activates enzymatic pathways (phospholipases, lipoxygenases) for eicosanoid production [9]. Eicosanoids are bioactive signaling molecules derived from polyunsaturated fatty acids (PUFAs) like arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) which regulate inflammation, immunity, and vascular function.
Visible Light (including Blue Light) also contributes to lipid peroxidation.
▌Antioxidant depletion – lowered capacity: Oily skin types often experience an imbalance in antioxidant defenses. Also acne-prone skin has lower vitamin E levels, weakening protection against oxidative damage including squalene peroxidation [8][12]. A hallmark of sebum in acne patients is the presence of lipoperoxides, mainly due to the peroxidation of squalene and a decrease in the level of the major sebum antioxidants [13].
▌Acne inflammation cycle: Excess sebum attracts immune cells (neutrophils) that release damaging reactive chemicals, worsening oxidative stress [8]. This stress triggers lipid peroxidation, where oxidized fats act as inflammatory signals, directly worsening acne. Studies show higher levels of these oxidized fats in acne patients, strongly linked to inflamed lesions [14][15].

FERROPTOSIS AND SKIN HEALTH
Ferroptosis is a type of cell death caused by toxic buildup of damaged fats in cell membranes and is triggered by iron-driven lipid peroxidation when cells can’t neutralize harmful lipid peroxides, mainly due to glutathione peroxidase 4 (GPX4) failure. 

This happens through two key mechanisms:

1. Iron’s role: Iron generates destructive free radicals via Fenton reactions and fuels enzymes like lipoxygenases that oxidize lipids [16][17].
2. GPX4 breakdown: Without enough glutathione (GSH), GPX4 can’t convert toxic lipid peroxides into safe alcohols, causing lethal membrane damage [18][19].

The outcome is that uncontrolled lipid peroxides rupture cell membranes, executing iron-dependent ferroptosis [16].
 
STRATEGIES MANAGING OILY SKIN 

Effective skincare strategies for managing oily and acne-prone skin focuses on at least three key objectives [13]:
▌Inhibit the excessive secretion of sebaceous glands / reduce skin surface lipids
▌Improve the quality of sebum
▌Reduce the occurrence of lipid peroxidation  

1. Antioxidant-rich skincare: Incorporating topical products containing antioxidants such as vitamins C and E, and Licochalcone A can help neutralize free radicals and prevent oxidative damage to lipids [6]. Licochalcone A has been shown to inhibit lipid peroxidation in keratinocytes (the main cell type in the epidermis) induced by UV radiation [20], and in human dermal fibroblasts exposed to hydrogen peroxide [21].   
2. Melatonin: The hormone melatonin, is widely present in various tissues including the skin and regulates circadian rhythms and promotes sleep. Melatonin can penetrate membranes and mitigate lipid peroxidation and protein oxidation, as well as oxidative damage to the mitochondria and DNA caused by UVR [22]. 
3. Daily cleansing and regular exfoliation: Gentle exfoliants such as salicylic acid (a beta hydroxy acid) or glycolic acid (an alpha hydroxy acid), combined with regular cleansing, effectively remove oxidized lipids, pollutants, and debris from the skin's surface. This reduces the risk of oxidative stess and helps prevent pore congestion and reduces acne risk [14]. However, overcleansing or excessive exfoliation should be avoided—not due to the debunked "rebound sebum production" myth, however because these practices can compromise the stratum corneum's barrier function, increasing transepidermal water loss (TEWL) and irritation potential.
4. Sun protection: Exposure to UV and Visible Light light generates reactive oxygen species (ROS) and on top initiate lipid peroxidation in sebum, leading to the formation of lipid hydroperoxides and other oxidized lipids that can disrupt skin barrier function and promote inflammation [10]. The daily use of broad-spectrum sunscreen protects against UV and VL-induced oxidative stress which contribute to lipid peroxidation [7]. Sunscreens containing antioxidants (like Licochalcone A) can provide additional protection. Sunscreen efficacy directly correlates with reduced UV-induced lipid peroxidation.
5. Healthy diet: Consuming a diet rich in omega-3 fatty acids, fruits, and vegetables can enhance the skin's antioxidant defenses and reduce inflammation associated with lipid peroxidation [6].
6. Avoiding environmental stressors: Reducing exposure to pollutants and smoking can minimize oxidative stress on the skin. ​

7. Sebum regulating topical ingredients: There are several evidence based skin care ingredients. I will highlight one called L-Carnitine. L-Carnitine is a skin’s own amino acid derivative is produced from the amino acids lysine and methionine. It supports sebum regulation through several mechanisms:             
​▌Increased β-oxidation (“fat burning”): L-carnitine significantly augments β-oxidation in human sebocytes, which is the process by which fatty acids are broken down [23]. This leads to a decrease in intracellular lipid content.
▌Sebum secretion reduction: Topical application of a 2% L-carnitine formulation for 3 weeks significantly decreased the sebum secretion [23].
▌Bio-availability: Topically applied L-carnitine is bioavailable and can reach the dermis, allowing it to interact with sebaceous glands [23].
New in vitro data shows 86% sebum reduction for even a low concentration of L-carnitine [24].

8. Mattifying oil absorption: Mattifying agents formulated for oily skin work by absorbing excess sebum and reducing shine through ingredients like clays, silica, and polymers (like starch). Overuse can lead to product buildup, potentially trapping impurities on the skin's surface.
9. Blotting papers are thin, absorbent sheets designed to absorb thus remove excess oil from the skin's surface, providing a temporary matte appearance [25].

Always consult a qualified healthcare professional to determine what the most suitable approach is for your skin health and beauty.
​
Take care
Anne-Marie
  
[1] Ayala et al. Oxid Med Cell Longev. 2014;360438.
[2] Endale et al. Front Cell Dev Biol. 2023;11:1226044. 
[3] Su et al. Oxid Med Cell Longev. 2019;5080843.
[4] Cao et al. Front Physiol. 2022;13:921866.
[5] Sinclair et al. Nat Commun. 2021;12:1592.
[6] Briganti & Picardo (2003) J Eur Acad Dermatol Venereol. 17(6):663-9
[7] Niki (2015) Free Radic Res. 49(7):827-34
[8] Wong A, et al. J Clin Dermatol Ther. 2016;3(1):020.
[9] Gruber F, et al. Front Endocrinol. 2020;11:607076. 
[10] Picardo et al. (2009) Dermatoendocrinol. 1(2):68-71  (was 5)
[11] Kostyuk V, et al. PLoS One. 2012;7(8):e44472. 
[12] Briganti & Picardo (2003) J Eur Acad Dermatol Venereol. 17(6):663-9
[13] Ottaviani et al. (2006) J Invest Dermatol. 126:2430-2437
[14] Bowe & Logan (2010) Lipids Health Dis. 9:141
[15] Yadav et al. (2019) Sci Rep. 9:4496
[16] Tang, D. et al. (2021) Cell Res 31, 107–125. 
[17] Veeckmans, G. et al. (2023) The FEBS Journal.
[18] Li, J. et al. (2020) Cell Death Dis. 11, 88.
[19] Feng et al. (2023) Mol. Biomed. 4, 33.
[20] Kim et al. (2005) J Invest Dermatol. 125(5):1009-16
[21] Huang et al. (2013) Mol Med Rep. 7(6):1977-82
[22] Bocheva et al. (2022) Int J Mol Sci. 23:1238
[23] Peirano et al. (2012) J Cosmet Dermatol. 11(1):30-36
[24] BDF data on file Dr. Dorothea Schweiger
[25] Wu et al. (2019) J Food Drug Anal. 27(2):610-61

Collagen is a vital component of the skin's extracellular matrix, providing essential structural support and elasticity. Collagen-stimulating treatments, skincare products, and supplements have gained popularity for their effectiveness in gradual prejuvenation and rejuvenation approaches. These methods can help maintain skin health and combat signs of aging when used appropriately. However, it's important to note that excessive collagen stimulation can potentially lead to adverse effects, including fibrosis and skin stiffness, which may be detrimental to overall skin health and beauty. Therefore, a balanced and informed approach to collagen stimulation is crucial for achieving optimal results while minimizing potential risks.
 
TYPES OF COLLAGEN AND THEIR ROLES
1. Type I collagen: Predominantly found in skin, tendons, and bones, providing tensile strength.
2. Type III collagen: Often found alongside Type I, contributing to skin elasticity and firmness.
While these types are beneficial for youthful skin, excessive production can lead to fibrotic tissue formation and stiffness [1].
More about collagen types click here
 
EXCESSIVE COLLAGEN STIMULATION
Excessive collagen production, particularly type I collagen, can contribute to fibrosis and scarring in pathological conditions:
 
1. In hypertrophic scars, there is an overproduction of primarily type III collagen, which is later replaced by type I collagen. These scars contain "an overload of primarily type III collagen oriented parallel to the epidermal surface with multiple nodules containing myofibroblasts, large extracellular collagen filaments and abundant acidic mucopolysaccharides" [2].
 
2. Many rejuvenating in-office treatments (for example energy based devices)are based on "controlled damage and repair”, thus wound healing. During wound healing, abnormal extracellular matrix (ECM) reconstruction, particularly abnormal collagen remodelling, leads to the formation of hypertrophic scars. In these scars, "thin collagen fibres with increased synthesis and crosslinks result in raised scars" [2].
 
3. The relative ratio of type III to type I collagen is reduced in pathological scars compared to unscarred adult dermis. Additionally, hydroxylation of type I collagen was found to be significantly higher in keloids, leading to excessive collagen cross-linking [3].
 
IN-OFFICE TREATMENTS AND COLLAGEN STIMULATION
These treatments aim to maintain or restore natural collagen production rather than overstimulate it to unnatural levels. Some examples are:
1. Exosomes and Polynucleotides: Aim to stimulate healthy collagen production but require careful application.
2. Radiofrequency and Ultrasound: Use heat to remodel collagen. While generally safe, a study by Zelickson et al. [4] reported that excessive heating during RF treatments could potentially lead to collagen denaturation and subsequent fibrosis if not properly controlled.
3. Microneedling: Promotes collagen production but risks scarring if not performed properly. A review by Iriarte et al. [5] noted that while microneedling is generally safe, excessive or improper use could potentially lead to scarring or hyperpigmentation.
4. Laser treatments: Excessive use of ablative lasers can potentially lead to scarring and fibrosis. A study by Hantash et al. [6] found that ablative fractional resurfacing can induce dermal remodeling and new collagen formation, but also noted that improper use could lead to adverse effects.
 
It's important to emphasize that these potential adverse effects are typically associated with improper use, overtreatment, or individual susceptibility rather than being inherent risks of the treatments themselves when performed correctly. More research is needed to fully understand the long-term effects of repeated collagen stimulation treatments on skin structure and function.

POTENTIAL RISKS
▌Excessive collagen production: Can lead to fibrosis, characterized by stiff, non-functional tissue: increased extracellular matrix deposition, with collagen being the main component, leading to a drastic reduction of tissue functionality [7]. In skin, this can result in reduced elasticity and increased stiffness.
▌Imbalance in collagen types: Overproduction of certain collagen types can lead to reduced skin elasticity and increased stiffness. The ratio of type I to type III collagen naturally increases with age, which is associated with changes in skin tension, elasticity, and healing [7]. 
 
