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Tuesday, July 01, 2014

The Skin's Circadian Rhythm: Skin Hydration Ebbs And Flows By The Clock

The Skin's Circadian Rhythm
Skin Hydration Ebbs And Flows By The Clock

A protein regulates the circadian flow of water in and out of skin pores, a study says. Christopher Serra

Researchers have discovered a protein that regulates the circadian ebb and flow of water in and out of the skin's pores, according to a report in the June issue of the Journal of Investigative Dermatology.

Recent studies have suggested the water content of skin, or skin hydration, has a circadian rhythm but the underlying mechanisms weren't known, researchers said.

Understanding the circadian rhythm of AQP3 may explain why certain topical medications are absorbed better in the evening, when moisture is greatest in the stratum corneum, the outermost layer of skin, and possibly lead to improved timing for drugs and cosmetic products, they said.

Anyone who’s ever gotten a bad night’s sleep knows that the effects show up in the mirror the next morning: dark circles, breakouts, sallow skin… the list goes on. Along the same lines, jet-lagged skin can look pretty rough, too. (Otherwise, nobody would need those giant sunglasses post-flight, right?)

The common thread between the two is your circadian rhythm – the 24-hour cycle that’s governed by your body’s biological clock.  And while your circadian rhythm isn’t the first thing that comes to mind when you think about your skin, research shows it’s actually crucial for maintaining a healthy, resilient and (you guessed it) younger-looking complexion.

It all has to do with your skin’s stem cells. For instance, an October 2013 study published by Cell Press shows that during daylight hours, your skin’s stem cells switch on certain genes to defend themselves from UV light. Daytime defenses also work against other environmental stressors, such as pollution, that contribute to aging by breaking down healthy skin cells.

At night, on the other hand, while you’re snoozing away in the dark, your skin’s stem cells don’t need to go into defense mode. Instead, they can focus on producing healthy cells to replace the damaged cells.

Your skin’s natural antioxidant protection is generally highest between the hours of 7 and 11 a.m. On the flip side, skin reaches its peak reparative levels between the hours of 10 p.m. and midnight. When its circadian rhythm is disrupted, your skin isn’t able to fend off damage or repair as effectively, causing a breakdown of collagen and elastin.

Reset Your Skin’s Circadian Rhythm

So what can you do about all this? First, don’t freak if you’ve gotten a few bad nights of sleep. It’s the chronic disruptions that bring all the side effects. Second, stack the deck in favor of your skin with products that help your skin’s circadian rhythm function in a healthy way. At night, use a retinol or prescription retinoid to stimulate additional skin cell turnover and keep your skin smooth and wrinkle-free.

Night is also the perfect time to treat skin to an intense does of hydration (try products containing hyaluronic acid), since sebum production (aka your skin’s natural oil) is lowest while you’re sleeping.

During the day, boost your skin’s levels of natural antioxidant protection with a broad spectrum sunscreen (you should be doing this already!) that contains additional antioxidants to protect against skin cancer and skin cell breakdown.

But above all else, make getting a good night’s sleep a priority!

Circadian Rhythms of Skin Medications

The effects of cream and patch medications show circadian periodicity. Twice as much of lidocaine is taken up by the skin when applied as a cream at 16:00 than at 08:00. The rate at which nicotine penetrates the skin is several-fold faster at 04:00 than in the afternoon . The pain-deadening effect of lidocaine lasts 2-3 times longer when injected into the skin at 15:00 than at 07:00 or 23:00; the pain-deadening effect of betoxycaine lasts 2 times longer when injected at 15:00 than in the morning or evening. The activity of a popular topical anti-inflammatory corticosteroid cream medication is greater when applied in the afternoon than morning.

Day-Night Differences in Skin Appearance

Circadian rhythms in skin biology give rise to day-night differences in the texture, radiance and overall appearance of facial skin. A group of French women self-rated the natural appearance of their facial skin best around 10:00 and worse at night. The same women found the effect of a restorative rejuvenating cosmetic preparation (Noctosome, Lancome) depended on the time of its application. Bedtime application had a significantly better effect, particularly in women between 25 and 35 years of age and ones of fair complexion. The better effect of the nighttime application was anticipated since the product was specifically designed to work in relation to the known circadian rhythms of facial skin.

