lable at ScienceDirect
Translational Medicine of Aging 3 (2019) 26e30Contents lists avaiTranslational Medicine of Aging
journal homepage: www.keaipubl ishing.com/TMARole of the circadian clock in fine-tuning the process of leaf senescence in plants
Hyunmin Kim, Sunghyun Hong*
Center for Plant Aging Research, Institute for Basic Science (IBS), Daegu, 42988, Republic of Koreaa r t i c l e i n f o
Article history:
Received 14 November 2018
Accepted 21 December 2018
Available online 11 January 2019
Keywords:
Leaf senescence
Circadian clock
Clock components
ORE1
Trifurcate feed-forward pathway* Corresponding author.
E-mail addresses: iamtisi@ibs.re.kr (H. Kim), shho
https://doi.org/10.1016/j.tma.2018.12.001
2468-5011/© 2019 KeAi Communications Co., Ltd. Pub
BY-NC-ND license (http://creativecommons.org/licensa b s t r a c t
Leaf senescence is a developmental process and a critical evolutionary strategy for fitness in plants,
involving highly organized regulatory mechanisms. Many environmental signals as well as internal
developmental aging trigger leaf senescence. Circadian clocks provide timing information for the
adaptation of organisms to changing environmental conditions via dynamic metabolic and physiological
regulatory networks. Interactions between aging and the circadian clock have been well characterized in
animals. In plants, recent studies reveal similar interactions between leaf senescence and the circadian
clock, supporting the evolutionary conservation of these interactions in both animal and plant kingdoms.
In this review, we discuss the major clock components and senescence regulators that connect these two
regulatory mechanisms, and the significance of this relationship in the plant life history.
© 2019 KeAi Communications Co., Ltd. Publishing Services by Elsevier B.V. on behalf of KeAi
Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).1. Introduction
Aging is inevitable in most living organisms. Each species has a
unique aging strategy. In plants, aging is associated with age-
dependent senescence and death of various organs, which is crit-
ical for maintaining fitness and productivity. Leaf senescence is a
representative example of age-dependent senescence. During leaf
senescence, plants mobilize nutrients accumulated in leaves during
the growing season via photosynthesis and nutrient uptake to the
newly developing leaves or seeds [1]. Thus, proper timing of leaf
senescence is a crucial process for maintaining the fitness of a
population. Numerous genetic and molecular studies suggest that
leaf senescence is regulated at several different levels, including
chromatin, transcriptional, post-transcriptional, translational, and
post-translational levels [2]. ‘Omics’ analyses have also expanded
our understanding of the molecular regulatory mechanisms un-
derlying the process of leaf senescence [3]. Plant-specific tran-
scription factor (TF) families, such as NAC (NAM/ATAF1,2/CUC2) and
WRKY (contains the conserved WRKY domain), serve as important
regulators of aging [4e6]. This implies that aging in plants proceeds
via unique regulatory pathways involving plant-specific TFs.
Among the several regulators of leaf senescence, ORESARA 1
(ORE1/ANAC092) has been widely studied in plants. The ORE1 gene
was isolated from Arabidopsis while screening mutants showingng@ibs.re.kr (S. Hong).
lishing Services by Elsevier B.V. on
es/by-nc-nd/4.0/).dark-induced leaf senescence [7]. It encodes one of the NAC TFs,
which positively regulates leaf senescence and mediates several
leaf senescence pathways by regulating the expression of
senescence-associated genes (SAGs) such as BIFUNCTIONAL
NUCLEASE 1 (BFN1) and SAG29 [8]. The ORE1 gene is located
downstream of the ETHYLENE INSENSITIVE 2 (EIN2) gene, which
regulates the ethylene signaling pathway. The expression of ORE1 is
increased during leaf aging, leading to age-induced cell death;
however, ORE1 expression is negatively regulated by microRNA164
(miR164). Thus, EIN2, ORE1, and miR164 form a trifurcate feed-
forward loop that modulates leaf senescence [9]. A recent report
also suggests that EIN3, a downstream regulator of EIN2, is more
closely involved in regulating ORE1 expression, and constitutes the
trifurcate feed-forward loop along with miR164 and ORE1 [10]. The
circadian clock also regulates the expression of ORE1, suggesting
the involvement of the circadian system in leaf senescence [11,12].
Almost all living organisms on earth are influenced by daily and
annual environmental cycles, including light/dark cycles and tem-
perature, caused by the rotation of the earth on its axis and its
revolution around the sun. The circadian clock senses the envi-
ronmental cycles and transduces this information to the endoge-
nous circadian system, which generates proper cyclic rhythms
adapted to the environment [13]. Thus, the circadian clock co-
ordinates most biological processes with a daily cyclic rhythm.
