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3/20/2024 Comments Telomeres: tiny caps with big impact
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
This consequently affects both health and beauty
FACTORS INFLUENCING TELOMERE SHORTENING Sleep quality Poor sleep quality significantly impacts telomere length:
INTERVENTIONS FOR TELOMERE PRESERVATION 1. Possible strategies to preserve telomere length
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:
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]
A study showed that diet, exercise, stress management, and social support could increase telomere length by approximately 10% over five years [20].
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
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].
RNAi technology in development RNAi-based skincare approaches could target genes involved in telomere maintenance or have effects on markers related to telomere biology:
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.
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
Comments
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]:
Mechanisms of skin cell senescence:
The presence of senescent cells accelerates the ageing process due to their communication with nearby cells through various molecules: [18]
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]
Skin care ingredients: [18]
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
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.
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
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]
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
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
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]
Effective homeodynamic space or buffering capacity (body's ability to maintain stability or balance in changing conditions) is characterized by:
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:
Hormetins can be categorized into three types:
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
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:
These epigenetic mechanisms can significantly impact hair biology
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
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)
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
3/3/2024 Comments The vitamin D dilemma
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.
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
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]
Type VI: 25.25 minutes [37]
Recommendation fair skin (Fitzpatrick Types I-III)
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
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 Our DNA faces thousands of damages daily, with sunlight being a major culprit. UVA, UVB, and High Energy Visible Light (HEVIS) harm our genetic material in different ways. These various types of DNA damage require diverse mechanisms for repair to maintain genomic integrity and prevent mutations that could lead to skin cancer and premature aging. This video explains (oversimplified) the key mechanisms of DNA damage by UVB, UVA and Hight Energy Visible Light (HEVIS) or Blue Light and repair.
UVA radiation (315-400 nm) causes damage primarily through indirect mechanisms: ▌ Photosensitization: Generates reactive oxygen species (ROS) via interaction with endogenous photosensitizers ▌ Oxidative stress: Leads to oxidative DNA damage, particularly 8-oxo-7,8-dihydroguanine (8-oxoG) lesions ▌ Indirect cyclobutane pyrimidine dimer (CPD) formation: Less efficient than UVB ▌ Direct DNA damage: Forms CPDs, especially at TT sequences ▌ DNA strand breaks: Both single-strand and double-strand breaks can occur ▌ Genomic instability: Long-term consequence of UVA exposure UVB radiation (280-315 nm) causes damage primarily through direct absorption by DNA: ▌ Direct CPD formation: Most abundant UVB-induced lesion ▌ 6-4 photoproduct (6-4PP) formation: Second most common UVB-induced lesion ▌ Dewar valence isomer generation: Derived from 6-4PPs upon further UVB exposure ▌ Oxidative DNA damage: Less prominent than with UVA ▌ DNA-protein crosslinks: Between DNA and nearby proteins ▌ Single-strand breaks: Can occur due to UVB exposure ▌ Pyrimidine hydrates: Minor UVB-induced lesions Blue light or HEVIS (400-700 nm) causes damage through mechanisms similar to UVA: ▌ Photosensitization: Generates ROS via interaction with endogenous photosensitizers ▌ Oxidative stress: Leads to oxidative DNA damage, particularly 8-oxoG lesions ▌ Mitochondrial DNA damage: Can lead to mitochondrial dysfunction ▌ Indirect CPD formation: Less efficient than UVA or UVB ▌ Single-strand DNA breaks: Caused by ROS-induced oxidative damage ▌ Lipid peroxidation: Indirectly affects DNA integrity ▌ Protein oxidation: Can damage DNA repair enzymes Take care Anne-Marie 
Our DNA faces a staggering number of damaging events each day. Estimates suggest that each cell in our body endures approximately 70,000 DNA lesions [1] up to 100.000 per day [2][3]. While this number includes all types of DNA damage, sunlight remains a major culprit, especially for skin cells, which may experience even higher rates of DNA damage. Oxidative stress, another significant contributor, is estimated to cause about 10,000 DNA lesions per cell per day [1][3].
Frequency types of DNA damage: [3] ▌Oxidative damage: 10,000 to 11,500 incidents per cell per day in humans ▌Depurinations: 2,000 to 10,000 per cell per day in mammalian cells ▌Single-strand breaks: About 55,200 per cell per day in mammalian cells ▌Double-strand breaks: 10 to 50 per cell cycle in human cells Factors influencing DNA damage and rates: [4] ▌Environmental factors: UV-radiation, pollution and lifestyle choices (e.g., smoking) can increase oxidative stress ▌Frequency of exposure: repeated UV exposure can overwhelm repair mechanisms ▌Age: DNA repair efficiency declines with age ▌Skin phototype: individuals with fair skin are more susceptible to UV-induced damage ▌Cell type and location in the body ▌Individual factors: like genetics and epigenetics SUNLIGHT INDUCED DNA DAMAGE UVA, UVB, and High Energy Visible Light (HEVIS) harm our genetic material in different ways. UVA makes up the majority of UV radiation reaching the Earth's surface, and both UVA and blue light are used in artificial UV exposure settings [5][6]. 50% of the damaging oxidative stress in human skin is generated in the VIS spectrum and the other 50% by UV light [7]. UVB-Induced DNA damage UVB (280-315 nm) is generally considered the most harmful due to its higher energy content and efficient absorption by DNA [6], and is known to directly interact with DNA, primarily causing the formation of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) [8]. These lesions can distort the DNA helix, potentially leading to mutations if left unrepaired. ▌Direct formation of cyclobutane pyrimidine dimers (CPDs): Most abundant UVB-induced lesion, formed between adjacent pyrimidines [6][5] ▌Formation of 6-4 photoproducts (6-4PPs): Second most common UVB-induced lesion [6][5] ▌Generation of Dewar valence isomers: Derived from 6-4PPs upon further UVB exposure [6] ▌Oxidative DNA damage: Through generation of reactive oxygen species (ROS), though less prominent than with UVA [9][10] ▌DNA-protein crosslinks: Formed between DNA and nearby proteins [6] ▌Single-strand breaks: Can occur as a result of UVB exposure [11] ▌Pyrimidine hydrates: Minor UVB-induced lesions [12] ▌Oxidative DNA-lesions, such as 8-oxodeoxyguanosine, when they are in proximity or on opposite DNA-strands, may generate double-strand breaks [5] UVB radiation is considered more genotoxic than UVA due to its direct absorption by DNA and efficient formation of mutagenic CPDs and 6-4PPs. However, both UVA and UVB contribute to solar UV-induced DNA damage and mutagenesis. UVA-Induced DNA damage UVA-induced (315-400 nm) DNA damage occurs through various mechanisms, primarily involving indirect effects but also some direct damage. ▌Photosensitization: Interaction with endogenous photosensitizers like riboflavin and porphyrins, leading to reactive oxygen species (ROS) generation [13] ▌Oxidative stress: ROS-induced oxidative DNA damage, with 8-oxo-7,8-dihydroguanine (8-oxoG) as a primary lesion [13][6][5] ▌Indirect cyclobutane pyrimidine dimer (CPD) formation: Through photosensitized triplet energy transfer, less efficient than UVB [13] ▌Direct DNA damage: Formation of CPDs, particularly at TT sequences [5][6] ▌Genomic instability [6] ▌Single-strand and double-strand DNA breaks [6][14] UVA-induced DNA double-strand breaks result from the repair of clustered oxidative DNA damages [6]. This means UVA doesn't directly cause DSBs, but rather creates oxidative damage that can lead to DSBs during the repair process. While UVA was originally not expected to induce DSBs due to its relatively low photonic energy, several studies have shown that UVA can induce DSBs in a replication-independent manner [6]. Oxidative DNA-lesions, such as 8-oxodeoxyguanosine, when they are in proximity or on opposite DNA-strands, may generate double-strand breaks [5]. Blue Light (HEViS)-induced DNA damage Blue light or high-energy visible light (HEVIS)-induced (400-700 nm) DNA damage occurs through mechanisms similar to UVA, primarily involving indirect effects mediated by reactive oxygen species (ROS). ▌Photosensitization: Interaction with endogenous photosensitizers like riboflavin and porphyrins, leading to ROS generation [15] ▌Oxidative stress: ROS-induced oxidative DNA damage, with 8-oxo-7,8-dihydroguanine (8-oxoG) as a primary lesion [5][16][17] ▌Mitochondrial DNA damage: Blue light can penetrate into cells and damage mitochondrial DNA, leading to mitochondrial dysfunction [6] ▌Indirect formation of cyclobutane pyrimidine dimers (CPDs): Through photosensitized triplet energy transfer, though less efficient than UVA or UVB [5][18] ▌Single-strand DNA breaks: Caused by ROS-induced oxidative damage [19] ▌Lipid peroxidation: ROS-induced damage to cellular membranes, indirectly affecting DNA integrity [20] ▌Protein oxidation: Damage to DNA repair enzymes and other proteins involved in maintaining genomic stability [21] ▌Chromosome aberrations (clastogenic/aneugenic effects) [5] ▌DNA double-strand breaks (DSBs), through indirect mechanisms Double-Strand Breaks (DSBs) While DSBs are less common than other types of UV-induced DNA damage, they are particularly dangerous because they affect both strands of the DNA helix and can lead to genomic instability if not properly repaired [14][22]. ▌UVA-induced DSBs: These often result from the repair of clustered oxidative DNA lesions. When repair enzymes attempt to fix closely spaced lesions on opposite strands simultaneously, it can lead to DSBs [6]. Some studies have found that UVA radiation can induce DSBs, particularly through oxidative stress mechanisms [6][23]. Other research suggests that UVA alone may not directly cause significant DSB formation or activate certain DNA damage response pathways associated with DSBs [24] ▌UVB-induced DSBs: UVB can cause DNA double-strand breaks. These can occur directly or as a result of replication fork collapse at sites of unrepaired lesions [22][25] ▌ROS-induced DSBs: UVA, UVB and Blue Light can generate reactive oxygen species (ROS), which can cause various types of DNA damage, including DSBs [5][6][14][23] The dose and wavelength of UV radiation can influence the types and extent of DNA damage, including DSB formation [25][26]. Cellular specificity of DNA damage Different skin cell types exhibit varying susceptibilities to DNA damage: 1. Keratinocytes: Most numerous and most exposed, they bear the brunt of UV-induced CPDs [6]. Blue light has been shown to cause DNA damage in human keratinocytes, potentially contributing to premature skin aging [5] 2. Melanocytes: Particularly vulnerable to oxidative damage due to melanin production [27] 3. Fibroblasts: While less directly exposed, they can accumulate damage over time, contributing to photoaging [27] Mitochondria, the powerhouses of the cell, have their own DNA and are particularly susceptible to DNA damage due to their proximity to reactive oxygen species (ROS) production. While oxidative stress in mitochondria can lead to damage, a certain level of ROS is actually necessary for proper cellular signaling and adaptation. Other types of DNA damage Beyond UV-induced damage, our DNA faces threats from various sources: 1. Hydrolytic Damage: Spontaneous hydrolysis can lead to depurination and depyrimidination [1] 2. Alkylation: Endogenous and exogenous alkylating agents can modify DNA bases [1] 3. Mismatch Errors: During DNA replication, incorrect nucleotides may be incorporated [1] MECHANISMS OF DNA REPAIR Cells have sophisticated DNA repair mechanisms, however, some damage may escape repair, potentially leading to mutations or cellular dysfunction over time. 1. Nucleotide Excision Repair (NER): ▌Primary mechanism for repairing UV-induced DNA damage, particularly cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs)[25][28][29] ▌Involves recognition of DNA distortion, excision of the damaged segment, and synthesis of new DNA to fill the gap [30]. 2. Base Excision Repair (BER): ▌Repairs oxidative DNA damage caused by UVA and HEViS-induced reactive oxygen species (ROS) [30][31] ▌Involves removal of damaged bases (including oxidative lesions like 8-oxoG [29], creation of an apurinic/apyrimidinic (AP) site, and DNA synthesis to fill the gap [29][30] 3. Homologous Recombination Repair (HRR): ▌Repairs double-strand breaks that can result from UV exposure, particularly during DNA replication [32] ▌Uses an undamaged DNA template (usually a sister chromatid) to accurately repair the break [32] 4. Mismatch Repair (MMR): ▌Corrects errors in DNA replication that result in mismatched base pairs and small insertion/deletion loops [29][30][33] ▌Important for maintaining genomic stability and preventing mutations [30] 5. Double-Strand Break Repair: Includes homologous recombination and non-homologous end joining [29] 6. Non-Homologous End Joining (NHEJ): [32] ▌An alternative mechanism for repairing double-strand breaks ▌Directly ligates broken DNA ends without the need for a homologous template NER is particularly crucial for UV-induced damage, while the repair of oxidative lesions through BER can be challenging due to the persistent nature of oxidative stress. Additionally, research has highlighted the role of the AMPK pathway in promoting UVB-induced DNA repair by increasing the expression of XPC, a key protein in the NER pathway [28]. OTHER DNA REPAIR MECHANISMS In addition to the mechanisms primarily responsible for repairing sunlight-induced damage, our bodies have several other DNA repair pathways: 1. Direct Reversal Repair: ▌Includes mechanisms like O6-methylguanine-DNA methyltransferase (MGMT), which directly removes alkyl groups from guanine bases [25] 2. Translesion Synthesis (TLS): ▌Not a repair mechanism per se, but allows DNA replication to bypass damaged sites [30] ▌Can be error-prone but prevents replication fork collapse and more severe DNA damage [30] 3. Interstrand Crosslink Repair: ▌Repairs covalent links between DNA strands that can block replication and transcription [30] ▌Involves a complex interplay of multiple repair pathways, including NER and homologous recombination [30] 4. Single-Strand Break Repair: ▌Repairs breaks in one strand of the DNA double helix [30] ▌Often involves components of the BER pathway [30] These repair mechanisms often work in concert, and there can be significant overlap and interaction between different pathways. The choice of repair mechanism depends on factors such as the type of damage, the cell cycle stage, and the availability of repair proteins [28][30]. CONSEQUENCES OF UNREPAIRED DNA DAMAGE When DNA repair mechanisms fail or are overwhelmed, several outcomes can occur: 1. Skin Aging: Accumulation of damage in epidermal keratinocytes and dermal fibroblasts leads to reduced collagen production and elastin degradation [34] 2. Hyperpigmentation: DNA damage in melanocytes can trigger increased melanin production [34] 3. Skin Cancer: Mutations in key genes like p53 can lead to uncontrolled cell growth [34] CORRELATION INCREASE DAMAGE, INCREASED RISK OF PREMATURE AGING & CANCER While a large amount of DNA damage does increase the workload on repair mechanisms and can potentially lead to more errors, it's not a simple direct relationship. The body has multiple layers of protection, including cell death pathways for severely damaged cells. The balance between efficient repair, controlled cell death, and mutation accumulation is crucial in determining outcomes related to cancer and aging. Both cancer and aging are complex, multifactorial processes influenced by many factors beyond DNA damage and repair. 1. DNA damage accumulation and cancer/aging risk ▌DNA damage does accumulate over time in cells, with estimates of 10,000 to 100,000 DNA lesions per cell per day [3] ▌This accumulated damage, if not properly repaired, ca n lead to mutations that contribute to both cancer development and aging [35][36] 2. DNA repair and mutation risk ▌While DNA repair mechanisms are generally beneficial, they are not perfect and can occasionally introduce errors [30] ▌High levels of DNA damage can overwhelm repair systems, potentially leading to more errors during the repair process [37] 3. Connection to cancer and premature aging ▌Defects in DNA repair pathways are associated with increased cancer risk and premature aging syndromes [37][38] ▌Some inherited mutations in DNA repair genes (like POLE/POLD1) can lead to higher mutation rates and increased cancer risk, though not necessarily premature aging in all aspects [36] 4. Balance between repair and consequences ▌There's a delicate balance between DNA repair, cell death, and mutation accumulation [38] ▌Excessive DNA damage can lead to increased cell death and stem cell exhaustion, potentially promoting premature aging [38] ▌However, if mutations accumulate without triggering cell death, this can increase cancer risk [38] 5. Stem cell considerations ▌Stem cells have special mechanisms to maintain low mutation rates, but when mutations do occur, clonal expansion can contribute to both aging and cancer risk [38] PREVENTION AND SUPPORT OF DNA REPAIR 1. Sun Protection: Broad-spectrum sunscreens (preferably including blue light protection), protective clothing, and avoiding peak UV hours remain the most effective strategies [39]. 2. Antioxidants: Both topical and oral antioxidants can help combat oxidative stress, though their efficacy in preventing DNA damage is still debated [40]. 3. Glycyrrhetinic Acid (GA): has protective effects against DNA damage and enhances DNA repair mechanisms both topical or as supplement. 3. DNA repair enzymes: Topical applications of enzymes like T4 endonuclease V have shown promise in enhancing repair [39]. 4. Lifestyle factors: Adequate sleep, a balanced diet, and stress management can support overall cellular health and DNA repair processes. 5. Supplements: ▌Vitamin C: Dose: 500 mg [41]. .Vitamin C has been shown to potentially induce nucleotide excision repair (most important for sun damage) through anti-oxidant properties, however in high concentrations may be acting as pro-oxidant. ▌Folic Acid and Vitamin B12: Dose 15 mg folic acid and 1 mg vitamin B12 thrice weekly [42] Folic acid has show promise in markers for genomic instability, but does not significantly affect DNA strand breakage and excess may even increase DNA mutations and affect DNA repair gene expression. Vitamin B12 plays a role in DNA synthesis and methylation, which are important for genomic stability. ▌Selenium (as selenomethionine): Dose: 100 μg/day [43] promising, not conclusive. ▌Zinc: Dose: 22 mg/day Molecular Nutrition & Food Research. A small increase in dietary zinc can reduce oxidative stress and DNA damage as shown by reduced leukocyte DNA strand breaks, however more comprehensive human studies are necessary to be conclusive. ▌Coenzyme Q10: Dose: 100 mg/day Associated with reduced baseline DNA damage [44]. Ubiquinol-10 may enhance DNA resistance to oxidative damage and reducing strand breaks in vitro. Further research is needed to be conclusive. ▌Taurine: Taurine supplementation has been shown to reduce DNA damage in several studies [45][46][47]. In one study, taurine (20 mM) reduced formation of DNA base adducts like 5-OH-uracil, 8-OH adenine, and 8-OH guanine by 21-49% [45]. Taurine (2 g three times daily) decreased DNA damage associated with exercise [49][50]. Taurine suppresses DNA damage and improves survival of mice after oxidative DNA damage [52]. Most studies used doses between 1-6 g per day [51]. A proposed safe level of taurine consumption is 3 g/day [49]. Doses as high as 10 g/day for 6 months have been tested [51]. For exercise benefits, 2 g three times daily was effective [49][50]. Taurine acts as an antioxidant and can protect against oxidative DNA damage [45][46]. It may activate DNA repair pathways involving p53 [48][53]. Taurine deficiency is associated with increased DNA damage and cellular senescence [52]. ▌ Magnesium: Plays a crucial role in DNA repair and recommended dose varies by gender and age. Magnesium Malate and Citrate or Orotate are good for energy, while Glycinate and Threonate have an additional bonus as both support sleep quality, DNA repair processes are influenced by circadian rhythms and more active overnight. Sleep enhances the repair over double-strand breaks. Dark chocolate and deep green vegetables contain Magnesium. The studies cited come mostly from reputable peer-reviewed journals. Supplements have shown benefits in specific studies, their effects may vary depending on individual factors, correct dose and overall health status. Always consult with a healthcare professional before starting any new supplement regimen. PARP (Poly ADP-ribose polymerase) plays a crucial role in DNA repair, particularly in the base excision repair (BER) pathway. PARP acts like a cellular "first responder" for DNA damage, initiating the repair process to keep our genetic material intact. 1. DNA damage sensing: PARP1, the most abundant PARP enzyme, acts as a DNA damage sensor, quickly binding to single-strand breaks (SSBs) in DNA [54][55]. 2. Recruitment of repair factors: Once bound to damaged DNA, PARP1 catalyzes the synthesis of poly(ADP-ribose) (PAR) chains on various proteins, including itself. This PARylation helps recruit other DNA repair factors to the site of damage [54][56]. 3. Base Excision Repair (BER): PARP is a key component of the BER complex, which also includes DNA ligase III, DNA polymerase beta, and the XRCC1 protein [55]. 4. Chromatin relaxation: PARylation of histones by PARP leads to chromatin relaxation, allowing better access for repair enzymes to the damaged DNA [55][56]. This is moreover an epigenetic mechanism. 5. Regulation of other repair pathways: PARP is also involved in other DNA repair pathways, including nucleotide excision repair (NER) and double-strand break repair [55][56]. Boosting PARP activity for enhanced DNA repair: 1. Raising NAD+ levels: PARP activation will decrease NAD+ levels. Increasing NAD+ levels through precursors like nicotinamide riboside or nicotinamide mononucleotide might support PARP activity [57], especially in response to oxidative stress and DNA damage [58][59]. .Although NMN supplementation does raise NAD+ levels and it´s health benefits are hyped by longevity experts, some scientists are skeptical as they find the data in humans not very convincing to date, with minor benefits for unhealthy and older volunteers in 14 publications. Fact is that NAD+ levels decrease as we age as a result of declining levels or activity of the NAD+ recycling enzyme NAMPT in the biosynthetic salvage pathway and other NAD+ consuming enzymes like CD38 and as mentioned before PARPs. 1. Lifestyle factors: Regular exercise and calorie restriction have been shown to increase NAD+ levels, which could indirectly support PARP function [57]. Both aerobic and resistance exercise have been shown to increase NMAPT levels, reversing age related declines [66][61]. 2. Avoiding PARP inhibitors: Certain medications and supplements (interestingly these include polyphenols like resveratrol, favonoids and Vitamin D) can inhibit PARP activity [62]. Avoiding these could help maintain normal PARP function, although PARP inhibition can also have significant therapeutic benefits too. 3. Managing oxidative stress: Reducing oxidative stress through antioxidant-rich diets and lifestyle modifications may help preserve PARP function, as excessive oxidative damage can lead to PARP overactivation and subsequent depletion [56]. VITAMIN D The biggest benefit of sunlight for humans, next to enhancing our mood, is that sunlight is the primary source of vitamin D3 synthesis for most people. UVB radiation (290-315 nm) converts 7-dehydrocholesterol in the skin to previtamin D3, which then isomerizes to vitamin D3 [1]. Click here to read more about Vitamin D. A study published in the International Journal of Molecular Medicine demonstrated that the active form of vitamin D inhibits PARP. The most effective protection against UV-induced DNA damage is avoiding excessive sun exposure and using protective clothing. Sunscreens help, however their efficacy depends on the formula, applied amount, distribution evenness and reapplication. Some research is exploring the topical delivery of repair enzymes [39], while the efficacy of Glycyrrhetinic Acid to enhance DNA repair is well established. Always consult a qualified healthcare professional to determine what the most suitable approach is for your health and beauty goals. Take care Anne-Marie
References
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Pyrroloquinoline quinone (PQQ), by some called "the fourteenth vitamin", also known as methoxatin deserves a full blog post due to its health & beauty benefits. PQQ, discovered in 1979, is an aromatic tricyclic o-quinone, a small quinone molecule, naturally found in various foods (Kumazawa et al., 1995; Mitchell et al., 1999), and plays a crucial role in various biological processes, particularly in cellular energy production and antioxidant defence [1].
