“Chrono” from greek means “time” and “ceutical” is a suffix meaning refined healing item or therapy. The term “circadian” was formed with the Latin words „circa“, which means “roughly”, and “dies” for “day”. Our skin has a rhythm all its own, echoing the wider rhythms of life. On a daily basis, the skin’s natural regenerative cycle oscillates between two fundamental functions. During the daytime hours, skin actively protects us from environmental stressors, including UV light and toxins. But at night, its focus changes, and during the first half of the sleep cycle the skin works at full capacity to make cellular repairs, undoing the day’s damage. When we give the skin exactly what it needs at the right time, it performs at its best, and especially when we boost the skin’s natural capacities with botanical formulas that our skin absorbs effortlessly. Getting in sync with the daily rhythms of this continuous cycle, a rich supply of natural antioxidants helps combat pollutants during the day, a phase that tends to peak between 7 – 11 am. At night, however, skin needs essential nutrients to rebuild collagen, ideally between the hours of 10pm – midnight, when the body’s natural anti-inflammatory levels are often at their highest. With this in mind, It’s easy to see how skin can become extra-stressed during travel, when jet-lag sets the natural cycles. Today’s chronobiology was born, when Physician Julien-Joseph Virey, noticed drugs had different effects depending on the time they were administered and  It all changed when American researchers Jeffrey C. Hall, Michael Rosbach, and Michael W. Young received the Nobel Prize in Medicine 2017discovering the suprachiasmatic nuclei in the brain, along with the ‘clock genes’ and molecular mechanisms controlling circadian rhythms. So, a new era is starting, and mìsula® is the world’s first company specialized to produce chronobiological skincare & chronoceuticals with optimal transdermal delivery, which combines various methods: 

• Skin Bio-Revitalisation & Restoration
• Reverse Dermal and Epidermal Signs of Photo & Chrono Aging
• Reduce Collagen Degradation
• Skin Barrier Against Allergens, Irritants and Radiations
• Reduction of Inflammation by Topical or Systemic Antioxidants
• Pore refining
• Clarifying & Pigmentation
• Microneedling
• Correctives
• Biostimulation
• Rebalancing
• Retextures

ABOUT CHRONOBIOLOGY & CIRCADIAN RHYTHMS:

The cyclical nature  of time affects virtually all aspects of our being and is the basis of the underlying rhythmicity which is typical of our lives. To „tell time,“ most living organisms use internal timing mechanisms known as ‚biological clocks‘. These „clocks“ coordinate our physiological and behavioral functions and interactions with our environment. One of the strongest influences on rhythmicity is the solar day. For example, the daily changes in sleep and wakefulness, the annual bird migrations and the tidal variations in behavior of coastal animals: these are all dictated by biological rhythms. The field of chronobiology studies these rhythms in living organisms and how they are tuned by cues from the outside world. Circadian rhythms last about a whole day, i.e. the 24 hours from one day to another. In chronobiological terminology, the term circamensual refers to one-month rhythms, circannual to one-year rhythms; “ultradian” to rhythms shorter than 24 hours and infradian is a rhythm with a period longer than the period of a circadian rhythm, i.e., with a frequency more than one cycle in 24 hours. Circadian rhythms are the most prominent biological rhythms. Not only sleep and wakefulness are influenced by circadian rhythms: many other bodily functions demonstrate a circadian rhythm, such as body temperature, the secretion of hormones, metabolism, and organ function. These rhythms allow organisms to anticipate and adapt to cyclic changes in the environment that are caused by the daily rotation of the Earth on its axis. In humans and in other mammals, circadian rhythms in the body are synchronized to the environment by a master clock that is located in the suprachiasmatic nuclei (SCN), a tiny brain region that is located just above the crossing of the optic nerves. The SCN receives information about light and darkness directly from the eyes, integrates this input, and relays it to cellular circadian clocks located throughout the rest of the body. In this way, circadian rhythms in behavior and physiology are synchronized to the external light-dark cycle. On a molecular level, circadian rhythms are generated by a feedback mechanism involving cyclic changes in the expression of certain genes. The proteins encoded by two of these genes, called CLOCK and BMAL1 switch on the activity of other genes, called PER and CCY. In turn, PER and CRY proteins turn down the activity of CLOCK and BMAL1 proteins, creating a recurring loop of genes being switched on and switched off that repeats approximately every 24 hours. This molecular feedback mechanism is present in virtually every cell in the body – from the cells in your liver to the cells in your skin. Ultimately, it drives the circadian rhythms in cellular processes,  ensuring all these functions are occurring at the right place at the right time of day.

