Seminars in Cell & Developmental Biology: Eva Terzibasi-Tozzini, Antonio Martinez-Nicolas, Alejandro Lucas-Sánchez

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

(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
Fig. 3. Diagram of cell line progression in the adult brain of a diurnal vertebrate
activated by P53 after DNA damage, and its mRNA levels result
(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 dramatically increased in Bmal1-null mice. The last observation in
loop (+) of the circadian clock, as showed by the time window of Clock expression (ZT particular, suggests that p21 is directly repressed by BMAL1, playing
11–15), whereas the end of the cycle and the next G1/S transition is strictly coupled to all effects the role of CCG [143–146].
to the negative feedback loop (−), driven by the upregulated expression of per1 (ZT
Also the protypical onco-gene c-Myc, a major positive regula-
20–23), at the subjective night end/early morning time.
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].
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
Fig. 4. Molecular interaction between circadian clock and cell cycle genes (modi- and importance of the cell cycle components in controlling the
fied from [143]) – Diagram shows how the cell cycle is connected to the circadian proliferation and differentiation of NSCs during the embryonic
clock pathway at multiple levels, via WEE1, PER1 and p21: due to these interaction
development of the nervous system, by providing a deep level of
molecules Clock signaling can regulate cell cycle at different phases, including G1,
G2/M transition and DNA damage response stage (G1/S). 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
The connection between cell cycle and circadian clock path- details, all the most recent and fundamental findings in the topic
ways occurs not only at transcriptional level, but also at the of cell cycle machinery involvement in the regulatory mechanisms
protein–protein interaction and signal transduction level. For on embryonic and adult neurogenesis are exhaustively reviewed
example, TIM protein is known to be essential for a normal circa- in [161]. However, despite a steady progress in understanding cell
dian rhythm in mice and human [147,148]. TIM directly interacts cycle control in the adult brain, several questions still lack answers.
with the checkpoint proteins of the cell cycle ATR and CHK1, so In this context, an aspect which certainly deserves attention is the
that downregulation of the circadian TIM protein interferes with analysis of the interactions between cell cycle machinery and the
the action of CHK1:ATR3 complex on DNA damage checkpoint circadian clock in the organ that is best suited to integrate any form
response. TIM acts in all respects as a cell cycle checkpoint pro- of external inputs: the brain.
tein [148]. In contrast with previous studies disclaiming the role
of TIM as clock protein [149–151], it has been recently shown that 5.1. Interaction between neurogenesis and clock genes
TIM represents a circadian component essential for the molecu-
lar clock pathway in the SCN [147]. The existence of two splicing In the last two decades, the introduction of nucleotide analo-
forms of mammalian TIM mRNA (the full-length Tim showing circa- gous, such as bromodeoxyuridine (BrdU), as lineage tracer [162]
dian oscillations, and the most abundant truncated form that does led to the detection of a life-long continuous neurogenesis process
not oscillate and does not have any clock function) can explain in almost all mammals examined, including humans [163]. Active
the strong discrepancy between experimental findings reported in adult neurogenesis is normally restricted to two “neurogenic” brain
the literature. TIM acts definitely as a key-element in the connec- regions, the subgranular zone (SGZ) placed in the dentate gyrus
tion between the two pathways, showing a bivalent role, on one (DG) of the hippocampus, and producing new granular neurons,
side as important cell cycle checkpoint protein [152–154], and as and the subventricular zone (SVZ) of the lateral ventricles which
active circadian clock protein on the other side [155,156]. Although produces new GABAergic and dopamenergic interneurons migrat-
the cellular mechanisms driving the coupling of cell and circa- ing to the OB through the olfactory migratory stream [164]. Several
dian cycle are far from being completely elucidated, it seems that aspects related to the adult neurogenesis molecular processes have
TIM protein can connect these two pathways by the contemporary been studied and exhaustively reviewed in literature [165].
physical interaction with molecules specifically controlling the two Adult neurogenesis can be regulated by intrinsic and extrin-
processes [148]. sic mechanisms at different levels, and many molecular factors
and signalling pathways have been recognised to play a promi-
5. Circadian rhythms, neurogenesis and ageing nent role in neurogenesis regulation, including niche-specific
factors/receptors, cytoplasmic molecules, transcriptional factors
During embryonic development, all neuron derive from a and epigenetic regulators [166–169].
dynamic process during which neuroepithelial cells of the neu- In the last years, it has been extensively demonstrated that the
ral crest and primary neural stem cells (NSCs) give rise to several circadian molecular clock plays an essential role in the regulation of
non-neuronal and neuronal cell types, through intense prolifer- adult neurogenesis in vertebrates, both in physiological and altered
ative events, migration, establishment of synaptic contacts and conditions, such as ageing, spontaneous diseases, associated or
subsequent controlled neuronal elimination by programmed death experimentally-induced neurodegenerative processes [170–178].
(apoptosis). It has been described that the quiescent NSCs of the hip-
Although it is uncontentious that terminal-differentiated cells, pocampus SGZ, which are able to re-enter in the cell cycle to
such as neurons, irreversibly exit from the cell cycle, entering a produce newborn neuron during adulthood, express molecular-
quiescent phase (G0) and lose the ability to divide [157], the incor- clock components, such as PER2 and BMAL1, and show a rhythmic
poration of [3H]-thymidine into the DNA of dividing neural stem proliferative behaviour, with higher proliferation during the sub-
and progenitor cells provided clear evidences for the generation jective night of the animals [171]. In particular, absence of PER2 has
of new neurons in postnatal mouse brain regions, such as the been shown to prevent the gating of cell cycle entrance of NSCs,
hippocampus and the olfactory bulb (OB) [158]. Postnatal neural whereas genetic ablation of Bmal1 caused constitutively high lev-
proliferation is modulated by physiological and pathological stim- els of proliferation, together with a delayed cell cycle exit. These
uli such as running and seizures and induction of this process is data establish a clear connection between the circadian clock and
envisaged as a promising strategy for regenerative medicine as the cell cycle control during adult hippocampal neurogenesis. On
the one hand, PER2 action limits the overall number and timing Although in the last two decades, the research on neurogen-
entrance of quiescent neuronal progenitors (QNPs) into the cell esis and correlated mechanisms has intensified significantly, the
cycle. On the other hand, BMAL1 is essential not only for main- neurobiological changes that contribute to the age-dependent neu-
taining rhythmicity in cell-cycle entry of QNPs, but also for limiting rogenesis decrease are not yet totally understood. Quantitative
the number of stem cells that leave the quiescent state. The role of analyses of cell division in both SGZ and SVZ of young adult and
clock genes in the regulation of hippocampus adult NSCs has also older animals, (by BrdU labelling of S-phase cells) have demon-
been demonstrated in vitro, using neurosphere cultures from the strated a huge decline in BrdU-labelled cells number present in
DG of Bmal1−/− and Cry−/− mice [170]: the absence of these clock the neurogenic regions, shortly after BrdU injection, indicating
genes slowed down the neurospheres growth, increased apoptosis that reduced mitotic activity contributes to age-dependent decline
and suppressed neuronal fate commitment (this last effect could [162,201–209]. Nevertheless, several studies support the idea that
be ascribed to non-clock functions of Bmal1). a large proportion of quiescent stem cells exist in the aged brain
The molecular mechanisms by which the clock might regulate and this population can be reactivated to restore neurogenesis at a
neurogenesis are manifold, and could explain, at least in part, the youthful level, as demonstrated by the fact that aged brains respond
presence of heterogeneous results in the literature. Circadian clock to many stimuli, by inducing levels of neurogenic activity compa-
could directly affect differentiation by acting on E-box elements in rable to young brains [202,203,206,207,209–214]. Other studies,
the promoter of neurogenic transcription factors, such as NeuroD1, always based on the BrdU labelling method, support the conclu-
Pax6, etc. [178], or else regulate fate commitment by modulating sion that ageing does not diminish the survival of newborn cells,
miRNAs. For example, the CLOCK:BMAL1 heterodimer regulates but rather that the decline in neurogenesis is mostly attributable
miRNA 219, which is involved in oligodendrocyte differentiation to a decreased proliferation [162,203,210]. However, although the
[179,180]. Finally, differences could be due to the use of animals survival of newborn cells in neurogenic regions appears to be unaf-
with different genetic background, age, and/or housing conditions. fected by age, the percentage of terminally differentiated neurons
It is well documented that enhanced hippocampal neurogenesis is much lower in middle-aged and old animals than in young
correlates with better cognitive performances in animals under dif- adults [201,203,210]. Finally, 24 h after BrdU labelling, a compara-
ferent experimental conditions [181–183] and the contribution of ble percentage of newborn cells expressing the neuroblast marker
hippocampal adult neurogenesis to vertebrates behavioural plas- doublecortin (Dcx) have been observed between young and old
ticity is extensively reviewed in [184]: indeed, circadian rhythms subjects. This finding suggests that the critical steps in the cell sur-
enable animals to prepare for cyclic events important for their vival determination could be not the neural commitment phase,
survival. Impairing the normal expression of core circadian clock but rather the migration and maturation phases [215].
proteins, typically expressed in the hippocampus, causes deficits Given the circadian control of mitotic activity in neuronal pre-
in habituation, exploratory behaviour and learning [185]. On the cursors, it is highly likely that impairments of circadian rhythms
other hand, reduction of adult neurogenesis in the hippocampus in the ageing brain affect neurogenesis. It remains to be elucidated
correlates with learning deficits and impaired memory func- whether also commitment, survival and integration of newborn
tions in experimental settings, neurodegeneration and ageing neurons is under control of circadian core genes.
[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- 6. Chronodisruption and circadian system ageing
fear memory, suppressed long-term potentiation, and diminished
CREB phosphorylation [190–192]. Circadian disruption or chronodisruption is the result of the mis-
In conclusion, a deep understanding of the Neural alignment between the internal clock and zeitgebers, or the unstable
Stem/Progenitor Cells proliferative activity rhythms can be and/or wrong phase relationship among circadian rhythms or their
fundamental to determine when the cells are least sensitive to combination. This syndrome appears to be favoured by artificial
negative effects of specific pharmacological treatment, as in the light [216] and it is frequent in people exposed to bright light at
case of cancer chemotherapies that could be cyclically adminis- night, darkness during daytime, chronic and/or social jet-lag and
tered at a specific NSCs cell cycle phase, in order to minimize toxic shift-work. However, other input anomalies, such as meal shift or
effects on NSCs and adult neurogenesis. 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,
5.2. Neurogenesis and ageing warm temperatures, irregular sleep time, low physical activity and
frequent meals or constant snacking [218]. The ageing process or
A large body of studies in mammals, based on incorporation lesions of the SCN can also produce internal misalignment, sup-
of thymidine analogous, retroviral tracing, genetic labelling as pressing overt rhythms, from activity to core body temperature
well as 14 C quantification and post-mortem immunohistochem- [219,220]. Chronodisruption is associated to a predisposition to
ical investigations in humans, demonstrated that neurogenesis metabolic syndrome, cardiovascular diseases, cognitive and affec-
persists in the adult brain with a clear age-dependent decrease tive impairments, sleep disorders, premature ageing, prostatic,
[159,193–195]. In humans, mice and dogs the number of dividing mammary and colorectal cancer and, in general, higher mortality
cells in the hippocampus decreases exponentially throughout post- [221–228].
natal life therefore resulting in an early decay of adult neurogenesis Ageing is a source of chronodisruption since it affects the cir-
[194,196–198]. Finally, age-dependent reduction of adult neuroge- cadian system at all levels as we mentioned above. In summary,
nesis has been demonstrated also in teleosts despite a much larger the ageing process produces: 1) light entrainment impairment by
population of adult neuronal stem cells [199]. Increased radial reducing light reception and blue light transmission [74]; 2) master
glia (i.e. stem cell) quiescence, decreased reactivation after injury clock degeneration due to the reduction of the number and func-
upon unaltered neuroblast (i.e. transient amplifying progenitor) tionality of neurons and synapses together to the attenuation of
behaviour underlies decreased neurogenesis in the ageing zebrafish SCN firing rate by the uncoupling of individual neurons [79–84]. In
telencephalon [200]. Finally, adult neurogenesis also in old age is addition, pineal size reduction and calcification impairs the main
highly plastic and can be enhanced by physiological stimulation SCN output [73,85,86]; 3) overt rhythms such as sleep-wake cycle
such as sensory stimulation, physical exercise and learning [159]. or activity fragmentation, phase advancing and amplitude reduc-
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Seminars in Cell & Developmental Biology 70 (2017) 164–176

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Seminars in Cell & Developmental Biology

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

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

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

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

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

The clock pathway controls the expression of a huge fraction

opposed to stem cell transplantations [159]. Conversely, NSCs also

tion provoke a dampening of day-night contrast in aged people References

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