- Email: [email protected]
Circadian Rhythms: Per2bations in the Liver Clock
Current Biology Vol 17 No 8 R292
Circadian Rhythms: Per2bations in the Liver Clock A master circadian clock resides in the brain and is required to synchronize the clocks in peripheral tissues such as the liver. Until now, it has been unclear how the central clock synchronizes the peripheral ones. New work points to one of the core clock genes, mPer2, as an essential link in this chain. Akhilesh B. Reddy and Elizabeth S. Maywood Circadian rhythms define our daily existence. By coordinating our metabolic status, hormonal milieu, body temperature and sleep–wake state over the day, circadian clocks act as an internal metronome [1]. In mammals, the master clock resides in the suprachiasmatic nuclei (SCN) of the brain’s hypothalamus — setting internal time for the rest of the body. The molecular SCN clockwork consists of interconnected negative feedback loops in which clock gene expression is repressed by their cognate proteins: activating transcription factors BMAL1 and CLOCK drive the loop, and the negative factors PER1, PER2, CRY1 and CRY2 close it, completing an approximately 24 hour cycle [1,2]. An accessory feedback loop, in which the orphan nuclear receptor REV-ERBa periodically represses Bmal1 transcription, enhances the oscillator’s stability, precision and robustness [3]. As well as this central clock, it is now well recognized that individual peripheral tissues, and indeed the cells within them, have autonomous circadian clocks, similar to those within the SCN [1,2]. But how does the SCN communicate with the rest of the body to synchronize the organism’s timing, and what are the molecular events involved in mediating peripheral clock resetting? Recent work by Kornmann et al. [4] has pushed us closer to understanding central-peripheral clock interactions by adopting an elegant systems-level approach. First, they cleverly created a transgenic mouse in which a tetracycline antibiotic (doxycycline) could be used to turn
the liver clock (and only the liver clock) on and off at will by switching REV-ERBa expression. With the liver clock turned on, they found that about 350 genes had a robust circadian rhythm of expression as assayed by Affymetrix GeneChip transcriptional profiling. When the liver’s clock was turned off by feeding the animals doxycycline, they were able to unmask the effects of systemic cues, arising from the still ticking SCN clock, on circadian expression in the liver. They found that almost 90% of the circadian genes failed to oscillate in the ‘timeless’ liver. But, amongst the 31 transcripts that continued to oscillate unabated, was the canonical clock gene mPer2. Thus, even though the liver clock was disabled, systemic cues were able to keep mPer2 expression ticking. So, is circadian mPer2 expression in the liver simply a result of systemic cues or does the liver’s own clock also control its transcription? To investigate this, Kornmann et al. [4] used a mouse in which the luciferase coding sequence had been knocked-in into the native mPer2 gene to make an mPer2::luciferase (mPer2::luc) fusion gene [5]. The resultant mice make mPER2:LUC fusion proteins which function just like the wild-type, untagged mPER2 protein [5]. With this technology, the group was able to monitor transcription of mPer2 in vitro by explanting liver tissue from these mice, and using luciferase to report mPer2 expression. When they did this, they found that the explanted livers displayed robust mPer2::luc rhythms ex vivo — in the absence of any systemic circadian cues. Thus, the group [4] has shown dissociable behaviours of mPer2: it is both part of the core oscillator but also a target of systemic
