J Neural Transm DOI 10.1007/s00702-013-1128-4
PSYCHIATRY AND PRECLINICAL PSYCHIATRIC STUDIES - REVIEW ARTICLE
Novel putative mechanisms to link circadian clocks to healthy aging Aurel Popa-Wagner • Bogdan Catalin Ana-Maria Buga
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Received: 20 October 2013 / Accepted: 21 November 2013 Ó Springer-Verlag Wien 2013
Abstract The circadian clock coordinates the internal physiology to increase the homeostatic capacity thereby providing both a survival advantage to the system and an optimization of energy budgeting. Multiple-oscillator circadian mechanisms are likely to play a role in regulating human health and may contribute to the aging process. Our aim is to give an overview of how the central clock in the hypothalamus and peripheral clocks relate to aging and metabolic disorders, including hyperlipidemia and hyperglycemia. In particular, we unravel novel putative mechanisms to link circadian clocks to healthy aging. This review may lead to the design of large-scale interventions to help people stay healthy as they age by adjusting daily activities, such as feeding behavior, and or adaptation to agerelated changes in individual circadian rhythms. Keywords Clock genes Aging Tissue repair Metabolic syndrome
Aging, a systems biology approach Aging is associated with a decline of locomotor, sensory, and cognitive performance in humans and experimental animals. This decline is partly due to the lifelong accumulation of damage at the molecular, cellular, tissue, and organ levels.
However, these insults alone cannot account for the systematic deterioration and loss of function that characterizes the senescent phenotype making it imperative for a multisystems, multidisciplinary, integrational approach to functional senescence. There are numerous theories of aging; however, no theory sufficiently explains all the changes of the aging process. Although some changes typically occur with aging, they occur at different rates and to different extents, i.e., we can speak of ‘‘mosaic aging’’ (Walker and Herndon 2010). To improve our understanding of cells and organisms as physiological, biochemical, and genetic systems, we have to study them as an integrated informational and metabolic system. Organismal senescence is the aging of whole organisms. Various types of damage have been proposed to accumulate with age, either due to an increased rate of production, or because of decreased repair or clearance of damage with time (Kirkwood 2005). However, none of these faults seem sufficiently numerous to cause the systematic deterioration and loss of function that characterizes the senescent phenotype (Kirkwood 2008). A first attempt to develop a ‘‘network theory of aging’’ that integrates the contributions of defective mitochondria, aberrant proteins, and free radicals in the aging process has been provided by Kirkwood and Kowald (1997).
Aging, autophagy, and clock genes A. Popa-Wagner (&) A.-M. Buga Department of Psychiatry and Psychotherapy, University Rostock Medical School, Rostock, Germany e-mail: [email protected] A. Popa-Wagner B. Catalin A.-M. Buga Center of Clinical and Experimental Research, University of Medicine and Pharmacy, Craiova, Romania
Aging at the molecular level is characterized by increased levels of damaged proteins due to various post-translational modifications that include oxidation by free radicals of amino acid side chains, racemization of aspartyl and asparaginyl residues, deamidation of asparaginyl and glutaminyl residues, and oxidation of sulfhydryl groups.
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There is extensive evidence that the increased concentration of oxidative damaged proteins can be a major contributing factor in aging (Ryazanov and Nefsky 2002). Protein misfolding is also likely to contribute to the increase in the concentration of abnormal enzymes and proteins in senescent tissues. To avoid aging, the cell structure within tissues must be maintained by a continuous synthesis and degradation of worn-out molecules process, i.e., a continuous turnover process. Efficient macromolecular turnover is integral to the normal function and survival of a biological system. Although there are large variations in the rates of degradation of individual proteins, it is generally observed that the overall protein turnover slows down during aging. The physiological consequences of decreased protein turnover include the accumulation of altered and abnormal proteins, an altered pattern of posttranslational modifications due to increased dwell time and a disruption of the organization of the cytoskeleton and extracellular matrix (Martinez-Vicente et al. 2005; Rattan 2010). One mechanism involved in the regeneration of metabolic precursors and clearing subcellular debris is autophagy. Autophagy participates in the turnover of organelle (mitochondria, endoplasmic reticulum, and peroxisomes) and is required for the clearance of oxidized proteins and removal of insoluble protein aggregates which accumulate during aging and disease. Indeed, modulators of autophagy-like caloric restriction or rapamycin lowers mTOR signaling and extends the average and maximum life span of a variety of organisms including yeast, flies, worms, fish, and rodents (Fabrizio et al. 2001; Fontana et al. 2010). Furthermore, the level of autophagy genes, such as ATG5, ATG7, and BECN1 decline in the aged brain (Choi et al. 2013). Therefore, the homeostatic functions of autophagy with respect to turnover of long-lived proteins and removal of damaged organelles, and cellular debris are believed to constitute an antiaging process (Rubinsztein et al. 2011). All tissular activities are under central nervous system (CNS) control. A recent study has shown that in the lung, more than two-thirds of the probe sets showing cyclic expression peaked during the animal’s light/inactive period. Many of the genes that peaked during the inactive period included genes related to extracellular matrix, cytoskeleton, and macromolecular trafficking, which appear to be mainly involved in the turnover and remodelling of the organ (Sukumaran et al. 2011). At the same time, light triggers coordinated cyclic AMP-response element-binding protein expression and mTOR activation in the suprachiasmatic nucleus (SCN) and neurons (Cao et al. 2008). Conversely, intraventricular infusion of the mTOR inhibitor rapamycin, led to a significant attenuation of the phase-delaying effect of early-night light, while abrogation of mTOR signaling led to a significant attenuation of light-
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evoked PERIOD protein expression (Cao and Obrietan 2010).
