Experimental Gerontology 44 (2009) 51–56

Contents lists available at ScienceDirect

Experimental Gerontology
journal homepage: www.elsevier.com/locate/expgero

Aging in the circadian system: Considerations for health,

disease prevention and longevity
Erin M. Gibson a, Wilbur P. Williams III a, Lance J. Kriegsfeld a,b,*
a
Department of Psychology, University of California, Berkeley, CA 94720, USA
b
The Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720, USA

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

Article history: The circadian system orchestrates internal physiology on a daily schedule to promote optimal health and
Received 2 May 2008 maximize disease prevention. Chronic disruptions in circadian function are associated with an increase in
Accepted 7 May 2008 a variety of disease states including, heart disease, ulcers and diabetes. With advanced age, the genes reg-
Available online 23 May 2008
ulating circadian function at the cellular level become disorganized and the ability of the brain clock to
entrain to local time diminishes. As a result, aged individuals exhibit a loss of temporal coordination
Keywords: among bodily systems, leading to deficits in homeostasis and sub-optimal functioning. Such disruptions
Senescence
in the circadian system appear to accelerate the aging process and contribute to senescence, with some
Clock gene
CCG
systems being more vulnerable than others. This review explores aging-associated changes in circadian
Estrus function and examines evidence linking such alterations to adverse health consequences in late life
Ovulation and promotion of the aging process.
Ó 2008 Elsevier Inc. All rights reserved.

1. Introduction: the circadian system in health, disease and between the circadian clock in the brain and the environment
aging leads to pronounced clinical pathologies. One recent study found
that elderly mice subjected to temporal disruptions equivalent to
In The Wisdom of the Body, Walter B. Cannon developed the con- a flight from Washington to Paris, once a week for eight weeks,
cept of homeostasis to describe the exquisite precision in which die as a result of their bodies being out of sync with local time
countless bodily systems are maintained within finely-tuned oper- (Davidson et al., 2006). Flight attendants frequently traveling
ating limits to promote optimal health and avoid disease states. across time zones exhibit cognitive deficits associated with reduc-
When we consider homeostasis, we often overlook the fact that tions in temporal lobe structures (Cho, 2001; Cho et al., 2000).
the optimal limits for a given physiological or biochemical process Numerous studies show that shift workers have a higher inci-
vary by time of day. The circadian system orchestrates internal dence of cancer (Conlon et al., 2007), diabetes (Morikawa et al.,
events on a daily schedule to ensure that bodily systems are coor- 2005), ulcers (Koda et al., 2000), hypertension and cardiovascular
dinated with environmental time and with each other on a daily disease (Kivimaki et al., 2006), psychological disorders (Bildt and
schedule (Fig. 1). Disruptions in temporal homeostasis have pro- Michelsen, 2002) and a host of other clinical issues. These find-
nounced impact on physiological functioning, overall health and ings, although largely correlational, point to a critical role for
disease susceptibility. An endogenous, daily time-keeping system internal circadian timing in maintaining normal brain functioning
is necessary to anticipate environmental change, initiate internal and peripheral physiology.
adjustments in advance of the appropriate environmental time, With advancing age, animals exhibit numerous circadian
and maintain proper phase relationships among internal systems. disruptions (Benloucif et al., 1997; Davidson et al., 2008; Li and
It is not difficult to imagine how physiological functioning Satinoff, 1995; Valentinuzzi et al., 1997; Weinert and Waterhouse,
would suffer without an internal circadian clock synchronized 1999) that contribute to poor health consequences and hastened
to the environment. Most of us have experienced this acutely, senescence. In fact, longevity is diminished by circadian perturba-
manifested by general feelings of malaise and other maladies tions and decelerated by restoration of youthful circadian behavior
following a long flight across time zones. This loss of synchrony by transplantation of a fetal clock into the brains of aged animals
(Hurd and Ralph, 1998). The following review underscores the sig-
nificance of two fundamental functions of the circadian system,
* Corresponding author. Address: Department of Psychology, University of
internal organization and entrainment to the environment, in the
California, Berkeley, CA 94720, USA. Tel.: +1 510 642 5148; fax: +1 510 642 5293.
E-mail address: Kriegsfeld@berkeley.edu (L.J. Kriegsfeld). aging process.

0531-5565/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.exger.2008.05.007
52 E.M. Gibson et al. / Experimental Gerontology 44 (2009) 51–56

homo-dimers. These newly formed dimers then feed back to the

nucleus where they bind to the CLOCK:BMAL1 protein complex
to turn off their own transcription (reviewed in (Ko and Takahashi,
2006)) (Fig. 2).
More recently, it has become clear that the cellular clockwork is
more complex, with a number of integrated feedback loops whose
regulators are often controlled by elements of the core clock mech-
anism. Two other promoter elements have emerged as important
for circadian rhythm generation, DBP/E4BP4 binding elements
(D boxes) and REV-ERBa/ROR binding elements (RREs) (Ueda et
al., 2005). REV-ERBa, an orphan nuclear receptor, negatively regu-
lates the activity of the CLOCK:BMAL1 complex and is also acted
Fig. 1. Examples of circadian rhythms in humans. Shaded area represents times of upon by PER and CRY. Transcription of REV-ERBa is controlled by
sleep while the unshaded area represents times of activity. Note that all parameters
the same mechanism controlling Per and Cry transcription. Simi-
exhibit unique peaks and troughs relative to each other. This phase relationship
among individual rhythms is critical for optimal functioning and homeostasis. larly, the transcription factor DPB is positively regulated by the
CLOCK:BMAL1 complex (Ripperger and Schibler, 2006) and acts
as an important output mechanism by driving rhythmic transcrip-
2. The circadian system tion of other output genes via a PAR basic leucine zipper (PAR bZIP)
(Lavery et al., 1999). Whereas most work to date has focused on
Whereas a ‘master’ circadian clock has been localized to the transcriptional regulation as the key mechanism driving cellular
suprachiasmatic nucleus (SCN) located in the anterior hypothala- rhythms, post-transcriptional and post-translational events are
mus in mammals (Moore and Eichler, 1972; Stephan and Zucker, also critical for circadian coordination (Baggs and Green, 2003;
1972), it is now more appropriate to conceptualize the ‘circadian Kramer et al., 2003; Reddy et al., 2006).
system’ as an assembly comprised not only of a master clock, but In addition to transcriptional/translational control of cellular
also a series of subordinate clocks whose phase and coordinated clock function, regulatory kinases also play a pronounced role in
activity is set by the SCN. Numerous lines of converging evidence regulation of circadian period. Over a decade ago, a circadian muta-
from a host of laboratories have confirmed the role of the SCN as tion named tau was identified that resulted in a shortened circa-
a master pacemaker. For example, transplants of donor SCN tissue dian period in Syrian hamsters (Ralph and Menaker, 1988). It is
into the brains of arrhythmic, SCN-lesioned hosts restore circadian now known that the tau locus is encoded by casein kinase I epsilon
rhythmicity in behavior (Lehman et al., 1987; Ralph et al., 1990). (CKIe) (Lowrey et al., 2000; Wang et al., 2007). In normal rodents,
Importantly, rhythms are restored with the period of the donor CKIe phosphorylates PER and ‘‘tags” it for degradation throughout
SCN, indicating that the transplanted tissue does not act by restor- the day. Eventually, PER acts to overwhelm CKIe, and dimerizes
ing host-brain function but that the ‘‘clock” is contained in the with CRY to feed back to the cell nucleus. The mutant form of CKIe
transplanted tissue. Furthermore, circadian rhythms in neural fir- is unable to phosphorylate PER, leading to a short circadian period
ing rate persist in isolated SCN tissue maintained in culture (Green in tau mutants due to premature nuclear entry of PER:CRY dimers
and Gillette, 1982), demonstrating that input from extra-SCN brain (Lowrey et al., 2000; Vielhaber et al., 2000).
sites is not necessary for circadian rhythms in this nucleus. As will
be described in the following sections, the SCN has direct access to 2.2. Entrainment of the circadian system
environmental time via retinal projections to the clock. Because
subordinate central and peripheral clocks do not have access to In addition to a direct visual pathway from retinal ganglion cells
such time cues, it is necessary for the SCN to communicate such to the visual cortex, there is also a direct retinohypothalamic tract
information throughout the CNS and periphery. In addition to the (RHT) projecting from the optic nerve to the SCN (Klein and Moore,
core clock genes responsible for circadian function at the cellular 1979; Moore and Klein, 1974). This second visual pathway is nec-
level, subordinate clock-controlled genes (CCGs) represent impor- essary and sufficient to entrain (synchronize) the SCN to the envi-
tant output and local coordination systems. The stability of this ronmental light:dark cycle. Early studies of circadian
hierarchical arrangement is disrupted with advancing age (David- photoreception investigated the role of traditional rod and cone
son et al., 2008). photoreceptors in entrainment. However, mice lacking both rod
and cone photoreceptors (rd/rd) exhibit grossly normal entrain-
2.1. The molecular clock ment even though they are visually blind (Foster et al., 1993;
Freedman et al., 1999; Lucas et al., 1999; Van Gelder, 2001). These
Within a cell, circadian rhythms are produced by autoregulato- findings led to a search for a novel non-rod, non-cone photorecep-
ry transcriptional/translational negative feedback loops that take tor necessary for photic entrainment. Several years of rapid discov-
approximately 24 h. While the general mechanism for circadian ery beginning in this millennium identified a subset of light-
oscillations at the cellular level is common among organisms, the responsive ganglion cells containing the photopigment, melanop-
components comprising the feedback loop differ. For the purpose sin (Berson et al., 2002; Hannibal and Fahrenkrug, 2002). These
of clarity, only the core mammalian feedback loop is described. ganglion cells project directly to the SCN and were initially thought
Earlier work proposed a core feedback loop that begins when to be the sole photoreceptors necessary for entrainment. However,
two proteins, CLOCK and BMAL1, bind to one another and drive melanopsin deficient mice exhibit only minor impairments in
the transcription of messenger RNA (mRNA) of the Period (Per) entrainment (Lucas et al., 2003; Panda et al., 2002; Ruby et al.,
and Cryptochrome (Cry) genes by binding to the E-box (CACGTG) 2002). This discrepancy was resolved by showing that entrainment
domain on these gene promoters. Three Period (Per1, Per2 and is abolished in mice doubly mutant for both melanopsin and tradi-
Per3) and two Cryptochrome (Cry1 and Cry2) genes have been iden- tional rod/cone photoreceptors (Hattar et al., 2003; Panda et al.,
tified. The mRNA for these genes is translated into PER and CRY 2003). These findings suggest that traditional rod/cone photore-
proteins in the cytoplasm of the cell over the course of the day. ceptors project to specialized light-responsive ganglion cells that
Throughout the day, these proteins build up within the cytoplasm, then transmit this integrated photic information directly to the
and when they reach high enough levels, they form hetero- and SCN. Thus, these two types of receptors likely work together to
 E.M. Gibson et al. / Experimental Gerontology 44 (2009) 51–56 53