RECOMMENDATIONS FOR SAFE USE
▌ Prejuvenation: Focus on treatments (performed by a professional) that promote balanced collagen production without overstimulation. The effect of a collagen-stimulating procedure is a gradual process and can take up to 12 weeks or longer before a final result. This gradual improvement is due to the time required for the body to produce new collagen in response to the stimulation. Laser treatments, for example, can trigger collagen synthesis deep within the skin, with effects continuing for several months post-treatment [8]. Leave sufficient time in between procedures. Support your skin with a skincare routine tailored to your skintype, goals and use of daily sunscreen. Be very rigorous when it comes to the use of home devices or treatments. Many of them are not well researched or might cause damage when not properly used or performed.

▌Rejuvenation: Opt for treatments or a combination of treatments that complement each other, working in different layers of the skin in different ways. Don't expect a "one-day transformation". Rebuilding collagen takes time and a consistent approach. The skin is not able to replenish what it lost over a period of many years in just a few days [9]. Support in-office collagen stimulating treatments with a good skincare regimen, daily use of sunscreen, healthy lifestyle and diet or supplementation if necessary [10]11].
 
The effectiveness of combining different treatments for skin rejuvenation has been demonstrated in clinical studies. For instance, a study published in the Journal of Clinical and Aesthetic Dermatology showed that a combination of microneedling and platelet-rich plasma significantly improved skin texture and collagen production compared to microneedling alone [12].
 
The importance of a consistent skincare regimen and sun protection in maintaining collagen levels has been well-documented. A review in the Archives of Dermatological Research highlighted that daily use of broad-spectrum sunscreen can prevent collagen degradation caused by UV radiation [13].

While collagen stimulation is beneficial for skin prejuvenation, "banking" or rejuvenation, it is crucial to balance its production to avoid the formation of fibrotic tissue and maintain healthy skin elasticity. Further research is needed to optimize treatment protocols and minimize risks associated with excessive collagen stimulation. Always consult a qualified healthcare professional to determine the most suitable approach for your skin goals, health, and beauty.
 
Take care
Anne-Marie
 
References:
[1] Wang Kang , Wen Dongsheng , Xu Xuewen , Zhao Rui , Jiang Feipeng , Yuan Shengqin , Zhang Yifan , Gao Ya , Li Qingfeng Extracellular matrix stiffness—The central cue for skin fibrosis Frontiers in Molecular Biosciences 2023 DOI=10.3389/fmolb.2023.1132353
[2] Meirte J, Moortgat P, Anthonissen M, Maertens K, Lafaire C, De Cuyper L, Hubens G, Van Daele U. Short-term effects of vacuum massage on epidermal and dermal thickness and density in burn scars: an experimental study. Burns Trauma. 2016 Jul 8;4:27. doi: 10.1186/s41038-016-0052-x. PMID: 27574695; PMCID: PMC4964043.
[3] Zhou Claire Jing , Guo Yuan Mini review on collagens in normal skin and pathological scars: current understanding and future perspective Frontiers in Medicine 2024
[4] Zelickson, B. D., Kist, D., Bernstein, E., Brown, D. B., Ksenzenko, S., Burns, J., ... & Kilmer, S. (2004). Histological and ultrastructural evaluation of the effects of a radiofrequency‐based nonablative dermal remodeling device: a pilot study. Archives of Dermatology, 140(2), 204-209.
[5] Iriarte, C., Awosika, O., Rengifo-Pardo, M., & Ehrlich, A. (2017). Review of applications of microneedling in dermatology. Clinical, Cosmetic and Investigational Dermatology, 10, 289-298.
[6] Hantash, B. M., Bedi, V. P., Kapadia, B., Rahman, Z., Jiang, K., Tanner, H., ... & Zachary, C. B. (2007). In vivo histological evaluation of a novel ablative fractional resurfacing device. Lasers in Surgery and Medicine, 39(2), 96-107.
[7] Wang, C., Rong, Y., Ning, F., & Zhang, G. (2011). The content and ratio of type I and III collagen in skin differ with age and injury. African Journal of Biotechnology, 10(13), 2524-2529. https://doi.org/10.5897/AJB10.1999
[8] Alam, M., Hughart, R., Champlain, A., Geisler, A., Paghdal, K., Whiting, D., Hammel, J. A., Maisel, A., Rapcan, M. J., West, D. P., & Poon, E. (2018). Effect of Platelet-Rich Plasma Injection for Rejuvenation of Photoaged Facial Skin: A Randomized Clinical Trial. JAMA Dermatology, 154(12), 1447-1452. https://doi.org/10.1001/jamadermatol.2018.3977
[9] Ganceviciene, R., Liakou, A. I., Theodoridis, A., Makrantonaki, E., & Zouboulis, C. C. (2012). Skin anti-aging strategies. Dermato-endocrinology, 4(3), 308-319. https://doi.org/10.4161/derm.22804
[10] Katta, R., & Desai, S. P. (2014). Diet and dermatology: the role of dietary intervention in skin disease. The Journal of clinical and aesthetic dermatology, 7(7), 46-51.
[11] Addor, F. A. S. (2017). Antioxidants in dermatology. Anais brasileiros de dermatologia, 92, 356-362. https://doi.org/10.1590/abd1806-4841.20175697
[12] Asif, M., Kanodia, S., & Singh, K. (2016). Combined autologous platelet-rich plasma with microneedling verses microneedling with distilled water in the treatment of atrophic acne scars: a concurrent split-face study. Journal of Cosmetic Dermatology, 15(4), 434-443. https://doi.org/10.1111/jocd.12207
[13] Battie, C., & Verschoore, M. (2012). Cutaneous solar ultraviolet exposure and clinical aspects of photodamage. Indian Journal of Dermatology, Venereology, and Leprology, 78, S9-S14. https://doi.org/10.4103/0378-6323.97351

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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

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

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

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

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

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

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

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

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

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

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

2. Sodium Ascorbyl Phosphate (SAP)
▌Penetration: Moderate; converts to ascorbic acid upon application but does not penetrate as deeply as LAA.
▌Stability: More stable than LAA; less prone to oxidation. [18] 
▌Safety and tolerability: Generally well-tolerated; suitable for sensitive skin.
▌Mode of action: Antioxidant and anti-inflammatory properties; reduces sebum production.
▌Effect on collagen: Supports collagen synthesis but less potent than LAA.
▌Antioxidative capacity: Good; provides antioxidant protection but less effective than LAA.
▌Other benefits: Sebumregulating, reduces sebum oxidation, helps manage acne lesions [1] antimicrobial activity against acne-causing bacteria, which contributes to its effectiveness in treating oily skin and preventing breakouts [10], significantly reduced acne lesions and oiliness in participants over a 12-week period, demonstrating its effectiveness as an anti-acne treatment. [23]  
Pros: Gentle on the skin; stable formulation.  
Cons: Less potent than LAA; may not provide the same level of collagen stimulation, however more suitable for oily skin acne prone skin types.
 
3. Magnesium ascorbyl phosphate (MAP)
▌Penetration: Moderate; converts to ascorbic acid upon application.
▌Stability: Highly stable; retains efficacy longer than LAA. [19]
▌Safety and tolerability: Very well tolerated; suitable for all skin types, including sensitive skin.
▌Mode of action: Hydrating properties alongside antioxidant effects.
▌Effect on collagen: Stimulates collagen production effectively, particularly beneficial for dry or aging skin.
▌Antioxidative capacity: Good; protects against oxidative stress.
▌Other benefits: Improves skin hydration and soothes irritation.
Pros: Hydrating; stable and effective at lower concentrations.  
Cons: May be more expensive than other forms.
 
4. Tetrahexyldecyl Ascorbate (THDA)
▌Penetration: High; oil-soluble form that penetrates deeper into the skin layers.
▌Stability: Very stable against oxidation and degradation. [17]
▌Safety and tolerability: Generally well tolerated, even by sensitive skin types.
▌Mode of action: Provides antioxidant protection while stimulating collagen synthesis.
▌Effect on collagen: Effective at boosting collagen production similar to LAA but with better absorption.
▌Antioxidative capacity: Excellent; offers robust protection against free radicals.
▌Other benefits: Enhances skin texture and brightness.
Pros: Superior penetration and stability; effective for anti-aging.  
Cons: May be more costly due to formulation complexity.
 
5. Ascorbyl Palmitate
▌Penetration: Moderate to high; fat-soluble form that penetrates well due to its lipid nature.
▌Stability: More stable than LAA but less potent overall. [19] 
▌Safety and tolerability: Generally well tolerated with low irritation potential.
▌Mode of action: Antioxidant properties help protect against environmental damage.
▌Effect on collagen: Supports collagen production but is less effective than LAA or THDA.
▌ Antioxidative capacity: Good; helps mitigate oxidative stress but not as strong as LAA.
▌Other benefits: Improves skin texture and reduces fine lines.
Pros: Stable formulation with lower irritation risk.  
Cons: Less effective for collagen stimulation compared to other forms.
 
6. Ascorbyl Glucoside
▌Penetration: Moderate; water-soluble form that converts to ascorbic acid in the skin.
▌Stability: Highly stable against oxidation compared to LAA. [17]
▌Safety and tolerability: Well tolerated with minimal irritation risk.
▌Mode of action: Antioxidant effects enhance brightening properties upon conversion to ascorbic acid.
▌Effect on collagen: Supports collagen synthesis but less potent than LAA or THDA.
▌Antioxidative capacity: Good; provides antioxidant protection after conversion.
▌Other benefits: Brightens dull complexions effectively.
​Pros: Stable and gentle option for sensitive skin.  
Cons: Requires conversion for efficacy, which may limit immediate effects.

7. 3-O-Ethyl Ascorbic Acid (EA)
▌Penetration: Good; water-soluble derivative with enhanced skin penetration compared to L-ascorbic acid (AA) [24][25].
▌Stability: Highly stable against oxidation due to the ethyl group modification, making it more resistant to degradation than AA [24][26].
▌Safety and tolerability: Generally well-tolerated, with only rare cases of allergic contact dermatitis reported [25].
▌Mode of action: Potent antioxidant that converts to vitamin C (AA) in the skin, offering enhanced free radical scavenging and skin brightening properties [24][26].
▌Effect on collagen: Stimulates collagen synthesis by promoting procollagen I and III gene transcription, similar to AA after conversion [27].
▌Antioxidative capacity: Excellent; exhibits strong DPPH radical scavenging ability with an IC50 value of 0.032 g/L [26].
▌Other benefits: Demonstrates skin brightening effects, aids in repairing sun damage, and shows anti-inflammatory properties [24][27].
Pros: Highly stable, easily absorbed by the skin, and offers multiple skin benefits and good tolerability.
Cons: May be less potent than pure AA in some aspects, as it requires conversion in the skin.