cues — a mediator of internal synchrony. Why should biomedicine be interested in this biological subsidiarity between central and peripheral clocks? Well, the role of peripheral clocks is to drive tissue-specific local metabolic programmes, as revealed by transcriptional profiling (as used above) [6–9] and by proteomic analyses [10]. This has shown that key metabolic pathways in the liver are under circadian control, with the clock directing the expression of rate-limiting enzymes, at both the transcriptional and protein level [6–10]. This tissue-level orchestration of gene and protein expression optimizes the tissue to perform its specialized role in vivo, most obviously temporally segregating incompatible catabolic and anabolic processes. Moreover, accumulating evidence points to the fact that, in the case of the liver, circadian clocks are important in the proper coordination of the cell cycle and the metabolism of drugs (including cytotoxic chemotherapeutic agents) and toxins [1,6,11,12]. This has obvious clinical and biological relevance. Although we now have a good understanding of circadian programming in peripheral tissues, and its importance to normal biological function, until now we have had little concrete information on how synchrony between the master central clock and peripheral oscillators is achieved: in particular, what are the systemic cues that could address local Per2 expression and thereby mediate synchronization between central and peripheral clocks? The master clock in the SCN regulates many rhythms that could be used as systemic cues, such as autonomic activity, hormone levels and body temperature [1,2]. The latter has been proposed as a key regulator by Kornmann et al. [4] because of their finding that oscillation of a variety of temperature-regulated proteins, like that of mPer2, is dependent on systemic cues [4]. Interestingly, both heat-inducible transcripts (encoding various heat-shock proteins) and an antiphasic
Dispatch R293
SCN
Central
Temp
Glu Per2 HNF4a
Peripheral
Liver Current Biology
Figure 1. A model for central-peripheral synchronization of the circadian system. Left: schematic view of peripheral tissue-based clocks synchronised by the SCN pacemaker. Right panel shows, specifically, how the central clock in the SCN transmits time information via a variety of systemic cues including glucocorticoids (Glu) and temperature (Temp). These systemic cues are then able to alter expression of mPer2 in the liver to synchronize local clocks. In addition to mPER2, key liver-specific proteins, such as the glucocorticoid-responsive HNF4a, likely play roles in local synchronization and circadian transcriptional programming.
cold-activated gene (cold-induced RNA-binding protein) were still rhythmic when the liver clock was turned off in vivo. The implication from this is that temperature cycles are important in entraining the liver in vivo. Furthermore, the team provided tantalising data suggesting that mPer2 is also heat-inducible, using transcription of mPer2::luc in explanted livers as a readout following heat-shock to 40 C in vitro. Is this the whole story though — do body temperature cycles explain central–peripheral synchronization? Generally, biological systems do not use a single method to achieve a goal, and this redundancy allows stability and robustness, so what other cues might be involved? Endocrine rhythms, in particular circadian glucocorticoid variation, have attracted recent attention. Glucocorticoid signalling has been found to affect transcription of a limited number of core clock genes both in cells and in vivo, implying a role in peripheral resetting [13–15]. Another recent study [16] complements the work of Kornmann et al. [4] by using SCNlesioned mice and transcriptional profiling to address the role of glucocorticoid signalling in synchronizing the liver clock in vivo. By removing the SCN from the equation, rhythmic systemic cues