Clock genes and aging European Union societies are all facing the effects of aging populations and the huge costs associated with age-related illnesses. Therefore, promoting healthy aging by adjusting daily activities, such as feeding behavior or adaptation to age-related changes in individual circadian rhythms is fundamental for the sustainable development of our society (Levi and Schibler 2007). The discovery of the molecular clocks that control cell activity has expanded our understanding of physiology and behavior. However, the rhythmic mechanisms by which transcriptional signals can coordinate behavioral and physiological processes are not fully elucidated (Cho et al. 2012). Anatomically, the circadian rhythms are organized in a hierarchical cascade starting from the CNS and ending in the periphery. Centrally, the circadian clock is encoded by master pacemaker neurons localized in the SCN. The input signal to the master pacemaker neurons of the SCN is provided by the light/dark cycle via the retina (Hastings et al. 2003). The circadian rhythm is driven by a molecular clock involving a transcriptional negative-feedback loop. Upon day-light stimulation, the E-box containing transcriptional activators BMAL1/NPAS2 and CLOCK will stimulate the activity of Period and Cryptochrome genes causing in turn an increase in the abundance of PER1-3 and CRY1-2 repressors that will then accumulate during the day. The PER1-3 and CRY1-2 repressors will have a negative feedback on CLOCK:NPAS2/BMAL1 transcription complex. This mechanism creates an autoregulatory loop that controls all circadian rhythms (Kume et al. 1999; Lee et al. 2001; Huang et al. 2011). The master clock in the SCN sends signals to the extraSCN neurons, which in turn modulate behavioral and physiological rhythms by aligning circadian gene oscillations within both extra-SCN neurons and peripheral tissue (Weaver 1998; Huang et al. 2011). In the peripheral tissues, local physiology is rhythmically regulated by tissue-specific networks of ligand-activated transcriptional factors that display with little or no overlap across tissues in humans (Fig. 1) and rodents (Fig. 2) (Yang et al. 2006; Hughes et al. 2009). Evolutionarily, the synchronization of circadian clocks provides an adaptive advantage by enhancing an organism’s ability to respond to daily changes in light, temperature and humidity (circadian resonance) (Woelfle et al. 2004). In invertebrates, the circadian clock coordinates the internal physiology to increase the homeostatic capacity,
Circadian clocks to healthy aging Fig. 1 Circadian rhythmicity of Bmal 1, Per3, and DBP in the human CNS. Circadian rhythmicity for physiological markers of body clock (cortisol, melatonin, temperature, and blood pressure) is also shown
thereby providing both a survival advantage to the system and an optimization of energy budgeting (Pittendrigh and Minis 1972; von Saint and Aschoff 1978; Dodd et al. 2005). In mammals, for example, a nocturnal rodent possessing a circadian timekeeper can anticipate dusk in his underground habitat and does not have to forage periodically to examine whether sunset is approaching and such anticipation may considerably reduce exposure to active daytime predators. However, with increasing age, the circadian rhythm becomes more and more disrupted. We hypothesize that age-associated disruptions in the central circadian oscillator will diminish the systemic advantage and accelerate the aging process. The hypothesized link between the circadian clock, aging, and systemic advantage is supported by several lines of evidence. A recent study investigating the association between mammalian lifespan and endogenous circadian free-running period (tau), reported that deviation of tau from 24 h was inversely related to the lifespans of rodent and primate species (Wyse et al. 2010). This result suggests that organismal efforts to redress the misalignment of endogenous rhythms and 24 h environmental cycles may be associated with a physiological cost that has a negative impact on longevity (Wyse et al. 2010). Indeed, lack of re-entrainment of endogenous circadian clock due to defective melatonin synthesis or melatonin receptors in naked mole rat leads to extended life span (Kim et al. 2011). Aging may result in selective reduced expression of the genes encoding the core clock genes like Bmal1, in the SCN, cortex, hippocampus, and caudate putamen or altered Per2 oscillations in the CA1, DG, dorsomedial