Fig. 2. A simplified model of the intracellular mechanisms responsible for mammalian circadian rhythm generation. The process begins when CLOCK and BMAL1 proteins
dimerize to drive the transcription of the Per (Per1, Per2 and Per3) and Cry (Cry1 and Cry2) genes. In turn, Per and Cry are translocated to the cytoplasm and translated into
their respective proteins. Throughout the day, PER and CRY proteins rise within the cell cytoplasm. When levels of PER and CRY reach a threshold, they form heterodimers,
feed back to the cell nucleus and negatively regulate CLOCK:BMAL1 mediated transcription of their own genes. This feedback loop takes approximately 24 h, thereby leading
to an intracellular circadian rhythm. (adapted from Kriegsfeld and Silver, 2006).

entrain the circadian clock, and either receptor type can support circadian system and treatments targeting this structure may act
entrainment in the absence of the other. to ameliorate some of the deterioration seen in aged individuals.

3. Age-related changes in the circadian system 3.1. Age-related changes in circadian entrainment

With advancing age, the circadian system exhibits loss of tem- When the circadian clock is not synchronized to the environ-
poral precision (Benloucif et al., 1997; Davidson et al., 2008; Li and ment, temporal homeostasis is severely disrupted, comparable to
Satinoff, 1995; Valentinuzzi et al., 1997; Weinert and Waterhouse, some of the changes seen with aging. Consequently, one potential
1999), contributing to a variety of age-related pathologies. Such target of aging in the circadian system is the entrainment appara-
age-related changes cannot be explained by cell death or atrophy tus. Aged animals are about 20 times less sensitive to the entrain-
in the SCN, as aging does not decrease cell size or numbers in the ing effects of light relative to young animals, despite the fact that
master pacemaker (Madeira et al., 1995). However, the aged SCN they exhibit unaltered retinal innervation of the SCN (Zhang et
shows alterations in peptide expression (vasoactive intestinal al., 1998). This finding suggests that deficits in entrainment result
polypeptide (VIP) (Kawakami et al., 1997); arginine vasopressin from alterations at the level of the retina or the master clock. As
(AVP) (Roozendaal et al., 1987)) and a reduction in the amplitude aged mice do not exhibit gross morphological retinal abnormalities
of circadian rhythms of electrical activity (Satinoff et al., 1993; (Oster et al., 2003), most research has focused on the SCN as the
Watanabe et al., 1995). Transplantation of a ‘young’ SCN into aged site of entrainment alterations. Because Per1 transcription is rap-
animals yields improvements in numerous rhythmic functions, idly induced by light and is required for entrainment (Wakamatsu
including the diurnal rhythm of corticotropin-releasing hormone et al., 2001), the induction of Per1 makes a convenient assay for
(CRH) and behavioral rhythms in locomotion (Cai et al., 1997; Li investigating the response of the SCN to a phase-resetting light
and Satinoff, 1995). Together, these studies suggest that the SCN pulse. In aged animals, Per1 expression following an entraining
is an important locus for age-related changes in the rodent light stimulus is markedly reduced with a significantly longer
54 E.M. Gibson et al. / Experimental Gerontology 44 (2009) 51–56

delay to resynchronization (Davidson et al., 2008; Kolker et al., hamsters, for example, the peak level of LH is delayed by as many
2003). In young animals, disruption of the Period genes leads to as three hours compared to the onset of the surge in young, repro-
aging-like declines in sensitivity to light (Asai et al., 2001; Weinert ductively healthy animals (Wise, 1982). The cadence seen in the
et al., 2001). These findings suggest that temporal disorganization timing and amplitude of the LH surge in middle-aged animals
with advancing age may result, in part, from reductions in the sen- has been linked to changes in GnRH activation by SCN neuropept-
sitivity of the SCN to retinal stimulation. Future studies using phar- idergic signals. The GnRH system represents the final pathway in
macological approaches to examine the response of the SCN to control of the reproductive axis in most mammalian species. It
neurochemical applications simulating retinal stimulation are nec- would be reasonable to assume that the deficit in LH surge ampli-
essary to rule out abnormal retinal signaling as a mechanism medi- tude may be a direct consequence of a decrease in GnRH peptide
ating age-related declines in entrainment. release. However, concentrations of GnRH peptide do not show
an age-related decline. Instead, the decline in reproductive capac-
ity appears to be due to changes in the activation of the GnRH sys-
3.2. Clock genes and aging
tem by the circadian clockwork. In regularly cycling young females,
34–40% of GnRH neurons express immediate early genes on the
Given the pronounced decrements in rhythmic function seen in
afternoon of proestrus compared to 9–14% in middle-aged ani-
aged animals, several studies have investigated the impact of aging
mals; the total number of GnRH-immunoreactive neurons does
on the expression of the core clock genes. The amplitude of daily
not differ between the two groups (Lloyd et al., 1994). This finding
Bmal1 expression is reduced in aged hamsters, with lower expres-
suggests that the SCN may not provide adequate stimulation to the
sion during the subjective night, when Bmal1 expression is nor-
GnRH system in aged animals. Two SCN peptides, VIP and AVP,
mally at its peak, compared to young animals (Kolker et al.,
have long been implicated in stimulation of the reproductive axis.
2003). Bmal1 knockout animals are arrhythmic (Bunger et al.,
VIP mRNA but not AVP mRNA becomes arrhythmic in the SCN of
2000), indicating the importance of this gene in normal circadian
middle-aged female hamsters (Krajnak et al., 1998), and suppres-
cycling, and lend support for the possibility that age-related
sion of SCN VIP in young female hamsters results in accelerated
changes in circadian rhythms may result from abnormal Bmal1
deficits in GnRH activation and an LH surge that mimics that of
expression. Interestingly, reductions in Bmal1 expression are not
an aged population (Gerhold et al., 2005; Harney et al., 1996). To-
associated with changes in Per1, Per2 and Cry1 amplitude in the
gether, these findings suggest that age-related deficits in the neu-
aged SCN, indicating that the downstream targets of Bmal1 respon-
roendocrine mechanisms mediating ovulation may result from loss
sible for circadian disruption with advanced age may be distinct
of function at the level of the SCN.
from the core clock machinery (Asai et al., 2001). Clock expression
is also reduced throughout the day in the SCN of aged animals
although, importantly, mutation of the Clock gene and resulting 5. Aging and circadian changes in energetics
arrhythmicity in constant conditions does not impact the aging
process (Kolker et al., 2003). As a result, Bmal1 has remained a fo- One of the most robust phenotypes associated with aging is
cus for research exploring the role of clock genes in aging. change in energy utilization, including body fat stores. Increases
Additional evidence for a role of Bmal1 in the aging process in body fat mass and deteriorations in insulin sensitivity are asso-
comes from studies of knockout mice. Mice deficient in Bmal1 have ciated with aging in many mammalian species as well as many
a reduced lifespan and develop a number of age-related patholo- clinical pathologies, including cardiovascular disease. Data from
gies including sarcopenia, cataracts and organ shrinkage signifi- clock gene mutants demonstrate a strong circadian mechanism
cantly earlier than their wild-type counterparts (Kondratov et al., regulating adipose stores, as well as the release of insulin, a pan-
2006). These age-related pathologies indicate that some circadian creatic hormone and leptin, an adipose hormone, all of which
proteins are important for physiological processes that are not di- activate the anorexigenic pathways of energy homeostasis and re-
rectly linked to circadian function. Since many peripheral tissues duce food intake. The nocturnal rise in circulating leptin levels of
express clock genes endogenously (Reppert and Weaver, 2002), younger animals is attenuated in older animals, including prima-
understanding the role of peripheral clock gene oscillations in tes (Downs and Urbanski, 2006). The phases and amplitudes of
maintaining organ homeostasis will aid in the development of rhythms of hormones associated with metabolic function, such
strategies to treat age-related pathologies. Future studies aimed as insulin, corticosterone and prolactin, are disrupted in obese
at understanding the extent to which endogenous oscillations of aged rodents and administration of these hormones at specific
peripheral clock genes versus synchronization of these peripheral times of day mimicking the rhythms of the younger phenotype
tissues with the master pacemaker will reveal changes in the are able to re-establish metabolic characteristics of younger ani-
maintenance of organ and tissue homeostasis in aging animals. mals (Cincotta et al., 1993). Age-related alterations in corticoste-
rone secretion are a direct result of the eradication of the diurnal
4. The circadian system and reproductive aging rhythm of its hypothalamic-releasing peptide CRH (Cai and Wise,
1996). Fetal SCN grafts implanted into the brains of middle-aged
Age-related decline in reproductive axis function is common rats restores the diurnal rhythm of CRH (Cai et al., 1997). The
across species, with initiation of this decline typically occurring reinstatement of CRH rhythms in middle-aged rats by fetal SCN
midway through life. Because females are affected earlier in life is unique, as other neuroendocrine rhythms are not restored by
and to a greater extent than males, research to date has focused such grafts (Kriegsfeld and Silver, 2006). Future studies are
on female reproductive aging and the circadian system. In regu- needed to fully delineate if re-establishing temporal rhythms in
larly cycling female rodents, a daily circadian signal from the aged populations through timed hormonal injections are able to
SCN coinciding with a threshold level of estrogen initiates the re-set energetic processes to allow for minimization of metabolic
gonadotropin-releasing hormone (GnRH) mediated luteinizing deficits.
hormone (LH) surge required for ovulation (reviewed in (Kriegsfeld
and Silver, 2006)). As female rodents age, the ability of the SCN to 6. Conclusions and perspectives
stimulate the surge weakens.
A delay in the timing, and attenuation of the amplitude, of the With increased understanding of the mechanisms driving age-
LH surge are hallmarks of reproductive aging. In middle-aged associated changes in the mammalian circadian clockwork, novel
 E.M. Gibson et al. / Experimental Gerontology 44 (2009) 51–56 55

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