are not present in lesioned mice, meaning that perturbations by potential synchronizers can be examined in vivo [16]. In this case, injections of the glucocorticoid analogue dexamethasone were used to probe circadian gene expression in the livers of SCN-lesioned animals. Importantly, this study also found that mPer2 is a target for glucocorticoids in vivo. But it also highlighted an integral liver transcription factor, hepatocyte nuclear factor 4 alpha (HNF4a) as a key target for circadian and glucocorticoid-mediated orchestration of liver gene expression [16]. Thus, glucocorticoids, as well as body temperature, are likely to be key synchronizers of the liver clock, acting through transcriptional cascades involving mPer2 and other regulators (Figure 1). Synchronization of central and peripheral clocks is important for proper coordination of different organs in the body. The findings discussed above clearly highlight that mPer2 is a convergent target for at least two systemic cues: body temperature and glucocorticoids (Figure 1). In this regard, it is special amongst the other ‘core’ clock genes. Compelling evidence for its importance in vivo is provided by numerous observations, such as
the striking phenotype of the mPer2 knockout mouse [17] and the significant finding that tumourgenesis is accelerated in mPer2-deficient mice [18,19]. Rather than mPer2 being a tumour-suppressor gene per se, its loss may instead result in aberrant circadian programming, producing excess cell turnover within tissues [11]. Certainly, to date, mPER2 seems to do it all — it is an integral part of the central and peripheral molecular clockwork but can respond to extraneous cues, such as light-activation of SCN cells, and internal cues, such as temperature and glucocorticoid effects in liver, to reset local tissue clock time [2]. Whether it is unique in this regard, however, remains to be seen. References 1. Hastings, M.H., Reddy, A.B., and Maywood, E.S. (2003). A clockwork web: circadian timing in brain and periphery, in health and disease. Nat. Rev. Neurosci. 4, 649–661. 2. Reppert, S.M., and Weaver, D.R. (2002). Coordination of circadian timing in mammals. Nature 418, 935–941. 3. Preitner, N., Damiola, F., Luis Lopez, M., Zakany, J., Duboule, D., Albrecht, U., and Schibler, U. (2002). The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110, 251–260. 4. Kornmann, B., Schaad, O., Bujard, H., Takahashi, J.S., and Schibler, U. (2007). System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock. PLoS Biol. 5, e34. 5. Yoo, S.H., Yamazaki, S., Lowrey, P.L., Shimomura, K., Ko, C.H., Buhr, E.D., Siepka, S.M., Hong, H.K., Oh, W.J., Yoo, O.J., et al. (2004). PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc. Natl. Acad. Sci. USA 101, 5339–5346. 6. Akhtar, R.A., Reddy, A.B., Maywood, E.S., Clayton, J.D., King, V.M., Smith, A.G., Gant, T.W., Hastings, M.H., and Kyriacou, C.P. (2002). Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr. Biol. 12, 540–550. 7. Storch, K.F., Lipan, O., Leykin, I., Viswanathan, N., Davis, F.C., Wong, W.H., and Weitz, C.J. (2002). Extensive and divergent circadian gene expression in liver and heart. Nature 417, 78–83. 8. Panda, S., Antoch, M.P., Miller, B.H., Su, A.I., Schook, A.B., Straume, M., Schultz, P.G., Kay, S.A., Takahashi, J.S., and Hogenesch, J.B. (2002). Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109, 307–320. 9. Ueda, H.R., Chen, W., Adachi, A., Wakamatsu, H., Hayashi, S., Takasugi, T., Nagano, M., Nakahama, K., Suzuki, Y., Sugano, S., et al. (2002). A transcription factor response element for gene expression during circadian night. Nature 418, 534–539.
Current Biology Vol 17 No 8 R294
10. Reddy, A.B., Karp, N.A., Maywood, E.S., Sage, E.A., Deery, M., O’Neill, J.S., Wong, G.K., Chesham, J., Odell, M., Lilley, K.S., et al. (2006). Circadian orchestration of the hepatic proteome. Curr. Biol. 16, 1107–1115. 11. Reddy, A.B., Wong, G.K., O’Neill, J., Maywood, E.S., and Hastings, M.H. (2005). Circadian clocks: neural and peripheral pacemakers that impact upon the cell division cycle. Mutat. Res. 574, 76–91. 12. Maywood, E.S., O’Neill, J., Wong, G.K., Reddy, A.B., and Hastings, M.H. (2006). Circadian timing in health and disease. Prog. Brain Res. 153, 253–269. 13. Balsalobre, A., Damiola, F., and Schibler, U. (1998). A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93, 929–937. 14. Balsalobre, A., Brown, S., Marcacci, L., Tronche, F., Kellendonk, C.,