hypothalamus, and piriform cortex (Duncan et al. 2013). Moreover, Bmal1-/- mice have reduced life span and develop various symptoms of premature aging like tissue atrophy and cognitive deficits that have been largely attributed to increased tissular level of reactive oxygen species (Kondratov et al. 2006). Age-related changes in circadian function are accelerated in Alzheimer disease (AD) and are most likely due to neurodegeneration of SCN cells (Cermakian et al. 2011; Bonaconsa et al. 2013; Coogan et al. 2013). AD patients exhibit less diurnal and increased nocturnal activity that becomes manifested by nocturnal awakening and increased daytime sleep bouts (McClung 2011). Similarly, the rhythmic expression of Bmal1, Cry1, Per1 in the pineal gland of AD is lost (Wu et al. 2007). Similar alterations in sleep–wake rhythms, but no significant changes in the daily activity rhythms have been recorded in the APP 9 PS1 mouse model of AD (Duncan et al. 2012). Along the same line of evidence, injection of aggregates of Abeta or cells overexpressing the toxic Abeta into the SCN of rodents causes alterations in circadian phase and a decrease in amplitude (Tate et al. 1992; Furio et al. 2002).
Circadian rhythm and health Disturbances in the circadian rhythm may have dramatic effects on our health. Circadian disruption is associated with increased morbidity and mortality (Kubo et al. 2006; Gery and Koeffler 2007), whereas robust and reset circadian rhythms could lead to better health and increased longevity (Gibson et al. 2009; Froy 2011). Moreover, phase
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A. Popa-Wagner et al. Fig. 2 Circadian rhythmicity of Clock and Bmal in the CNS and various peripheral rodent organs along with circadian variation of organ-specific genes, such as Scd1 and Srebf1 (liver), Cpl1b and Falp1 (striated muscle), Dgat1 and Mgat (fat tissue), Glut4 and Hlf (heart), Dbp (smooth muscle), Pai1 (blood vessels), and Tim (pancreas). Circadian rhythmicity for physiological markers of body clock (cortisol, melatonin, temperature, and blood pressure) is also shown. Please note the mirrored expression pattern for Bmal in the striated muscle, heart, blood vessels, and pancreas vs SNC suggesting that in the periphery each organ has a specific expression pattern
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Circadian clocks to healthy aging
shifts of the light/dark cycle induced significant mortality in aged animals (Davidson et al. 2006). It is well documented that the circadian rhythm becomes disorganized with increasing age (Kolker et al. 2003). Therefore, it comes at no surprise that transgenic mice exhibiting regular circadian patterns of food intake and body temperature during aging have increased life spans (Froy et al. 2006).
Circadian rhythm and metabolic disorders Shift workers are at an unusually high risk of metabolic syndrome, obesity, and diabetes (Bass and Takahashi 2010; Spiegel et al. 2009), not because of the nature of shift work, but because of the resulting disruptions of the circadian rhythms of meals and sleep (Pulivarthy et al. 2007). Rhythmic oscillations with a 24 h period for insulin, glucose, and leptin levels are well known (Sinha et al. 1996; Dupuis et al. 2010). Furthermore genome-wide association studies have linked clock gene variation to fasting glucose levels (Woon et al. 2007; Dupuis et al. 2010), obesity and metabolic syndrome (Scott et al. 2008). Many other studies have showed that aging-associated diseases, such as diabetes, metabolic syndrome, sleep disorders (Van Cauter et al. 1997; Bass and Turek 2005), narcolepsy (Howell et al. 2009), and obesity (Taheri et al. 2004; Spiegel et al. 1999) are tightly linked to the disturbances of the environmental light/dark cycle circadian rhythm. Mice and humans with disrupted circadian rhythms have been shown to develop metabolic disorders, including hyperlipidemia and hyperglycemia, suggesting a link between clock function and metabolic functions (Huang et al. 2011). The link is provided by an accessory feedback loop made of two nuclear receptors REV-ERB-a and REVERB-b that contribute primarily to clock stabilization. In addition, REV-ERB-a and REV-ERB-b have been also proposed to have a role in the regulation of energy metabolism (Levi and Schibler 2007; Preitner et al. 2002; Liu et al. 2008). The nuclear receptor REV-ERB alpha plays a key role in lipid metabolism and adipocyte differentiation, hepatic gluconeogenesis, and Bmal1 transcription (Yin et al. 2007; Han et al. 2012). Moreover, double knockout Rev-erb-a and Rev-erb-b mice displayed markedly altered circadian wheel running behavior and deregulated lipid homeostatic gene networks (Cho et al. 2012). In peripheral tissue like the liver, circadian oscillators may help to respond to feeding-fasting cycles by separating glycogen synthesis and degradation in time, limiting the former to the absorptive phase and the latter to the postabsorptive phase (Luna-Moreno et al. 2012). It has been demonstrated, at molecular level, that interactions between
clock networks and peripheral nutrient sensors are bidirectional: acute nutrient withdrawal or caloric restriction will induce NAD?-dependent deacetylase sirtuin 1 (SIRT1), a gene heavily involved in the regulation of life span in lower organisms and aging (Nemoto et al. 2004; Cohen et al. 2004). SIRT1 in turn can bind to CLOCK/ BMAL1 complex to regulate expression of clock genes (Asher et al. 2008; Nakahata et al. 2009; Ramsey et al. 2009). Conversly, the Clock gene can also directly regulate the energetic status of a cell by modulating the NAD? circadian oscillations and closing the regulatory loop (Nakahata et al. 2009; Ramsey et al. 2009). Recently, it was shown that Sirt1 regulates central circadian control in the brains of mice to determine the period, activity levels, and ability to adjust to re-entrainment of the central circadian clock by amplying the activity of Bmal1 (Chang and Guarente 2013). SIRT1 is an NADdependent protein deacetylase that is involved in aging and energy metabolism (Finkel et al. 2009). SIRT1 mediates the beneficial effects of caloric restriction, and its activity is thus critical in the maintenance of health (Guarente 2012; Chang and Guarente 2013).
Modulators of clock genes expression Orphan nuclear receptor ROR alpha and Rev-erba are output regulators of the circadian clock that target tissue metabolic functions (Lin et al. 2008). The loop is closed by peroxisome proliferator-activated receptors (PPAR) which are sensors of intracellular lipids and regulate lipid synthesis, storage, and fatty acid oxidation, and convey signals to the central clock by interfering with the expression of Bmal1/Clock. The nuclear receptors PPARa and c bind to the Reverba and Bmal1 promoters and up-regulate their expression. Finally, PPARc co-activator (PGC)1a potentiates RORa transcriptional activity and enhances Rev-erba and Bmal1 transcription (Lin et al. 2005). As a result, the PPAR alpha and PPAR gamma can compete with REV-ERB alpha in binding to Bmal1 promoter and inducing Bmal1 expression (Sato et al. 2004). PPAPR transcriptional factor has different roles depending on its subtype. PPAR gamma induces Bmal1 expression in blood vessels and has an important role in adipocyte differentiation and triglyceride synthesis (Semple et al. 2006). PPARa stimulates fatty acids oxidation and regulates genes controlling lipid homeostasis and as such may prevent atherosclerosis (Canaple et al. 2006). It has also been showed that SIRT1, a sensor of the energetic status of a cell, can influence clock networks through multiple mechanisms by suppressing PPAR gamma activity (Picard et al. 2004) or activating Peroxisome
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proliferator-activated receptor-gamma coactivator (Rodgers et al. 2005; Huang et al. 2011). Such studies on the circadian clock have opened new ways to treat metabolic and brain diseases with huge impact in the fields of cardiology, neurology and psychiatry (Solt et al. 2011). For example, REV-ERB alpha expression has been showed to be affected via glycogen synthase kinase 3 by lithium which is used to treat bipolar disorder, thus establishing Rev-erb alpha as a critical component of the peripheral clock and a biological target of lithium therapy (Yin et al. 2006). Other animal studies have showed that synthetic REV-ERB agonists can decrease fat mass in mice that where diet-induced to become obese, and also reduced dyslipidemia and hyperglycemia syndromes (Solt et al. 2012).
Conclusion Further research is required to understand how the master clock responds to environmental changes, such as food intake, light/dark and sleep/awake cycles, and how these affect peripheral clocks. In the end we shall be able to develop target-specific drugs that specifically interfere with the master clock or peripheral tissue clocks. Acknowledgments This work was supported by UEFISCDI, PN-IIID-PCE-2011-3-0848 and UEFISCDI FLARE2 (to A.M.B.). Conflict of interest
None.