Chronobiology of Skin and Skin Disorders

Many skin functions are circadian rhythmic. The proliferation of skin cells varies by up to 30-fold in the 24 hours, being greatest at midnight and least at noon. In women, blood flow, amino acid content and water loss are roughly 25 percent higher at night than morning or afternoon. These rhythms persist in oral contraceptive pill users, although the rate of water loss and blow flow is greater by 10 percent while the content of amino acid is reduced by 35 percent. Oil production by skin glands is twice as great at noon than between 02:00 and 04:00. The skin is more acidic during sleep than around midday and its temperature is higher in the evening than morning. Skin temperature must be about a degree higher at 16:00 compared to 04:00 before sweating begins, although sweat production is greater in the afternoon than morning.

Circadian Rhythms in Skin Disorders

Psoriasis: Psoriasis is a chronic inflammatory disease that typically produces a bumpy, flaky condition of the skin especially areas of the scalp, elbows, knees, and back. The cell proliferation rate of the affected skin is much higher than normal skin and shows marked circadian variation. In the epidermis, the cell proliferation rate in areas of psoriasis is highest between 21:00 and 03:00 and least at 09:00. However, in the dermis the rhythm is reversed; cell proliferation is greatest at 09:00 and least at 03:00. The inflammatory activity of psoriasis also varies greatly. It is highest at night and lowest in the morning.

Atopic Dermatitis: Atopic dermatitis is a chronic inflammatory disease which shows marked circadian variation in the intensity of symptoms. Itching is most intense late in the evening and may disrupt nighttime sleep. The day-night pattern in the severity of the itching seems to be dependent on the circadian rhythm of the skin’s sensitivity to histamine, which is highest at night.

Skin Cancer: The experimental study of circadian rhythms in the susceptibility of skin to tumor induction in humans is not possible. However, it can be easily done in laboratory animals by applying tumor-causing chemicals at various times of the day and night. Results show the risk of developing skin cancer differs dramatically with the time of the day of their application. Generally, tumor development is greater when contact occurs in the animal’s activity span (when the genetic or DNA material of skin cells is replicating) than in the rest period. These findings may imply that human beings are at greater risk when regularly coming in contact with cancer-causing agents in the late afternoon and evening.

Skin Rhythms Affect Diagnostic Allergy Tests

Allergy Testing: Most allergy tests involve the injection of a small quantity of allergens like house dust extract or different kinds of pollens just under the skin of the upper arm or back. Positive responses are shown by the development of large red areas with light-colored swelling in the center. The time of day and time of menstrual cycle allergy tests are done influence their results. The skin is much less reactive to testing early in the day than afternoon and evening. This means the severity of allergies and even exact identification of specific sensitivities may be misjudged when tests are conducted early in the day. Menstrual cycle variation in skin reactivity also occurs in young women not using oral contraceptives; it is greater by about 25 percent at menstruation than ovulation.

Tuberculosis Testing: The tuberculin skin reaction of persons who had past exposure to the bacteria is nearly 3-fold greater when testing is done at 07:00 rather than at 22:00.

Skin Hydration Ebbs And Flows By The Clock

The latest study identified a molecular link between the circadian clock and aquaporin 3 (AQP3), a protein called an aquaglyceroporin, which is involved in the transport of water and glycerol molecules through the pores of the skin.

Water and glycerol are key components of skin hydration, which is key to maintaining a protective barrier against infection and dehydration, researchers said.

Researchers in Japan studied AQP3 in skin from normal mice and mice lacking the circadian-clock gene. Both groups were housed in rooms with the lights on from 7 a.m. to 7 p.m.

In normal mice, the water content of skin fluctuated from 9 a.m. to 9 p.m., reaching peak levels at the end of the day. But this pattern didn't occur in mice lacking the clock gene. Fluctuations in skin hydration resembled AQP3 levels, which also peaked at 9 p.m., in the normal mice. Further research showed a clock gene activates AQP3.