According to the circadian resonance hypothesis, organisms
generate accurate endogenous rhythmicity with these environ-
mental cycles to enhance their fitness [14]. In many organismsbehalf of KeAi Communications Co., Ltd. This is an open access article under the CC
H. Kim, S. Hong / Translational Medicine of Aging 3 (2019) 26e30 27including Arabidopsis, a cyclic rhythm of approximately 24 h is
generated via interconnected feedback loops of core circadian os-
cillators. In Arabidopsis, CIRCADIAN CLOCK ASSOCIATED 1 (CCA1),
LATE ELONGATED HYPOCOTYL (LHY), PSEUDO-RESPONSE REGU-
LATOR 7 (PRR7), and PRR9 comprise a morning loop, whereas
TIMING OF CAB EXPRESSION 1 (TOC1), GIGANTEA (GI), EARLY
FLOWERING 3 (ELF3), ELF4, and LUX ARRYTHMO (LUX) comprise an
evening loop. Among these proteins, ELF3, ELF4, and LUX play
similar roles in circadian regulation as components of the evening
complex (EC) [15]. The morning and evening loops are inter-
connected, and generate circadian rhythmicity according to envi-
ronmental cycles [16]. The circadian clock regulates many aspects
of plant development and physiology throughout the life cycle [17].
Flowering is a well-known example of circadian clock regulated
developmental processes. The circadian clock perceives the
photoperiod length and activates CONSTANS (CO), a key flowering
regulator, when the endogenous rhythm of plants coincides with
the photoperiod length, according to the external coincidence hy-
pothesis [18].
In animal models, the interaction between aging and the
circadian clock is reciprocal. Aging is associated with a change in
circadian rhythmicity, such as period length and amplitude of clock
gene expression [19e21]; in turn, the disruption of circadian
rhythm affects aging processes in several animal models. For
example, mutations in CLOCK and BMAL1, core clock genes, causes
age-dependent diseases including cancer and neurodegeneration
in mice [22e24]. Recent reports suggest that sirtuin1 (SIRT1), a
longevity factor, controls core clock regulators BMAL1 and CLOCK in
an age-dependent manner. Expression of SIRT1 decreases with
aging, leading to low levels of SIRT1 and low amplitude of clock
gene expression in old age [25]. Two new studies suggest that aging
reprograms the circadian transcriptome [26,27]. While the
expression of core clock genes is maintained at a constant level
during aging, the expression of circadian oscillating genes changes
with aging. The circadian clock modulates homeostasis genes in
young stage and stress response genes in old stage [26]. These
changes are reversed with a calorie restriction diet, suggesting that
age-associated physiology can be reversed by modulating the
circadian clock [27]. Thus, it is important to study the interactions
between the circadian clock and aging. In this review, we sum-
marize recent studies investigating the interactions between the
circadian clock and aging in plants.
2. Aging affects the circadian clock
Environmental cues such as light and temperature reset the
circadian rhythm of organisms daily [28]. Thus, endogenous circa-
dian rhythmicity is measured in the absence of environmental cues.
Previously, several studies in animal models have shown that the
length of the circadian period is altered during aging. The circadian
period is lengthened during aging in invertebrates, Neurospora [29]
and Drosophila [30]. Among mammals, some rodents including
hamster exhibit shortening of the circadian period with aging [31],
whereas some mouse strains show lengthening of this period with
age [32,33]. In humans, the circadian period is shortened with age
[34]. Because the endogenous circadian period is an important
parameter for enhancing the fitness of organisms, each organism
may choose to lengthen or shorten its circadian period according to
the surrounding environment. In Arabidopsis, Kim et al. (2016) have
shown that the circadian period is shortened during leaf aging [35].
The authors showed that the circadian period length of each leaf
varies; early emerging leaves exhibit a shorter circadian period
than late emerging leaves within a single plant. Additionally, third
and fourth leaves of plants of different ages exhibit shortening of
the circadian period during leaf aging. Leaf aging is faster underlong day (LD; 16 h light/8 h dark) conditions than under short day
(SD; 8 h light/16 h dark) conditions [36]. With aging, the rate of
circadian period shortening is more severe under LDs than under
SDs [35]. This explains that age is tightly associated with circadian
period changes in Arabidopsis. Among several clock mutants, only
the toc1mutant does not show a shortened circadian period during
leaf aging, indicating that TOC1 is a key clock component that links
the circadian clock and aging in Arabidopsis [35].