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PSYCHIATRY AND PRECLINICAL PSYCHIATRIC STUDIES - REVIEW ARTICLE
Novel putative mechanisms to link circadian clocks to healthy aging Aurel Popa-Wagner • Bogdan Catalin Ana-Maria Buga
•
Received: 20 October 2013 / Accepted: 21 November 2013 Ó Springer-Verlag Wien 2013
Abstract The circadian clock coordinates the internal physiology to increase the homeostatic capacity thereby providing both a survival advantage to the system and an optimization of energy budgeting. Multiple-oscillator circadian mechanisms are likely to play a role in regulating human health and may contribute to the aging process. Our aim is to give an overview of how the central clock in the hypothalamus and peripheral clocks relate to aging and metabolic disorders, including hyperlipidemia and hyperglycemia. In particular, we unravel novel putative mechanisms to link circadian clocks to healthy aging. This review may lead to the design of large-scale interventions to help people stay healthy as they age by adjusting daily activities, such as feeding behavior, and or adaptation to agerelated changes in individual circadian rhythms. Keywords Clock genes Aging Tissue repair Metabolic syndrome
Aging, a systems biology approach Aging is associated with a decline of locomotor, sensory, and cognitive performance in humans and experimental animals. This decline is partly due to the lifelong accumulation of damage at the molecular, cellular, tissue, and organ levels.
However, these insults alone cannot account for the systematic deterioration and loss of function that characterizes the senescent phenotype making it imperative for a multisystems, multidisciplinary, integrational approach to functional senescence. There are numerous theories of aging; however, no theory sufficiently explains all the changes of the aging process. Although some changes typically occur with aging, they occur at different rates and to different extents, i.e., we can speak of ‘‘mosaic aging’’ (Walker and Herndon 2010). To improve our understanding of cells and organisms as physiological, biochemical, and genetic systems, we have to study them as an integrated informational and metabolic system. Organismal senescence is the aging of whole organisms. Various types of damage have been proposed to accumulate with age, either due to an increased rate of production, or because of decreased repair or clearance of damage with time (Kirkwood 2005). However, none of these faults seem sufficiently numerous to cause the systematic deterioration and loss of function that characterizes the senescent phenotype (Kirkwood 2008). A first attempt to develop a ‘‘network theory of aging’’ that integrates the contributions of defective mitochondria, aberrant proteins, and free radicals in the aging process has been provided by Kirkwood and Kowald (1997).
Aging, autophagy, and clock genes A. Popa-Wagner (&) A.-M. Buga Department of Psychiatry and Psychotherapy, University Rostock Medical School, Rostock, Germany e-mail: [email protected] A. Popa-Wagner B. Catalin A.-M. Buga Center of Clinical and Experimental Research, University of Medicine and Pharmacy, Craiova, Romania
Aging at the molecular level is characterized by increased levels of damaged proteins due to various post-translational modifications that include oxidation by free radicals of amino acid side chains, racemization of aspartyl and asparaginyl residues, deamidation of asparaginyl and glutaminyl residues, and oxidation of sulfhydryl groups.
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There is extensive evidence that the increased concentration of oxidative damaged proteins can be a major contributing factor in aging (Ryazanov and Nefsky 2002). Protein misfolding is also likely to contribute to the increase in the concentration of abnormal enzymes and proteins in senescent tissues. To avoid aging, the cell structure within tissues must be maintained by a continuous synthesis and degradation of worn-out molecules process, i.e., a continuous turnover process. Efficient macromolecular turnover is integral to the normal function and survival of a biological system. Although there are large variations in the rates of degradation of individual proteins, it is generally observed that the overall protein turnover slows down during aging. The physiological consequences of decreased protein turnover include the accumulation of altered and abnormal proteins, an altered pattern of posttranslational modifications due to increased dwell time and a disruption of the organization of the cytoskeleton and extracellular matrix (Martinez-Vicente et al. 2005; Rattan 2010). One mechanism involved in the regeneration of metabolic precursors and clearing subcellular debris is autophagy. Autophagy participates in the turnover of organelle (mitochondria, endoplasmic reticulum, and peroxisomes) and is required for the clearance of oxidized proteins and removal of insoluble protein aggregates which accumulate during aging and disease. Indeed, modulators of autophagy-like caloric restriction or rapamycin lowers mTOR signaling and extends the average and maximum life span of a variety of organisms including yeast, flies, worms, fish, and rodents (Fabrizio et al. 2001; Fontana et al. 2010). Furthermore, the level of autophagy genes, such as ATG5, ATG7, and BECN1 decline in the aged brain (Choi et al. 2013). Therefore, the homeostatic functions of autophagy with respect to turnover of long-lived proteins and removal of damaged organelles, and cellular debris are believed to constitute an antiaging process (Rubinsztein et al. 2011). All tissular activities are under central nervous system (CNS) control. A recent study has shown that in the lung, more than two-thirds of the probe sets showing cyclic expression peaked during the animal’s light/inactive period. Many of the genes that peaked during the inactive period included genes related to extracellular matrix, cytoskeleton, and macromolecular trafficking, which appear to be mainly involved in the turnover and remodelling of the organ (Sukumaran et al. 2011). At the same time, light triggers coordinated cyclic AMP-response element-binding protein expression and mTOR activation in the suprachiasmatic nucleus (SCN) and neurons (Cao et al. 2008). Conversely, intraventricular infusion of the mTOR inhibitor rapamycin, led to a significant attenuation of the phase-delaying effect of early-night light, while abrogation of mTOR signaling led to a significant attenuation of light-
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evoked PERIOD protein expression (Cao and Obrietan 2010).