Reichardt, H.M., Schutz, G., and Schibler, U. (2000). Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science 289, 2344–2347. 15. Le Minh, N., Damiola, F., Tronche, F., Schutz, G., and Schibler, U. (2001). Glucocorticoid hormones inhibit foodinduced phase-shifting of peripheral circadian oscillators. EMBO J. 20, 7128–7136. 16. Reddy, A.B., Maywood, E.S., Karp, N.A., King, V.M., Inoue, Y., Gonzalez, F.J., Lilley, K.S., Kyriacou, C.P., and Hastings, M.H. (2007). Glucocorticoid signaling synchronizes the liver circadian transcriptome. Hepatology, in press. 17. Bae, K., Jin, X., Maywood, E.S., Hastings, M.H., Reppert, S.M., and Weaver, D.R. (2001). Differential functions of mPer1, mPer2, and mPer3
Aging: A Young Mind in Old Bees A new surprising study suggests that various cognitive abilities and motosensory functions remain perfectly intact as honeybee workers age. How do these findings fit in with a buzzing life? Stephanie Jemielity and Laurent Keller You can’t reach old age by another man’s road. These are Mark Twain’s words on the observation that each person is affected by a slightly different palette of ailments when getting older. From the speed of our heart beat to cognitive abilities and locomotor functions, there is a general decline in performance with age in humans. This phenomenon, often referred to as functional senescence, has also been documented in many other species. Although the speed and onset of decline may vary with genetic and environmental factors, functional senescence is thought to be the prime culprit for the widely observed environment-independent increase in mortality rate with age — demographic aging — as well as the limited lifespan of organisms [1]. In a new study reported in this issue of Current Biology, Rueppell and colleagues [2] challenge this view with evidence that several behavioral and motosensory functions are not subject to an age-related drop in performance in honeybee workers. To determine the association between functional senescence and demographic aging, Rueppell
et al. [2] subjected 26- to 52-day-old worker bees that had started foraging to a series of well-established behavioral tests. They found no negative association between the age of foragers and their ability to respond to light, their responsiveness to sucrose, their ease at associative olfactory learning or the speed at which they exit the hive upon external perturbation. At the demographic level, however, signs of aging were clear: the mortality of foraging workers increased significantly with age during the behavioral experiments, and residual lifespan decreased significantly with age across forager cohorts transferred to undisturbed laboratory cages. The apparent decoupling of demographic and specific physiological aging patterns in the honey bee workers are in sharp contrast with findings in Drosophila, where similar behavioral tests revealed a clear decrease in performance with age (reviewed in [3]). Rueppell et al. [2] suggest that this discrepancy might stem from the particular social life characteristic of the honey bee and other social insects. Indeed, the evolution of social life in bees, ants, wasps and termites has been accompanied by an almost 100-fold increase in average lifespan compared to their solitary
in the SCN circadian clock. Neuron 30, 525–536. 18. Fu, L., Pelicano, H., Liu, J., Huang, P., and Lee, C. (2002). The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 111, 41–50. 19. Fu, L., and Lee, C.C. (2003). The circadian clock: pacemaker and tumour suppressor. Nat. Rev. Cancer 3, 350–361.
Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, UK. E-mail: [email protected]
DOI: 10.1016/j.cub.2007.02.031
ancestors [4]. In our view, however, there is currently no theoretical reason to expect that functional senescence should be entirely absent from social insect workers. Rueppell et al.’s [2] reasoning is based on a review by Amdam and Page [5], which provides an interesting explanation for why the lifespan and aging rate of honey bee workers is so extraordinarily plastic compared to other organisms. But there is no reason to expect, nor do Amdam and Page [5] attempt to conclude, that plasticity in aging rate should lead to a complete lack of functional senescence. That some physiological traits in honey bee workers do show a decline in performance with age is supported by a recent study [6] which measured the age-specific resistance of workers to three different physiological stressors. The results showed that resistance to oxidative stress, starvation and heat stress was significantly better in 10-day old nurse bees than in 50-day-old ‘overage nurse bees’ (worker bees that had been experimentally forced to continue nursing activity). This finding cannot be due to differences in activity between young and old workers, because both groups performed similar tasks. Furthermore, the result is unlikely to be caused by higher nutritional reserves in younger bees, since lipid stores in young and overage nurse bees were comparable. There are several possible explanations for the seemingly contradicting findings of the two
Circadian Rhythms: Per2bations in the Liver Clock A master circadian clock resides in the brain and is required to synchronize the clocks in peripheral tissues such as the liver. Until now, it has been unclear how the central clock synchronizes the peripheral ones. New work points to one of the core clock genes, mPer2, as an essential link in this chain. Akhilesh B. Reddy and Elizabeth S. Maywood Circadian rhythms define our daily existence. By coordinating our metabolic status, hormonal milieu, body temperature and sleep–wake state over the day, circadian clocks act as an internal metronome [1]. In mammals, the master clock resides in the suprachiasmatic nuclei (SCN) of the brain’s hypothalamus — setting internal time for the rest of the body. The molecular SCN clockwork consists of interconnected negative feedback loops in which clock gene expression is repressed by their cognate proteins: activating transcription factors BMAL1 and CLOCK drive the loop, and the negative factors PER1, PER2, CRY1 and CRY2 close it, completing an approximately 24 hour cycle [1,2]. An accessory feedback loop, in which the orphan nuclear receptor REV-ERBa periodically represses Bmal1 transcription, enhances the oscillator’s stability, precision and robustness [3]. As well as this central clock, it is now well recognized that individual peripheral tissues, and indeed the cells within them, have autonomous circadian clocks, similar to those within the SCN [1,2]. But how does the SCN communicate with the rest of the body to synchronize the organism’s timing, and what are the molecular events involved in mediating peripheral clock resetting? Recent work by Kornmann et al. [4] has pushed us closer to understanding central-peripheral clock interactions by adopting an elegant systems-level approach. First, they cleverly created a transgenic mouse in which a tetracycline antibiotic (doxycycline) could be used to turn
the liver clock (and only the liver clock) on and off at will by switching REV-ERBa expression. With the liver clock turned on, they found that about 350 genes had a robust circadian rhythm of expression as assayed by Affymetrix GeneChip transcriptional profiling. When the liver’s clock was turned off by feeding the animals doxycycline, they were able to unmask the effects of systemic cues, arising from the still ticking SCN clock, on circadian expression in the liver. They found that almost 90% of the circadian genes failed to oscillate in the ‘timeless’ liver. But, amongst the 31 transcripts that continued to oscillate unabated, was the canonical clock gene mPer2. Thus, even though the liver clock was disabled, systemic cues were able to keep mPer2 expression ticking. So, is circadian mPer2 expression in the liver simply a result of systemic cues or does the liver’s own clock also control its transcription? To investigate this, Kornmann et al. [4] used a mouse in which the luciferase coding sequence had been knocked-in into the native mPer2 gene to make an mPer2::luciferase (mPer2::luc) fusion gene [5]. The resultant mice make mPER2:LUC fusion proteins which function just like the wild-type, untagged mPER2 protein [5]. With this technology, the group was able to monitor transcription of mPer2 in vitro by explanting liver tissue from these mice, and using luciferase to report mPer2 expression. When they did this, they found that the explanted livers displayed robust mPer2::luc rhythms ex vivo — in the absence of any systemic circadian cues. Thus, the group [4] has shown dissociable behaviours of mPer2: it is both part of the core oscillator but also a target of systemic