3. Resonance between endogenous and exogenous cycles
improves fitness
The circadian clock has evolved by selection force for adaption
to changing environments [37]. The circadian resonance hypothesis
derives from the role of the circadian clock in adaptation. According
to this hypothesis, the fitness of organisms is enhanced when the
endogenous circadian period is synchronized with the environ-
mental cycle [14]. Several reports support this hypothesis in both
plant and animal model systems. In Arabidopsis, clock mutant
plants with a long or short circadian period are healthier in con-
ditions that coincide with the endogenous cycle than in conditions
with ~24 h period [38]. For example, toc1mutant plants have ~20 h
circadian period, and exhibit greater survival and chlorophyll
content than ztlmutant plants with ~28 h endogenous period when
grown in a growth chamber with 20 h period; under ~28 h growth
condition, the fitness of ztl mutant plants is increased compared
with that of toc1mutants [38]. In themousemodel, deviation of the
circadian period from 24 h is inversely correlated with lifespan
[39,40]. The lifespan of mice with a cycle of ~24 h is increased by
approximately 20% compared with that of mice with a long or short
endogenous period [40]. In humans, several recent studies suggest
that disruption of circadian resonance due to shift work increases
the incidence of age-related diseases [41]. These results suggest
that resonance of period between endogenous and environmental
cycles is important for organismal aging.
4. Circadian components regulate leaf senescence
Investigation of leaf senescence has identified several
senescence-regulating genes including clock components. The ELF3
protein, one of the components of the EC, functions as a negative
senescence regulator by repressing PHYTOCHROME-INTERACTING
FACTOR 4 (PIF4) and PIF5 at the transcriptional level [42]. The elf3
mutants and ELF3 overexpressor (ELF3-OX) plants exhibit enhanced
and delayed leaf senescence, respectively, suggesting a novel
function of ELF3 in regulating leaf senescence. The PIF family is a
member of the basic helix-loop-helix (bHLH) TF superfamily; one of
the PIF family members, PIF3, was originally isolated as a
phytochrome-interacting molecule in yeast two-hybrid screening
[43,44]. Initially, biological functions of PIF4 and PIF5 in hypocotyl
elongation and cotyledon expansion were characterized in Arabi-
dopsis seedlings, while focusing on light signaling pathways
[45,46]. Later, Sakuraba et al. (2014) showed that PIF4/PIF5 regulate
leaf senescence by directly activating ABI5, EEL, and EIN3. It was
further revealed that PIF4/PIF5, EIN3, ABI5, and EEL directly activate
the expression of ORE1, an aging regulator, thus forming coherent
feed-forward loops [42].
ELF3 also functions in response to salt stress, one of the many
senescence-inducing factors, through the regulation of GI and PIF4
at the post-translational and transcriptional level, respectively [47].
The elf3 mutants are sensitive to salt stress, whereas ELF3-OX
plants are tolerant to salt stress. Additionally, the expression of
many salt stress-related genes and SAGs is altered in elf3 and ELF3-
OX plants, suggesting that ELF3 mediates salt stress-induced leaf
senescence. GI, a clock component, is the main inducer of
H. Kim, S. Hong / Translational Medicine of Aging 3 (2019) 26e3028photoperiod-regulated flowering [48], and is involved in the salt
stress response by inhibiting the activity of SALT OVERLY SENSITIVE
2 (SOS2), one of the main regulators of salt tolerance, via direct
physical interaction [49]. Kim et al. (2013) have shown that GI
protein is degraded under salt stress conditions, albeit via an un-
known mechanism. Sakuraba et al. (2017) have shown that ELF3
interacts with GI and promotes its degradation under salt stress
conditions. In addition, ELF3 influences SOS2-mediated salt stress
response through GI, suggesting that ELF3 directly decreases the
activity of SOS proteins [47].
In addition to ELF3, other EC components also act as negative
regulators of leaf senescence [11,50]. The EC is a key component of
the circadian clock; it maintains circadian rhythms, and integrates
light and temperature signals for coordinating the growth and
development of plants [51]. Loss-of-function mutations of EC
components (elf3, elf4, or lux) cause similar phenotypes, such as
arrhythmicity, long hypocotyl, and early flowering, regardless of
day length [52e54]. The EC has been shown to regulate PIF4 and
PIF5 expression under diurnal conditions by directly targeting the
promoters of these genes in vivo [15]. Therefore, it is reasonable to
speculate that all EC components induce early leaf senescence both
in an age-dependent manner and in dark-induced condition. Kim
et al. (2018) suggest that early flowering in EC mutants induces
early leaf senescence because both these developmental processes
(flowering and leaf senescence) are coupled by the circadian clock.
Zhang et al. (2018) propose a molecular mechanism that explains
how EC regulates phytohormone jasmonate (JA)-induced leaf
senescence in Arabidopsis. Transcriptomic profiling analyses show
that not only well-known senescence regulatory genes, such as
WRKY53, WRKY70, ORE1, and NAP, but also JA signaling and
response genes are up-regulated during EC-mediated leaf senes-
cence. Consistently, elf3, elf4, and lux loss-of-function mutants
exhibit accelerated leaf senescence phenotypes, whereas ELF3-OX
lines exhibit delayed leaf senescence phenotype following JA
treatment. Additionally, Zhang and colleagues showed that EC re-
presses the expression of MYC2, a key activator of JA-induced leaf
senescence, by directly binding to its promoter region. Genetic
analyses show that the accelerated JA-induced leaf senescence
phenotype of EC mutants is reverted by the introgression of myc2,
myc3, and myc4 mutations [50]. Collectively, these data indicate
that a core circadian complex represses leaf senescence by directly
binding to the promoter regions of genes involved in light and JA
signaling pathways.
Twomorning loop components of the circadian clock, CCA1 and
PRR9, also coordinate leaf senescence in Arabidopsis [11,12]. Song
et al. (2018) showed that cca1 and lhy single mutants exhibit
accelerated leaf senescence phenotypes compared with the wild
type under LD conditions, and the early senescence phenotype was
exacerbated in cca1lhy double mutants. Interestingly, the early
senescence phenotype of cca1 and lhy mutants is exaggerated
when the LD photoperiod is changed to day-neutral (DN; 12 h light/
12 h dark) photoperiod, suggesting that CCA1/LHY-mediated leaf
senescence could be altered by different photoperiods. Bioinfor-
matics screening of SAG promoter sequences revealed the enrich-
ment of two well-known circadian-related cis-elements, including
CCA1-binding site (CBS; AAMAATCT) and evening element (EE;
AAAATATCT). ORE1 and GOLDEN2-LIKE 2 (GLK2), a chloroplast ac-
tivity maintainer, exhibit oscillating expression patterns and harbor
putative CBSs in the promoter regions. Additionally, CCA1 nega-
tively regulates leaf senescence by repressing ORE1 expression and
activating GLK2 expression by directly binding to the promoter
regions of these genes.
Most recently, Kim et al. (2018) showed that PRR9 positively
regulates leaf senescence via the circadian control of ORE1. The
authors examined age-dependent leaf senescence in clock mutantsto determine interactions between the circadian system and leaf
senescence. Results showed that the leaf senescence phenotype of
many clock mutants is altered; however, this alteration is tightly
correlated with flowering, suggesting that the circadian clock reg-
ulates leaf senescence and flowering simultaneously. Among
several clock mutants, only the prr9 mutant showed delayed dark-
induced senescence compared with the wild type. However, no
delayed senescence (aging) phenotypes of circadian mutants have
been reported in animals [55,56]. This suggests a fundamental
difference in the interplay between senescence and circadian sys-
tem in plants vs. animals; plant senescence requires a functional
circadian system, while animal aging results from disruption of the
circadian system. They also found that many senescence-related
genes encoding TFs such as NAC and WRKY exhibit circadian
expression patterns. Among these genes, ORE1 is negatively regu-
lated by the clock-controlled miR164, a post-transcriptional
repressor of ORE1, suggesting that post-transcriptional regulation
via miRNAs in the circadian clock system is a general regulatory
mechanism in both plants and animals [57]. Furthermore, PRR9
promotes cyclic transcription of ORE1 directly by binding to the
ORE1 promoter region, and indirectly via the suppression of
miR164.
5. Perspectives and future issues
In this review, we summarized the molecular mechanisms un-
derlying the interaction between the circadian system and leaf
senescence in Arabidopsis. Recent studies have enhanced our un-
derstanding of the relationship between leaf senescence and clock
components, and initiated a newphase of clock function research in
the aging process. Circadian oscillators maintain ~24 h rhythm in
cells, tissues, organs, and organisms for the adaptation to and
anticipation of diurnal environmental cycles. Leaf aging changes
the circadian period, and TOC1 is involved in this regulation,
implying that aging information is transmitted to the circadian
system via TOC1. However, we do not yet understand why the
circadian period changes with aging. One possible reason is that
misalignment between the endogenous rhythm and 24 h environ-
mental cycles is associated with a physiological cost, which affects
longevity [40]. Another possibility is that the lengthening or
shortening of circadian period triggers age-associated physiological
processes via a species-specific strategy. We suggest that the
dissonance of the period between endogenous and environmental
cycles triggers leaf senescence. Further molecular, genetic, and
physiological analyses are required for elucidating the regulatory
mechanisms and biological significance of age-dependent period
shortening in Arabidopsis.
