Seminars in Cell & Developmental Biology 70 (2017) 164–176

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Seminars in Cell & Developmental Biology

journal homepage: www.elsevier.com/locate/semcdb

Review

The clock is ticking. Ageing of the circadian system: From physiology

to cell cycle
Eva Terzibasi-Tozzini a , Antonio Martinez-Nicolas b,c , Alejandro Lucas-Sánchez b,c,∗
a
Laboratory of Biology, Scuola Normale Superiore, Pisa, Italy
b
Department of Physiology, Faculty of Biology, University of Murcia, Campus Mare Nostrum, IUIE. IMIB—Arrixaca, Murcia, Spain
c
Ciber Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain

a r t i c l e i n f o a b s t r a c t

Article history: The circadian system is the responsible to organise the internal temporal order in relation to the envi-
Received 14 April 2017 ronment of every process of the organisms producing the circadian rhythms. These rhythms have a fixed
Received in revised form 12 June 2017 phase relationship among them and with the environment in order to optimise the available energy
Accepted 13 June 2017
and resources. From a cellular level, circadian rhythms are controlled by genetic positive and negative
Available online 16 June 2017
auto-regulated transcriptional and translational feedback loops, which generate 24 h rhythms in mRNA
and protein levels of the clock components. It has been described about 10% of the genome is controlled
Keywords:
by clock genes, with special relevance, due to its implications, to the cell cycle. Ageing is a deleterious
Circadian system
Ageing
process which affects all the organisms’ structures including circadian system. The circadian system’s
Physiology ageing may produce a disorganisation among the circadian rhythms, arrhythmicity and, even, discon-
Cell cycle nection from the environment, resulting in a detrimental situation to the organism. In addition, some
Neurogenesis environmental conditions can produce circadian disruption, also called chronodisruption, which may
produce many pathologies including accelerated ageing. Finally, some strategies to prevent, palliate or
counteract chronodisruption effects have been proposed to enhance the circadian system, also called
chronoenhancement. This review tries to gather recent advances in the chronobiology of the ageing
process, including cell cycle, neurogenesis process and physiology.
© 2017 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
2. Structure and organisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
2.1. Inputs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
2.2. Central pacemaker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
2.3. Outputs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
3. When the age sets the rhythm. Circadian system ageing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
3.1. Inputs ageing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
3.2. Central pacemaker ageing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
3.3. Outputs ageing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
4. Circadian rhythms and cell cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
4.1. Role of clock genes in the cell cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
4.2. Interaction with other molecules of interest: Wee1, p21, c-Myc and human timeless (h-tim) protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
5. Circadian rhythms, neurogenesis and ageing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
5.1. Interaction between neurogenesis and clock genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
5.2. Neurogenesis and ageing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
6. Chronodisruption and circadian system ageing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
7. Chronoenhancement: a new strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

∗ Corresponding author at: Department of Physiology, Faculty of Biology, University of Murcia, Campus Mare Nostrum. IUIE. IMIB—Arrixaca, Murcia, Spain.
E-mail address: alucas@um.es (A. Lucas-Sánchez).

http://dx.doi.org/10.1016/j.semcdb.2017.06.011
1084-9521/© 2017 Elsevier Ltd. All rights reserved.
 E. Terzibasi-Tozzini et al. / Seminars in Cell & Developmental Biology 70 (2017) 164–176 165

Declaration of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

1. Introduction tion is transmitted to the master clock in the hypothalamus by the

retinohypothalamic tract [14–16].
From the life’s origin, Earth has been rounding on its axis and Thermocycle is also an important zeitgeber to the circadian sys-
around the sun, generating daily and annual cycles. Under these tem, which is capable to entrain cellular cultures in vitro [17], core
conditions, organisms evolved a biological clock as an adaptation body temperature of mice in vivo [18] and ectotherm organisms
to anticipate the predictable periodical environmental changes. [19]. In addition, some overt rhythms present also a synchroniser
Thus, possible damage to biomolecules produced by the most ener- effect such as feeding time, scheduled sleep and activity [4]. Food
getic electromagnetic waves could be diminished by predicting the availability has an important role in the circadian physiology, since
daytime, metabolic processes could be scheduled improving their digestion, motility, nutrient absorption and mobilisation are organ-
efficiency and cyclic events like breeding, hibernation or preda- ised around the feeding schedule to improve the efficiency of the
tor/prey antagonism can be prepared in advance. processes. Regular exercise exerts a synchronising effect on the
Almost all living beings have a biological clock, which predicts, human circadian system improving physical health and affective
adapts and prepares the organism to the cyclical environment disorders [1], while sleep habits are a weak synchroniser probably
changes. The circadian timekeeping system (from Latin circa and due to their ability to determine light exposure and to drift mela-
diem, means approximately one day) is responsible for predicting tonin secretion and core body temperature by a fixed schedule [20].
environmental cyclical cues, also called zeitgebers (“time giver” in Although social contacts have been considered for a long time as a
German), and organising the internal temporal order of physiolog- synchroniser [21], recent reports failed to confirm the existence of
ical processes. The circadian system is constituted by a series of this effect [3,22].
structures hierarchically organised like a clock with inputs to wind-
up the clock, the main pacemaker as the central machinery, and the 2.2. Central pacemaker
circadian rhythms as the clock hands.
The master clock is embedded in specialised neural structures
with specific anatomical organisation in different organisms: for
2. Structure and organisation
example, the optic and cerebral lobes in insects; the eyes in certain
invertebrates and vertebrates; the pineal gland in low vertebrates
The circadian system differs in its cellular and molecular organi-
(several fish, amphibians, and reptiles). In mammals, the master
zation among species. However, its general structure is very similar
clock is located in the suprachiasmatic nucleus of the hypothalamus
and consists of: 1) inputs, i.e. sensors that receive and process the
(SCN), consisting of two small groups of around 20,000 heteroge-
information from the main zeitgebers such as light, environmen-
neous neurons with small somata together with glial cells. Each
tal temperature or food availability; 2) a central pacemaker, which
single suprachiasmatic nucleus consists of two regions in terms of
is in charge of keeping the temporal structure of the organism at
anatomical and physiological differences, the dorsomedial “shell”
pace with the inputs, of its integration in useful information and of
and the ventrolateral “core” [23–25]. The dorsomedial area has low
the transmission of this information to the organism; 3) outputs,
neuronal density and expresses arginine-vasopressin (AVP) as its
which transmit temporal signal transmission from the main clock
main neurotransmitter. The ventrolateral area is highly packed and
to every cell of the organism (Fig. 1A). In addition to the central
expresses the vasoactive intestinal polypeptide (VIP) as its main
pacemaker, in mammals there are additional oscillators in brain
neurotransmitter [24]. The light information from the retina via the
and other organs such as kidney, liver, intestine or adipose tissue,
retinohypothalamic tract to the SCN is mainly received in the ven-
whose function is to sustain the central clock. Some of the outputs
trolateral region, where expression of immediate genes is induced
present also a synchronizer effect such as scheduled sleep, activity
by light, synchronising the dorsomedial region. Therefore, it is the
and feeding time [1–3]. These overt rhythms with both components
place of reception of ventral projections and the origin of pro-
(synchroniser(s) and rhythmic physiological outputs) are known as
jections to other brain nuclei [26]. Thus, ventrolateral area is the
zeitnehmer (“time taker” in German), which is defined as an input
responsible for light synchronisation, while output regulation is
pathway that is itself rhythmically regulated by feedback from an
mediated by dorsomedial area [13,24].
oscillator [4].
At cellular level, each neuron is able to act as an independent
oscillator with a cell-autonomous period, however, the neuronal
2.1. Inputs ensemble is synchronised to produce a common periodicity [27,28].
The nature of the molecular clock residing in each neuron is a series
Living beings appeared and evolved in a cyclic environment of genetic positive and negative auto regulated transcriptional and
with the light-dark cycle as the most important environmental translational feedback loops (TTFL), evolutionarily conserved in
cue and, thus, the organisms used light information as the main metazoans [29], showing 24 h rhythms in mRNA and protein levels
zeitgeber. However, there are non-photic synchronisers that send of key clock components, even in the absence of external rhythmic
information to the main clock in order to maintain the organism inputs [30]. The transcription factors BMAL1 and CLOCK (alterna-
synchronisation [5]. tively NPAS2 in the SCN) constitute a heterodimer, which activates
In mammals, circadian photoreception occurs mainly by a sub- the expression of the clock genes Period, Cryptochromes (Per and Cry,
group of intrinsically photosensitive ganglion cells in the retina respectively) Rev-Erb˛ and Ror, as well as other clock controlled
(ipRGCs) due to the presence of melanopsin [6,7], which shows genes (CCGs, representing approximately a 10% of the complete
a maximum sensitivity in vivo from 440 to 480 nanometres [8]. genome), by binding to E-box enhancement elements [29]. PER and
In addition, these ipRGCs receive also information from rods and CRY dimerize and inhibit their own expression by translocation
cones [9,10], integrating different information sources to provide into the nucleus, and also acting as repressor of the CLOCK:BMAL1
a unique input for the central pacemaker [11–13]. This informa- heterodimer with a delay of several hours [31]. A second regula-
166 E. Terzibasi-Tozzini et al. / Seminars in Cell & Developmental Biology 70 (2017) 164–176

Fig. 1. Simplified model of the mammalian circadian system and its molecular clock.
A) Mammalian circadian system involves the inputs (mainly environmental cues that entrain the central pacemaker and sometimes the peripheral clocks independently),
central pacemaker (located on the suprachiasmatic nucleus, it maintains the internal temporal order), peripheral clocks (located in every cell of the organism, they are under
the central pacemaker control but they can desynchronise from the main clock) and outputs (overt rhythms generated by the central pacemaker and the peripheral clocks,
some of them act also as input providing feedback to the main clock and peripheral oscillators). OB: olfactory bulb; SCN, suprachiasmatic nucleus.
The molecular clock comprises of the interaction between two feedback loops: two positive ( ) including CLOCK (alternatively NPAS2 in the SCN) and BMAL1 heterodimer
as main component promoting Per, Cry, Rev-Erb˛, Rora and clock controlled genes (CCG) transcription and RORA as Bmal1 transcription activator, and two negative ( )
involving PER-CRY heterodimer which inhibits Per, Cry, Rev-Erb˛ and Rora transcription while REV-ERB␣ proteins inhibit Bmal1 transcription. See the text for more details.

