INTRODUCTION
Our circadian rhythm is an endogenous timing system
generated from the body’s central pacemaker, the suprachiasmatic
nucleus (SCN). Located in the hypothalamus
and superior to the optic chiasm, its position optimizes
its ability to monitor light and darkness. The SCN exhibits oscillations
approximately every 24 hours and coordinates specific
physiologic and biochemical processes to occur at the optimal
time of day. The primary chronobiological functions of the SCN
are to control core body temperature and mitotic gene expression,
thereby regulating cell differentiation and proliferation.
Animal models demonstrate increased mitotic activity during
the late night and early morning hours, a time designated for
growth and repair.1,2
While the body has a central circadian clock, specific organs,
such as the skin, contain peripheral circadian oscillators that
regulate local processes. Peripheral oscillators are composed
of specific proteins with regulated expression patterns throughout
the day.2–6 With tight regulation of time-sensitive genes,
signals generated by the SCN are amplified at the level of the
specific peripheral tissue.7–9
Molecular Mechanisms
Skin functions are influenced by clock genes, which generate
proteins that work in a complex network of molecular feedback
loops to generate circadian patterns of cellular functions.10 The
expression of these genes has been studied in vitro in cultured
human skin cells, including keratinocytes, melanocytes, and
dermal fibroblasts.11 The clock genes Bmal1, Per1, and Cry1 also
demonstrated circadian rhythms in vivo in human skin biopsies.
12 Each of the different types of skin cells contain distinct
circadian clock machinery that autonomously drives its particular
skin functions.10 Recently, Krüppel-like factor 9 (Klf9) has been
identified as a circadian transcription factor in human epidermis
that regulates keratinocyte proliferation by controlling the expression
of target genes in a daytime-dependent manner.9
Circadian Rhythms in the Skin
The skin is uniquely positioned at the interface between body
and external environment. As such, it is naturally exposed to diurnal
changes in the environment, including temperature, light,
humidity, UV radiation, and pathogens. Regulated circadian activities
allow the skin to adapt its daily functions to variations
in environmental conditions.10 Predictable daily periodicity has
been reported in skin cell proliferation rates, hydration and
transepidermal water loss (TEWL), capillary blood flow, sebum
production, temperature, surface pH, and appearance of rhytides
in humans.9,10,13–18
Both humans and animals exhibit diurnal variations in mitotic
activity. In animal models, mitoses have been shown to be lightresponsive,
with active cell division occurring preferentially in
the late night to early morning.1 Human epidermal cells also
divide and proliferate in a finely-timed circadian manner.17 DNA
synthesis (cell cycle S-phase) peaks at roughly 3:30 PM, while
mitosis (M-phase) peaks at approximately 11:30 PM. Thus, cell
growth and repair occur mainly in the evening.17 This knowledge
can be correlated clinically, with strategic scheduling of
drug delivery to take advantage of differences in cell proliferation
rates throughout the day.17
Skin hydration depends on many factors, including skin permeability
and the amount of water lost across the epidermis.
Transepidermal water loss (TEWL) is significantly higher in