A variety of biotic and abiotic environmental stresses, such as
drought, shade, high salinity, nutrient toxicity and deficiency,
pollution, and microbial attacks, induce senescence [1]. Most of the
phytohormone-regulated signaling networks play critical roles in
the response of plants to these environmental changes [58].
Moreover, leaf senescence processes are interwoven with compli-
cated crosstalk among phytohormones, including JA, abscisic acid
(ABA), salicylic acid (SA), ethylene, gibberellin (GA), cytokinin (CK),
and auxin [1]. The circadian clock provides plants with an adaptive
advantage for responding to these environmental changes by
regulating phytohormone biosynthesis and signaling pathways,
and many clock components are involved in these regulations [59].
Therefore, it is possible that circadian clock components regulate
leaf senescence through hormonal signaling. Zhang et al. (2018)
provide substantial evidence supporting the role of EC in the
regulation of JA-induced leaf senescence. Further studies are
needed to understand the molecular mechanisms employed by
clock components for the coordination of stress-induced leaf
H. Kim, S. Hong / Translational Medicine of Aging 3 (2019) 26e30 29senescence via hormonal regulation.
Recent studies in Arabidopsis show that all senescence-
associated clock components regulate leaf senescence via ORE1,
which suggests ORE1 as a novel molecular hub that links circadian
components with leaf senescence processes (Fig. 1). Most senes-
cence regulatory mechanisms involving ORE1 form trifurcate feed-
forward pathways (Fig. 1), which are required for fine-tuning leaf
senescence. In addition, CCA1 and PRR9, two morning clock com-
ponents, act as negative and positive regulators of ORE1 expression,
respectively [11,12]. ORE1 expression peaks twice (once during the
day and again during the night) under LD conditions but only once
(during the day) when transferred from LD to constant light (LL)
conditions [11], indicating that the circadian clock is responsible for
the day-time peak of ORE1 expression. However, the exposure of
plants to DN growth conditions following LL reduces the intensity
of day-time peak of ORE1 expression compared with that of night-
time peak [12], suggesting that the circadian clock tightly regulates
ORE1 expression under different photoperiods, which facilitates the
adaptation of plants to seasonal changes and ensures appropriate
aging. Over the last few decades, many studies have been con-
ducted to discover aging regulators, which sense the passage of
time and control developmental transitions at the appropriate
time. ORE1 is one such aging regulator; ORE1 transcript levels are
not only gradually increased by EIN3 and miR164 during aging but
also dynamically regulated by the circadian clock during the day
(Fig. 1). The circadian clock is an endogenous self-sustained
mechanism that measures the passage of time and affects devel-
opmental processes such as flowering and leaf senescence in
plants; thus the circadian clock is a potential candidate for agingFig. 1. Reciprocal interaction networks between the circadian clock and aging in
Arabidopsis. Many circadian components are involved in the regulation of leaf
senescence in Arabidopsis. The evening complex (EC) regulates jasmonate-induced leaf
senescence by controlling MYC2 expression. ELF3, a component of EC, negatively af-
fects ORE1 expression by repressing PIF4. ELF3 also plays a role in salt-induced leaf
senescence together with GI by regulating the SOSs. A trifurcate feed-forward pathway,
comprising EIN3, miR164, and ORE1, regulates leaf senescence. CCA1 negatively reg-
ulates ORE1 expression, and forms two kinds of trifurcate feed-forward pathways with
GLK2 or PRR9, and PRR9 forms another trifurcate feed-forward pathway with ORE1
and miR164. Reciprocally, the aging signal integrates with the circadian clock through
TOC1, one of the core oscillators, resulting in the shortening of the circadian period
with leaf aging. Colored triangles surrounded by regulatory lines indicate trifurcate
feed-forward pathways.regulators. Understanding the mechanisms of leaf senescence by
exploring the regulatory relationships among these aging regula-
tors will provide further insights into the aging process.
Acknowledgments
We thank J. H. Park for designing figure. This research was
supported by the Institute for Basic Science (IBS-R013-D1).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tma.2018.12.001.
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