Clock genes and aging European Union societies are all facing the effects of aging populations and the huge costs associated with age-related illnesses. Therefore, promoting healthy aging by adjusting daily activities, such as feeding behavior or adaptation to age-related changes in individual circadian rhythms is fundamental for the sustainable development of our society (Levi and Schibler 2007). The discovery of the molecular clocks that control cell activity has expanded our understanding of physiology and behavior. However, the rhythmic mechanisms by which transcriptional signals can coordinate behavioral and physiological processes are not fully elucidated (Cho et al. 2012). Anatomically, the circadian rhythms are organized in a hierarchical cascade starting from the CNS and ending in the periphery. Centrally, the circadian clock is encoded by master pacemaker neurons localized in the SCN. The input signal to the master pacemaker neurons of the SCN is provided by the light/dark cycle via the retina (Hastings et al. 2003). The circadian rhythm is driven by a molecular clock involving a transcriptional negative-feedback loop. Upon day-light stimulation, the E-box containing transcriptional activators BMAL1/NPAS2 and CLOCK will stimulate the activity of Period and Cryptochrome genes causing in turn an increase in the abundance of PER1-3 and CRY1-2 repressors that will then accumulate during the day. The PER1-3 and CRY1-2 repressors will have a negative feedback on CLOCK:NPAS2/BMAL1 transcription complex. This mechanism creates an autoregulatory loop that controls all circadian rhythms (Kume et al. 1999; Lee et al. 2001; Huang et al. 2011). The master clock in the SCN sends signals to the extraSCN neurons, which in turn modulate behavioral and physiological rhythms by aligning circadian gene oscillations within both extra-SCN neurons and peripheral tissue (Weaver 1998; Huang et al. 2011). In the peripheral tissues, local physiology is rhythmically regulated by tissue-specific networks of ligand-activated transcriptional factors that display with little or no overlap across tissues in humans (Fig. 1) and rodents (Fig. 2) (Yang et al. 2006; Hughes et al. 2009). Evolutionarily, the synchronization of circadian clocks provides an adaptive advantage by enhancing an organism’s ability to respond to daily changes in light, temperature and humidity (circadian resonance) (Woelfle et al. 2004). In invertebrates, the circadian clock coordinates the internal physiology to increase the homeostatic capacity,
Circadian clocks to healthy aging Fig. 1 Circadian rhythmicity of Bmal 1, Per3, and DBP in the human CNS. Circadian rhythmicity for physiological markers of body clock (cortisol, melatonin, temperature, and blood pressure) is also shown
thereby providing both a survival advantage to the system and an optimization of energy budgeting (Pittendrigh and Minis 1972; von Saint and Aschoff 1978; Dodd et al. 2005). In mammals, for example, a nocturnal rodent possessing a circadian timekeeper can anticipate dusk in his underground habitat and does not have to forage periodically to examine whether sunset is approaching and such anticipation may considerably reduce exposure to active daytime predators. However, with increasing age, the circadian rhythm becomes more and more disrupted. We hypothesize that age-associated disruptions in the central circadian oscillator will diminish the systemic advantage and accelerate the aging process. The hypothesized link between the circadian clock, aging, and systemic advantage is supported by several lines of evidence. A recent study investigating the association between mammalian lifespan and endogenous circadian free-running period (tau), reported that deviation of tau from 24 h was inversely related to the lifespans of rodent and primate species (Wyse et al. 2010). This result suggests that organismal efforts to redress the misalignment of endogenous rhythms and 24 h environmental cycles may be associated with a physiological cost that has a negative impact on longevity (Wyse et al. 2010). Indeed, lack of re-entrainment of endogenous circadian clock due to defective melatonin synthesis or melatonin receptors in naked mole rat leads to extended life span (Kim et al. 2011). Aging may result in selective reduced expression of the genes encoding the core clock genes like Bmal1, in the SCN, cortex, hippocampus, and caudate putamen or altered Per2 oscillations in the CA1, DG, dorsomedial