The study's experiments conducted on human keratinocytes, the most common cells in the outer skin, suggested the AQP3 gene also controls circadian rhythm in human skin function.

Caveat: The experiments were conducted on mice and a human cell line. Mouse and human skin are structurally different, researchers said.

24-Hour Rhythm of Aquaporin-3 Function in the Epidermis Is Regulated by Molecular Clocks

Aquaporin 3 (AQP3) is located in the basal layer of the epidermis and regulates biological functions of skin such as water content and trans-epidermal water loss. A recent study showed that the biological function of skin exhibits a 24-hour rhythm, but the molecular mechanism of the variation remains poorly understood. Here we show that mice mutated in the core clock component CLOCK (Clk/Clk) show decreased stratum corneum hydration. An extensive search for the underlying cause led us to identify AQP3 as a new regulator to control the 24-hour variation in biological functions of skin. In mouse epidermis of wild-type mice, mAqp3 exhibits circadian rhythms; however, these are significantly decreased in Clk/Clk. Luciferase reporter gene analysis revealed that transcription of mAqp3 is activated by D-site-binding protein, a clock gene.

A human homolog, hAQP3, also exhibited significant oscillation in human keratinocyte (HaCaT) cells synchronized with medium containing 50% serum, and this rhythm was regulated by the endogenous CLOCK/BMAL1 heterodimer. These data indicate that although the molecular mechanisms underlying the rhythmic expression of mAqp3 and hAQP3 are different, clock genes are involved in time-dependent skin hydration. Our current findings provide a molecular link between the circadian clock and AQP3 function in mouse dorsal skin and HaCaT cells.

Circadian Rhythms In Skin Stem Cells Protect Us Against UV Rays

By activating genes involved in UV protection during the day, these cells protect themselves against radiation-induced DNA damage. The findings could pave the way for new strategies to prevent premature aging and cancer in humans.

"Our study shows that human skin stem cells posses an internal clock that allows them to very accurately know the time of day and helps them know when it is best to perform the correct function," says study author Salvador Aznar Benitah an ICREA Research Professor who developed this project at the Centre for Genomic Regulation (CRG, Barcelona), and who has recently moved his lab to the Institute for Research in Biomedicine (IRB Barcelona). "This is important because it seems that tissues need an accurate internal clock to remain healthy."

A variety of cells in our body have internal clocks that help them perform certain functions depending on the time of day, and skin cells as well as some stem cells exhibit circadian behaviors. Benitah and his collaborators previously found that animals lacking normal circadian rhythms in skin stem cells age prematurely, suggesting that these cyclical patterns can protect against cellular damage. But until now, it has not been clear how circadian rhythms affect the functions of human skin stem cells.

To address this question, Benitah teamed up with his collaborators Luis Serrano and Ben Lehner of the Centre for Genomic Regulation. They found that distinct sets of genes in human skin stem cells show peak activity at different times of day. Genes involved in UV protection become most active during the daytime to guard these cells while they proliferate -- that is, when they duplicate their DNA and are more susceptible to radiation-induced damage.

"We know that the clock is gradually disrupted in aged mice and humans, and we know that preventing stem cells from accurately knowing the time of the day reduces their regenerative capacity," Benitah says. "Our current efforts lie in trying to identify the causes underlying the disruption of the clock of human skin stem cells and hopefully find means to prevent or delay it."


(1) Scheving LE. Mitotic activity in the human epidermis. Anatomical Record. 1959;135:7-20.

(2) Reinberg A, Touitou Y, Soudant E, et al. Oral contraceptives alter circadian rhythm parameters of cortisol, melatonin, blood flow, transepidermal water loss and skin amino acids of healthy young women. Chronobiology International. 1996;13:199-211.

(3) Verschoore M, Ponet M, Krebs B, Ortonne J-P. Circadian rhythms in the number of actively secreting sebaceous follicles and androgen circadian rhythms. Chronobiology International. 1993;5:349-359.

