In skin biology, senescence is a process by which a cell ages and permanently stops dividing but does not die. This is why they are also referred to as "zombie cells". Age-related accumulation of senescent cells is caused by of increased levels of senescence-inducing stressors and/or reduced elimination of senescent cells. Under normal physiological conditions, senescent cells play an important role maintaining cellular homeostasis and inhibiting proliferation of abnormal cells. However, over time, large numbers of zombie cells can build up in the skin and contribute to the overall reduction in skin's regenerative properties, impacting both its beauty and health.
There are 2 forms of cell senescence: Acute senescence: Senescent cells are produced in response to acute stressors to facilitate for example tissue repair, wound healing. They are cleared by our immune system. Chronic senescence: A not programmed process as response to prolonged stress or damage and these senescent cells are not cleared by our immune system, leading to the accumulation of zombie cells impacting our skin health and beauty. It has been suggested that inflammageing is mainly related to senescent cells and their associated SASP (Senescence Associated Secretory Phenotype) which increase in the body with age and contribute to inflammageing. Senescent cells cause inflammageing and inflammageing causes cell senescence. [1] Senescence can be triggered by a number of stress signals to the cell [1]: ▌DNA damage (main cause) - including ROS-induced ▌Telomere shortening or dysfunction ▌Oncogene activation or loss of tumor suppressor functions ▌Mitochondrial dysfunction ▌Nutrient deprivation ▌Epigenetic changes ▌Inflammageing - including tabacco induced [7] Mechanisms of skin cell senescence:
The presence of senescent cells accelerates the ageing process due to their communication with nearby cells through various molecules: [18] ▌Matrix metalloproteinases (MMPs) ▌Growth factors ▌Cytokines ▌Chemokines ▌Matrix-modeling enzymes ▌Lipids ▌Extracellular vesicles (EVs) Fibroblast senescence could be the main driver of the skin ageing. [3] The increased number of senescent fibroblasts results in the production of SASPs rich in pro-inflammatory cytokines, including interleukin (IL)-1, IL-6, IL-8, IL-18, matrix metalloproteinases (MMPs), and a variety of other inflammatory chemokines [2] resulting in the breakdown of collagen, loss of elasticity and wrinkle formation. [3] Autophagy in dermal fibroblasts is essential for maintaining skin balance and managing the ageing process, particularly in response to external stressors like UV radiation and particulate matter (PM), by repairing cellular machineries. [4] Insufficient autophagy leads to an exaggerated skin inflammation triggered by inflammasome activation, resulting in accelerated ageing characteristics. When exposed to UVB (in vitro), skin cell types like fibroblasts and keratinocytes show DNA damage and increased senescence markers, such as increased SASPs. [3] Dermal fibroblasts also release insulin-like growth factor (IGF)-1, essential for epidermal cell proliferation and differentiation. [5] IGF-1 signalling in senescent fibroblasts is significantly decreased [6]. Inhibition of the IGF-1 pathway decreases collagen production in the dermis, causing epidermal thinning. Additionally, mitochondrial dysfunction and increased levels of superoxide anions prompt fibroblast ageing, thereby speeding up the skin ageing process. [5] Fibroblasts isolated from photo-aged skin produce a greater amount of pro-melanogenic growth factors. [14] Ageing-associated pigmentation has also been reported to be driven by (UVA-induced) fibroblast senescence. [15-16] Keratinocyte senescence The epidermis shows less impact of senescent keratinocytes due to their quicker turnover in comparison to fibroblasts. Senescent keratinocytes experience reduced ECM production and cell adhesions [8], along with elevated MMP expression in UV-induced senescence [9], and increased SASP levels, including pro-inflammatory cytokines. [10] Airborn particulate matter (PM2.5) can penetrate a disrupted skin barrier. PM2.5-induced ROS leads to epigenetic modification: reduced DNA methyltransferase, elevated DNA demethylase expression, p16INK4a promotor hypomethylation and therewith accelerated keratinocyte senescence. [11] Keratinocytes are the main type of cells that signal the need for melanogenesis. [12] UVR-induced DNA damage in keratinocytes activates melanogenesis. [13] Melanocyte senescence Senescent melanocytes express markers of inflammageing and dysfunctional telomeres. Senescent melanocyte SASPs induce telomere dysfunction and limit the proliferation of the surrounding cells, hence, senescent melanocytes affect and impair basal keratinocyte proliferation and contribute to epidermal atrophy. [17] STRATEGIES TO COMBAT CELL SENESCENCE PREVENTION Sunscreen: Protection against UV radiation combined with blue light defense (Licochalcone A: powerful anti-oxidant, Nrf2-Activator & increasing Glutathione + Colour pigments) and prevention + repair DNA damage (Glycyrrhetinic Acid) INTERVENTION Senotherapeutics can be classified into three development strategies: [25]
Skin care ingredients: [18] Most of the following senotherapeutic effects are demonstrated in vitro or ex vivo; robust, controlled clinical evidence for selective senolysis in human skin is still limited, and these ingredients should currently be seen as senomorphic or pro‑homeostatic rather than definitive ‘senolytics’. ▌Aquatide™ (Heptasodium hexacarboxymethyl dipeptide-12): Known to protect the skin from pollution and sun radiation, activating SIRT-1 to decrease cellular senescence ▌Crepidiastrum Denticulatum Extract: This ingredient has shown potential in reducing senescent cells and rejuvenating the skin ▌Exosomes: Found in products like Plated SkinScience Intense Serum, exosomes have been linked to a reduction in the number of senescent cells after use. Read more about exosomes ▌Melatonin: Known for its anti-inflammatory properties, melatonin can help prevent senescent cells in the skin ▌Pollux CD™ (Crepidiastrum Denticulatum Extract): Another ingredient that may aid in reducing senescent cells and promoting skin rejuvenation ▌Saururus Chinensis: This ingredient has shown promise in addressing cellular senescence and supporting skin health ▌Ulmus Davidiana: Known for its potential to reduce cellular senescence and improve skin condition ▌Natural polyphenols have shown anti-senescent effects on skin cells [19] ▌OS-1 peptide protects skin cells from UVB-induced cellular senescence [24] ▌Anti-oxidants like Vitamin C combined with anti-inflammatory ingredients help to reduce ox-inflammageing ▌Cleansing + toners: Gently removing debris (incl. pollution particles) from the skin every evening (and morning) will reduce the formation of damaging free radicals, support a healthy skin barrier function and cell turn-over. Read more ▌Lactic acid (L‑lactic acid): Lactic acid in higher concentrations has been reported in in‑vitro models to induce apoptosis and cell‑cycle arrest in keratinocytes and to modulate pathways linked to senescence and autophagy; however, a targeted, senolytic effect on cutaneous ‘zombie cells’ has not yet been demonstrated in vivo in humans [26] Life-style modifications Of course a healthy life-style and diet (consider also intermittent fasting) will support both your body & skin longevity and beauty Prevention and intervention of skin cell senescence offers a promising approach to improve skin health and beauty. Always consult a qualified healthcare professional or dermatologist to determine the most suitable approach for your particular skin condition and rejuvenation goals. Take care! Anne-Marie References
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