tory loop is induced by CLOCK:BMAL1 heterodimers that activates
the transcription of retinoic acid-related orphan nuclear recep-
tors, Rev-erb␣ and Ror␣. At a second stage, REV-ERB␣ and ROR␣
compete to bind retinoic acid-related orphan receptor response
elements (ROREs) present on the Bmal1 promoter. REV-ERB pro-
teins repress Bmal1 transcription [32], while ROR proteins activate
it [33] (Fig. 1B). However, transcription oscillation of the gene Clock
is very weak, if not arrhythmic in the mammalian circadian sys-
tem [34]. Members of the Ror family (␣, ␤ and ␦) also present
strikingly different expression patterns across tissues with vary-
ing circadian peak times [33]. Data from several studies ultimately
suggest that ROR proteins may contribute differently to promote
rhythmic Bmal1 expression in a tissue-dependent manner [35],
implying a Bmal1 essential role in a variety of functions, depending
on the tissue in which it is activated [36–38]. Finally, several iso-
forms of Casein Kinase I are involved in the degradation of PER by
the proteasome, regulating the negative TTFL [39].
This molecular clock was demonstrated to be ubiquitous in
every cell-type studied [40], a question therefore emerged about
as to the molecular differences between the master clock and
all the other peripheral clocks. In this context, it was suggested
that the SCN generates oscillations autonomously and synchro-
nises the peripheral clocks [41]. Most peripheral oscillators follow
the circadian pacemaker with a 6–8 h delay and the coupling
between peripheral oscillators and central pacemaker is affected
and modulated by the cellular energetic metabolism, in a manner
that can overcome the SCN pacemaker action. For example, it has
been described that time restricted feeding can uncouple the liver
peripheral clock from the SCN central clock [42]; in addition, it is
possible to alter also the SCN by means of ultradian feeding [43]. At
present, the cellular processes that allow such a fine-tuned control
of the central pacemaker on the peripheral oscillators of the differ-
ent organs and tissues are far from being totally understood and
they represent a field of current intense investigation.
2.3. Outputs
The SCN drives the organism by means of neural or humoral
mediators that synchronise peripheral clocks inside and outside
the brain. The SCN has connections to the subparaventricular
 E. Terzibasi-Tozzini et al. / Seminars in Cell & Developmental Biology 70 (2017) 164–176
zone (SPZ), dorsomedial hypothalamus (DMH) and paraventricu-
lar nucleus (PVN) [44]. The SPZ regulates core body temperature
by projections to the medial preoptic area [45]. In addition, SPZ
sends connections to DMH, which controls sleep-wake pattern
through projections to the ventrolateral preoptic area [46]. Feeding
behaviour and activity are also controlled by DMH by connect-
ing with the lateral hypothalamus (LH) and the orexygenic system
[47–49]. Moreover, SCN has preautonomic neurons which regu-
late the sympathetic-parasympathetic balance innervating LH and
PVN [50]. At last, SCN drives the release of a variety of releasing
hormones such as corticoids, gonadotropin and thyrotropin [51].
For the study of the human circadian clock, a direct measure of
SCN activity is not possible. Thus, a reliable overt rhythm is neces-
sary for assessing the SCN functionality (known as circadian marker
rhythm). From the wide range of physiological variables showing
circadian oscillation, only a few present all the characteristics that
are expected for a circadian marker: i) large amplitude, ii) reliable
and easy-quantification, iii) specific phase relationship with the cir-
cadian clock. The most commonly used marker rhythms are core
body temperature, cortisol secretion and melatonin secretion pat-
terns [52–56]. From these, the melatonin pattern is considered the
gold standard because its synthesis and release is directly depen-
dent on the activity of the SCN [57]. Melatonin (N-acetyl-5-metoxy
tryptamine) is a pineal hormone that transmits the timekeeping
signal [58]. The key enzyme in its biosynthetic pathway is arylalky-
lamine N-acetil transferase (AA-NAT) that is modulated by nervous
input from SCN to the pineal gland through PVN [59,60]. During
night, PVN neuronal activity promotes melatonin secretion, while
light increases SCN electrical activity, which inhibits PVN neurons
and, thus, melatonin secretion [51,61]. Melatonin is produced dur-
ing the subjective night whenever the light input is absent. Thus,
the melatonin concentration shows peak at night and a minimum
during daytime. These characteristics converts melatonin into the
endocrine daily clock since high melatonin levels in blood indicate
night phase, while low values of melatonin mean daytime. Cortisol
secretion pattern is also considered a marker rhythm because it has
a stable phase relationship with melatonin and shows a circadian
pattern with the peak in the morning related to the usual awak-
ening. Another marker rhythm is core body temperature, which
shows higher values during daytime improving neurons’ trans-
mission velocity and muscular strength [62], suffering a decrease
before the sleep necessary to initiate sleep [63]. Finally, core body
temperature nadir coincides with the peak of melatonin pattern
[53].
In addition, distal skin temperature is increasingly considered as
a marker rhythm because its measurement is more comfortable for
the experimental subject than other marker rhythms, it has a stable
phase relationship with other marker rhythms such as core body
temperature or melatonin. In fact, distal skin temperature results in
antiphase and slightly phase advanced with core body temperature
[63–65] and its evening increase coincides with the onset of mela-
tonin release [66]. In addition, distal skin temperature is directly
controlled by the master clock by the sympathetic balance [50] and
favours the heat loss producing the core body temperature fall to
initiate sleep onset [56,63,67]. Finally, distal skin temperature is
maintained during constant routine protocols [68], persists after