cues — a mediator of internal synchrony. Why should biomedicine be interested in this biological subsidiarity between central and peripheral clocks? Well, the role of peripheral clocks is to drive tissue-specific local metabolic programmes, as revealed by transcriptional profiling (as used above) [6–9] and by proteomic analyses [10]. This has shown that key metabolic pathways in the liver are under circadian control, with the clock directing the expression of rate-limiting enzymes, at both the transcriptional and protein level [6–10]. This tissue-level orchestration of gene and protein expression optimizes the tissue to perform its specialized role in vivo, most obviously temporally segregating incompatible catabolic and anabolic processes. Moreover, accumulating evidence points to the fact that, in the case of the liver, circadian clocks are important in the proper coordination of the cell cycle and the metabolism of drugs (including cytotoxic chemotherapeutic agents) and toxins [1,6,11,12]. This has obvious clinical and biological relevance. Although we now have a good understanding of circadian programming in peripheral tissues, and its importance to normal biological function, until now we have had little concrete information on how synchrony between the master central clock and peripheral oscillators is achieved: in particular, what are the systemic cues that could address local Per2 expression and thereby mediate synchronization between central and peripheral clocks? The master clock in the SCN regulates many rhythms that could be used as systemic cues, such as autonomic activity, hormone levels and body temperature [1,2]. The latter has been proposed as a key regulator by Kornmann et al. [4] because of their finding that oscillation of a variety of temperature-regulated proteins, like that of mPer2, is dependent on systemic cues [4]. Interestingly, both heat-inducible transcripts (encoding various heat-shock proteins) and an antiphasic
Dispatch R293
SCN
Central
Temp
Glu Per2 HNF4a
Peripheral
Liver Current Biology
Figure 1. A model for central-peripheral synchronization of the circadian system. Left: schematic view of peripheral tissue-based clocks synchronised by the SCN pacemaker. Right panel shows, specifically, how the central clock in the SCN transmits time information via a variety of systemic cues including glucocorticoids (Glu) and temperature (Temp). These systemic cues are then able to alter expression of mPer2 in the liver to synchronize local clocks. In addition to mPER2, key liver-specific proteins, such as the glucocorticoid-responsive HNF4a, likely play roles in local synchronization and circadian transcriptional programming.
cold-activated gene (cold-induced RNA-binding protein) were still rhythmic when the liver clock was turned off in vivo. The implication from this is that temperature cycles are important in entraining the liver in vivo. Furthermore, the team provided tantalising data suggesting that mPer2 is also heat-inducible, using transcription of mPer2::luc in explanted livers as a readout following heat-shock to 40 C in vitro. Is this the whole story though — do body temperature cycles explain central–peripheral synchronization? Generally, biological systems do not use a single method to achieve a goal, and this redundancy allows stability and robustness, so what other cues might be involved? Endocrine rhythms, in particular circadian glucocorticoid variation, have attracted recent attention. Glucocorticoid signalling has been found to affect transcription of a limited number of core clock genes both in cells and in vivo, implying a role in peripheral resetting [13–15]. Another recent study [16] complements the work of Kornmann et al. [4] by using SCNlesioned mice and transcriptional profiling to address the role of glucocorticoid signalling in synchronizing the liver clock in vivo. By removing the SCN from the equation, rhythmic systemic cues
