Circadian rhythms are found in almost all organisms from cyanobacteria to humans, where most behavioral and physiological processes occur over a period of approximately 24 h in tandem with the day/night cycles. In general, these rhythmic processes are under regulation of circadian clocks. The role of circadian clocks in regulating metabolism and consequently cellular and metabolic homeostasis is an intensively investigated area of research. However, the links between circadian clocks and aging are correlative and only recently being investigated. A physiological decline in most processes is associated with advancing age, and occurs at the onset of maturity and in some instances is the result of accumulation of cellular damage beyond a critical level. A fully functional circadian clock would be vital to timing events in general metabolism, thus contributing to metabolic health and to ensure an increased "health-span" during the process of aging. Here, we present recent evidence of links between clocks, cellular metabolism, aging and oxidative stress (one of the causative factors of aging). In the light of these data, we arrive at conceptual generalizations of this relationship across the spectrum of model organisms from fruit flies to mammals.

Institute of Entomology Biology Centre Academy of Science Branišovská 31 České Budějovice 370 05 CZ Czech Republic

Zobrazit více v PubMed

Chen Z., Odstrcil E.A., Tu B.P., McKnight S.L. Restriction of DNA replication to the reductive phase of the metabolic cycle protects genome integrity. Science. 2007;316:1916–1919. PubMed

Lamia K.A., Storch K.F., Weitz C.J. Physiological significance of a peripheral tissue circadian clock. Proc. Natl. Acad. Sci. USA. 2008;105:15172–15177. PubMed PMC

Turek F.W., Joshu C., Kohsaka A., Lin E., Ivanova G., McDearmon E., Laposky A., Losee-Olson S., Easton A., Jensen D.R., et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science. 2005;308:1043–1045. PubMed PMC

Woelfle M.A., Ouyang Y., Phanvijhitsiri K., Johnson C.H. The adaptive value of circadian clocks: An experimental assessment in cyanobacteria. Curr. Biol. 2004;14:1481–1486. PubMed

Pittendrigh C.S. On Temperature Independence in the Clock System Controlling Emergence Time in Drosophila. Proc. Natl. Acad. Sci. USA. 1954;40:1018–1029. PubMed PMC

Green C.B., Takahashi J.S., Bass J. The meter of metabolism. Cell. 2008;134:728–742. PubMed PMC

Takahashi J.S., Hong H.K., Ko C.H., McDearmon E.L. The genetics of mammalian circadian order and disorder: Implications for physiology and disease. Nat. Rev. Genet. 2008;9:764–775. PubMed PMC

Claudel T., Cretenet G., Saumet A., Gachon F. Crosstalk between xenobiotics metabolism and circadian clock. FEBS Lett. 2007;581:3626–3633. PubMed

Kang T.H., Sancar A. Circadian regulation of DNA excision repair: Implications for chrono-chemotherapy. Cell Cycle. 2009;8:1665–1667. PubMed

Antoch M.P., Gorbacheva V.Y., Vykhovanets O., Toshkov I.A., Kondratov R.V., Kondratova A.A., Lee C., Nikitin A.Y. Disruption of the circadian clock due to the Clock mutation has discrete effects on aging and carcinogenesis. Cell Cycle. 2008;7:1197–1204. PubMed PMC

Gauger M.A., Sancar A. Cryptochrome, circadian cycle, cell cycle checkpoints, and cancer. Cancer Res. 2005;65:6828–6834. PubMed

Kondratov R.V., Kondratova A.A., Gorbacheva V.Y., Vykhovanets O.V., Antoch M.P. Early aging and age-related pathologies in mice deficient in BMAL1, the core component of the circadian clock. Genes Dev. 2006;20:1868–1873. PubMed PMC

Lee C.C. Tumor suppression by the mammalian Period genes. Cancer Causes Control. 2006;17:525–530. PubMed

Gachon F., Nagoshi E., Brown S.A., Ripperger J., Schibler U. The mammalian circadian timing system: From gene expression to physiology. Chromosoma. 2004;113:103–112. PubMed

Helfrich-Forster C. The circadian clock in the brain: A structural and functional comparison between mammals and insects. J. Comp. Physiol. A Neuroethol. Sens. Neural. Behav. Physiol. 2004;190:601–613. PubMed

Nitabach M.N., Taghert P.H. Organization of the Drosophila circadian control circuit. Curr. Biol. 2008;18:R84–R93. PubMed

Giebultowicz J.M. Peripheral clocks and their role in circadian timing: Insights from insects. Phil. Trans. R. Soc. B. 2001;356:1791–1799. PubMed PMC

Giebultowicz J.M. Multiple oscillators. In: Sehgal A., editor. Molecular Biology of Circadian Rhythms. John Wiley & Sons; Hoboken, NJ, USA: 2004. pp. 213–230.

Glossop N.R., Hardin P.E. Central and peripheral circadian oscillator mechanisms in flies and mammals. J. Cell Sci. 2002;115:3369–3377. PubMed

Bae K., Edery I. Regulating a circadian clock’s period, phase and amplitude by phosphorylation: Insights from Drosophila. J. Biochem. 2006;140:609–617. PubMed

Stanewsky R., Kaneko M., Emery P., Beretta B., Wager-Smith K., Kay S.A., Rosbash M., Hall J.C. The cryb mutation identifies cryptochrome as a circadian photoreceptor in Drosophila. Cell. 1998;95:681–692. PubMed

Naidoo N., Song W., Hunter-Ensor M., Sehgal A. A role for the proteasome in the light response of the timeless clock protein. Science. 1999;285:1737–1741. PubMed

van der Linden A.M., Beverly M., Kadener S., Rodriguez J., Wasserman S., Rosbash M., Sengupta P. Genome-wide analysis of light- and temperature-entrained circadian transcripts in Caenorhabditis elegans. PLoS Biol. 2010;8:e1000503. PubMed PMC

Simonetta S.H., Golombek D.A. An automated tracking system for Caenorhabditis elegans locomotor behavior and circadian studies application. J. Neurosci. Methods. 2007;161:273–280. PubMed

Hasegawa K., Saigusa T., Tamai Y. Caenorhabditis elegans opens up new insights into circadian clock mechanisms. Chronobiol. Int. 2005;22:1–19. PubMed

Banerjee D., Kwok A., Lin S.Y., Slack F.J. Developmental timing in C. elegans is regulated by kin-20 and tim-1, homologs of core circadian clock genes. Dev. Cell. 2005;8:287–295. PubMed

Timpano A., James T., Chin L. let-7 family microRNAs directly regulate the developmental timing gene lin-42 and the circadian timing gene period. Proceedings of the International Worm Meeting 715; Los Angeles, CA, USA. 24– 28 June 2009..

Ando H., Takamura T., Matsuzawa-Nagata N., Shima K.R., Eto T., Misu H., Shiramoto M., Tsuru T., Irie S., Fujimura A., et al. Clock gene expression in peripheral leucocytes of patients with type 2 diabetes. Diabetologia. 2009;52:329–335. PubMed

Kusanagi H., Mishima K., Satoh K., Echizenya M., Katoh T., Shimizu T. Similar profiles in human period1 gene expression in peripheral mononuclear and polymorphonuclear cells. Neurosci. Lett. 2004;365:124–127. PubMed

Yamamoto T., Nakahata Y., Soma H., Akashi M., Mamine T., Takumi T. Transcriptional oscillation of canonical clock genes in mouse peripheral tissues. BMC Mol. Biol. 2004;5:18. PubMed PMC

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. PERIOD2: LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc. Natl. Acad. Sci. USA. 2004;101:5339–5346. PubMed PMC

Zheng X., Sehgal A. Probing the relative importance of molecular oscillations in the circadian clock. Genetics. 2008;178:1147–1155. PubMed PMC

Lowrey P.L., Takahashi J.S. Mammalian circadian biology: Elucidating genome-wide levels of temporal organization. Annu. Rev. Genomics Human Genet. 2004;5:407–441. PubMed PMC

Reppert S.M., Weaver D.R. Coordination of circadian timing in mammals. Nature. 2002;418:935–941. PubMed

Bunger M.K., Wilsbacher L.D., Moran S.M., Clendenin C., Radcliffe L.A., Hogenesch J.B., Simon M.C., Takahashi J.S., Bradfield C.A. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell. 2000;103:1009–1017. PubMed PMC

Gekakis N., Staknis D., Nguyen H.B., Davis F.C., Wilsbacher L.D., King D.P., Takahashi J.S., Weitz C.J. Role of the CLOCK protein in the mammalian circadian mechanism. Science. 1998;280:1964–1569. PubMed

Kume K., Zylka M.J., Sriram S., Shearman L.P., Weaver D.R., Jin X., Maywood E.S., Hastings M.H., Reppert S.M. mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell. 1999;98:193–205. PubMed

Okamura H., Miyake S., Sumi Y., Yamaguchi S., Yasui A., Muijtjens M., Hoeijmakers J.H., van der Horst G.T. Photic induction of mPer1 and mPer2 in cry-deficient mice lacking a biological clock. Science. 1999;286:2531–2534. PubMed

Vitaterna M.H., Selby C.P., Todo T., Niwa H., Thompson C., Fruechte E.M., Hitomi K., Thresher R.J., Ishikawa T., Miyazaki J., et al. Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2. Proc. Natl. Acad. Sci. USA. 1999;96:12114–12119. PubMed PMC

Bovbjerg D.H. Circadian disruption and cancer: Sleep and immune regulation. Brain Behav. Immun. 2003;17(Suppl 1):S48–50. PubMed

Fu L., Lee C.C. The circadian clock: Pacemaker and tumour suppressor. Nat. Rev. Cancer. 2003;3:350–361. PubMed

Gorbacheva V.Y., Kondratov R.V., Zhang R., Cherukuri S., Gudkov A.V., Takahashi J.S., Antoch M.P. Circadian sensitivity to the chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK/BMAL1 transactivation complex. Proc. Natl. Acad. Sci. USA. 2005;102:3407–3412. PubMed PMC

Krishnan N., Davis A.J., Giebultowicz J.M. Circadian regulation of response to oxidative stress in Drosophila melanogaster. Biochem. Biophys. Res. Commun. 2008;374:299–303. PubMed PMC

Krishnan N., Kretzschmar D., Rakshit K., Chow E., Giebultowicz J. The circadian clock gene period extends healthspan in aging Drosophila melanogaster. Aging. 2009;1:937–948. PubMed PMC

Krishnan N., Rakshit K., Chow E.S., Wentzell J.S., Kretzschmar D., Giebultowicz J.M. Loss of circadian clock accelerates aging in neurodegeneration-prone mutants. Neurobiol. Dis. 2012;45:1129–1135. PubMed PMC

Xu K., Zheng X., Sehgal A. Regulation of feeding and metabolism by neuronal and peripheral clocks in Drosophila. Cell Metab. 2008;8:289–300. PubMed PMC

Jeon M., Gardner H.F., Miller E.A., Deshler J., Rougvie A.E. Similarity of the C. elegans developmental timing protein LIN-42 to circadian rhythm proteins. Science. 1999;286:1141–1146. PubMed

Akhtar R.A., Reddy A.B., Maywood E.S., Clayton J.D., King V.M., Smith A.G., Gant T.W., Hastings M.H., Kyriacou C.P. Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr. Biol. 2002;12:540–550. PubMed

Duffield G.E., Best J.D., Meurers B.H., Bittner A., Loros J.J., Dunlap J.C. Circadian programs of transcriptional activation, signaling, and protein turnover revealed by microarray analysis of mammalian cells. Curr. Biol. 2002;12:551–557. PubMed

Kornmann B., Preitner N., Rifat D., Fleury-Olela F., Schibler U. Analysis of circadian liver gene expression by ADDER, a highly sensitive method for the display of differentially expressed mRNAs. Nucleic Acids Res. 2001;29:E51–E51. PubMed PMC

McCarthy J.J., Andrews J.L., McDearmon E.L., Campbell K.S., Barber B.K., Miller B.H., Walker J.R., Hogenesch J.B., Takahashi J.S., Esser K.A. Identification of the circadian transcriptome in adult mouse skeletal muscle. Physiol. Genomics. 2007;31:86–95. PubMed PMC

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., Hogenesch J.B. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell. 2002;109:307–320. PubMed

Schibler U., Ripperger J., Brown S.A. Peripheral circadian oscillators in mammals: Time and food. J. Biol. Rhythms. 2003;18:250–260. PubMed

Storch K.F., Lipan O., Leykin I., Viswanathan N., Davis F.C., Wong W.H., Weitz C.J. Extensive and divergent circadian gene expression in liver and heart. Nature. 2002;417:78–83. PubMed

Ueda H.R., Matsumoto A., Kawamura M., Iino M., Tanimura T., Hashimoto S. Genome-wide transcriptional orchestration of circadian rhythms in Drosophila. J. Biol. Chem. 2002;277:14048–14052. PubMed

Zvonic S., Floyd Z.E., Mynatt R.L., Gimble J.M. Circadian rhythms and the regulation of metabolic tissue function and energy homeostasis. Obesity (Silver Spring) 2007;15:539–543. PubMed PMC

La Fleur S.E., Kalsbeek A., Wortel J., Buijs R.M. A suprachiasmatic nucleus generated rhythm in basal glucose concentrations. J Neuroendocrinol. 1999;11:643–652. PubMed

Ruiter M., La Fleur S.E., van Heijningen C., van der Vliet J., Kalsbeek A., Buijs R.M. The daily rhythm in plasma glucagon concentrations in the rat is modulated by the biological clock and by feeding behavior. Diabetes. 2003;52:1709–1715. PubMed

Ando H., Yanagihara H., Hayashi Y., Obi Y., Tsuruoka S., Takamura T., Kaneko S., Fujimura A. Rhythmic messenger ribonucleic acid expression of clock genes and adipocytokines in mouse visceral adipose tissue. Endocrinology. 2005;146:5631–5636. PubMed

De Boer S.F., Van der Gugten J. Daily variations in plasma noradrenaline, adrenaline and corticosterone concentrations in rats. Physiol. Behav. 1987;40:323–328. PubMed

Bodosi B., Gardi J., Hajdu I., Szentirmai E., Obal F., Jr, Krueger J.M. Rhythms of ghrelin, leptin, and sleep in rats: Effects of the normal diurnal cycle, restricted feeding, and sleep deprivation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2004;287:R1071–R1079. PubMed

Chawla A., Repa J.J., Evans R.M., Mangelsdorf D.J. Nuclear receptors and lipid physiology: Opening the X-files. Science. 2001;294:1866–1870. PubMed

Francis G.A., Fayard E., Picard F., Auwerx J. Nuclear receptors and the control of metabolism. Annu. Rev. Physiol. 2003;65:261–311. PubMed

Yang X. A wheel of time: The circadian clock, nuclear receptors, and physiology. Genes Dev. 2010;24:741–747. PubMed PMC

Guillaumond F., Dardente H., Giguere V., Cermakian N. Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors. J. Biol. Rhythms. 2005;20:391–403. PubMed

Preitner N., Damiola F., Lopez-Molina L., Zakany J., Duboule D., Albrecht U., Schibler U. The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell. 2002;110:251–260. PubMed

Sato T.K., Panda S., Miraglia L.J., Reyes T.M., Rudic R.D., McNamara P., Naik K.A., FitzGerald G.A., Kay S.A., Hogenesch J.B. A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron. 2004;43:527–537. PubMed

Teboul M., Guillaumond F., Grechez-Cassiau A., Delaunay F. The Nuclear Hormone Receptors Family Round the Clock. Mol. Endocrinol. 2008;22:2573–2582. PubMed PMC

Schmutz I., Ripperger J.A., Baeriswyl-Aebischer S., Albrecht U. The mammalian clock component PERIOD2 coordinates circadian output by interaction with nuclear receptors. Genes Dev. 2010;24:345–357. PubMed PMC

Meermeier N., Krishnan N. Circadian regulation of cellular homeostasis—implications for cell metabolism and clinical diseases. Med. Hypotheses. 2012;79:17–24. PubMed

Roenneberg T., Merrow M. Circadian systems and metabolism. J. Biol. Rhythms. 1999;14:449–459. PubMed

Harley C.W., Farrell R.C., Rusak B. Daily variation in the distribution of glycogen phosphorylase in the suprachiasmatic nucleus of Syrian hamsters. J. Comp. Neurol. 2001;435:249–258. PubMed

Harley C., Rusak B. Daily variation in active glycogen phosphorylase patches in the molecular layer of rat dentate gyrus. Brain Res. 1993;626:310–317. PubMed

Yamazaki S., Ishida Y., Inouye S. Circadian rhythms of adenosine triphosphate contents in the suprachiasmatic nucleus, anterior hypothalamic area and caudate putamen of the rat--negative correlation with electrical activity. Brain Res. 1994;664:237–240. PubMed

Harman D. Free radical theory of aging: Increasing the average life expectancy at birth and the maximum life span. J. Anti-Aging Med. 1999;2:199–208.

Ho Y.S., Magnenat J.L., Bronson R.T., Cao J., Gargano M., Sugawara M., Funk C.D. Mice deficient in cellular glutathione peroxidase develop normally and show no increased sensitivity to hyperoxia. J. Biol. Chem. 1997;272:16644–16651. PubMed

Melov S., Coskun P., Patel M., Tuinstra R., Cottrell B., Jun A.S., Zastawny T.H., Dizdaroglu M., Goodman S.I., Huang T.T., et al. Mitochondrial disease in superoxide dismutase 2 mutant mice. Proc. Natl. Acad. Sci. USA. 1999;96:846–851. PubMed PMC

Shefner J.M., Reaume A.G., Flood D.G., Scott R.W., Kowall N.W., Ferrante R.J., Siwek D.F., Upton-Rice M., Brown R.H., Jr Mice lacking cytosolic copper/zinc superoxide dismutase display a distinctive motor axonopathy. Neurology. 1999;53:1239–1246. PubMed

Barnard A.R., Nolan P.M. When clocks go bad: Neurobehavioral consequences of disrupted circadian timing. PLoS Genet. 2008;4:e1000040. PubMed PMC

Simonetta S.H., Romanowski A., Minniti A.N., Inestrosa N.C., Golombek D.A. Circadian stress tolerance in adult Caenorhabditis elegans. J. Comp. Physiol. A Neuroethol. Sens. Neural. Behav. Physiol. 2008;194:821–828. PubMed

Miller B.H., McDearmon E.L., Panda S., Hayes K.R., Zhang J., Andrews J.L., Antoch M.P., Walker J.R., Esser K.A., Hogenesch J.B., Takahashi J.S. Circadian and CLOCK-controlled regulation of the mouse transcriptome and cell proliferation. Proc. Natl. Acad. Sci. USA. 2007;104:3342–3347. PubMed PMC

Everitt A.V. The hypothalamic-pituitary control of ageing and age-related pathology. Exp. Gerontol. 1973;8:265–277. PubMed

Dilman V.M. Age-associated elevation of hypothalamic, threshold to feedback control, and its role in development, ageing, and disease. Lancet. 1971;1:1211–1219. PubMed

Araki T., Sasaki Y., Milbrandt J. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science. 2004;305:1010–1013. PubMed

Mack T.G., Reiner M., Beirowski B., Mi W., Emanuelli M., Wagner D., Thomson D., Gillingwater T., Court F., Conforti L., et al. Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene. Nat. Neurosci. 2001;4:1199–1206. PubMed

Nakahata Y., Kaluzova M., Grimaldi B., Sahar S., Hirayama J., Chen D., Guarente L.P., Sassone-Corsi P. The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell. 2008;134:329–340. PubMed PMC

Zheng X., Yang Z., Yue Z., Alvarez J.D., Sehgal A. FOXO and insulin signaling regulate sensitivity of the circadian clock to oxidative stress. Proc. Natl. Acad. Sci. USA. 2007;104:15899–15904. PubMed PMC

Blander G., Guarente L. The Sir2 family of protein deacetylases. Annu. Rev. Biochem. 2004;73:417–435. PubMed

Dali-Youcef N., Lagouge M., Froelich S., Koehl C., Schoonjans K., Auwerx J. Sirtuins: The “magnificient seven”, function, metabolism and longevity. Ann. Med. 2007;39:335–345. PubMed

Imai S., Guarente L. Sirtuins: A universal link between NAD, metabolism and aging. In: Guarente L., Partridge L., Wallace D., editors. The Molecular Biology of Aging. Cold Spring Harbor Laboratory Press; New York, NY, USA: 2007. pp. 39–72.

Michan S., Sinclair D. Sirtuins in mammals: Insights into their biological function. Biochem. J. 2007;404:1–13. PubMed PMC

Schwer B., Verdin E. Conserved metabolic regulatory functions of sirtuins. Cell Metab. 2008;7:104–112. PubMed

Astrom S.U., Cline T.W., Rine J. The Drosophila melanogaster sir2+ gene is nonessential and has only minor effects on position-effect variegation. Genetics. 2003;163:931–937. PubMed PMC

Howitz K.T., Bitterman K.J., Cohen H.Y., Lamming D.W., Lavu S., Wood J.G., Zipkin R.E., