Circadian Rhythm and the Skin: A Review of the Literature

Abstract

Disruption of the circadian rhythm has been implicated in a wide variety of dermatologic conditions. Research has shown that previous ultraviolet light exposure can continue to damage the deoxyribonucleic acid (DNA) of the skin, even in the dark, and has demonstrated that repair of these skin cells peaks at night. In this article, the authors reviewed the current literature on circadian rhythm effects on the skin and describe and discuss its basic principles. Better understanding of the role circadian rhythm plays in overall skin health will assist physicians in providing optimal treatment to patients, including appropriate recommendations regarding the use of topical medications and skin care at their most effective times during a 24-hour cycle. Dermatologists should also be aware that adequate sleep is necessary for optimal DNA repair activity in the skin.

Full text

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JCAD JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY September 2019 • Volume 12 • Number 9
REVIEW
T
The term circadian rhythm refers to the body’s
endogenous 24-hour physiologic, metabolic,
and behavioral rhythms.1 The circadian rhythm
is controlled by the central regulator, or master
clock, which is located in the suprachiasmatic
nucleus (SCN) of the anterior hypothalamus
and is greatly in uenced by light and the
environment.1,2 The clock mechanisms function
by transcription and translation feedback loops
of circadian clock genes and their proteins.3
Peripheral organs, such as the skin, also
contribute to the circadian rhythm and possess
endogenous rhythmicity.2
The pineal gland secretes melatonin, which is
considered to be a major regulator of circadian
homeostasis.4 Melatonin levels  uctuate with the
circadian rhythm and are typically high at night
and low during the day.5 Exposure to light leads to
an acute drop in melatonin levels and a decrease
in melatonin production secondary to feedback
inhibition.6 Melatonin has been associated
with hair growth, suppression of ultraviolet
(UV) damage in skin cells, wound healing, and
antitumor e ec ts.4,5,7 Oral melatonin supplements
are commonly used to promote sleep, and studies
have shown melatonin can advance the onset
of nocturnal melatonin secretion.8,9 Because it
has antioxidant e ects, topical melatonin has
been used in wound healing, sun protection, and
antiaging products with varying results.10–14
Circadian rhythm disruption has been studied
in detail and is thought to contribute to the risk of
cancer and other diseases, as well as have various
e ects on the skin, ranging from transepidermal
water loss to keratinocyte proliferation.15 Studies
have also shown that repair of DNA-damaged skin
cells, as a result of UV exposure, peaks at night.16
Additionally, previous exposure to UV light can
continue to damage skin DNA, even in the dark.17
By understanding the basic principles of
the circadian rhythm, including skin changes
throughout the day, physicians might
better target therapy for their patients by
recommending use of topical medications and
skin care products at optimal times of the day,
(e.g., sunscreen during the day, DNA repair
enzyme cream at night). Dermatologists should
also be aware that adequate sleep is necessary
for optimal DNA repair activity in the skin. In this
article, we review the current literature regarding
circadian rhythm and its e ects on overall skin
health as well as implications that time of day can
impact the e ectiveness of topical medications
and skin care products.
CIRCADIAN RHYTHM AND THE SKIN
In addition to the SCN, the circadian system
is also composed of peripheral circadian
oscillators in many other cells, including the
skin.18 The skin contains circadian clock genes,
ABSTRACT
Disruption of the circadian rhythm has been
implicated in a wide variety of dermatologic
conditions. Research has shown that previous
ultraviolet light exposure can continue to damage
the deoxyribonucleic acid (DNA) of the skin, even
in the dark, and has demonstrated that repair of
these skin cells peaks at night. In this article, the
authors reviewed the current literature on circadian
rhythm e ects on the skin and describe and discuss
its basic principles. Better understanding of the role
circadian rhythm plays in overall skin health will
assist physicians in providing optimal treatment to
patients, including appropriate recommendations
regarding the use of topical medications and skin
care at their most e ective times during a 24-hour
cycle. Dermatologists should also be aware that
adequate sleep is necessary for optimal DNA repair
activity in the skin.
KEYWORDS: Circadian rhythm, DNA repair,
melatonin
Circadian Rhythm and
the Skin: A Review of the
Literature
by ALEXIS B. LYONS, MD; LAUREN MOY, MD; RONALD MOY, MD;
and REBECCA TUNG, MD
Dr. Lyons is with the Department of Dermatology at Henry Ford Hospital in Detroit, Michigan. Drs. L. Moy and Tung are with
the Department of Dermatology at Loyola University Medical Center in Chicago, Illinois. Dr. R. Moy is with Moy, Fincher, Chipps
Facial Plastics and Dermatology in Beverly Hills, California.
J Clin Aesthet Dermatol. 2019;12(9):42–45
FUNDING: No funding was provided for this study.
DISCLOSURES: The authors have no con icts of interest relevant to the content of this article.
CORRESPONDENCE: Alexis Lyons, MD; Email: alexisblyons@gmail.com

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REVIEW
which play a role in the regulation of the
circadian rhythm.18 Transepidermal water loss,
keratinocyte proliferation, skin blood  ow, and
skin temperature have all been shown to have
circadian variations.
The stratum corneum undergoes circadian
rhythm changes, with skin permeability being
higher in the evening than in the morning.16
Aquaporin 3 (AQP3) is expressed in the epidermis
and is regulated by molecular clocks, which
contribute to transepidermal water loss.15 Because
transepidermal water loss is associated with
increased pruritus in cases of atopic dermatitis,
this increase in water loss from the skin in the
evening coincides increased itchiness at night.19
These factors of increased in ammation and
skin permeability at night could be important
clinically. Thus, moisturizers and topical steroids
might o er increased bene ts when used in the
evening hours.
The e ect that topical medications have on
the skin also varies throughout the day. Skin
penetration of hydrophilic and lipophilic topical
medications is at its maximum at around 04:00
hours (4:00am), with absorption slowing
throughout the daylight hours.20 The penetration
of topical lidocaine is also greater at night.21 This
is likely due to the increase in skin permeability at
night, as discussed above.
Another component that may a ect the
e cacy of topical medications and absorption is
the rate of blood  ow in the skin. The skin blood
 ow rate has also been shown to be a ected
by the circadian rhythm, increasing in the late
afternoon and at night.22 A study by Yosipovitch
et al16 demonstrated that these circadian
rhythm blood  ow rates were maintained even
during treatment with topical corticosteroids.
Vasodilation and increased skin blood  ow have
been shown to accelerate drug passage through
the skin and di usion through the tissues into the
systemic circulation.23
Proliferation of keratinocytes has also been
found to vary during the day, with the highest
rate of proliferation occurring around midnight.24
Cancerous skin cells have been shown to lose
their rhythmicity, while healthy cells appear to
peak around midnight and trough at midday.25
Sebaceous gland activity also varies throughout
the day, with minimal activity around 04:00 hours
and maximum activity at midday.16 This variation
is not thought to be linked to variations in skin
temperature or hormone production, but the
cause of the rhythmicity is unknown.26
Human hair follicles have been shown to
experience circadian changes and express the
core clock genes CLOCK, BMAL1, and Period1,
which modulate the hair follicle cycle even in
the absence of input from the SCN.27 A study
by Al-Nuaimi et al27 suggested that these clock
genes could be potential therapeutic targets for
stimulating hair growth. In a study by Hardman
et al,28 researchers found that hair follicle
melanin content was increased by silencing
BMAL1 and PER1, suggesting that the circadian
clock genes play a role in pigmentation.
Targeting these genes could potentially aid in
treatment of hair pigmentation disorders.
Cortisol levels also  uctuate throughout
the day. There is a natural trough in cortisol
levels during the evening, which could
be a contributing factor in patients with
in ammatory skin conditions who have
increased pruritus at night.6 Approximately
65 percent of patients with in ammatory
dermatoses, including atopic dermatitis and
psoriasis, have increased pruritus at night.7
The circadian rhythm also controls the core
body temperature and skin temperature.16,29
The core body temperature has predictable
 uctuations with higher temperatures in the
daylight hours than during the night hours, with
a trough in the early morning,6 whereas skin
temperature peaks in the afternoon and has
a trough at night.16 Relating to this, psoriasis
has been associated with problems related
to thermoregulation , which might lead to
di culty falling asleep and disruption of the
circadian rhythm.30
Psoriasis has also been linked to circadian
rhythm abnormalities, although the
pathophysiology is still unclear. A study by
Mozzanica31 found that patients with psoriasis
had reduced levels of melatonin. Another study
showed an increased incidence of psoriasis
in night-shift workers.32 Additionally, the
CLOCK gene has been linked to the regulation
of psoriasis by regulating interleukin-23R
expression in mice.33 Further studies are needed
to elucidate the relation of the circadian clock
with psoriasis.
CIRCADIAN RHYTHM AND CANCER
Numerous studies have shown that
alterations in sleep/wake cycles that interfered
with the circadian rhythm resulted in an
increased cancer risk. Nurses who work the
night shift have been shown to have an
increased risk of breast cancer compared to
those who work the day shift.5,34 The incidence
of breast cancer has also been shown to
be higher in female  ight attendants, who
frequently cross time zones and experience
disruptions in their circadian rhythm.35
In breast and endometrial cancer, the
expression of the circadian period gene,
Per2, is inhibited, possibly leading to tumor
development.1 This disruption in circadian
rhythm suggests that shift workers have lower
levels of melatonin. Sleep deprivation leads
to melatonin suppression and subsequent
immunode ciency via the suppression of
natural killer-cell activity and changes in
T-helper cell cytokine balance.36–38
The circadian rhythm in rodent models
has also been studied. As mentioned above,
the pineal gland secretes melatonin, which
regulates the circadian rhythm.39 Rodents
in which the pineal gland was removed
experienced an increased number of tumors.40
Exposure to light during non-daylight hours
in mice resulted in inactivation of Per2, which
promoted tumor development.41
In contrast with other malignancies, the
risk of skin cancer in night-shift workers
has been shown to be reduced compared
to individuals who worked during the day.
In a study by Schernhammer et al,42 there
was an overall 14-percent decreased risk for
skin cancer and 44-percent decreased risk
for melanoma among night-shift workers.
These  ndings are in contrast with the
 ndings of studies that showed an association
between lower levels of melatonin and
an increased risk of other cancers among
night-shift workers.5,34,35 Schernhammer et
al41attributes these lower rates of skin cancer
 ndings to the protection against melanoma
and nonmelanoma skin cancers that lower
melatonin levels might o er.42 Despite this, a
true cause-and-e ect relationship between
melatonin and the development of melanoma
is not well-established. While causality is not
established, perhaps getting a good night’s
sleep following exposure to the sun is not
su cient for repair to occur using the body’s
own defenses. Another theory for this lower
rate of skin cancer is that the night-shift
workers presumably have less sun exposure,
since they are typically sleeping during the
day and are awake at night. Nevertheless,
additional studies examinining incidence of skin

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REVIEW
cancer in shift workers have found no signi cant
di erences when compared with to the general
population.43,44
CIRCADIAN RHYTHM,
IMMUNODEFICIENCY, AND DNA REPAIR
The repair of skin cells with DNA damage
from the sun appears to peaks at night.16 A
recent study by Manzella et al45 found that
oxidative damage followed a circadian rhythm,
where the DNA damage was less in the morning
hours than later on in the day. This variation
was thought to be due to 8-oxoguanine DNA
glycosylase (OGG1), which acts to repair
8-Oxoguanine (8-oxoG) DNA damage via the
DNA base excision repair pathway.45 OOG1 DNA
repair activity was higher in the morning and,
thus, 8-oxoG DNA damage levels were lower
in the morning.45 This same study found that
night-shift workers had decreased levels of
OGG1 DNA repair expression compared to the
control group.45 This suggests that during the
early morning hours, the body best performs
DNA repair and that optimal DNA repair occurs
with optimal sleep.
A study by Premi et al17 found that sun
exposure continued to damage skin DNA for
up to three hours following exposure via a
chemical process called the “dark pathway.”
These investigators found that direct exposure
to UV light caused DNA damage in all skin
cells, but only the melanocytes accumulated
DNA damage in the absence of light. Premi et
al17 also proposed that α-tocopherol (vitamin
E) and ethyl sorbate could stop DNA damage
from occurring after UV exposure.Studies
have also shown that vitamin D exhibits anti-
in ammatory e ects after UV exposure and
reduces sunburn, thymidine dimer formation,
and photocarcinogenesis.46–48 A recent
combination supplement containing vitamin D
resulted in an increased minimal erythema dose
in patients, thus providing photoprotection and
reducing sunburn risk.49 These studies suggest
that daytime sun protection with sunscreens
and nighttime application with topical DNA
repair enzyme creams might be the optimal
regimen for preventing skin cancer.
CONCLUSION
The important role that circadian rhythm
plays in skin health is a fundamental concept
and is regulated by the SCN and peripheral
oscillators. Physicians should be aware of
variations in skin function and characteristics
throughout the day to better understand
patient symptoms and to maximize
therapeutic bene t. By understanding the
basic principles of the circadian rhythm
including skin changes that occur throughout
the day, physicians can better target therapy
for their patients by recommending the use of
topical medications and skin care products at
optimal times of the day, including sunscreens
during the day and DNA repair enzyme creams
at night. Dermatologists should also be aware
that adequate sleep is necessary for optimal
DNA repair activity to occur in the skin.
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