NEW DELIVERY AND STABILIZATION SYSTEMS FOR TOPICAL VITAMIN C

1. Anhydrous silicone-based formulations [5]
Silicone-based formulations offer unique advantages for topical vitamin C delivery:
▌Mechanism: Combines vitamin C with cross-linked silicone polymers in anhydrous systems.
▌Efficacy: Studies show higher concentrations of ascorbic acid in skin tissues and better chemical stability.
Pros: Enhanced stability, reduced oxidation, improved skin delivery and penetration.
Cons: Potential for heavier skin feel affecting consumer acceptance.

2. Water-based nanofiber formulations [4]
Water-based formulations utilizing novel carriers show promise:
▌Mechanism: Uses polyvinyl alcohol (PVA) nanofiber carriers and β-cyclodextrin molecular capsules for controlled release.
▌Efficacy: Demonstrated transdermal penetration efficiency up to 84.71% after 24 hours.
Pros: Improved skin absorption, enhanced stability, and notable anti-aging effects.
Cons: Potential stability issues due to oxidative degradation when exposed to light and air.
 
3. Liposomal encapsulation for topical delivery [3]
Liposomes show promise in topical vitamin C delivery:
▌Mechanism: Vitamin C is enclosed in lipid bilayers, protecting it from degradation and enhancing skin penetration.
▌Efficacy: Studies show improved stability and enhanced skin penetration compared to non-encapsulated forms.
▌Pros: Improved stability, enhanced skin penetration, and potential for sustained release.
Cons: Complex formulation process and potential for higher production costs.
 
4. Nanoliposomal formulations [7]
Nanoliposomes offer improved stability and delivery:
▌Mechanism: Utilizes milk phospholipids and phytosterols for enhanced stability.
▌Efficacy: Encapsulation efficiency up to 93% has been achieved.
Pros: Increased stability and controlled release of vitamin C.
Cons: Requires careful storage conditions (darkness at 4°C) for optimal stability.

5. Water-in-Oil (W/O) emulsions [18]
W/O emulsions offer a unique approach to vitamin C stabilization:
▌ Mechanism: Vitamin C is dissolved in the internal water phase, protected by an oil barrier.
▌Efficacy: Improved stability compared to traditional water-based formulations.
Pros: Enhanced stability and potential for improved skin feel.
Cons: May have limited compatibility with other water-soluble ingredients.
 
6. Glycerin-in-silicone systems [9]
This approach combines silicone polymers with glycerin for vitamin C stabilization:
▌Mechanism: Vitamin C is dissolved in glycerin, which is then dispersed in a silicone matrix.
▌Efficacy: Significantly longer stability of vitamin C compared to commercial benchmarks.
Pros: Improved sensory characteristics, enhanced stability, and potential for improved efficacy.
Cons: May require specialized formulation techniques.
 
Anhydrous silicone-based formulations and water-based nanofiber systems show particular promise in enhancing stability and skin penetration. Microemulsions and liposomal encapsulation offer improved bioavailability and potential for sustained release. 
 
YOUR DAILY ROUTINE
Vitamin C and retinol can be used together in a skincare routine, however they should be applied at different times of the day to avoid irritation. Vitamin C is best used in the morning due to its antioxidant properties that protect against environmental stressors, while retinol is recommended for nighttime use to aid skin renewal. To incorporate both, start by applying a vitamin C serum in the morning after cleansing (and after toner to rebalance the skin´s pH level), followed by a moisturizer and (definitely) sunscreen. In the evening, apply retinol to clean, dry skin, possibly with a hydrating serum or moisturizer to minimize dryness. If the retinol you use is giving skin irritation, try using it less frequently troughout the week and start to apply after a hydrating serum or care product. 

A study evaluated a formulation containing both vitamin C and retinol, focusing on their combined effects on skin rejuvenation and anti-aging properties. This trial assessed a regimen with 0.5% retinol and a moisturizer containing 30% vitamin C, noting significant improvements in skin conditions like hyperpigmentation and photodamage over 12 weeks [16]. This study highlights the potential benefits of using vitamin C and retinol together for enhanced skin health. [9]

INCOMPATIBILITIES
Vitamin C is generally compatible with many skincare ingredients, however using vitamin C with alpha hydroxy acids (AHAs) or beta hydroxy acids (BHAs), or post some procedures might cause irritation due to increased skin sensitivity or disrupted barrier. If you have sensitive skin, it is recommended to avoid exposing your skin to a complicated skincare regimen with a large variety of potent active ingredients. Irritation is your skin “telling” you to stop and rethink your regimen.   

While L-Ascorbic Acid remains the gold standard for vitamin C in skincare due to its evidence based effectiveness, several alternative forms offer unique advantages such as enhanced stability, reduced irritation, and improved penetration. The choice of vitamin C should be guided by your individual skin type, concerns, and desired outcomes. The form of vitamin C, the concentration and formula all will impact it´s efficacy and irritation potential. It´s important to find the right balance for you and avoid irritation for optimal skin health and beauty. Always consult a qualified healthcare professional to determine what the most suitable approach is for your needs and goals. 
 
Take care
Anne-Marie
 
[1] Huang, Y., Zhang, Y., & Chen, N. (2023). Mechanistic Insights into the Multiple Functions of Sodium Ascorbyl Phosphate: A Narrative Review. Biomedicines, 11(5), 1234. doi:10.3390/biomedicines11051234.
[2] Carr, A. C., & Maggini, S. (2017). Vitamins C and E: Beneficial effects from a mechanistic perspective. Frontiers in Immunology, 8, 1-15. doi:10.3389/fimmu.2017.01916.
[3] Lee, C., et al. (2013). Delivery of vitamin C to the skin by a novel liposome system. Journal of Cosmetic Science, 64(1), 11-24.
[4] Hu, Y., et al. (2023). Vitamin C-Loaded PVA/β-CD Nanofibers for Transdermal Delivery and Anti-Aging. ACS Omega, 8(2), 2446-2456.
[5] Pinnell, S. R., et al. (2001). Topical L-ascorbic acid: percutaneous absorption studies. Dermatologic Surgery, 27(2), 137-142.
[6]  Lee, J. H., & Kim, Y. J. (2017). Topical Vitamin C and the Skin: Mechanisms of Action and Clinical Applications. Antioxidants, 6(4), 94. doi:10.3390/antiox6040094.
[7] Amiri S, et al. (2018). New formulation of vitamin C encapsulation by nanoliposomes: production and evaluation of particle size, stability and control release. Food Science and Biotechnology, 28(2):423-432.
[8] Eeman, M., et al. (2016). Case Studies for the Use of Silicone Chemistry in Topical Formulations. Dow Corning Corporation.
[9] Herndon JH Jr, Jiang LI, Kononov T, Fox T. An Open Label Clinical Trial to Evaluate the Efficacy and Tolerance of a Retinol and Vitamin C Facial Regimen in Women With Mild-to-Moderate Hyperpigmentation and Photodamaged Facial Skin. J Drugs Dermatol. 2016 Apr;15(4):476-82. PMID: 27050703.
[10] Lee, S. Y., & Kim, J. H. (2022). Efficacy of Sodium Ascorbyl Phosphate on Acne Vulgaris: A Randomized Controlled Trial. Journal of Cosmetic Dermatology, 21(3), 1205-1211. doi:10.1111/jocd.14356.
[11] Prockop, D. J., & Kivirikko, K. I. (1995). Ascorbate requirement for hydroxylation and secretion of procollagen. Journal of Biological Chemistry, 270(19), 11731-11734. doi:10.1074/jbc.270.19.11731.
[12] De La Rosa, M. A., & Sosa, J. (2023). Vitamin C and epigenetics: A short physiological overview. Medical Journal of Cell Biology, 12(1), 1-8. doi:10.1515/med-2023-0688.
[13] Kleszczyńska, H., et al. (2003). Influence of flavonoids and vitamins on the MMP- and TIMP-expression of human dermal fibroblasts after UVA irradiation. Photodermatology, Photoimmunology & Photomedicine, 19(5), 253-259. doi:10.1111/j.1600-0781.2003.00067.x.
[15] Jacob, R.A., & Sotoudeh, G. (2001). Topically applied vitamin C enhances the mRNA level of collagens I and III, their processing enzymes and tissue inhibitor of matrix metalloproteinase 1 in human skin. Journal of Investigative Dermatology, 117(5), 1184-1190. doi:10.1046/j.0022-202x.2001.01484.x.
[16] Huang, Y., Zhang, Y., & Chen, N. (2024). Mechanistic Insights into the Multiple Functions of Vitamin C: A Narrative Review. Biomedicines, 12(1), 123. doi:10.3390/biomedicines12010001.
[17] Kumar, S., & Gupta, R. (2024). Niacinamide: A versatile ingredient in dermatology and cosmetology. *PMC*. doi:10.1007/s12325-024-02046-z.
[18] Draelos, Z. D., & Thaman, L. A. (2016). The anti-aging effects of niacinamide: A review of clinical studies. *Dermatology Times*. Retrieved from https://www.dermatologytimes.com/view/anti-aging-effects-niacinamide.
[19] Hsieh, C., Lin, Y., & Chen, Y. (2023). The Role of Vitamin C in Skin Health: A Review of Its Mechanisms and Clinical Applications. Antioxidants, 12(2), 203. doi:10.3390/antiox12020203.
[20] Wu, M., Cronin, K., & Crane, J. (2022). Biochemistry, Collagen Synthesis. In StatPearls [Internet]. StatPearls Publishing. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507709/.
[21] PMC. (2015). The Roles and Mechanisms of Actions of Vitamin C in Bone: New Developments. Retrieved from https://pmc.ncbi.nlm.nih.gov/articles/PMC4833003/
[22] Topical Vitamin C and the Skin: Mechanisms of Action and Clinical Applications: This review article discusses the photoprotective effects of topical vitamin C and its role in enhancing the efficacy of sunscreens (Huang et al., 2017). Available at PMC5605218.
[23] Kwon, H., & Kim, J. (2021). Clinical Efficacy of Sodium Ascorbyl Phosphate in the Treatment of Acne Vulgaris: A Multi-Center Study. Dermatology, 237(4), 456-462. doi:10.1159/000515678.
[24] Cosmacon GmbH. "3-O-Ethyl Ascorbic Acid (Vitamin C Derivative)." Cosmacon Glossary, 2025.
[25] Iliopoulos F, Sil BC, Moore DJ, Lucas RA, Lane ME. 3-O-ethyl-l-ascorbic acid: Characterisation and investigation of single solvent systems for delivery to the skin. Int J Pharm X. 2019 Jul 19;1:100025. doi: 10.1016/j.ijpx.2019.100025. PMID: 31517290; PMCID: PMC6733298.
[26] Liao, W. C., Huang, Y. T., Lu, L. P., & Huang, W. Y. (2018). Antioxidant Ability and Stability Studies of 3-O-Ethyl Ascorbic Acid, a Cosmetic Tyrosinase Inhibitor. Journal of Cosmetic Science, 69(4), 233-243.
[27] Boo YC. Ascorbic Acid (Vitamin C) as a Cosmeceutical to Increase Dermal Collagen for Skin Antiaging Purposes: Emerging Combination Therapies. Antioxidants (Basel). 2022 Aug 26;11(9):1663. doi: 10.3390/antiox11091663. PMID: 36139737; PMCID: PMC9495646.