ABOUT CHRONOBIOLOGY OF THE SKIN:

All life on earth and each organ in our body follows circadian rhythms that revolve around the 24-hour light/dark cycle. You are probably not aware that your skin follows its own circadian rhythm, but this cycle determines every action of your skin cells from the growth of new tissue to damage repair. Understanding the chronobiology of the skin can help you to better take care and protect against some of the damage that occurs with aging. During the day, your skin is exposed to a variety of damaging elements from the environment. Radiation from normal sunlight can cause the formation of free radicals, and even DNA damage. The wind, pollution and other harsh environmental factors also damage delicate skin cells. Our skin would quickly become aged and dysfunctional if we didn’t have cell cycles that allow for repair and rejuvenation. Most of the repair and growth of our skin cells occurs at night, which makes sense, as  nighttime is when skin is least likely to be exposed to damaging environmental stressors. Throughout most of human history, people spent the night asleep in dark areas where further damage was unlikely to occur. At night, DNA repair agents begin fixing the DNA damage from the day, while toxic elements and waste products are removed. Cells begin to replicate, undergoing mitosis to generate new cells to replace those that are dead or damaged. Blood and lymph flow to the skin also increases at this time, so that cells have the nutrient supply that they need to complete these essential processes. Skin cells are most susceptible to damage when they are actively repairing themselves. Circadian clocks are endogenous oscillators that regulate the temporal organization of physiology, metabolism and behavior. They provide organisms, ranging from unicellular algae to humans, with an internal representation of local time, thus allowing them to anticipate daily recurring changes and challenges in their environment. Circadian clocks oscillate in a self-sustained manner with an endogenous (free-running) period close to 24 hours. In a natural environment, these free-running rhythms are synchronized (entrained) to external time cues (Zeitgeber), such as 24-hour light-dark and ambient temperature cycles. The master circadian clock resides in the (SCN) and coordinates daily rhythms of sleep and wakefulness, core body temperature and hormone secretion. In addition, it keeps the clocks in peripheral tissues in synchrony with the outside world. Such peripheral clocks are present in virtually every cell of the body including dermal fibroblasts and epidermal keratinocytes. Whole-genome microarray analysis of epidermis and dermis obtained throughout the day revealed a functional circadian clock in epidermal keratinocytes and dermal fibroblasts with hundreds of transcripts regulated in a daytime-dependent manner contributing to the daily rhythms of a huge variety of physiological and metabolic activities in skin such as proliferation and wound healing. “Internal clocks” control not only our moods, energy levels and hormones, but our skin health as well. Many functions of circadian rhythms are controlled by the suprachiasmatic nucleus of the brain. However, many different cell types have their own internal clocks. These clocks create waves in activity according to the time of day. Skin cells also have these clocks. Stem cells in the epidermis reproduce mainly at night, creating new skin cells that replace aged cells and reduce the appearance of aging. In addition, DNA repair occurs mainly during specific times of day, which is important because this is the body’s first line of defense against UV damage and skin cancer. Because skin cells are engaged in different activities during different parts of the day, they are also more sensitive to damage at certain times. The latest research indicates that CLOCK genes, previously identified in other cell types, are the likely gene affecting the internal clocks of skin cells. The epidermis plays an important role in health. It separates our vital organs from the damaging influences of the outside environment, including UV rays, chemicals, oxidation and mechanical stress. The CLOCK genes in epidermal cells appear to anticipate times of greatest stress and schedule repairs. It appears that DNA repair in skin cells occurs in the afternoon and evening. These are the times when skin is most likely to be exposed to direct UV rays. This is followed late at night by epidermal stem cell proliferation. It is believed that proliferation occurs at night because this is the time when these delicate processes are less likely to be interrupted or disturbed. The result is that DNA damage in the morning and night, especially UV damage, is less likely to be repaired in a timely manner, while people who are up late exposing their skin to light and chemicals such as alcohol and tobacco may suffer premature aging. Before CLOCK genes were discovered, scientists had already observed that skin condition varies predictably over a 24-hour cycle. For example, women routinely rate their skin as more attractive in the morning rather than the evening, which we now know is likely due to the proliferation of new skin cells at night. In addition, anti-aging creams have been proven to be more effective when used before bedtime. Furthermore, skin appears to be more sensitive to inflammation at certain times of the day. The symptoms of atopic dermatitis are worse at night, which is also when psoriasis is most severe. People who get allergy tests and tuberculosis skin tests are less likely to test positive when the test is given in the morning rather than the afternoon or evening. Although the study of the skin’s circadian rhythm is still in its beginning phases, it is possible that this knowledge can be used to better prevent and treat skin disorders. For instance, psoriasis and dermatitis medications may be most effective when given at night as this is the time when flare-ups occur. If people must be out in unblocked UV rays, they can plan to do so in the afternoon or early evening. Skin cancer treatments such as chemotherapy may be most effective when planned to coincide with the most effective times in the skin cell cycle. Chronobiology is an emerging field that is proving to be more and more important in human health. Understanding CLOCK genes and their effects on skin cells may be an important way of preventing skin cancer, premature aging and a variety of skin disorders.