mathematical demasking procedures [69] and it has demonstrated
its utility to assay the circadian phase [66,70,71].
3. When the age sets the rhythm. Circadian system ageing
Ageing is a universal, progressive and irreversible deleterious
process that affects all physiological functions of complex organ-
isms. The pace of this process is genetically determined and its
progression causes an increase of age-specific mortality. The cir-
167
cadian system is also affected by the ageing process at all its
structures, from the inputs to the outputs through the circadian
clock, and at all levels: morphological, physiological and biochem-
ical [72–74]. Here we will delineate circadian aging as observed in
vertebrates.
3.1. Inputs ageing
As it was mentioned above, the retina, through the retinohy-
pothalamic tract, is the main input pathway for the central clock.
Ageing affects the light reception by pupillary myosis or crystalline
lens yellowing impairing specifically blue light transmission, which
is the most important wavelength to induce the circadian entrain-
ment [74]. Interestingly, a 55 years old adult receives less than half
the circadian photoreception of a 25 years old adult. This fact pro-
duces a general weakening of the circadian system light input [75].
Thus, elderly people should exposure longer to bright light (higher
than 1000 lx) in order to counteract the light transmission impair-
ment. However, duration of bright light exposure in young adults is
shorter than 120 min [76], whereas in the elderly exposure time is
only around 30–60% of this value [77]. Furthermore, light exposure
levels are related to subjects’ well-being; in this way, individuals
with low light exposure experience sleep disorders, depression and
rhythm alterations [78].
3.2. Central pacemaker ageing
The main disturbances of the SCN during the ageing process
are the reduction in the number of neurons [79] the alteration
and/or reduction of synapses connecting them [80], functionality
impairment measured by electrical activity [81] and attenuation
of the firing rate pattern that results in a reduced day-night con-
trast [82]. In addition, there are alterations in neurotransmitters
secretion, such as the neuropeptide AVP [83]. Furthermore, using
advanced imaging systems for PER2:LUCIFERASE revealed that
each SNC individual neuron shows a normal rhythm, but there is
strong rhythm dissociation in the neuronal ensemble during age-
ing [84]. Thus, each SCN individual neuron produces an attenuated
rhythm that compounds with the lack of synchronisation to cause
an impairment of the temporal signal. In addition to the alter-
ation of the neuronal clock activity, biochemical and morphological
alterations of the suprachiasmatic nuclei occur: the rhythmicity
of the main output, melatonin, is indeed dampened by pinealo-
cyte secretion impairment, pineal size reduction and calcification
[73,85,86]. In mammals, the molecular clock experiences a gen-
eral dampening during ageing. Clock, Bmal1 and Per2 experience
an amplitude reduction, while Per1, Cry1 and Cry2 remain without
change [87–89].
3.3. Outputs ageing
Since they represent the last link in the chain of the circadian
system, it is noteworthy that output changes could be due to the
direct effect of ageing on the effector cells/organs and/or to the
indirect effect of ageing on inputs and the master clock. As it was
mentioned above, the main output of the SCN is the SPZ, which
undergoes a similar ageing process as the SCN in terms of the neural
activity rhythm [82]. Thus, the main output of the master clock is
affected by the ageing process.
In the overt rhythms, the main changes observed are a phase
advance, rhythm fragmentation, amplitude dampening and period
shortening [73]. However, as far as circadian period is concerned,
there is not a total agreement between different studies in the lit-
erature. So, it has been reported that period length of elderly is
similar to young people in a forced sleep desynchrony protocol
for melatonin and core body temperature [90]. Melatonin secre-
168 E. Terzibasi-Tozzini et al. / Seminars in Cell & Developmental Biology 70 (2017) 164–176
tion pattern experiences a consistent decrease and phase advanced
as ageing progresses [91], while activity pattern shows a damp-
ening due to the increase of night time values and a reduction of
daytime values [92,93]. Sleep-wake cycle and the core body tem-
perature pattern are characterized by a dampening, fragmentation
and phase advance during ageing [73,94]; however, women seems
to be protected since their decline is less pronounced for slow wave
sleep and sleep related brain structures and cells [95]. The ageing
of distal skin temperature rhythm shows a clear phase advance
[96]. In addition, animal models experienced the loss of anticipa-
tion capacity (lights on/off or feeding time for example), which is
an evidence of the circadian system impairment [97,98]. Recently,
a gradual and sequential process of circadian system disconnec-
tion of the environment during the last days of the organism’s life
has been described. This process ends with total disconnection and
disorganisation of the circadian system, leading to death of the
individual [99]. Finally, and in contrast to the general behaviour,
there is a group of oxidative stress inducible genes named as late
life cyclers (LLC), which gain rhythmicity or even show a circadian
rhythm for the first time in aged individuals, suggesting the exis-
tence of processes that partially compensates for the deterioration
of the central clock [100,101].
4. Circadian rhythms and cell cycle
The two main cyclic regulatory mechanisms affecting biochem-
ical reactions in cells are the cell cycle and the circadian clock (Figs.
Fig. 1B and 2). Although these two regulatory systems are charac-
terized by distinct mechanisms, many evidence indicate that these
cycles are indeed linked. For example, most mammalian diploid
cells show a 24 h cell cycle period, and the involvement of the cir-
cadian clock in the regulation of the cell cycle phases has been
widely demonstrated in the literature [102]. Based on these find-
ings, the emerging field of chronotherapy aims to identify the
optimal daytime of chemotherapeutics delivery to minimise side
effects and optimise the efficacy of different pharmacological treat-
ments [103].
Cell cycle is characterised by well-defined biochemical phases
finely tuned by a pool of regulatory factors that are synthesised,
activated and degraded during precise phases of the cell cycle
(Fig. 2) and a tight regulation of the cell cycle is crucial for the
survival of the cell. This control includes the detection and repair
of genetic damage, as well as the prevention of uncontrolled cell
division. As a demonstration of the essential role of this pro-
cess, eukaryotic cell cycle is controlled by a regulatory network
whose features are evolutionary conserved from yeast to humans
[104–106]. A fundamental role in this regulation is played by
the two protein families of Cyclins and Cyclin-dependent Kinases
(CDKs), that are responsible for the progression of the cycle by act-
ing in the form of Cyclin:CDK complexes, where they represent
the regulatory subunits and the catalytic subunits of an activated
heterodimer, respectively [107–114]. On the other hand, cell cycle
progression is prevented by the repressive action of several phase-
specific inhibitors: two major groups of inhibitory factors are
known: the cip/kip and the INK4 families (Fig. 2). Cip/kip fam-
ily includes the genes p21, p27 and p57, which stop cell cycle in
G1 phase, by binding to, and inactivating, cyclin:CDK complexes
[115,116]. Indeed, the regulatory action of the Cip/Kip family mem-
bers results to be essential for the normal developmental processes
in mammals [117]. The second group of CKIs is represented by the
INK4 family, whose members specifically bind CDK4 and CDK6 and
inhibit cyclin D association: among them, p15INK4B and p16INK4A
both have an important role in checkpoint control rather than dif-
ferentiation [118,119], and p18INK4C and p19INK4D that emerged as
a subset of CKIs essential for preventing terminal differentiation, at
least in a cell line model system [120].
Cell cycle is characterised by three main “checkpoints”, where
the cell cycle can be stopped if specific molecular/cellular require-
ments are not fulfilled [121]: the G1/S checkpoint (or “restriction
point”), where the amount of raw materials necessary to fully
accomplish DNA replication is assessed; the G2/M checkpoint,
where the presence of the right amount and composition of
cytoplasmic material to sustain the formation of two daughter
cells (and define symmetrical/asymmetrical division, for exam-
ple) is assessed; finally, the metaphase (mitotic) checkpoint,
where the correct alignment of chromosomes along the spindle
is assessed before proceeding to anaphase. The above mentioned
checkpoints are characterised by a network of regulatory pro-
teins that check and regulate the progression of the cell through
the different cell cycle phases. Regulation of cell cycle check-
points plays an important role in many physiological processes,
such as development, or embryonic and adult neurogenesis,
and their dysregulation is frequently involved in a number of
pathologies, such as several types of cancer [122–126] and devel-
opmental defects in many experimental organisms [127,128].
Therefore, they also represent ideal candidate entry points through
which the cell cycle can reciprocally interact with other key-
pathways of the cell metabolism, such as the circadian cellular
clock.
4.1. Role of clock genes in the cell cycle
At a general level, we can state that the interaction of clock-
and cell cycle-genes takes place at the level of specific cell cycle
checkpoints: more in detail, the mammalian period paralogues Per1
and Per2 seem to be part of the molecular network involved in
the repression of G1-S transition, while the circadian transcrip-
tion factors BMAL1 and CLOCK take part to the molecular network
that regulates G2-M transition [129–132]: indeed, Per1 and Clock1
involvement in the cell cycle control has been recently confirmed
in diurnal low vertebrates such as the zebrafish (Fig. 3). Moreover,
it has been reported, that PER1 associates with both CHK2 and ATM
proteins and directly participates to the signalling of ATM3-CHK2
DNA damage pathway [133].
Cell proliferation is synchronised under physiological condi-
tions and often shows asynchrony between normal and malignant
tissues, so highlighting the importance of the circadian clock in the
context of cancer and providing a strong theoretical support to the
emerging field of cancer chronotherapy approaches [134]. In par-
ticular, the tumour suppressive action of Per2, mediated through
its cell cycle control action − as indicated by the induction of apo-
ptosis, inhibition of cell growth, reduced colony formation and
growth in soft agar − has been clearly shown in several studies
[135–137]. In cancer (which obviously includes a prominent a dys-
regulation of the cell cycle) it has been reported that many CCGs,
such as c-Myc, p53, and cyclins, are involved in the regulation of
cell cycle and apoptosis [135]. Absence of p53, for example, is asso-
ciated with impaired cell cycle regulation, apoptosis inhibition and
genomic instability in many tumour conditions and the main way
by which p53 mediates tumour suppression is through elimina-
tion of abnormally proliferating cells [132,136,138]. It has been
shown that Per2 expression in MCF-7 cells significantly raises P53
levels and in Per2 expressing breast cancer cells there is an eleva-
tion in P53 expression, which contributes to promote G1 arrest and
apoptosis [136]. Indeed, it has been described that the overexpres-
sion of PER1 leads to cell death in numerous cancerous cell lines,
presumably through the activation of the ATM3-CHK2 signalling
pathway, by halting proliferation of cell and stimulating apoptosis
[133].
 E. Terzibasi-Tozzini et al. / Seminars in Cell & Developmental Biology 70 (2017) 164–176 169

Fig. 2. Cell Cycle regulation: the progression through the cell cycle is driven by the concerted action of two families of proteins, Cyclins and Cyclin-dependent kinases (CDKs),
which regulate by phosphorylation phase-specific downstream effectors, such us the Retinoblastoma-associated protein (Rb), E2F transcription factor (which promotes S
phase specific genes transcription, once relieved of its inhibitory complex with Rb by phosphorylation of the latter) and the Protein phosphatase 2A (PP2A). In turn, cyclins
and CDKs are also regulated by two main families of Cyclin-Kinases Inhibitors (CKIs): the Kip/Cip family and the INK4 family, which inhibits specific Cyclin/CDKs complexes
during different phases of the cycle.

Finally, although Per2 can function as a tumour suppressor inde-

pendently, its activity is significantly enhanced in the presence of
Cry2, its clock partner [136].

4.2. Interaction with other molecules of interest: Wee1, p21,

c-Myc and human timeless (h-tim) protein

The clock pathway controls the expression of a huge fraction

Fig. 3. Diagram of cell line progression in the adult brain of a diurnal vertebrate
(zebrafish) under 14-10 light/dark cycle (modified from [175]). S phase takes place at
the subjective evening time, and is coupled to the activation of the positive feedback
loop (+) of the circadian clock, as showed by the time window of Clock expression (ZT
11–15), whereas the end of the cycle and the next G1/S transition is strictly coupled
to the negative feedback loop (−), driven by the upregulated expression of per1 (ZT
20–23), at the subjective night end/early morning time.
(up to 10%) of all mammalian genes [100,101], most of which are
tissue- and/or organ-specifically expressed. However, some genes
of the cell cycle/DNA repair pathways are expresses in more than
one organ [139] and are functionally and molecularly linked with
specific clock genes: these interactions are essential for the main-
tenance of the genome integrity and stability [140].
The cell cycle and circadian clock are two main regulatory
systems of the cellular and organismic physiology and therefore,
the existence of reciprocal interactions between different compo-
nents of the two pathways is not surprising (Fig. 4). Indeed, the
two systems interface at some critical points. For example, it has
been demonstrated that, in proliferating cells, main clock compo-
nents affect the cell cycle by controlling Wee1 expression, a kinase
that regulates G2-M phases transition by acting on Cdc2 activi-
ties, and vice-versa Wee1 is positively regulated by CLOCK:BMAL1
heterodimers [129,141,142]
Another molecule playing a key role in the interconnection
between the two pathways is P21: this protein belongs to the
Cip/Kip family of cyclin-dependent kinase inhibitors and represses
cell cycle progression by inhibiting cyclin E-cdk2 complexes activ-
ity during G1, as well as inhibiting DNA replication via binding
to proliferating cell nuclear antigen (PCNA). Moreover, P21 is
activated by P53 after DNA damage, and its mRNA levels result
dramatically increased in Bmal1-null mice. The last observation in
particular, suggests that p21 is directly repressed by BMAL1, playing
to all effects the role of CCG [143–146].
Also the protypical onco-gene c-Myc, a major positive regula-
tor of cellular proliferation, behaves in many contexts as a CCG:
it is repressed by CLOCK:BMAL1 and, consequently, its expression
is significantly increased in Per2 mutant mice, where the Bmal1
expression is down-regulated, due to loss of its transcriptional acti-
vator PER2 [135].
170 E. Terzibasi-Tozzini et al. / Seminars in Cell & Developmental Biology 70 (2017) 164–176
Fig. 4. Molecular interaction between circadian clock and cell cycle genes (modi-
fied from [143]) – Diagram shows how the cell cycle is connected to the circadian
clock pathway at multiple levels, via WEE1, PER1 and p21: due to these interaction
molecules Clock signaling can regulate cell cycle at different phases, including G1,
G2/M transition and DNA damage response stage (G1/S).
The connection between cell cycle and circadian clock path-
ways occurs not only at transcriptional level, but also at the
protein–protein interaction and signal transduction level. For
example, TIM protein is known to be essential for a normal circa-
dian rhythm in mice and human [147,148]. TIM directly interacts
with the checkpoint proteins of the cell cycle ATR and CHK1, so
that downregulation of the circadian TIM protein interferes with
the action of CHK1:ATR3 complex on DNA damage checkpoint
response. TIM acts in all respects as a cell cycle checkpoint pro-
tein [148]. In contrast with previous studies disclaiming the role
of TIM as clock protein [149–151], it has been recently shown that
TIM represents a circadian component essential for the molecu-
lar clock pathway in the SCN [147]. The existence of two splicing
forms of mammalian TIM mRNA (the full-length Tim showing circa-
dian oscillations, and the most abundant truncated form that does
not oscillate and does not have any clock function) can explain
the strong discrepancy between experimental findings reported in
the literature. TIM acts definitely as a key-element in the connec-
tion between the two pathways, showing a bivalent role, on one
side as important cell cycle checkpoint protein [152–154], and as
active circadian clock protein on the other side [155,156]. Although
the cellular mechanisms driving the coupling of cell and circa-
dian cycle are far from being completely elucidated, it seems that
TIM protein can connect these two pathways by the contemporary
physical interaction with molecules specifically controlling the two
processes [148].
5. Circadian rhythms, neurogenesis and ageing
During embryonic development, all neuron derive from a
dynamic process during which neuroepithelial cells of the neu-
ral crest and primary neural stem cells (NSCs) give rise to several
non-neuronal and neuronal cell types, through intense prolifer-
ative events, migration, establishment of synaptic contacts and
subsequent controlled neuronal elimination by programmed death
(apoptosis).
Although it is uncontentious that terminal-differentiated cells,
such as neurons, irreversibly exit from the cell cycle, entering a
quiescent phase (G0) and lose the ability to divide [157], the incor-
poration of [3H]-thymidine into the DNA of dividing neural stem
and progenitor cells provided clear evidences for the generation
of new neurons in postnatal mouse brain regions, such as the
hippocampus and the olfactory bulb (OB) [158]. Postnatal neural
proliferation is modulated by physiological and pathological stim-
uli such as running and seizures and induction of this process is
envisaged as a promising strategy for regenerative medicine as
opposed to stem cell transplantations [159]. Conversely, NSCs also
are deeply embedded in the etiology of gliomas, one of the most
lethal forms of cancer [160]. According to what stated above, we
can easily understand the importance of a strict and finely-tuned
cell cycle regulation, to ensure the realisation of the correct cen-
tral nervous system (CNS) formation process during mammalian
development. Indeed, the deep comprehensions of the cellular
mechanisms underlying neuronal proliferation during adulthood
is an essential factor to develop further therapeutic strategies to
prevent brain damages under many different contexts, such as
age-related neurodegenerative pathologies, stroke-induced brain
injuries, etc. . .
In the past, many studies focused the attention on the role
and importance of the cell cycle components in controlling the
proliferation and differentiation of NSCs during the embryonic
development of the nervous system, by providing a deep level of
knowledge as to the cellular and molecular mechanisms underly-
ing the control of these developmental processes. However, more
recently, the interest of research in this field was attracted by the
regulatory processes carried by cell cycle control of adult NSCs. For
details, all the most recent and fundamental findings in the topic
of cell cycle machinery involvement in the regulatory mechanisms
on embryonic and adult neurogenesis are exhaustively reviewed
in [161]. However, despite a steady progress in understanding cell
cycle control in the adult brain, several questions still lack answers.
In this context, an aspect which certainly deserves attention is the
analysis of the interactions between cell cycle machinery and the
circadian clock in the organ that is best suited to integrate any form
of external inputs: the brain.
5.1. Interaction between neurogenesis and clock genes
In the last two decades, the introduction of nucleotide analo-
gous, such as bromodeoxyuridine (BrdU), as lineage tracer [162]
led to the detection of a life-long continuous neurogenesis process
in almost all mammals examined, including humans [163]. Active
adult neurogenesis is normally restricted to two “neurogenic” brain
regions, the subgranular zone (SGZ) placed in the dentate gyrus
(DG) of the hippocampus, and producing new granular neurons,
and the subventricular zone (SVZ) of the lateral ventricles which
produces new GABAergic and dopamenergic interneurons migrat-
ing to the OB through the olfactory migratory stream [164]. Several
aspects related to the adult neurogenesis molecular processes have
been studied and exhaustively reviewed in literature [165].
Adult neurogenesis can be regulated by intrinsic and extrin-
sic mechanisms at different levels, and many molecular factors
and signalling pathways have been recognised to play a promi-
nent role in neurogenesis regulation, including niche-specific
factors/receptors, cytoplasmic molecules, transcriptional factors
and epigenetic regulators [166–169].
In the last years, it has been extensively demonstrated that the
circadian molecular clock plays an essential role in the regulation of
adult neurogenesis in vertebrates, both in physiological and altered
conditions, such as ageing, spontaneous diseases, associated or
experimentally-induced neurodegenerative processes [170–178].
It has been described that the quiescent NSCs of the hip-
pocampus SGZ, which are able to re-enter in the cell cycle to
produce newborn neuron during adulthood, express molecular-
clock components, such as PER2 and BMAL1, and show a rhythmic
proliferative behaviour, with higher proliferation during the sub-
jective night of the animals [171]. In particular, absence of PER2 has
been shown to prevent the gating of cell cycle entrance of NSCs,
whereas genetic ablation of Bmal1 caused constitutively high lev-
els of proliferation, together with a delayed cell cycle exit. These
data establish a clear connection between the circadian clock and
the cell cycle control during adult hippocampal neurogenesis. On
 E. Terzibasi-Tozzini et al. / Seminars in Cell & Developmental Biology 70 (2017) 164–176
the one hand, PER2 action limits the overall number and timing
entrance of quiescent neuronal progenitors (QNPs) into the cell
cycle. On the other hand, BMAL1 is essential not only for main-
taining rhythmicity in cell-cycle entry of QNPs, but also for limiting
the number of stem cells that leave the quiescent state. The role of
clock genes in the regulation of hippocampus adult NSCs has also
been demonstrated in vitro, using neurosphere cultures from the
DG of Bmal1−/− and Cry−/− mice [170]: the absence of these clock
genes slowed down the neurospheres growth, increased apoptosis
and suppressed neuronal fate commitment (this last effect could
be ascribed to non-clock functions of Bmal1).
The molecular mechanisms by which the clock might regulate
neurogenesis are manifold, and could explain, at least in part, the
presence of heterogeneous results in the literature. Circadian clock
could directly affect differentiation by acting on E-box elements in
the promoter of neurogenic transcription factors, such as NeuroD1,
Pax6, etc. [178], or else regulate fate commitment by modulating
miRNAs. For example, the CLOCK:BMAL1 heterodimer regulates
miRNA 219, which is involved in oligodendrocyte differentiation
[179,180]. Finally, differences could be due to the use of animals
with different genetic background, age, and/or housing conditions.
It is well documented that enhanced hippocampal neurogenesis
correlates with better cognitive performances in animals under dif-
ferent experimental conditions [181–183] and the contribution of
hippocampal adult neurogenesis to vertebrates behavioural plas-
ticity is extensively reviewed in [184]: indeed, circadian rhythms
enable animals to prepare for cyclic events important for their
survival. Impairing the normal expression of core circadian clock
proteins, typically expressed in the hippocampus, causes deficits
in habituation, exploratory behaviour and learning [185]. On the
other hand, reduction of adult neurogenesis in the hippocampus
correlates with learning deficits and impaired memory func-
tions in experimental settings, neurodegeneration and ageing
[186–188]. For example, Bmal1−/− mice showed reduced learn-
ing performances and displayed accelerated ageing phenotypes
[189]. Further, Per1−/− and Per2−/− mice showed impaired trace-
fear memory, suppressed long-term potentiation, and diminished
CREB phosphorylation [190–192].
In conclusion, a deep understanding of the Neural
Stem/Progenitor Cells proliferative activity rhythms can be
fundamental to determine when the cells are least sensitive to
negative effects of specific pharmacological treatment, as in the
case of cancer chemotherapies that could be cyclically adminis-
tered at a specific NSCs cell cycle phase, in order to minimize toxic
effects on NSCs and adult neurogenesis.
5.2. Neurogenesis and ageing
A large body of studies in mammals, based on incorporation
of thymidine analogous, retroviral tracing, genetic labelling as
well as 14 C quantification and post-mortem immunohistochem-
ical investigations in humans, demonstrated that neurogenesis
persists in the adult brain with a clear age-dependent decrease
[159,193–195]. In humans, mice and dogs the number of dividing
cells in the hippocampus decreases exponentially throughout post-
natal life therefore resulting in an early decay of adult neurogenesis
[194,196–198]. Finally, age-dependent reduction of adult neuroge-
nesis has been demonstrated also in teleosts despite a much larger
population of adult neuronal stem cells [199]. Increased radial
glia (i.e. stem cell) quiescence, decreased reactivation after injury
upon unaltered neuroblast (i.e. transient amplifying progenitor)
behaviour underlies decreased neurogenesis in the ageing zebrafish
telencephalon [200]. Finally, adult neurogenesis also in old age is
highly plastic and can be enhanced by physiological stimulation
such as sensory stimulation, physical exercise and learning [159].
171
Although in the last two decades, the research on neurogen-
esis and correlated mechanisms has intensified significantly, the
neurobiological changes that contribute to the age-dependent neu-
rogenesis decrease are not yet totally understood. Quantitative
analyses of cell division in both SGZ and SVZ of young adult and
older animals, (by BrdU labelling of S-phase cells) have demon-
strated a huge decline in BrdU-labelled cells number present in
the neurogenic regions, shortly after BrdU injection, indicating
that reduced mitotic activity contributes to age-dependent decline
[162,201–209]. Nevertheless, several studies support the idea that
a large proportion of quiescent stem cells exist in the aged brain
and this population can be reactivated to restore neurogenesis at a
youthful level, as demonstrated by the fact that aged brains respond
to many stimuli, by inducing levels of neurogenic activity compa-
rable to young brains [202,203,206,207,209–214]. Other studies,
always based on the BrdU labelling method, support the conclu-
sion that ageing does not diminish the survival of newborn cells,
but rather that the decline in neurogenesis is mostly attributable
to a decreased proliferation [162,203,210]. However, although the
survival of newborn cells in neurogenic regions appears to be unaf-
fected by age, the percentage of terminally differentiated neurons
is much lower in middle-aged and old animals than in young
adults [201,203,210]. Finally, 24 h after BrdU labelling, a compara-
ble percentage of newborn cells expressing the neuroblast marker
doublecortin (Dcx) have been observed between young and old
subjects. This finding suggests that the critical steps in the cell sur-
vival determination could be not the neural commitment phase,
but rather the migration and maturation phases [215].
Given the circadian control of mitotic activity in neuronal pre-
cursors, it is highly likely that impairments of circadian rhythms
in the ageing brain affect neurogenesis. It remains to be elucidated
whether also commitment, survival and integration of newborn
neurons is under control of circadian core genes.
6. Chronodisruption and circadian system ageing
Circadian disruption or chronodisruption is the result of the mis-
alignment between the internal clock and zeitgebers, or the unstable
and/or wrong phase relationship among circadian rhythms or their
combination. This syndrome appears to be favoured by artificial
light [216] and it is frequent in people exposed to bright light at
night, darkness during daytime, chronic and/or social jet-lag and
shift-work. However, other input anomalies, such as meal shift or
frequent snacking may also result in chronodisruption [217]. In
fact, citizens of modern societies live most of their life indoors,
a very chronodisruptive environment, characterised by dim light,
warm temperatures, irregular sleep time, low physical activity and
frequent meals or constant snacking [218]. The ageing process or
lesions of the SCN can also produce internal misalignment, sup-
pressing overt rhythms, from activity to core body temperature
[219,220]. Chronodisruption is associated to a predisposition to
metabolic syndrome, cardiovascular diseases, cognitive and affec-
tive impairments, sleep disorders, premature ageing, prostatic,
mammary and colorectal cancer and, in general, higher mortality
[221–228].
Ageing is a source of chronodisruption since it affects the cir-
cadian system at all levels as we mentioned above. In summary,
the ageing process produces: 1) light entrainment impairment by
reducing light reception and blue light transmission [74]; 2) master
clock degeneration due to the reduction of the number and func-
tionality of neurons and synapses together to the attenuation of
SCN firing rate by the uncoupling of individual neurons [79–84]. In
addition, pineal size reduction and calcification impairs the main
SCN output [73,85,86]; 3) overt rhythms such as sleep-wake cycle
or activity fragmentation, phase advancing and amplitude reduc-
172 E. Terzibasi-Tozzini et al. / Seminars in Cell & Developmental Biology 70 (2017) 164–176
tion provoke a dampening of day-night contrast in aged people
[92,93], which will cause chronodisruption in the long-term.
7. Chronoenhancement: a new strategy
Chronodisruption is becoming a new health concern in the XXI
century. Thus, modern societies need countermeasures to reduce
its impact on human health. There are three main intertwined
strategies to prevent chronodisruption consisting of:
1) Circadian resonance: the perfect entrainment of the internal
clock to the environmental cues [229]. In this sense, ageing with
the circadian pacemaker not entrained with the environment is
clearly deleterious to health [230]; ageing in the absence of envi-
ronmental cues seems to be less deleterious to health [231] and
ageing with the master clock perfectly entrained to environmen-
tal cycles is the approach that can best preserve physiological
functions [84].
2) Physiological and behavioural chronoenhancement: this is
based on the enhancement of the circadian inputs to obtain an
increase in day-night contrast [218]. Because of that, the number
of possible strategies is as large as the number of circadian sys-
tem inputs. As main zeitgeber the solar light exposure shows a
strong effect increasing day-night contrast [76] and bright light
therapy reduces cognitive and affective disorders [232,233]. As
antagonist of light, darkness is also necessary, since constant
light provokes chronodisruption in short-term [234] and it is
related to some types of cancer in long-term [235]. Regular exer-
cise helps to synchronise the circadian system in humans [1] and
regular meal schedule synchronises circadian rhythms in animal
models [2]. Social interaction is able to entrain animal models;
however these results are not confirmed in humans [3]. Finally,
sleep habits have a weak synchronising power, but in humans it
partially determines light exposure and drives melatonin secre-
tion and core body temperature [20].
3) Pharmacological and genetic chronoenhancement: circadian
clocks empowering by means of chronobiotics, such as mela-
tonin, is a worldwide known strategy to delay or reduce ageing
symptoms [98,236]. In addition, dexamethasone is able to syn-
chronise the cell clock by activating Per expression in tumour
cells, which would be useful for cancer chronotherapy [237].
However, there are new chronoenhancement strategies like
genetic engineering. In this sense, overexpression of Cry delays
the onset of age-related symptoms in the fruit fly [238]. This
topic is in the cutting edge of the chronobiological research and
opens a new promising objective in cancer therapeutics.
Declaration of interest
The authors report no conflicts of interest.
Acknowledgements
Financial support: This work was supported by the Ministry
of Economy and Competitiveness, the Instituto de Salud Carlos III
through the RETICEF Network (The Aging and Frailty Cooperative
Research Network, RD12/0043/0011), CIBERFES (CB16/10/00239)
and grants 19899/GERM/15 and SAF2013-49132-C2-1-R awarded
to JA Madrid (co-financed by FEDER). This work was also funded by
A.I.R.C. (Associazione Italiana per la Ricerca sul Cancro). Thanks to
Dr. Alessandro Cellerino for the review invitation.
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