Circadian Rhythm Cosmeceuticals

Summary and Key Features

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Circadian rhythm affects the natural metabolism of human skin.
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During daytime, skin is in its lowest state of proliferation and is focused on preventing environmental damage.
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During nighttime, skin is in an enhanced mode of repair and recovery with lower protection.
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Cosmeceutical products must be designed to address the varying needs of the skin during the day and night.
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Specific blends of antioxidants formulated to provide targeted benefits during the day or night have demonstrated ability to provide excellent protection and enhanced recovery of skin.

Introduction

Circadian rhythm is the natural internal process that regulates the sleep-wake cycle and other behaviors in living beings, influenced by environmental cues such as light and temperature, over a 24-hour period. It also helps synchronize physiologic processes such as hormone secretion and metabolism. Circadian rhythms are characterized as fluctuations in mental, physical, and emotional well-being based on the clock. Other rhythms that affect the human body include ultradian rhythms that occur at a faster pace than circadian rhythms and include the 90-minute sleep cycle, the hunger rhythm, and the cortisol rhythm. Infradian rhythms occur over a longer period and include the menstrual cycle in females, which typically occurs every 28–32 days. Marine animals respond to additional rhythms such as changes in ocean tides (tidal rhythms), while many land animals and birds are affected by geologic events such as earthquakes (seismic rhythms).

Circadian rhythms are endogenous and adjusted to the local environment by cues called zeitgebers , meaning “time giver” in German. The 2017 Nobel prize in Physiology or Medicine was awarded for research in molecular mechanisms controlling circadian rhythms in fruit flies. Circadian rhythm is controlled by a group of genes collectively known as the core circadian clock genes that regulate the production of proteins that form the circadian clock. In humans, the circadian clock is in the suprachiasmatic nucleus, located in the hypothalamus. Information is transmitted to the suprachiasmatic nucleus via the retina, which contains specialized photosensitive ganglion cells. Circadian rhythmicity can also be found in other parts of the body, such as the liver, heart, and skin. In skin, robust autonomic clocks control the activity of keratinocytes, fibroblasts, melanocytes, mast cells, and hair follicles. The most well-known circadian clock gene is CLOCK (circadian locomotor output cycles kaput), which helps regulate circadian rhythm by controlling the expression of other circadian clock genes including BMAL1 (brain and muscle Arnt-like protein-1), PER1 and PER2 (Period 1 and Period 2), CRY1 and CRY2 (cryptochrome 1 and cryptochrome 2), and others. These circadian clock genes interact with one another and with environmental cues, such as light and temperature, to regulate circadian rhythm. At least 1400 genes involved in different functions show circadian expression changes in skin.

Effect of Circadian Rhythm on Skin

Important skin functions affected by circadian rhythm include free radical production and neutralization, DNA damage and repair, keratinocyte/fibroblast differentiation and proliferation, hydration, barrier and immune functioning, and hormone secretion. There are key differences between skin activities that occur during the day and night ( Fig. 19.1 ). During the day, the skin has the highest pH, sebum production, and thickness with the lowest cell proliferation. Conversely, during the night, the skin has the highest DNA repair, cell proliferation, barrier permeability, penetration, blood flow, and moisture loss and the lowest barrier recovery rate. Therefore, as skin’s needs change throughout the day and night, using different products can help address specific skin concerns at different times.

During the day, the skin is exposed to environmental aggressors such as solar radiation, pollution, and blue light from electronic devices. The ultraviolet (UV) and infrared (IR) spectra of solar radiation generate reactive oxygen species (ROS) by direct interaction with cellular components in skin. Visible light, especially high-energy visible or blue light, can also increase free radical formation. Particulate matter and ozone in polluted air increase ROS in skin. Visible light and particulate matter induce pigmentation in individuals with darker skin, exacerbating melasma and other hyperpigmentation disorders. In response to daytime exposures, skin cells increase their production of antioxidants and repair enzymes to help protect against oxidative damage. However, in aged skin the repair processes are not able to keep up with the extent of damage, leading to accumulation of damaged DNA, RNA, vital proteins, and extracellular matrix (ECM) components, the process collectively known as photoaging or environmental aging. It is therefore important to provide strong protection against environmental aggressors during daytime using sun protection, topical or systemic antioxidants, and barrier enhancement products.

At night, the skin is in its natural repair and regeneration phase, where several genes are upregulated. PER1 and PER2 help regulate the skin’s circadian rhythm and promote skin repair; BMAL1 helps regulate skin cell metabolism and DNA repair; opsin helps regulate skin cell hydration and barrier function; transforming growth factor beta (TGF-β) promotes skin cell growth and wound healing; and interleukin 10 (IL-10) helps reduce skin inflammation. Autophagy and mitochondrial repair are two critical cellular maintenance processes that are upregulated at night. Autophagy removes and recycles damaged proteins and organelles, while maintaining mitochondrial health ensures the supply of adenosine triphosphate (ATP) needed for all cellular processes. However, damaged and aged mitochondria produce excess ROS that is believed to be one of the important causes of intrinsic aging. Mitophagy removes damaged mitochondria and improves the efficiency of cellular energy production. Expression of antioxidant genes, such as those regulated by the nuclear factor erythroid 2–related factor 2 (NRF2) transcription factor, may increase at night, leading to increased production of antioxidants such as glutathione, superoxide dismutase, and catalase. These antioxidants help protect cells against oxidative stress and other forms of cellular damage. Therefore it is important to provide enhancement of mitochondrial repair, autophagy, antioxidant enzymes, and detoxification enzymes at nighttime.

Cosmeceutical Strategies for Daytime Skin Support

Protection of skin from environmental aggressors should be the primary role of any cosmeceutical during daytime. Table 19.1 lists some of the key strategies and biomarkers for assessment of successful intervention.

Table 19.1

Strategies for Development of Daytime and Nighttime Antioxidant Products With Selected Cosmeceutical Actives and Biomarkers

Daytime Strategies	Cosmeceutical Actives	Assessments/Biomarkers
Protection against UV radiation	Sunscreens, antioxidants	Sunburn cells, erythema
Protection against infrared and heat	Polygonum aviculare, Polypodium leucotomos	Tropoelastin, matrix metalloproteinase-1
Protection against visible/blue light	Cocoa seed, marigold, butterfly ginger plant, antioxidants astaxanthin and beta-carotene	Fibrillin, pigmentation
Protection against pollution (ozone, particulate matter, smoke, nitric oxide, etc.)	Antioxidant combination with varying redox potential	Lipid peroxidation, protein carbonylation

Nighttime Strategies	Cosmeceutical Actives	Assessments/Biomarkers
Improve mitochondrial function	Mitoquinol mesylate, ellagic acid derivatives, Szeto–Schiller peptides, xanthones	Sirtuin3, aconitase
Increase cellular energy production		Adenisone triphosphate
Increase autophagy	Coffee, rosemary, Myrothamnus flabellifolius , and Serratia species	Beclin1, LC3-II, Autopagy-related Gene 5
Reduce cellular oxidation	Activators of nuclear factor erythroid 2–related factor 2 include curcumin, sulforaphane, resveratrol, quercetin and epigallocatechin gallate from green tea	8-Hydroxydesoxyguanosin, malondialdehyde, Protein Carbonyl
Increase cellular antioxidant production		Superoxide dismutase, Catalase, Glutathione reductase, Sulfiredoxin 1
Increase cellular defense enzymes		Xeroderma pigmentosa group A, Thioredoxin reductase 1 and 2