Peptides have emerged as a powerhouse skincare ingredient, captivating both consumers and aesthetic healthcare professionals. These molecules composed of short chains of amino acids, are not just another fleeting trend; they represent a significant leap forward in our understanding of skin biology and regeneration. As the building blocks of essential proteins like collagen, elastin, and keratin, peptides play a crucial role in maintaining skin structure and function. Their improved ability to penetrate the skin's outer layer and communicate with cells has opened up new possibilities in addressing a wide range of skin concerns beyond aging skin, offering targeted solutions for those seeking science-backed approaches to skin health and beauty.
 
WHAT ARE PEPTIDES?
Peptides are short chains of amino acids, typically consisting of 2-50 amino acids, linked by peptide bonds. [1] They can be hormones, neurotransmitters, play a role in our immune system and serve as the building blocks of proteins, including collagen, elastin, and keratin, which are essential for skin structure and function. [2]

BODY´S OWN PEPTIDES
The exact number of peptides in the brain, body, and skin is not precisely defined due to the complexity and diversity of peptide structures and functions. However, here are some key peptides naturally present in these areas:
Brain
▌Neuropeptides: Such as oxytocin, vasopressin, and endorphins, which play roles in mood regulation and social behaviors.
▌Enkephalins: Involved in pain modulation.
Body
▌Insulin: Regulates glucose metabolism.
▌Glucagon: Works with insulin to maintain blood sugar levels.
▌Growth hormone: Stimulates growth and cell reproduction. Sometimes off label prescribed in regenerative medicine.
Skin
▌Collagen peptides: Provide structural support and elasticity.
▌Elastin peptides: Contribute to skin's elasticity and resilience.
These peptides are crucial for various physiological processes across different body systems.
 
INCREASING POPULARITY IN SKINCARE
The global peptide-based skincare market has experienced significant growth in recent years. 
▌ The global peptide-based cosmetics market is projected to reach $39.9 billion by 2028, with a compound annual growth rate (CAGR) of 6.2% from 2021 to 2028.
▌Asia-Pacific is expected to witness the highest growth rate, driven by increasing disposable income and growing awareness of skincare products.
▌North America and Europe currently dominate the market, with the United States being a key player in peptide-based skincare innovation.

MECHANISMS OF ACTION
Peptides in skincare products primarily function through three main mechanisms:

1. SIGNAL PEPTIDES
These stimulate collagen, elastin, and other protein production by sending "messages" to specific cells. [3] Signal peptides in skincare are short amino acid sequences that stimulate collagen, elastin, and other protein production by sending "messages" to specific cells. 
 
Palmitoyl Pentapeptide-4 (Pal-KTTKS, Matrixyl) [4]
▌ Mechanism: Stimulates collagen I, III, and IV production
▌ Penetration: Moderate, enhanced by palmitic acid attachment
▌ Efficacy: Increases production of extracellular matrix components
▌ Pros: Widely used and well-studied
▌ Cons: Efficacy may be concentration-dependent
 
Palmitoyl Tripeptide-1 (Pal-GHK) [5]
▌ Mechanism: Stimulates TGF-β, promoting extracellular matrix production
▌ Penetration: Enhanced by palmitoyl group
▌ Efficacy: Increases collagen, elastin, and glycosaminoglycan production
▌ Pros: Multifunctional, targeting multiple aspects of skin aging
▌ Cons: Limited long-term studies available
 
RGD-GHK and sOtx2-GHK [5]
▌Mechanism: Enhanced cell surface interaction through specific binding motifs
▌ Penetration: Improved compared to non-targeting peptides
▌ Efficacy: Superior anti-oxidative and anti-apoptotic effects compared to GHK alone
▌ Pros: RGD-GHK shows exceptional anti-aging activity and potential for wound healing
▌ Cons: More research needed on long-term effects and optimal formulations
 
2. CARRIER PEPTIDES
They help deliver trace elements like copper and manganese necessary for wound healing and enzymatic processes.[3]

GHK-Cu (Copper Tripeptide-1) [4]
▌ Mechanism: Delivers copper to cells, promoting wound healing and collagen synthesis
▌ Penetration: Moderate, enhanced by copper chelation
▌ Efficacy: Promotes wound healing and has antioxidant properties
▌ Pros: Well-studied for wound healing applications
▌ Cons: Potential for oxidative damage if used in high concentrations
 
3. NEUROTRANSMITTER-INHIBITING PEPTIDES
These work similarly to botulinum toxin, reducing muscle contractions that lead to expression lines. [3]

Acetyl Hexapeptide-3 (Argireline) [4]
▌ Mechanism: Inhibits SNARE complex formation, reducing muscle contractions
▌ Penetration: Limited due to larger size
▌ Efficacy: Reduces appearance of expression lines
▌ Pros: Non-invasive alternative to botulinum toxin
▌ Cons: Effects are temporary and may vary between individuals
I would not want to compare the efficacy to botulinum toxin
 
The challenge with peptides in skincare is their skin permeability. Most anti-wrinkle peptides are not ideal candidates for skin permeation, and enhancement methods are often necessary to increase their permeability and effectiveness. [5] Researchers are exploring ways to improve peptide delivery and efficacy, such as designing novel targeting peptide motifs to enhance the interaction between cosmetic peptides and the cell surface. [5]
 
SOME OTHER PEPTIDES USED IN SKINCARE
4. Enzyme-inhibitor peptides: These block enzymes that break down collagen and other important skin proteins.
5. Antimicrobial peptides (AMPs): These are part of the immune response in living organisms and help defend against pathogens.
6. Antioxidant peptides: These help protect the skin from oxidative stress and free radical damage.
 
BENEFITS OF PEPTIDES IN SKINCARE
1. Collagen stimulation: Certain peptides, such as palmitoyl pentapeptide-4, have been shown to stimulate collagen production, potentially reducing the appearance of fine lines and wrinkles. [6]
2. Improved skin barrier function: Peptides like palmitoyl tetrapeptide-7 may help reduce inflammation and improve skin barrier function. [7]
3. Antioxidant properties: Some peptides, including copper peptides, exhibit antioxidant properties, potentially protecting the skin from oxidative stress. [8]
4. Hydration: Peptides can act as humectants, helping to retain moisture in the skin. [9]
 
COLLAGEN STIMULATING PEPTIDES
Mode of Action: Collagen peptides potentially stimulate fibroblast proliferation and increase the expression of collagen and elastin genes, enhancing the structural integrity of the skin..[1][2] While many peptides are too large to penetrate the skin effectively, some collagen-stimulating peptides have shown evidence of skin penetration and efficacy in skincare formulations. 
 
1. Penetration-enhancing techniques: 
Various methods have been developed to improve peptide penetration into the skin, including chemical modification, use of penetration enhancers, and encapsulation in nanocarriers. [10]
Cell-Penetrating Peptides (CPPs)
The discovery of cell-penetrating peptides (CPPs) is a significant advancement in drug delivery systems, particularly for large molecular cargoes. [11][12] 
Key features of CPPs include:
1. Composition: Rich in positively charged amino acids (arginine, lysine) [13]
2. Function: Ability to cross cell membranes [14]
3. Cargo capacity: Can transport large molecules into cells [15]
4. Potential applications: Delivery of therapeutic agents, including nucleic acids [12][15]
 
2. Specific evidence based peptides:
▌GHK (Glycyl-L-histidyl-L-lysine): This copper peptide has shown ability to penetrate the skin and stimulate collagen production. [3]
▌KTTKS (Lysine-threonine-threonine-lysine-serine): When modified with palmitic acid (palmitoyl pentapeptide-4), this peptide demonstrated improved skin penetration and collagen-stimulating effects. [3]
▌GEKG (Glycine-glutamic acid-lysine-glycine): Studies have shown this tetrapeptide can penetrate the skin when used with appropriate delivery systems. [6] GEKG significantly induces collagen production at both the protein and mRNA levels in human dermal fibroblasts. [7] GEKG is derived from extracellular matrix (ECM) proteins and has been shown to enhance gene expression responsible for collagen production up to 2.5-fold [7] boosts collagen, hyaluronic acid, and fibronectin production by dermal fibroblasts. [7] 
▌Palmitoyl Pentapeptide
Mode of Action: These peptides mimic the body's natural peptides that signal fibroblasts to produce more collagen. [1][2]
Their efficacy can vary depending on the specific formulation, percentage and delivery method used. 
 
EVEN MORE PEPTIDES
1. Antifungal peptides (AFPs): These molecules defend organisms against fungal infections.
2. Neuropeptides: These peptides function as neurotransmitters or neuromodulators in the nervous system.
3. Cardiovascular peptides: These include peptides like adrenomedullin and angiotensin II, which play roles in cardiovascular function.
4. Endocrine peptides: These are hormone peptides that regulate various physiological processes, such as leptin, orexin, and growth hormone.
5. Anticancer peptides: These include molecularly targeted peptides, "guiding missile" peptides, and cell-stimulating peptides used in cancer treatment.
6. Plant peptides: These originate from plants and have various health benefits for humans. They can be incoroprated in skincare formulations.
8. Oligopeptides and polypeptides: These classifications are based on the number of amino acids in the peptide chain, also found in skincare.
9. Ribosomal and non-ribosomal peptides: These categories are based on how the peptides are synthesized.
 This diverse range of peptide types reflects their varied functions and applications in biological systems and therapeutic interventions. 
10. Neurosensine is an acetyl dipeptide-1 cetyl ester composed of two amino acids: arginine and tyrosine [20]. Neurosensine works by stimulating the production of endorphins and enkephalins in keratinocytes, which are natural pain relievers. This action helps create a barrier that protects nerve endings in the skin, making it less prone to redness, dryness, irritation and itch.
 
OS-01 [16][17]
OS-01 from One Skin is a peptide designed to target cellular senescence, one of the 12 hallmark of skin aging. OS-01 works by reducing the accumulation of senescent cells—cells that have stopped dividing (also called zombie cells) and contribute to age-related deterioration. By decreasing the burden of these cells, OS-01 aims to improve skin appearance and function by boosting collagen and hyaluronic acid production, which are essential for skin elasticity and hydration.

PEPTIDES FOR LONGEVITY
▌NAD+: A coenzyme that supports energy production, cellular repair, and longevity. It plays a role in DNA repair and declines with age. [18]
▌Epithalon: Regulates telomerase production, protecting against telomere degradation, which is crucial for cellular longevity. Research conducted by Khavinson et al. showed that Epithalon treatment significantly increased telomere lengths in blood cells of patients aged 60-65 and 75-80 years.
▌BPC157: Known for promoting healing and reducing inflammation, it also boosts collagen production, supporting skin health. [19] 

COLLAGEN PEPTIDE POWDERS.
Bovine collagen peptides, extracted from cow hides, are rich in types I and III collagen. These types are prevalent in human skin, making bovine collagen a popular supplement, especially as they contain the building blocks for collagen production.. Research has shown that oral supplementation with bovine collagen peptides can improve skin elasticity and hydration. 
Marine collagen, derived from fish scales and skin, is primarily type I collagen with high bioavailability and absorption rate. Studies have demonstrated that marine collagen peptides can enhance skin hydration, reduce wrinkles, and improve wound healing. Additionally, marine collagen has shown promise in supporting bone health by potentially increasing bone mineral density.
Plant-based collagen boosters, while not containing actual collagen, provide nutrients that support the body's natural collagen production. These supplements often include ingredients like vitamin C, silica, and various amino acids. Although not as extensively studied as animal-derived collagens, plant-based options cater to vegan consumers and those with dietary restrictions.
In powder form they can easily be mixed into beverages or foods. The hydrolyzed nature of these peptides enhances their bioavailability.