Chemical structure and properties PQQ is water-soluble and it´s molecular formula is C14H6N2O8 - see picture. It is structurally similar to other quinones, like for example Coenzyme Q10, however possesses unique redox (oxidation reduction) properties that contribute to its biological activities [1]. PQQ is highly stable and efficient in redox cycling, can undergo multiple redox cycles, allowing it to participate in numerous biochemical reactions with various compounds. It does not easily self-oxidize or condense into inactive forms [2]. When compared on a molar basis, PQQ can be 100 to 1000 times more efficient in redox cycling assays than other enediols, such as ascorbic acid (vitamin C) and menadione, as well as many isoflavonoids, phytoalexins and polyphenolic compounds [2]. The reduced form of PQQ (PQQH2) can act as an aroxyl radical scavenger, even more effectively than α-tocopherol against peroxyl radicals [2]. Peroxyl radicals (ROO•) are involved in lipid peroxidation and contribute oxidative stress in biological systems, potentially damaging DNA, proteins, and lipids. 
PQQ is thus an exceptionally potent antioxidant: [3]
▌Direct scavenging of reactive oxygen species (ROS) ▌Regeneration of other antioxidants like vitamin E ▌Induction of antioxidant enzymes such as superoxide dismutase and catalase [4] Mitochondrial function and biogenesis One of the most significant roles of PQQ is its impact on mitochondrial function and biogenesis. Mitochondria are the powerhouses of cells, responsible for producing the majority of cellular energy in the form of ATP (adenosine triphosphate) [5]. PQQ has been show to
Anti-inflammatory effects PQQ exhibits anti-inflammatory properties, which may contribute to its potential in managing chronic inflammatory conditions: Reduction of inflammatory markers: PQQ has been shown to decrease levels of pro-inflammatory cytokines such as TNF-α and IL-6 [10] Modulation of NF-κB signaling: PQQ can inhibit the activation of NF-κB, a key transcription factor involved in inflammatory responses [11] Neuroprotection PQQ has demonstrated significant neuroprotective effects in various studies, particularly in the areas of cognitive function, protection against neurotoxins, and nerve growth factor (NGF) production.
Metabolic health ▌Glucose metabolism: Some studies suggest that PQQ can enhance insulin sensitivity and glucose tolerance. ▌Lipid metabolism: PQQ has been shown to activate AMPK (AMP-activated protein kinase), a key regulator of energy metabolism and linked to cellular increases in the NAD+/NADH ratio and increased sirtuins expression [16]. Both NAD+ and sirtuins were key topics of David Sinclair´s longevity research. Sirtuins are a family of proteins known to be involved in epigenetic regulation through their deacetylase activity. Sleep quality & quantity Sleep quality and quantity are crucial for overall health and beauty, with experts generally recommending 7-9 hours of sleep daily for adults. Recent research has shown that Pyrroloquinoline quinone (PQQ) can significantly improve sleep quality, offering a promising avenue for those struggling with sleep issues. A clinical trial involving 17 adults who took 20 mg of PQQ daily for eight weeks demonstrated notable improvements in sleep onset, maintenance, and duration. These improvements were measured using two well-established sleep assessment tools: the Oguri-Shirakawa-Azumi Sleep Inventory and the Pittsburgh Sleep Quality Index [9][17]. The study also found a correlation between these improvements and changes in the cortisol awakening response, providing biomarker-supported evidence of enhanced sleep quality. The mechanisms behind PQQ's sleep-enhancing effects are multifaceted:
PQQ is naturally present in various foods, including: ▌Fermented soybeans (natto) ▌Green peppers ▌Kiwi ▌Parsley ▌Tea ▌Papaya ▌Spinach ▌Celery [1] ▌Dark chocolate PQQ can be present in human body, even in breast milk due to diet, because only bacteria can synthesise PQQ. SKIN HEALTH AND BEAUTY Clinical Studies on PQQ in Skincare A clinical study conducted by Dr. Zoe Diana Draelos and colleagues investigated the effects of a topical formulation containing a modified form of PQQ called topical allyl pyrroloquinoline quinone (TAP) on skin aging. on 40 subjects over a 12 week period. The study findings included: ▌Improved skin texture and dullness: Significant improvements were observed in skin texture and dullness after 4 weeks of twice-daily application (both p<0.0001) ▌Reduced appearance of lines and wrinkles: The study reported improvements in the appearance of fine lines and wrinkles (p=0.01) ▌Histological improvements: Histologic evaluation demonstrated reductions in solar elastosis from baseline at 6 weeks (33%, p=0.01) and 12 weeks (60%, p=0.002). ▌Improvements were also noted in skin tone at week 4 (p=0.01). ▌Significantly increased expression of DNA methyltransferase (DNMT3A, DNMT3B), cytochrome oxidase assembly factor-10 (COX10), and tumor protein-53 (TP53) genes (all p<0.05), indicating enhanced support of epidermal homeostasis, renewal, and repair. Increasing or decreasing DNA methyltransferase is considered an epigenetic modification:
▌Increased expression of heat shock protein 60 (HSPD1) and thioredoxin reductase (TXNRD1) occurred in tissues treated with TAP versus control (p<0.05), indicating enhanced antioxidative response and adaptation. Cell senescence PQQ protected human dermal fibroblasts (HDFs) from UVA-induced senescence [22]. This is supported by the study showing that PQQ treatment reduced the percentage of senescent cells stained by X-gal following UVA irradiation compared to the UVA-only group [22]. PQQ has demonstrated significant anti-senescence properties in various studies. In a study using Bmi-1 deficient mice, which exhibit accelerated aging, PQQ supplementation was found to reduce cell senescence markers in the skin [23]. The researchers observed that PQQ intake decreased levels of matrix metalloproteinases (MMPs), which are associated with cellular senescence and tissue degradation. PQQ supplementation was shown to rescue cellular senescence parameters in articular cartilage [24]. The researchers found that PQQ inhibited the development of the senescence-associated secretory phenotype (SASP), which is characterized by increased secretion of inflammatory cytokines and contributes to tissue degeneration. DNA damage In the skin aging study (mice), PQQ supplementation was found to significantly reduce oxidative stress and DNA damage [23]. This protective effect was attributed to PQQ's ability to maintain redox balance and inhibit the DNA damage response pathway. Furthermore, in the osteoarthritis study, PQQ treatment was observed to mitigate DNA damage in chondrocytes [24]. Skin barrier & collagen PQQ has been shown to have positive effects on the skin barrier (mice). The study revealed that PQQ supplementation improved skin thickness and collagen structure, which are important components of the skin's barrier function [23]. Recommended dosage for supplementation The optimal dosage of PQQ for supplementation can vary depending on the intended use and individual factors. However, based on available research and expert recommendations: 1. General health benefits: Typical doses range from 10 to 20 mg per day [1]. 2. Cognitive function: Studies have used doses of 20 mg per day for cognitive benefits. 3. Skin health: For skin benefits, doses of 10 to 20 mg per day have been suggested, although more research is needed to establish optimal dosages for dermatological applications. It is important to consult with a healthcare provider before starting any new supplement regimen, as dosage requirements may vary based on individual health status and needs. PQQ in skincare products PQQ is an interesting bioactive ingredient to be incorporated into skincare products due to its potential benefits for skin health, beauty and regeneration. When looking for PQQ in skincare products, it may be listed under various names, including: ▌Pyrroloquinoline quinone ▌Methoxatin ▌BioPQQ (a patented form of PQQ) The efficacy and safety in skincare products depends on the concentration of PQQ, overall formulation and other ingredients in the formula. Safety and tolerability PQQ has generally been found to be safe and well-tolerated in both animal and human studies. However, as with any supplement or new skincare ingredient, there are some considerations: 1. Oral supplementation: Studies using oral PQQ supplements at doses up to 20 mg per day have reported no significant adverse effects in short-term use. 2. Topical application: The Draelos study on topical PQQ application reported that the product was highly tolerable, with no significant adverse reactions. 3. Long-term safety: While short-term studies have shown good safety profiles, more research is needed to establish the long-term safety of PQQ supplementation and topical use. 4. Potential interactions: As with any supplement, PQQ may interact with certain medications or other supplements. Individuals taking medications or with pre-existing health conditions should consult a healthcare provider before using PQQ supplements. 5. Pregnancy and breastfeeding: Due to limited research, pregnant and breastfeeding women are generally advised to avoid PQQ supplementation unless directed by a healthcare provider [1]. PQQ could be a game-changer for (skin) health and beauty. While the science looks promising, we're still in the early stages of understanding all that PQQ can do. As with any supplement or skincare ingredient, always consult a qualified healthcare professional to determine what the most suitable approach is for your health and beauty goals. Take care Anne-Marie References: [1] Harris, C. B., et al. (2013). Dietary pyrroloquinoline quinone (PQQ) alters indicators of inflammation and mitochondrial-related metabolism in human subjects. J Nutr Biochem, 24(12), 2076-2084. [2] Akagawa M, et al. Recent progress in studies on the health benefits of pyrroloquinoline quinone. Bioscience, Biotechnology, and Biochemistry. 