are not present in lesioned mice, meaning that perturbations by potential synchronizers can be examined in vivo [16]. In this case, injections of the glucocorticoid analogue dexamethasone were used to probe circadian gene expression in the livers of SCN-lesioned animals. Importantly, this study also found that mPer2 is a target for glucocorticoids in vivo. But it also highlighted an integral liver transcription factor, hepatocyte nuclear factor 4 alpha (HNF4a) as a key target for circadian and glucocorticoid-mediated orchestration of liver gene expression [16]. Thus, glucocorticoids, as well as body temperature, are likely to be key synchronizers of the liver clock, acting through transcriptional cascades involving mPer2 and other regulators (Figure 1). Synchronization of central and peripheral clocks is important for proper coordination of different organs in the body. The findings discussed above clearly highlight that mPer2 is a convergent target for at least two systemic cues: body temperature and glucocorticoids (Figure 1). In this regard, it is special amongst the other ‘core’ clock genes. Compelling evidence for its importance in vivo is provided by numerous observations, such as
the striking phenotype of the mPer2 knockout mouse [17] and the significant finding that tumourgenesis is accelerated in mPer2-deficient mice [18,19]. Rather than mPer2 being a tumour-suppressor gene per se, its loss may instead result in aberrant circadian programming, producing excess cell turnover within tissues [11]. Certainly, to date, mPER2 seems to do it all — it is an integral part of the central and peripheral molecular clockwork but can respond to extraneous cues, such as light-activation of SCN cells, and internal cues, such as temperature and glucocorticoid effects in liver, to reset local tissue clock time [2]. Whether it is unique in this regard, however, remains to be seen. References 1. Hastings, M.H., Reddy, A.B., and Maywood, E.S. (2003). A clockwork web: circadian timing in brain and periphery, in health and disease. Nat. Rev. Neurosci. 4, 649–661. 2. Reppert, S.M., and Weaver, D.R. (2002). Coordination of circadian timing in mammals. Nature 418, 935–941. 3. Preitner, N., Damiola, F., Luis Lopez, M., Zakany, J., Duboule, D., Albrecht, U., and Schibler, U. (2002). The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110, 251–260. 4. Kornmann, B., Schaad, O., Bujard, H., Takahashi, J.S., and Schibler, U. (2007). System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock. PLoS Biol. 5, e34. 5. Yoo, S.H., Yamazaki, S., Lowrey, P.L., Shimomura, K., Ko, C.H., Buhr, E.D., Siepka, S.M., Hong, H.K., Oh, W.J., Yoo, O.J., et al. (2004). PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc. Natl. Acad. Sci. USA 101, 5339–5346. 6. Akhtar, R.A., Reddy, A.B., Maywood, E.S., Clayton, J.D., King, V.M., Smith, A.G., Gant, T.W., Hastings, M.H., and Kyriacou, C.P. (2002). Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr. Biol. 12, 540–550. 7. Storch, K.F., Lipan, O., Leykin, I., Viswanathan, N., Davis, F.C., Wong, W.H., and Weitz, C.J. (2002). Extensive and divergent circadian gene expression in liver and heart. Nature 417, 78–83. 8. Panda, S., Antoch, M.P., Miller, B.H., Su, A.I., Schook, A.B., Straume, M., Schultz, P.G., Kay, S.A., Takahashi, J.S., and Hogenesch, J.B. (2002). Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109, 307–320. 9. Ueda, H.R., Chen, W., Adachi, A., Wakamatsu, H., Hayashi, S., Takasugi, T., Nagano, M., Nakahama, K., Suzuki, Y., Sugano, S., et al. (2002). A transcription factor response element for gene expression during circadian night. Nature 418, 534–539.
Current Biology Vol 17 No 8 R294
10. Reddy, A.B., Karp, N.A., Maywood, E.S., Sage, E.A., Deery, M., O’Neill, J.S., Wong, G.K., Chesham, J., Odell, M., Lilley, K.S., et al. (2006). Circadian orchestration of the hepatic proteome. Curr. Biol. 16, 1107–1115. 11. Reddy, A.B., Wong, G.K., O’Neill, J., Maywood, E.S., and Hastings, M.H. (2005). Circadian clocks: neural and peripheral pacemakers that impact upon the cell division cycle. Mutat. Res. 574, 76–91. 12. Maywood, E.S., O’Neill, J., Wong, G.K., Reddy, A.B., and Hastings, M.H. (2006). Circadian timing in health and disease. Prog. Brain Res. 153, 253–269. 13. Balsalobre, A., Damiola, F., and Schibler, U. (1998). A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93, 929–937. 14. Balsalobre, A., Brown, S., Marcacci, L., Tronche, F., Kellendonk, C.,
Reichardt, H.M., Schutz, G., and Schibler, U. (2000). Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science 289, 2344–2347. 15. Le Minh, N., Damiola, F., Tronche, F., Schutz, G., and Schibler, U. (2001). Glucocorticoid hormones inhibit foodinduced phase-shifting of peripheral circadian oscillators. EMBO J. 20, 7128–7136. 16. Reddy, A.B., Maywood, E.S., Karp, N.A., King, V.M., Inoue, Y., Gonzalez, F.J., Lilley, K.S., Kyriacou, C.P., and Hastings, M.H. (2007). Glucocorticoid signaling synchronizes the liver circadian transcriptome. Hepatology, in press. 17. Bae, K., Jin, X., Maywood, E.S., Hastings, M.H., Reppert, S.M., and Weaver, D.R. (2001). Differential functions of mPer1, mPer2, and mPer3