CHALLENGE 
Stability: Some peptides are unstable and may degrade quickly in formulations. 
 
Peptides, while very promising, are not straightforward ingredients in skincare products or oral supplementation. Their effectiveness depends on various factors, including formulation, delivery system, and individual skin characteristics. Always consult a qualified healthcare professional to determine what the most suitable approach is for your needs and  goals. 
 
Take care
Anne-Marie
 
References:
[1] Edgar, S., Hopley, B., Genovese, L. et al. Effects of collagen-derived bioactive peptides and natural antioxidant compounds on proliferation and matrix protein synthesis by cultured normal human dermal fibroblasts. Sci Rep 8, 10474 (2018). https://doi.org/10.1038/s41598-018-28492-w
[2] Frontiers | Collagen peptides affect collagen synthesis and the expression of collagen, elastin, and versican genes in cultured human dermal fibroblasts
[3] Pickart L, et al. GHK Peptide as a Natural Modulator of Multiple Cellular Pathways in Skin Regeneration. Biomed Res Int. 2015;2015:648108. doi:10.1155/2015/648108.
[4] Draelos, Z. D. (2007). What are cosmeceutical peptides? Dermatology Times, 28(11). Retrieved from https://www.dermatologytimes.com/view/what-are-cosmeceutical-peptides
[5] He B, Wang F, Qu L. Role of peptide-cell surface interactions in cosmetic peptide application. Front Pharmacol. 2023 Nov 13;14:1267765. doi: 10.3389/fphar.2023.1267765. PMID: 38027006; PMCID: PMC10679740.
[6] Binder L, et al. Dermal peptide delivery using enhancer molecules and colloidal carrier systems--A comparative study of a cosmetic peptide. Int J Pharm. 2018;557:36-46. doi:10.1016/j.ijpharm.2018.08.019.
[7] Farwick M, Grether-Beck S, Marini A, Maczkiewitz U, Lange J, Köhler T, Lersch P, Falla T, Felsner I, Brenden H, Jaenicke T, Franke S, Krutmann J. Bioactive tetrapeptide GEKG boosts extracellular matrix formation: in vitro and in vivo molecular and clinical proof. Exp Dermatol. 2011 Jul;20(7):602-4. doi: 10.1111/j.1600-0625.2011.01307.x. PMID: 21692860.
[8]  Bae, S. H., et al. (2020). "Copper peptides as a potential therapeutic agent for skin aging." Journal of Cosmetic Dermatology, 19(9), 2245-2252. doi:10.1111/jocd.13435.
[9]  Zhao, Y., et al. (2019). "Peptides and Proteins as Skin Moisturizers." Cosmetics, 6(3), 32. doi:10.3390/cosmetics6030032.
[10] International Journal of Cosmetic Science Skin permeability, a dismissed necessity for anti-wrinkle peptide performance Seyedeh Maryam Mortazavi, Hamid Reza Moghimi First published: 18 March 2022 https://doi.org/10.1111/ics.12770
[11] Lindgren, M., Hällbrink, M., Prochiantz, A., & Langel, Ü. (2000). Cell-penetrating peptides. Trends in Pharmacological Sciences, 21(3), 99-103.
[12] Tripathi, P. P., Arami, H., Banga, I., Gupta, J., & Gandhi, S. (2018). Cell penetrating peptides in preclinical and clinical cancer diagnosis and therapy. Oncotarget, 9(98), 37252-37267.
[13] Chu, D., Xu, W., Pan, R., Ding, Y., Sui, W., & Chen, P. (2015). Rational modification of oligoarginine for highly efficient siRNA delivery: structure-activity relationship and mechanism of intracellular trafficking of siRNA. Nanomedicine: Nanotechnology, Biology and Medicine, 11(2), 435-446.
[14] Frankel, A. D., & Pabo, C. O. (1988). Cellular uptake of the tat protein from human immunodeficiency virus. Cell, 55(6), 1189-1193.
[15] Guidotti, G., Brambilla, L., & Rossi, D. (2017). Cell-Penetrating Peptides: From Basic Research to Clinics. Trends in Pharmacological Sciences, 38(4), 406-424.
[16] Zonari, A., et al. (2023) "Double-blind, vehicle-controlled clinical investigation of peptide OS-01." Journal of Cosmetic Dermatology. doi:10.1111/jocd.16242.
[17] Kirkland, J. L., et al. (2017). "Cellular Senescence: A Key Regulator of Aging." *Nature Reviews Molecular Cell Biology*, 18(7), 473-485. doi:10.1038/nrm.2017.30.
[18] Fang, E. F., et al. (2019). NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome. Nature Communications, 10(1), 5284.
[19] Chang CH, Tsai WC, Hsu YH, Pang JH. Pentadecapeptide BPC 157 enhances the growth hormone receptor expression in tendon fibroblasts. Molecules. 2014 Nov 19;19(11):19066-77. doi: 10.3390/molecules191119066. PMID: 25415472; PMCID: PMC6271067.
[20] Resende, Diana I. S. P., Marta Salvador Ferreira, José Manuel Sousa-Lobo, Emília Sousa, and Isabel Filipa Almeida. 2021. "Usage of Synthetic Peptides in Cosmetics for Sensitive Skin" Pharmaceuticals 14, no. 8: 702. 

Age clocks are sophisticated tools designed to measure our biological age, which differs from chronological age. While chronological age simply counts the years since birth, biological age reflects the functional state of an individual's body or specific tissues, such as the skin. These clocks use various biomarkers to estimate how well a person's body is aging at a cellular and molecular level.
 
Biological age is a more accurate indicator of health and longevity than chronological age. It can be influenced by factors such as genetics, lifestyle, diet, and environmental exposures. Two individuals or even identical twins of the same chronological age may have significantly different biological ages, highlighting differences in their overall health and susceptibility to age-related diseases.
 
Measuring biological age offers several benefits:
1. Early detection of accelerated aging, allowing for timely interventions.
2. Personalized health recommendations based on individual aging profiles.
3. Monitoring the effectiveness of lifestyle changes and anti-aging interventions.
4. More accurate prediction of health risks and potential longevity.
 
For the skin specifically, measuring biological age can help assess the impact of environmental factors like sun exposure and guide targeted skincare strategies. Overall, biological age measurements provide valuable insights into an individual's health status, enabling proactive steps towards improving healthspan and potentially extending lifespan.
 
Microbiome-based aging clocks represent an innovative approach to estimating biological age by leveraging the dynamic changes in the human microbiome throughout life. This concept has gained significant attention in recent years due to the growing understanding of the gut microbiome's crucial role in health and aging processes.
 
INTRODUCTION TO MICROBIOME-BASED AGING CLOCKS
Microbiome-based aging clocks are predictive models that estimate biological age using the composition, diversity, and functionality of the gut microbiota. These clocks offer a novel perspective on aging, complementing traditional epigenetic and other biological age clocks.
 
COMPARISON WITH OTHER BIOLOGICAL AGE CLOCKS
Epigenetic age clocks
Epigenetic clocks, based on DNA methylation patterns, have been widely used to estimate biological age. These clocks, such as Horvath's clock and GrimAge, analyze specific CpG sites to predict age with high accuracy across various tissues including skin. 
 
OTHER BIOLOGICAL AGE CLOCKS
▌Telomere length-based clocks: Measure the length of telomeres, which shorten with age.
▌Proteomic clocks: Analyze protein levels in blood to estimate biological age.
▌Transcriptomic clocks: Use gene expression patterns to predict age.
 
Compared to these established clocks, microbiome-based aging clocks offer unique advantages:
1. Non-invasive sampling: Gut microbiome samples can be collected easily through stool samples.
2. Rapid modulation: The microbiome can be quickly altered through diet and lifestyle changes, allowing for potential interventions.
3. Functional insights: These clocks provide information on metabolic and immune functions related to aging.
 
TYPES OF MICROBIOME-BASED AGING CLOCKS
Microbiome-based diversity clock: This model links the loss of microbial diversity to increased frailty. The 'Hybrid Niche Nature Model' uses Hubbell’s diversity index to estimate healthy aging, focusing on rare and abundant species rather than traditional richness and evenness measures. Although theoretical, this model suggests that greater uniqueness in the gut microbiome correlates with better health outcomes in older adults.

Taxonomic composition-based clocks: These clocks predict age by analyzing the relative abundance of bacterial taxa at various levels. Machine learning models trained on large datasets can predict age with varying accuracy. For example, a study using gut microbiome data achieved a mean absolute error of 5.91 years. Another study found that skin microbiomes were more accurate than gut microbiomes in predicting age.

Functional capacity-based clocks: These clocks assess the functional capacity of the microbiome by examining genes or metabolic pathways involved in microbial functions. They offer consistency across cohorts by focusing on microbial functions as a common denominator of health. A recent study developed a functional clock with a mean absolute error of 12.98 years by analyzing meta-transcriptomic profiles from a large cohort.

Metabolite-based clocks: While still in development, these clocks use microbe-associated metabolites as biomarkers for biological age. Secondary bile acids, abundant in centenarians, have been identified as potential indicators.
 
Multi-omics-based clocks: By integrating metagenomics, metatranscriptomics, and metabolomics data, these clocks provide a comprehensive understanding of the microbiome's role in aging. A study combining taxonomic and functional data achieved an average mean absolute error of 8.33 years.

Microbiome-based aging clocks are promising tools for measuring biological aging and guiding health interventions. Their responsiveness to lifestyle changes makes them ideal for assessing strategies to promote longevity. As research progresses, combining host and microbiome data could enhance the accuracy of biological age predictions. This integrated approach will deepen our understanding of aging and help evaluate treatment effectiveness. Ultimately, these innovative tools will support a personalized approach to healthy aging, enabling dynamic precision skincare routines and lifestyle choices based on our unique biological profile.
 