2016;80(1):13-22 [3] Misra, H. S., et al. (2012). Pyrroloquinoline-quinone: a reactive oxygen species scavenger in bacteria. FEBS Lett, 586(22), 3825-3830. [4] Qiu, X. L., et al. (2009). Protective effects of pyrroloquinoline quinone against Abeta-induced neurotoxicity in human neuroblastoma SH-SY5Y cells. Neurosci Lett, 464(3), 165-169. [5] Chowanadisai, W., et al. (2010). Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1alpha expression. J Biol Chem, 285(1), 142-152. [6] Stites, T., et al. (2006). Pyrroloquinoline quinone modulates mitochondrial quantity and function in mice. J Nutr, 136(2), 390-396. [7] Bauerly, K., et al. (2011). Altering pyrroloquinoline quinone nutritional status modulates mitochondrial, lipid, and energy metabolism in rats. PLoS One, 6(7), e21779. [8] Zhang, Y., et al. (2009). Neuroprotective effects of pyrroloquinoline quinone against rotenone injury in primary cultured midbrain neurons. Neurosci Lett, 455(3), 174-179. [9] Nakano, M., et al. Effects of oral supplementation with pyrroloquinoline quinone on stress, fatigue, and sleep. Funct Foods Health 2012 [10] Liu, Y., Jiang, Y., Zhang, M., Tang, Z., He, M., Bu, P., & Li, J. (2020). Pyrroloquinoline quinone ameliorates skeletal muscle atrophy, mitophagy and fiber type transition induced by denervation via inhibition of the inflammatory signaling pathways. Annals of Translational Medicine, 8(5), 207. [11] Wen, J., Shen, J., Zhou, Y., Zhao, X., Dai, Z., & Jin, Y. (2020). Pyrroloquinoline quinone attenuates isoproterenol hydrochloride-induced cardiac hypertrophy in AC16 cells by inhibiting the NF-κB signaling pathway. International Journal of Molecular Medicine, 45(3), 873-885. [12] Tamakoshi, M., Suzuki, T., Nishihara, E., Nakamura, S., & Ikemoto, K. (2023). Pyrroloquinoline quinone disodium salt improves brain function in both younger and older adults. Food & Function, 14(6), 3201-3211. [13] Zhang, Q., Zhang, J., Jiang, C., Qin, J., Ke, K., & Ding, F. (2014). Involvement of ERK1/2 pathway in neuroprotective effects of pyrroloquinoline quinine against rotenone-induced SH-SY5Y cell injury. Neuroscience, 270, 183-191. [14] Zhang, Q., Shen, M., Ding, M., Shen, D., & Ding, F. (2011). The neuroprotective effect of pyrroloquinoline quinone on traumatic brain injury. Journal of Neurotrauma, 28(3), 359-366. [15] Yamaguchi, K., Sasano, A., Urakami, T., Tsuji, T., & Kondo, K. (1993). Stimulation of nerve growth factor production by pyrroloquinoline quinone and its derivatives in vitro and in vivo. Bioscience, Biotechnology, and Biochemistry, 57(7), 1231-1233. [16] Mohamad Ishak NS, Ikemoto K. Pyrroloquinoline-quinone to reduce fat accumulation and ameliorate obesity progression. Front Mol Biosci. 2023 [17] Mitsugu Akagawa et al. Bioscience, Biotechnology, and Biochemistry Recent progress in studies on the health benefits of pyrroloquinoline quinone 2015 [18] Kazuto Ikemoto et al. The effects of pyrroloquinoline quinone disodium salt on brain function and physiological processes The Journal of Medical Investigation 2024 [19] Kowalczyk P, Sulejczak D, Kleczkowska P, Bukowska-Ośko I, Kucia M, Popiel M, Wietrak E, Kramkowski K, Wrzosek K, Kaczyńska K. Mitochondrial Oxidative Stress-A Causative Factor and Therapeutic Target in Many Diseases. Int J Mol Sci. 2021 [20] Guo C, Sun L, Chen X, Zhang D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res. 2013 [21] Jonscher KR, Chowanadisai W, Rucker RB. Pyrroloquinoline-Quinone Is More Than an Antioxidant: A Vitamin-like Accessory Factor Important in Health and Disease Prevention. Biomolecules. 2021 [22] Zhang C, Wen C, Lin J, Shen G. Protective effect of pyrroloquinoline quinine on ultraviolet A irradiation-induced human dermal fibroblast senescence in vitro proceeds via the anti-apoptotic sirtuin 1/nuclear factor-derived erythroid 2-related factor 2/heme oxygenase 1 pathway. Mol Med Rep. 2015 [23] Li J, Liu M, Liang S, Yu Y, Gu M. Repression of the Antioxidant Pyrroloquinoline Quinone in Skin Aging Induced by Bmi-1 Deficiency. Biomed Res Int. 2022 [24] Qin R, Sun J, Wu J, Chen L. Pyrroloquinoline quinone prevents knee osteoarthritis by inhibiting oxidative stress and chondrocyte senescence. American Journal of Translational Research. 2019 [25] Lee, J.-J.; Ng, S.-C.; Hsu, J.-Y.; Liu, H.; Chen, C.-J.; Huang, C.-Y.; Kuo, W.-W. Galangin Reverses H2O2-Induced Dermal Fibroblast Senescence via SIRT1-PGC-1α/Nrf2 Signaling. Int. J. Mol. Sci. 2022, 23, 1387. |
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