ABOUT BARRIER FUNCTION RHYTHMS:

The skin has its own chronobiological rhythms. It is even one of the first circadian rhythms to develop in children. At birth, children do not know a day lasts 24 hours, which explains why they do not sleep through the night, but their skin acquires its circadian variations very early, in particular as regards hydration. There is also a mitosis peak in the epidermis – mitosis is the cell division process that helps the skin regenerate – around one in the morning, whereas it is very low during the day. It is a natural way to prevent any mitosis in the sun, which may trigger too many mutations. That is another reason why we should protect our skin from UV rays. Variations were also observed in the skin microcirculation or trans-epidermal water loss, which is the lowest around noon and the highest around midnight. This last observation suggests the skin may be more permeable at night than during the day, and the penetration of certain substances, including cosmetics, may be more efficient at night than during the day.

ABOUT DEREGULATION OF THE SKIN’S CIRCADIAN RHYTHM:

Stress, jetlag, shift working hours, intense lifestyles and even exposure to blue light emissions from the screens of ubiquitous electronic devices such as laptops, tablets and mobile phones, disrupt the body’s circadian clock, which leads to the deregulation of the skin’s circadian rhythm. As a consequence, the skin essentially becomes “lost in time,“ showing signs of fatigue and becoming more prone to external aggressors. Genes that should be in full evidence in the morning are no longer well expressed and the same happens to gene activity in the evening, resulting in the rhythm of both being deregulated. These variations are what is known as “phase” and “amplitude” deregulation. Phase deregulation means that a gene is not expressed at the right time, while amplitude deregulation occurs when the difference between the higher and lower expression of a gene is altered. These deregulated phenomena in the circadian cycle weaken many biological functions of the skin which normally respect this rhythmicity. Such is the case of aquaporin-3, which, as noted earlier, is a vital function to maintain skin moisture levels and acts as a marker of skin homeostasis, and the critical detoxification Nrf2 pathway. Once this occurs, overall skin well-being is impacted, skin becoming more vulnerable, dull and tired-looking.

ABOUT SKIN ANTI-AGING STRATEGIES:

Skin aging is a complex biological process influenced by a combination of endogenous (intrinsic) and exogenous (extrinsic) factors. Since skin health and beauty is considered one of the principal factors that represent overall “well-being” and the perception of “health” in humans, several anti-aging strategies have been developed during recent years. Skin aging is part of a natural human “aging mosaic” which becomes evident over time and follows different trajectories in different organs, tissues and cells. While the aging signs of internal organs are masked from the ambient “eyes,” the skin provides the first obvious marks of the passing time. Skin aging is a complex biological process influenced by combination of endogenous (genetics, cellular metabolism, hormone and metabolic processes) and exogenous (chronic light exposure, pollution, ionizing radiation, chemicals, toxins) factors. These factors together lead to cumulative structural and physiological alterations and progressive changes in each skin layer as well as changes in skin appearance, especially, on sun-exposed skin areas. In contrast to thin and atrophic, finely wrinkled and dry intrinsically aged skin, premature photoaged skin typically shows a thickened epidermis, mottled discoloration, deep wrinkles, laxity, dullness and roughness. Gradual loss of skin elasticity leads to the phenomenon of sagging. Slowing of the epidermal turnover rate and cell cycle lengthening coincides with slower wound healing and less effective desquamation in older adults. This fact is important when esthetic procedures are scheduled. Many products and procedures are intended to accelerate the cell cycle, in the belief that a faster turnover rate will yield improvement in skin appearance and will speed wound healing. A marked loss of fibrillin-positive structures as well as a reduced content of collagen type VII (Col-7), may contribute to wrinkles by weakening the bond between dermis and epidermis of extrinsically-age skin. Sun-exposed aged skin is characterized by the solar elastosis. The sparse distribution and decrease in collagen content in photoaged skin can be due to increased collagen degradation by various matrix metalloproteinases, serine, and other proteases irrespective of the same collagen production. In older skin, collagen looks irregular and disorganized, the ratio of Col-3, to Col-1 has been shown to increase, due, significantly, to a loss of Col-1. The overall collagen content per unit area of the skin surface is known to decline approximately 1%/year. Glycosaminoglycans (GAGs) are among the primary dermal skin matrix constituents assisting in binding water. In photo-aged skin, GAGs may be associated with abnormal elastotic material and thus be unable to function effectively. The total hyaluronic acid (HA) level in the dermis of skin that age intrinsically remains stable; however, epidermal HA diminishes markedly. Three primary structural components of the dermis, collagen, elastin and GAGs have been the subjects of the majority of anti-aging research and efforts for aesthetic-anti-aging strategies pertaining to the skin, from ”anti-wrinkle creams” to various filling agents. Aging of the entire face is associated with gravity impact, muscles action, loss of volume, diminishing and redistribution of superficial and deep fat, loss of bony skeleton support, etc.  All of the above lead to the sagging of skin and changes in shape and contour. Regardless of the fact that aging is a biological – and inevitable –  process, and not a pathological condition, it is correlated with various skin and body pathologies, including degenerative disorders such as benign and malignant neoplasms. The „successful-aging“ paradigm, focuses on health and active participation in life, counters traditional conceptualizations of aging as a time of disease and is increasingly equated with minimizing age signs on the skin, face and body. From this perspective, preventative aesthetic dermatology might supplement the request for healthy aging, treat or prevent certain cutaneous disorders, notably skin cancer, and delay skin aging combining local and systemic methods of therapy, instrumental devices and invasive procedures. The mainspring of any skin anti-aging therapy is to achieve healthy, smooth, blemish-free, translucent and resilient skin. In clinical practice, “to look better” does not mean to “look younger.” That is why it is so important to understand patients’ wishes and to orientate them to the treatment modality that will give the most satisfying results after informing them as to all available treatment techniques. The age, previous procedures or surgery, general health status, type of skin,  lifestyle and many other factors should be taken into consideration before choosing a strategy for the individual case. The desired therapeutic anti-aging effect of the skin is a continuous, step-by step process, which combines various methods of  skin bio-revitalization and rejuvenation, augmentation, restoration of each skin layer individually, and must take into consideration many other factors—from the individual’s lifestyle to the immune, genetic, emotional and health status in general.

ABOUT PHOTO-PROTECTION & SYSTEMIC ANTIOXIDANTS:

Chronic photodamage of the skin manifests itself as extrinsic skin aging (photoageing). DNA photodamage and UV-generated reactive oxygen species (ROS) are the initial molecular events that lead to most of the typical histological and clinical manifestations of chronic photodamage of the skin. Wrinkling and pigmentary changes are directly associated with premature photo-aging and are considered its most important cutaneous manifestations. The strategies aimed at preventing photo-aging include sun avoidance, sun protection using sunscreens to block or reduce skin exposure to UV radiation, retinoids in order to inhibit collagenase synthesis and to promote collagen production, and anti-oxidants, particularly in combination, to reduce and neutralize free radicals (FR). Interventional studies indicate that it is in fact possible to delay skin aging and to improve skin conditions through administration of selected nutritional supplements. Nutritional antioxidants act through different mechanisms and in different compartments, but are mainly FR- scavengers: they directly neutralize FRs; reduce the peroxide concentrations and repair oxidized membranes and quench iron to decrease ROS production, via lipid metabolism, short-chain free fatty acids and cholesteryl esters neutralize ROS. Endogenous antioxidant defenses are both non-enzymatic (e.g., uric acid, glutathione, bilirubin, thiols, albumin, and nutritional factors, including vitamins and phenols) and enzymatic [e.g., superoxide dismutases, glutathione peroxidases (GSHPx), and catalase]. The most important source of antioxidants is provided by nutrition.