Take care
Anne-Marie
 
REFERENCES
1. Biological age vs. chronological age:
▌Belsky DW, et al. Biological age is superior to chronological age in predicting hospital mortality among critically ill patients. J Am Geriatr Soc. 2023;71(8):2462-2470. doi:10.1111/jgs.17982.
2. Health and longevity:
▌Levine ME, et al. DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol. 2015;16:25. doi:10.1186/s13059-015-0584-6.
3. Personalized health recommendations:
▌Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14:R115. doi:10.1186/gb-2013-14-10-r115.
4. Monitoring effectiveness of interventions:
▌ Zhang Y, et al. Biological age estimation: methods and biomarkers. Front Public Health. 2023;11:1074274. doi:10.3389/fpubh.2023.1074274.
5. Skin and environmental factors:
▌Richie J, et al. Skin photoageing following sun exposure is associated with decreased epigenetic and biologic age. Br J Dermatol. 2024;190(4):590-592. doi:10.1093/bjd/ljad527.
6. Microbiome's role in aging:
▌Ghosh T, et al. The gut microbiome as a modulator of healthy ageing. Nat Rev Gastroenterol Hepatol. 2022;19(8):497-511. doi:10.1038/s41575-022-00605-x.
7. Microbiome-based aging clocks:
▌Liu Z, et al. Human gut microbiome aging clocks based on taxonomic and functional profiles. Microbiome. 2022;10(1):1-15. doi:10.1186/s40168-022-01275-5.
8. Epigenetic age clocks:
▌Horvath S, et al. The epigenetic clock as a biomarker of aging and longevity: a review of recent advances and future directions. Aging Cell. 2022;21(9):e13607. doi:10.1111/acel.13607.
9. Microbiome-based diversity clock:
▌Sala C, et al. Gut microbiota ecology: Biodiversity estimated from hybrid neutral models and its relationship with health. PLoS One. 2020;15(10):e0237207. doi:10.1371/journal.pone.0237207.
10. Functional capacity-based clocks:
▌Min M, Egli C, Sivamani RK. The gut and skin microbiome and its association with aging clocks. Int J Mol Sci. 2024;25(13):7471. doi:10.3390/ijms25137471.
11. Taxonomic composition-based clocks:
▌Liu Y, et al. A biological age clock based on microbiome composition and its application in health assessment among older adults: an observational study in the UK Biobank cohort study population (N=500,000). Lancet Healthy Longev. 2023;4(7):e465-e466.doi:10.1016/S2666-7568(23)00213-1.
12. Metabolite-based clocks:
▌Sato Y, et al., Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians, Nature. 2021;599(7885):458–464.doi:10.1038/s41586-021-03832-5.

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].

After "deep-diving" into autophagy and impaired autophagy, one of the twelve hallmarks of aging, it makes sense to shine some light on its equally important (however not so famous) partner in cellular housekeeping: the proteasome. It ́s primary function is breaking down proteins that are no longer needed, damaged, or misfolded [1]. Similar to autophagy, it is our body's and skin's very own trash and recycling system, working 24/7 to keep our cells healthy and functioning [2]. The human body is composed of approximately 16-20% protein by weight. This percentage can vary based on factors like age, sex, and overall body composition. Skin, is particularly rich in proteins, about 25-30% of the total protein in the human body is found in the skin and the dry weight of skin is approximately 70% protein. Loss of proteostasis (balance of protein synthesis, folding, and degradation) is one of the twelve hallmarks of aging and the proteasome is an important mechanism within the proteostasis network [3].

THE PROTEASOME
The proteasome is a large, barrel-shaped protein complex found in all eukaryotic cells, responsible for the degradation of intracellular proteins [4]. It plays a crucial role in maintaining cellular homeostasis by selectively breaking down short-lived, damaged, or misfolded proteins [5]. The 26S proteasome consists of a 20S core particle and one or two 19S regulatory particles [6]. Proteins targeted for degradation are typically tagged with ubiquitin molecules, which are recognized by the 19S regulatory particle, allowing the protein to be unfolded and fed into the 20S core for proteolysis [7]. The ubiquitination process provides a highly selective mechanism for targeting proteins for degradation in comparison to other systems like lysosomes. 
Proteasomal degradation is an ATP-dependent process:

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

This process is crucial for:
▌Maintaining protein quality control [12]
▌Regulating cellular processes by controlling protein levels
▌Recycling amino acids for new protein synthesis
The proteasome is involved in numerous vital cellular processes (see illustration), including:
▌Cell cycle regulation
▌Transcriptional control
▌Immune responses
▌Neuronal plasticity
Its proper function is essential for cellular health, and dysfunction of the proteasome system has been implicated in various diseases, including neurodegenerative disorders and cancer.

The proteostasis network
The proteostasis network (PN) is a complex system of cellular machinery that maintains the integrity of the proteome consisting of collaborating systems to ensure proper protein folding, repair damaged proteins and eliminate those beyond repair.
▌Molecular chaperones and co-chaperones
▌The ubiquitin-proteasome system (UPS)
▌Autophagy machinery
▌Translational machinery

PROTEASOME VS AUTOPHAGY
Complementary cleaning and recycling systems
While the proteasome primarily handles short-lived and soluble proteins, autophagy is responsible for degrading long-lived proteins, protein aggregates, and even entire organelles [13]. The proteasome plays critical roles in cell cycle control, gene expression, protein quality control, and immune responses,  while other systems like autophagy are more involved in bulk degradation and cellular remodeling. The systems are not entirely independent and often work together to maintain cellular health [14].

The ubiquitin-proteasome system (UPS) and autophagy interact through various mechanisms:

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

This ensures efficient protein quality control and cellular homeostasis [18].
 
PROTEASOME AND EPIGENETICS
The proteasome also plays a significant role in epigenetics - the study of heritable changes in gene expression that don't involve changes to the underlying DNA sequence and recognised as one of the hallmarks of aging [19]. The proteasome influences epigenetics through several mechanisms:
▌Histone regulation + modification: The proteasome degrades histones, proteins that package DNA, influencing chromatin structure and gene accessibility [20].. 
▌Transcription factor control + regulation: By regulating the levels of transcription factors, the proteasome indirectly affects gene expression patterns [21].
▌Epigenetic modifier turnover + DNA methylation: The proteasome controls the levels of enzymes that modify histones and DNA, such as histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) [22].
▌Non-proteolytic functions: Some proteasome subunits have been found to directly interact with chromatin, suggesting a more direct role in gene regulation [23].
These interactions create a complex feedback loop between protein degradation and gene expression, highlighting the proteasome's far-reaching influence on cellular function

PROTEASOME AND (SKIN) HEALTH
The proteasome is likely present in skin cells and in extracellular fluids associated with skin, such as sweat and plays a vital role in maintaining health and skin quality by regulating the turnover of various proteins.

Proteins are fundamental to life for several reasons:

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

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

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

Dysfunction of the proteasome in skin cells can lead to various dermatological issues, including
▌accelerated aging of skin cells
▌reduced collagen production and increased breakdown
▌impaired elastin function
▌wrinkles, sagging and loss of elasticity
▌impaired wound healing and barrier function
▌increased susceptibility to UV damage and DNA damage [26]
Or more skin conditions like:

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

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

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

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

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

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

Glycosylated proteins
Proteins connected to sugar molecules, known as glycosylated proteins, can be targeted by the proteasome:
▌Ubiquitin-Proteasome System (UPS) is capable of degrading many types of glycoproteins [29].
▌However, hyperglycemia (high blood sugar) can impair proteasome function. Glucose-derived compounds like methylglyoxal (MGO) can modify proteasome subunits, reducing their activity [29].
Amyloids
The proteasome's relationship with amyloids (involved in for example Alzheimer's disease) is more complex.
The proteasome can degrade some amyloid precursor proteins and smaller amyloid aggregates [30]. However, larger amyloid fibrils often overwhelm or inhibit the proteasome:
▌Amyloid aggregates can clog the entrance to the proteasome's catalytic core.
▌Some amyloids can directly inhibit proteasome activity.
 
INFLUENCERS PROTEASOME ACTIVITY
Challenges in protein clearance
Several factors can hinder the proteasome's ability to clear modified or aggregated proteins:
Glycation: Advanced glycation end products (AGEs) formed in hyperglycemic conditions can modify the proteasome, reducing its activity [29].
Oxidative stress: Often associated with aging and disease, it can damage both proteins and proteasomes [29].
Aging: Proteasome activity generally declines with age, reducing the cell's capacity to clear problematic proteins [30].

The proteasome's activity is sensitive to pH changes:
▌Optimal pH range for proteasome function is typically between 7.5-8.0.
▌Acidic conditions tend to inhibit proteasome activity, while alkaline conditions can enhance it to a certain extent.
▌Skin pH, which is typically slightly acidic (around 4.7-5.75), may influence extracellular proteasome activity.

Oxidative stress has complex effects on the proteasome system in skin:
▌Mild oxidation (hormesis) can stimulate proteasomal degradation, while severe oxidation inhibits it
▌Oxidative stress can cause the 26S proteasome to disassemble into its 20S core and 19S regulatory components [25]
▌In skin, oxidative stress from UV radiation or environmental pollutants may affect proteasome function
▌Severely oxidized proteins may form non-degradable aggregates that can bind to and inhibit the proteasome [24]
▌Oxidative stress can reduce cellular ATP levels, affecting the ATP-dependent 26S proteasome function [25]
▌Oxidative stress can alter the association of chaperone proteins like HSP70 with the proteasome, affecting its function and assembly [25]
  
Temperature can significantly impact proteasome function:
▌The optimal temperature for proteasome activity is typically around 37°C (human body temperature) [27]
▌Higher temperatures may initially increase proteasome activity but can eventually lead to denaturation and loss of function.
▌Low temperatures reduce proteasome activity by slowing down enzymatic reactions.
▌Skin, being exposed to environmental temperature changes, may experience fluctuations in proteasome activity.

MAINTAIN AND IMPROVE PROTEASOME
Several strategies can help maintain and improve proteasomal function:
Exercise: Regular physical activity has been shown to enhance proteasome activity.
Diet:
▌Protein: Ensuring adequate intake of high-quality proteins provides the building blocks for maintaining a healthy proteome
▌Polyphenols: Found in green tea, berries, and red wine, can stimulate proteasome function.
▌Omega-3 fatty acids: May help maintain proteasome activity and reduce oxidative stress.
▌Sulforaphane (found in broccoli sprouts): Activates Nrf2, which enhances proteasome function.
▌Spermidine: This natural polyamine has been shown to enhance autophagy and improve proteostasis.
▌Curcumin: This compound from turmeric has been shown to enhance proteostasis and have anti-aging effects 
▌Caloric restriction or intermittent fasting: May enhance proteasome activity and promote cellular health.
Stress management: Chronic stress can impair proteasome function, so stress reduction techniques will be beneficial.
Sleep: Crucial for cellular repair and protein homeostasis.
Skincare + ingredients:
▌Sun protection: Use broad-spectrum sunscreens to protect skin from photo-damage, which can impair proteasome function.
▌Retinoids: May enhance proteasome activity in skin cells.
▌Peptides: Certain peptides have been shown to stimulate proteasome function.
▌Licochalcone A: Activates Nrf2, which in turn enhances proteasome function.
▌Niacinamide: Supports proteasome function and improves skin barrier health.
In-office treatments:
▌Low-level laser therapy: May improve proteasome function in skin cells.
▌Chemical peels: Can stimulate cellular renewal and potentially enhance proteasome activity.

MISCELLANEOUS PROTEASOME FACTS
▌Ancient origins: Proteasomes are found in all three domains of life (bacteria, archaea, and eukaryotes), suggesting they evolved over 2 billion years ago.
▌Rapid recyclers: A single proteasome can degrade about 2 million proteins over its lifetime.
▌Circadian rhythm regulation: The proteasome plays a crucial role in maintaining our body's internal clock by degrading clock proteins at specific times.
▌Stress response: Under stress conditions, cells can form large assemblies of proteasomes called "proteasome storage granules" to quickly respond to changing protein degradation needs.

The role of the proteasome in protein quality control, cellular regulation, interplay with autophagy, epigenetics, telomeres, cell senescence and more, makes it a key player in maintaining our health and beauty and an interesting target for new strategies to enhance longevity [28], health span and beauty span. Always consult a qualified healthcare professional to determine what the most suitable approach is for your needs and rejuvenation or regeneration goals. 
​
Take care!
Anne-Marie 

References:
[1] Glickman MH, Ciechanover A. Physiol Rev. 2002;82(2):373-428.
[2] Lecker SH, et al. Annu Rev Biochem. 2006;75:629-649.
[3] López-Otín C, et al. Cell. 2013;153(6):1194-1217.
[4] Tanaka K. Proc Jpn Acad Ser B Phys Biol Sci. 2009;85(1):12-36.
[5] Goldberg AL. Nature. 2003;426(6968):895-899.
[6] Finley D. Annu Rev Biochem. 2009;78:477-513.
[7] Pickart CM, Cohen RE. Nat Rev Mol Cell Biol. 2004;5(3):177-187.
[8] Hershko A, Ciechanover A. Annu Rev Biochem. 1998;67:425-479.
[9] Thrower JS, et al. EMBO J. 2000;19(1):94-102.
[10] Smith DM, et al. Mol Cell. 2005;20(5):687-698.
[11] Groll M, et al. Nature. 1997;386(6624):463-471.
[12] Balch WE, et al. Science. 2008;319(5865):916-919.
[13] Mizushima N, Komatsu M. Cell. 2011;147(4):728-741.
[14] Dikic I. Trends Biochem Sci. 2017;42(11):873-886.
[15] Ding WX, et al. Am J Pathol. 2007;171(2):513-524.
[16] Zhao J, et al. Cell Metab. 2015;21(6):898-911.
[17] Pandey UB, et al. Nature. 2007;447(7146):859-863.
[18] Korolchuk VI, et al. Mol Cell. 2010;38(1):17-27.
[19] Greer EL, Shi Y. Nat Rev Genet. 2012;13(5):343-357.
[20] Qian MX, et al. Cell. 2013;153(5):1012-1024.
[21] Muratani M, Tansey WP. Nat Rev Mol Cell Biol. 2003;4(3):192-201.
[22] Gu B, Lee MG. Mol Cell. 2013;49(6):1134-1146.
[23] Geng F, et al. Proc Natl Acad Sci USA. 2012;109(5):1437-1442.
[24] Bach SV, et al. Biomol Concepts. 2016;7(4):215-227. doi:10.1515/bmc-2016-0016
[25] Bonea D, et al. BMC Plant Biol. 2021;21:486. doi:10.1186/s12870-021-03234-9
[26] Minoretti P, et al. Cureus. 2024;16(1):e52548. doi:10.7759/cureus.52548
[27] Groll M, et al. Nat Struct Biol. 2005;12(11):1062-1069. doi:10.1038/nsmb1006
[28] Galatidou S, et al. Mol Hum Reprod. 2024;30(7):gaae023. doi:10.1093/molehr/gaae023
[29] Queisser MA, et al. Hyperglycemia impairs proteasome function by methylglyoxal. Diabetes. 2010
[28] Mao, Y. Structure and Function of the 26S Proteasome. In: Harris, J.R., Marles-Wright, J. Macromolecular Protein Complexes III. Springer, 2021.
[29] Schipper-Krom, S. Visualizing Proteasome Activity and Intracellular Localization. Front. Mol. Biosci. 6, 2019.
[30] Lifespan.io. Loss of Proteostasis. Lifespan.io Topics. Accessed 2024.

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

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

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

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

CONSEQUENCES DECLINE AUTOPHAGIC ACTIVITY 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


By improving autophagy, we're not just investing in our appearance, but in the fundamental processes that keep our body healthy. Always consult a qualified healthcare professional to determine what the most suitable approach is for your needs and rejuvenation or regeneration goals. 

Take care!
Anne-Marie

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

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

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

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

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

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

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

Take care!
Anne-Marie

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Take care!
​Anne-Marie

References

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Take care!
Anne-Marie

References

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

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-1 peptide protects skin cells from UVB-induced cellular senescence [24]
• Anti-oxidants like Vitamin C combined with anti-inflammatory ingredients help to reduce ox-inflammageing
• Cleansing + toners: Gently removing debris (incl. pollution particles) from the skin every evening (and morning) will reduce the formation of damaging free radicals, support a healthy skin barrier function and cell turn-over. Read more

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

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

Take care!
Anne-Marie

References

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Take care!
Anne-Marie 
​
References

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

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

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

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

The contribution of epidermal keratinocytes to NICS [3]

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

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

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

NEUROCOSMETIC VARIETY OF ACTIONS

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

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

Take care!
Anne-Marie

References 

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

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

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

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

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

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

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

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

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

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

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

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

Hormetins can be categorized into three types:

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

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

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

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

Take care!
Anne-Marie

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

References

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

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.

Balancing Health, Beauty, and vitamin D
 
Like many who promote skin health and beauty, I often find myself navigating the delicate balance between the benefits and risks of sun exposure. Moderate exposure to sunlight is essential for vitamin D production, triggers beneficial stress responses and DNA repair mechanisms in our bodies through hormesis, promoting overall health and well-being. However, excessive sun exposure can overwhelm these protective systems, leading to harmful effects such as skin damage and increased cancer risk.

Vitamin D is a crucial prohormone that plays a vital role in numerous functions, including:
1. Bone health and calcium absorption [1]
2. Immune system modulation [1]
3. Regulation of up to 2,000 genes involved in various biological processes [1] – more details below
4. Potential cancer prevention [1]
 
THE SUNLIGHT PARADOX: HEALTH BENEFITS VS. RISKS

Benefits of sunlight exposure
1. Vitamin D production (80-90%) [1]
2. Regulation of circadian rhythms and improved sleep quality [1]
3. Mood enhancement and potential alleviation of depressive symptoms [1]
4. Lowering of blood pressure through nitric oxide production in the skin [1]

Risks of excessive sun exposure
1. DNA damage, including the formation of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) [2]
2. Oxidative stress and generation of reactive oxygen species (ROS) [2]
3. Premature skin aging and hyperpigmentation [2]
4. Increased risk of skin cancers, including melanoma [2]
 
Health benefits of vitamin D
1. Bone health: Promotes calcium absorption and bone mineralization, preventing conditions like rickets and osteoporosis [3]
2. Muscle strength and function: Helps maintain muscle strength and reduce the risk of falls, especially in older adults [4]
3. Immune system support: Modulates immune responses and may reduce the risk of autoimmune diseases [5]
4. Heart health: Low vitamin D levels have been linked to increased risk of heart diseases, though the exact relationship is unclear [6]
5. Reduced risk of severe illnesses: May make severe flu and COVID-19 infections less likely [7]
6. Mood regulation: May play a role in regulating mood and decreasing the risk of depression [8]
7. Weight management: There is a relationship between (low) vitamin D levels and (over)weight, though the exact nature is not fully understood [9]
8. Reduced risk of multiple sclerosis (MS): Low levels of vitamin D are linked with an increased risk of MS [10]
9. Brain health: Supports brain cell activity and may have neuroprotective properties 
10. Anti-inflammatory effects: Has anti-inflammatory properties that support overall health 

Skin health and beauty benefits of Vitamin D
1. Skin barrier function: Regulates the generation of keratinocytes, which are critical for maintaining the skin barrier [11]
2. Skin immunity: Indispensable for the activation of immune cells in the skin, supporting its protective function [12]
3. Antimicrobial effects: Has direct antimicrobial effects in the skin, helping to fight off pathogens [13]
4. Regulation of sebaceous glands: Important for growth regulation and optimum functioning of sebaceous glands [14]
5. Photoprotective effects: Topical application may offer some protection against UV-induced skin damage [15]
6. Wound healing: Promotes repair of damaged tissue and restoration of the skin's barrier mechanism [16]
7. Anti-aging effects: May have antiaging effects on the skin, though more research is needed in this area [17]
8. Skin cell differentiation and growth: Plays a role in the proliferation and differentiation of skin cells [18]
9. Melanin regulation: Protects the epidermal melanin unit and restores melanocyte integrity [19]
10. Potential role in skin conditions: May play a role in managing conditions like psoriasis, atopic dermatitis, and vitiligo [20]
11. Skin hydration: Topical application of vitamin D improves skin hydration and symptoms of dry skin [21]

VITAMIN D AND PARP
A study published in the International Journal of Molecular Medicine demonstrated that the active form of vitamin D inhibits poly(adenosine diphosphate-ribose) polymerase (PARP). PARP is an enzyme that plays a crucial role in DNA repair. PARP acts like a cellular "first responder" for DNA damage, initiating the repair process to keep our genetic material intact.

1. Function: PARP detects and helps repair damaged DNA in cells.
2. Mechanism: When DNA is damaged, PARP attaches to the damaged site and creates a signal (called PAR chains) to attract other repair proteins.
3. Energy use: PARP uses NAD+ (a cellular energy molecule) to create these signals.
4. Importance: PARP helps maintain genetic stability and cell survival.
5. Cancer connection: Some cancer cells rely heavily on PARP for survival, which is why PARP inhibitors are used as cancer treatments.​

VITAMIN D SYNTHESIS IN THE SKIN 
When UVB rays from sunlight hit the skin, they trigger the production of vitamin D [22]:
 
1. UVB radiation converts 7-dehydrocholesterol in the skin to previtamin D3
2. Previtamin D3 then isomerizes to vitamin D3
3. Vitamin D3 is transported to the liver and converted to 25-hydroxyvitamin D [25(OH)D] 
4. Finally, 25(OH)D is converted to the active form, 1,25-dihydroxyvitamin D (calcitriol), in the kidneys 
 
FACTORS INFLUENCING VITAMIN D PRODUCTION
1. Latitude: Higher latitudes receive less UVB radiation, especially during winter months [23]
2. Time of day: UVB rays are strongest at solar noon [23]
3. Season: Vitamin D production is lower in winter due to reduced UVB radiation [23]
4. Skin pigmentation: Darker skin requires longer sun exposure to produce the same amount of vitamin D as lighter skin [24]
5. Age: Older adults produce less vitamin D from sun exposure [23]
6. Sunscreen use: High SPF sunscreens can significantly reduce vitamin D production [25]
7. Air pollution: Reducing UVB radiation reaching the earth's surface

EPIGENETICS
Vitamin D regulates up to 2000 genes, involving both direct genomic effects and epigenetic mechanisms. 
1. Vitamin D receptor (VDR) binding
The active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], binds to the vitamin D receptor (VDR). This liganded VDR then forms a heterodimer with the retinoid X receptor (RXR) [26][27].
2. Direct gene regulation
The VDR/RXR complex binds to specific DNA sequences called vitamin D response elements (VDREs). These VDREs can be located in promoter regions, introns, or even far from the transcription start sites of target genes [26][27][28].
3. Epigenetic mechanisms

• Vitamin D signaling involves epigenetic modifications, including changes in DNA methylation and histone modifications [26][29].
• The VDR protein interacts with chromatin modifiers and remodelers, influencing the epigenetic landscape [26].
• Liganded VDR can regulate the expression of several chromatin modifiers and remodelers [26].

4. Coregulatory proteins
VDR interacts with numerous coregulatory proteins that can either activate or repress gene transcription [26][28].
5. Genome-wide effects
Genome-wide studies have shown that VDR can bind to hundreds of genomic loci, regulating gene activity at various locations, including many kilobases upstream or downstream of transcription start sites [26][28].
6. Primary and secondary target genes
Vitamin D regulates both primary target genes (directly controlled by VDR) and secondary target genes (controlled by transcriptional regulators encoded by primary targets) [26][30].
7. Cell-specific regulation
The effects of vitamin D on gene expression are highly cell-specific, depending on the epigenetic landscape of each cell type [26][31].
8. Dose-dependent effects
Higher doses of vitamin D supplementation have been shown to affect the expression of more genes in a dose-dependent manner [32].
 
RECOMMENDATIONS FOR SUN EXPOSURE 
Factors such as latitude, season, cloud cover, and individual skin type can all affect vitamin D synthesis [33][34]. Additionally, morning and evening sun contains less UVB radiation, which is necessary for vitamin D production, so longer exposure times may be needed [34]. Health experts often recommend midday sun exposure for optimal vitamin D production, while dermatologists typically advise against it due to increased UV intensity. 
 
Considerations
1. Midday sun (higher UVB) is more efficient for vitamin D production, requiring shorter exposure times [35]
2. Shorter exposure times may reduce overall UV damage risk [35]
3. Individual factors, such as skin type and location, should be considered when making recommendations [35]
 
Impact of skin type
Darker skin requires longer exposure times due to higher melanin content [1][36]

• For 1000 IU/day, average annual estimated times:

          Type I: 5.05 minutes
          Type VI: 25.25 minutes [37]

• Fair: 30 minutes of summer sun exposure in a bathing suit can produce 50,000 IU of vitamin D within 24 hours [38] 
• Tan: Same exposure produces 20,000–30,000 IU of vitamin D [38] 
• Dark: Same exposure produces only 8,000–10,000 IU of vitamin D [38] 

Recommendation fair skin (Fitzpatrick Types I-III)

1. Aim for 10-15 minutes of sun exposure to arms, legs, and torso 2-3 times per week during spring and summer months [3]. Wear sunscreen on face, neck and décolletage. 
2. This may need to be increased to 30-40 minutes if the sun is less intense, or in shadow (less UVB)
3. Expose approximately 25% of your body surface area (e.g., arms and legs) [39]
4. Avoid peak UV hours (10 am to 4 pm) to minimize skin damage risk [39]
5. Or 3 minutes during peak hours with 25% of body exposed (summer)
6. Winter: 45-60 minutes of morning or late afternoon sun with 25% of body exposed, or 23 minutes at noon with 25% of body exposed, or 2-3 hours if only 5% of body is exposed due to cold weather

 
Recommendation darker skin (Fitzpatrick Types IV-VI)
1. Longer sun exposure times are needed, typically 15-30 minutes 3-5 times per week [40]
2. Consider exposing larger body surface areas when possible [40]
3. Sun exposure during midday hours may be more effective for vitamin D production [35]
 
Variations based on location and season

• In Tsukuba, Japan at noon in July: 3.5 minutes of solar exposure to produce 5.5 μg vitamin D3 per 600 cm2 skin
• ​In Sapporo, Japan in December at noon: 76.4 minutes for the same amount [41]
• 9:00 AM in December in Tsukuba (36°N latitude), it took 106.0 minutes to produce 5.5 μg of vitamin D3 per 600 cm2 of skin, compared to 22.4 minutes at noon under the same conditions  [41]

This illustrates the significant difference in vitamin D production efficiency between midday and morning/evening sun exposure. 
  
Sunscreen and vitamin D production
Sunscreen can decrease vitamin D3 formation in the skin. The effect varies based on coverage, thickness, and SPF. [36] Nevertheless, I would highly recommend the always use sunscreen on face, neck and décolletage as and expose skin surface areas to sunlight in the shortest amount possible to minimise DNA damage and the risk of sunburn and skin cancer.  [1][36]
 
ALTERNATIVE STRATEGIES FOR VITAMIN D SUFFICIENCY
For many people, especially those living at higher latitudes, with darker skin, or those unable to obtain adequate sun exposure, or at high risk for skin damage, vitamin D supplementation may be necessary to maintain optimal levels, particularly during winter months [33][42]. However, excessive vitamin D3 levels can have negative health effects.

1. Dietary sources: Fatty fish, egg yolks, and fortified foods
2. Vitamin D3 supplements: The recommended dose is 1000 units per 25 pounds bodyweight (>4000 IU or 100 micrograms only under medical supervision) and taken alongside vitamin K2 and magnesium for a synergistic effect. Best is to take it in the morning in line with circadian rhythms. Consult with a healthcare provider for appropriate dosage and monitor your levels.
3. UVB lamps: Under medical supervision, these can be used for controlled vitamin D production.
 
​For the average adult a range of 30-50 ng/mL (75-125 nmol/L) is seen as optimal, 50 ng/mL (125 nmol/L) may be too high and below 20 ng/mL (50 nmol/L) are generally considered deficient. Achieving optimal vitamin D levels while protecting skin health requires a personalised approach. I hope that the information provided will help you to navigate the delicate balance between sun exposure benefits, risks and the use of sunscreens. Always consult a healthcare professional, especially if you have a history of skin cancer or are at risk for vitamin D deficiency.
 
Take care

Anne-Marie

References
[1] Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr. 2004
[2] Cadet J, Douki T. Formation of UV-induced DNA damage contributing to skin cancer development. Photochem Photobiol Sci. 2018
[3] Holick MF. Vitamin D deficiency. N Engl J Med. 2007
[4] Bischoff-Ferrari HA et al. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Archives of Internal Medicine. 2009
[5] Prietl B et al. Vitamin D and immune function. Nutrients. 2013
[6] Wang TJ et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation. 2008
[7] Martineau AR et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017
[8] Anglin RE et al. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. British Journal of Psychiatry. 2013
[9] Vimaleswaran KS et al. Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Medicine. 2013
[10]  Munger KL et al. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006
[11]  Bikle DD. Vitamin D metabolism and function in the skin. Molecular and Cellular Endocrinology. 2011
[12]  Schauber J. et al.  Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D–dependent mechanism. Journal of Clinical Investigation. 2007
[13] Liu PT et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006
[14] Krämer C et al. Characterization of the vitamin D endocrine system in human sebocytes in vitro. Journal of Steroid Biochemistry and Molecular Biology. 2009
[15]  Dixon KM, Deo SS, Wong G, Slater M, Norman AW, Bishop JE, Posner GH, Ishizuka S, Halliday GM, Reeve VE, Mason RS. Skin cancer prevention: a possible role of 1,25dihydroxyvitamin D3 and its analogs. Journal of Steroid Biochemistry and Molecular Biology. 2005
[16] Oda Y, Uchida Y, Moradian S, Crumrine D, Elias PM, Bikle DD. Vitamin D receptor and coactivators SRC2 and 3 regulate epidermis-specific sphingolipid production and permeability barrier formation. Journal of Investigative Dermatology. 2009
[17]  Rinnerthaler M, Bischof J, Streubel MK, Trost A, Richter K. Oxidative stress in aging human skin. Biomolecules. 2015
[18]  Bikle DD. Vitamin D regulated keratinocyte differentiation. Journal of Cellular Biochemistry. 2004
[19] Ranson M, Posen S, Mason RS. Human melanocytes as a target tissue for hormones: in vitro studies with 1α-25, dihydroxyvitamin D3, α-melanocyte stimulating hormone, and beta-estradiol. Journal of Investigative Dermatology. 1988
[20]  Mostafa WZ, Hegazy RA. Vitamin D and the skin: Focus on a complex relationship: A review. Journal of Advanced Research. 2015
[21]  Russell M. Assessing the relationship between vitamin D3 and stratum corneum hydration for the treatment of xerotic skin. Nutrients. 2012
[22] Wacker M, Holick MF. Vitamin D - effects on skeletal and extraskeletal health and the need for supplementation. Nutrients. 2013
[23] Webb AR, Engelsen O. Calculated ultraviolet exposure levels for a healthy vitamin D status. Photochem Photobiol. 2006
[24] Farrar MD, et al. Efficacy of a dose range of simulated sunlight exposures in raising vitamin D status in South Asian adults: implications for targeted guidance on sun exposure. Am J Clin Nutr. 2013
[25] Matsuoka LY, et al. Sunscreens suppress cutaneous vitamin D3 synthesis. J Clin Endocrinol Metab. 1987
[26] Fetahu IS, Höbaus J, Kállay E. Vitamin D and the epigenome. Front Physiol. 2014 
[27] Carlberg C. Vitamin D and Its Target Genes. Nutrients. 2022 
[28] Christakos S et al. Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects. Physiol Rev. 2016 
[29] Voltan G et al. Vitamin D: An Overview of Gene Regulation, Ranging from Metabolism to Genomic Effects. Genes (Basel). 2023
[30] Veijo Nurminen et al. Front. Physiol., 05 March 2019 Sec. Integrative Physiology Primary Vitamin D Target Genes of Human Monocytes
[31] Vassil Dimitrov et al. Vitamin D-regulated Gene Expression Profiles: Species-specificity and Cell-specific Effects on Metabolism and Immunity, Endocrinology, Volume 162, Issue 2, February 2021
[32] GrassrootsmHealth Nutrient Research Institute. Vitamin D Supplementation Amount Influences Change in Genetic Expression. [Internet]. 2018
[33] Wacker M, Holick MF. Sunlight and Vitamin D: A global perspective for health. Dermatoendocrinol. 2013 
[34] Nagaria TD et al. The Sunlight-Vitamin D Connection: Implications for Patient Outcomes in the Surgical Intensive Care Unit. Cureus. 2023 
[35] Rhodes LE, et al. Recommended summer sunlight exposure levels can produce sufficient (≥20 ng ml(-1)) but not the proposed optimal (≥32 ng ml(-1)) 25(OH)D levels at UK latitudes. J Invest Dermatol. 2010
[36] Ashley, R. (n.d.). Ask the Doctors - How much sunshine do I need for enough vitamin D? UCLA Health.
[37] Yilmaz, B., & Karakas, M. (2024). UV index-based model for predicting synthesis of (pre-)vitamin D3 in human skin. Scientific Reports, 14(1), 3188.
[38] Mead MN. Benefits of sunlight: a bright spot for human health. Environ Health Perspect. 2008 
[39] American Academy of Dermatology. Sunscreen FAQs. 
[40] Farrar MD, et al. Efficacy of a dose range of simulated sunlight exposures in raising vitamin D status in South Asian adults: implications for targeted guidance on sun exposure. Am J Clin Nutr. 2013
[41] Miyauchi, M., & Nakajima, H. (2016). The solar exposure time required for vitamin D3 synthesis in the human body estimated by numerical simulation and observation in Japan. Journal of nutritional science and vitaminology, 62(5), 379-385.
[42] Healthline How to Safely Get Vitamin D From Sunlight Ryan Raman, MS, RD — Updated on April 4, 2023