Aging: A Young Mind in Old Bees A new surprising study suggests that various cognitive abilities and motosensory functions remain perfectly intact as honeybee workers age. How do these findings fit in with a buzzing life? Stephanie Jemielity and Laurent Keller You can’t reach old age by another man’s road. These are Mark Twain’s words on the observation that each person is affected by a slightly different palette of ailments when getting older. From the speed of our heart beat to cognitive abilities and locomotor functions, there is a general decline in performance with age in humans. This phenomenon, often referred to as functional senescence, has also been documented in many other species. Although the speed and onset of decline may vary with genetic and environmental factors, functional senescence is thought to be the prime culprit for the widely observed environment-independent increase in mortality rate with age — demographic aging — as well as the limited lifespan of organisms [1]. In a new study reported in this issue of Current Biology, Rueppell and colleagues [2] challenge this view with evidence that several behavioral and motosensory functions are not subject to an age-related drop in performance in honeybee workers. To determine the association between functional senescence and demographic aging, Rueppell
et al. [2] subjected 26- to 52-day-old worker bees that had started foraging to a series of well-established behavioral tests. They found no negative association between the age of foragers and their ability to respond to light, their responsiveness to sucrose, their ease at associative olfactory learning or the speed at which they exit the hive upon external perturbation. At the demographic level, however, signs of aging were clear: the mortality of foraging workers increased significantly with age during the behavioral experiments, and residual lifespan decreased significantly with age across forager cohorts transferred to undisturbed laboratory cages. The apparent decoupling of demographic and specific physiological aging patterns in the honey bee workers are in sharp contrast with findings in Drosophila, where similar behavioral tests revealed a clear decrease in performance with age (reviewed in [3]). Rueppell et al. [2] suggest that this discrepancy might stem from the particular social life characteristic of the honey bee and other social insects. Indeed, the evolution of social life in bees, ants, wasps and termites has been accompanied by an almost 100-fold increase in average lifespan compared to their solitary
in the SCN circadian clock. Neuron 30, 525–536. 18. Fu, L., Pelicano, H., Liu, J., Huang, P., and Lee, C. (2002). The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 111, 41–50. 19. Fu, L., and Lee, C.C. (2003). The circadian clock: pacemaker and tumour suppressor. Nat. Rev. Cancer 3, 350–361.
Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, UK. E-mail: [email protected]
DOI: 10.1016/j.cub.2007.02.031
ancestors [4]. In our view, however, there is currently no theoretical reason to expect that functional senescence should be entirely absent from social insect workers. Rueppell et al.’s [2] reasoning is based on a review by Amdam and Page [5], which provides an interesting explanation for why the lifespan and aging rate of honey bee workers is so extraordinarily plastic compared to other organisms. But there is no reason to expect, nor do Amdam and Page [5] attempt to conclude, that plasticity in aging rate should lead to a complete lack of functional senescence. That some physiological traits in honey bee workers do show a decline in performance with age is supported by a recent study [6] which measured the age-specific resistance of workers to three different physiological stressors. The results showed that resistance to oxidative stress, starvation and heat stress was significantly better in 10-day old nurse bees than in 50-day-old ‘overage nurse bees’ (worker bees that had been experimentally forced to continue nursing activity). This finding cannot be due to differences in activity between young and old workers, because both groups performed similar tasks. Furthermore, the result is unlikely to be caused by higher nutritional reserves in younger bees, since lipid stores in young and overage nurse bees were comparable. There are several possible explanations for the seemingly contradicting findings of the two