hypothalamus, and piriform cortex (Duncan et al. 2013). Moreover, Bmal1-/- mice have reduced life span and develop various symptoms of premature aging like tissue atrophy and cognitive deficits that have been largely attributed to increased tissular level of reactive oxygen species (Kondratov et al. 2006). Age-related changes in circadian function are accelerated in Alzheimer disease (AD) and are most likely due to neurodegeneration of SCN cells (Cermakian et al. 2011; Bonaconsa et al. 2013; Coogan et al. 2013). AD patients exhibit less diurnal and increased nocturnal activity that becomes manifested by nocturnal awakening and increased daytime sleep bouts (McClung 2011). Similarly, the rhythmic expression of Bmal1, Cry1, Per1 in the pineal gland of AD is lost (Wu et al. 2007). Similar alterations in sleep–wake rhythms, but no significant changes in the daily activity rhythms have been recorded in the APP 9 PS1 mouse model of AD (Duncan et al. 2012). Along the same line of evidence, injection of aggregates of Abeta or cells overexpressing the toxic Abeta into the SCN of rodents causes alterations in circadian phase and a decrease in amplitude (Tate et al. 1992; Furio et al. 2002).
Circadian rhythm and health Disturbances in the circadian rhythm may have dramatic effects on our health. Circadian disruption is associated with increased morbidity and mortality (Kubo et al. 2006; Gery and Koeffler 2007), whereas robust and reset circadian rhythms could lead to better health and increased longevity (Gibson et al. 2009; Froy 2011). Moreover, phase
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A. Popa-Wagner et al. Fig. 2 Circadian rhythmicity of Clock and Bmal in the CNS and various peripheral rodent organs along with circadian variation of organ-specific genes, such as Scd1 and Srebf1 (liver), Cpl1b and Falp1 (striated muscle), Dgat1 and Mgat (fat tissue), Glut4 and Hlf (heart), Dbp (smooth muscle), Pai1 (blood vessels), and Tim (pancreas). Circadian rhythmicity for physiological markers of body clock (cortisol, melatonin, temperature, and blood pressure) is also shown. Please note the mirrored expression pattern for Bmal in the striated muscle, heart, blood vessels, and pancreas vs SNC suggesting that in the periphery each organ has a specific expression pattern
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Circadian clocks to healthy aging
shifts of the light/dark cycle induced significant mortality in aged animals (Davidson et al. 2006). It is well documented that the circadian rhythm becomes disorganized with increasing age (Kolker et al. 2003). Therefore, it comes at no surprise that transgenic mice exhibiting regular circadian patterns of food intake and body temperature during aging have increased life spans (Froy et al. 2006).
Circadian rhythm and metabolic disorders Shift workers are at an unusually high risk of metabolic syndrome, obesity, and diabetes (Bass and Takahashi 2010; Spiegel et al. 2009), not because of the nature of shift work, but because of the resulting disruptions of the circadian rhythms of meals and sleep (Pulivarthy et al. 2007). Rhythmic oscillations with a 24 h period for insulin, glucose, and leptin levels are well known (Sinha et al. 1996; Dupuis et al. 2010). Furthermore genome-wide association studies have linked clock gene variation to fasting glucose levels (Woon et al. 2007; Dupuis et al. 2010), obesity and metabolic syndrome (Scott et al. 2008). Many other studies have showed that aging-associated diseases, such as diabetes, metabolic syndrome, sleep disorders (Van Cauter et al. 1997; Bass and Turek 2005), narcolepsy (Howell et al. 2009), and obesity (Taheri et al. 2004; Spiegel et al. 1999) are tightly linked to the disturbances of the environmental light/dark cycle circadian rhythm. Mice and humans with disrupted circadian rhythms have been shown to develop metabolic disorders, including hyperlipidemia and hyperglycemia, suggesting a link between clock function and metabolic functions (Huang et al. 2011). The link is provided by an accessory feedback loop made of two nuclear receptors REV-ERB-a and REVERB-b that contribute primarily to clock stabilization. In addition, REV-ERB-a and REV-ERB-b have been also proposed to have a role in the regulation of energy metabolism (Levi and Schibler 2007; Preitner et al. 2002; Liu et al. 2008). The nuclear receptor REV-ERB alpha plays a key role in lipid metabolism and adipocyte differentiation, hepatic gluconeogenesis, and Bmal1 transcription (Yin et al. 2007; Han et al. 2012). Moreover, double knockout Rev-erb-a and Rev-erb-b mice displayed markedly altered circadian wheel running behavior and deregulated lipid homeostatic gene networks (Cho et al. 2012). In peripheral tissue like the liver, circadian oscillators may help to respond to feeding-fasting cycles by separating glycogen synthesis and degradation in time, limiting the former to the absorptive phase and the latter to the postabsorptive phase (Luna-Moreno et al. 2012). It has been demonstrated, at molecular level, that interactions between
clock networks and peripheral nutrient sensors are bidirectional: acute nutrient withdrawal or caloric restriction will induce NAD?-dependent deacetylase sirtuin 1 (SIRT1), a gene heavily involved in the regulation of life span in lower organisms and aging (Nemoto et al. 2004; Cohen et al. 2004). SIRT1 in turn can bind to CLOCK/ BMAL1 complex to regulate expression of clock genes (Asher et al. 2008; Nakahata et al. 2009; Ramsey et al. 2009). Conversly, the Clock gene can also directly regulate the energetic status of a cell by modulating the NAD? circadian oscillations and closing the regulatory loop (Nakahata et al. 2009; Ramsey et al. 2009). Recently, it was shown that Sirt1 regulates central circadian control in the brains of mice to determine the period, activity levels, and ability to adjust to re-entrainment of the central circadian clock by amplying the activity of Bmal1 (Chang and Guarente 2013). SIRT1 is an NADdependent protein deacetylase that is involved in aging and energy metabolism (Finkel et al. 2009). SIRT1 mediates the beneficial effects of caloric restriction, and its activity is thus critical in the maintenance of health (Guarente 2012; Chang and Guarente 2013).
Modulators of clock genes expression Orphan nuclear receptor ROR alpha and Rev-erba are output regulators of the circadian clock that target tissue metabolic functions (Lin et al. 2008). The loop is closed by peroxisome proliferator-activated receptors (PPAR) which are sensors of intracellular lipids and regulate lipid synthesis, storage, and fatty acid oxidation, and convey signals to the central clock by interfering with the expression of Bmal1/Clock. The nuclear receptors PPARa and c bind to the Reverba and Bmal1 promoters and up-regulate their expression. Finally, PPARc co-activator (PGC)1a potentiates RORa transcriptional activity and enhances Rev-erba and Bmal1 transcription (Lin et al. 2005). As a result, the PPAR alpha and PPAR gamma can compete with REV-ERB alpha in binding to Bmal1 promoter and inducing Bmal1 expression (Sato et al. 2004). PPAPR transcriptional factor has different roles depending on its subtype. PPAR gamma induces Bmal1 expression in blood vessels and has an important role in adipocyte differentiation and triglyceride synthesis (Semple et al. 2006). PPARa stimulates fatty acids oxidation and regulates genes controlling lipid homeostasis and as such may prevent atherosclerosis (Canaple et al. 2006). It has also been showed that SIRT1, a sensor of the energetic status of a cell, can influence clock networks through multiple mechanisms by suppressing PPAR gamma activity (Picard et al. 2004) or activating Peroxisome
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proliferator-activated receptor-gamma coactivator (Rodgers et al. 2005; Huang et al. 2011). Such studies on the circadian clock have opened new ways to treat metabolic and brain diseases with huge impact in the fields of cardiology, neurology and psychiatry (Solt et al. 2011). For example, REV-ERB alpha expression has been showed to be affected via glycogen synthase kinase 3 by lithium which is used to treat bipolar disorder, thus establishing Rev-erb alpha as a critical component of the peripheral clock and a biological target of lithium therapy (Yin et al. 2006). Other animal studies have showed that synthetic REV-ERB agonists can decrease fat mass in mice that where diet-induced to become obese, and also reduced dyslipidemia and hyperglycemia syndromes (Solt et al. 2012).
Conclusion Further research is required to understand how the master clock responds to environmental changes, such as food intake, light/dark and sleep/awake cycles, and how these affect peripheral clocks. In the end we shall be able to develop target-specific drugs that specifically interfere with the master clock or peripheral tissue clocks. Acknowledgments This work was supported by UEFISCDI, PN-IIID-PCE-2011-3-0848 and UEFISCDI FLARE2 (to A.M.B.). Conflict of interest
None.
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