(4) Yosipovitch G, Xiong GL, Haus E, et al. Time-dependent variations of the skin barrier function in humans: Transdermal water loss, stratum corneum hydration, skin surface pH, and skin temperature. Journal of Investigative Dermatology. 1998;110:20-23.

(5) Stephenson LA, Wenger CB, OíDonovan BH, Nadel ER. Circadian rhythm in sweating and cutaneous blood flow. American Journal of Physiology. 1984;246:R321-324.

(6) Timbal J, Colin, J, Boutelier C. Circadian variation in the sweating mechanism. Journal of Applied Physiology. 1975;39:226-230.

(7) Reinberg A, Koulbains C, Soudant E., et al. Day-night differences in effects of cosmetic treatments on facial skin. Effects on facial skin appearance. Chronobiology International. 1990;7:69-79.

(8) Gelfant S, Ozawa A, Chalker DK, Smith JG jr. Circadian rhythms and differences in uninvolved and involved psoriatic skin in vitro. Journal of Investigative Dermatology. 1982;78:58-62.

(9) Rubin NH, Scheving LE. Circadian Rhythm (Letter). Journal of Investigative Dermatology. 1983;80:79-80.

(10) Pigatto PD, Radaelli A, Tadini G, et al. Circadian rhythm of the in vivo migration of neutrophils in psoriatic patients. Archives of Dermatological Research. 277:185-189,1985.

(11) Borelli S, Chlebarov S, Flach E. Atopic neurodermatitis, and the problem of its 24-hour rhythm and its dependence on weather and climate. Munchen Medicinishe Wochenschrift. 1966;108:474-480.

(12) Cormia FE. Experimental histamine pruitus. I. Influence of physical and psychological factors on threshold reactivity. Journal of Investigative Dermatology. 1952;19:21-34.

(13) Mottram JC. A diurnal variation in the production of tumors. Journal of Pathology and Bacteriology. 1945;57:265-267.

(14) Frei JV, Ritchie AC. Diurnal variation in the susceptibility of mouse epidermis to carcinogen and its relationship to DNA synthesis. Journal of the National Cancer Institute. 1964;32:1213-1220.

(15) Iversen OH, Iversen UM. A diurnal variation in the tumorigenic effect response of mouse epidermis to a single application of the strong short-acting chemical carcinogen methylnitrosourea. A dose-response study of 1, 2 and 10 mg. In Vivo. 1995;9:117-132.

(16) McGovern JP, Smolensky MH, Reinberg A. Circadian and circamensual rhythmicity in cutaneous reactivity to histamine and allergenic extracts. In: McGovern JP, Smolensky MH, Reinberg A. (eds.) Chronobiology in Allergy and Immunology. Thomas, Springfield, IL. 1977, pp. 79-116.

(17) McGovern JP, Smolensky MH, Reinberg A., Ibid.

(18) Cove-Smith JR, Pownall R, Kabler TA, Knapp MS. Circadian variation in cell-mediated immune response in man and their response to prednisolone. In: Reinberg A, Halberg F (eds.) Chronopharmacology. Pergamon, Oxford. 1979, pp. 369-374.

(19) Bruguerolle B, Giaufre E, Prat M. Temporal variations in transcutaneous passage of drugs: The example of lidocaine in children and in rats. Chronobiology International. 1991;8:277-282.

(20) Reinberg AE, Soudant, E, Koulbanis C, et al. Circadian dosing time dependency in the forearm skin penetration of methyl and hexyl nicotinate. Life Sciences. 1995;57:1507-1513.

(21) Reinberg A, Reinberg M-A. Circadian changes of the duration of action of local anaesthetic agents. Naunyn-Schmiedeberg’s Archives of Pharmacology. 1977;297:149-159.

(22) Pershing LK, Corlett JL, Lambert LD, Ponclet CE. Circadian rhythm of topical 0.05% betamethasone diproprionate in human skin in vivo. Journal of Investigative Dermatology. 1994;102: 734-739.

Monty Henry, Owner

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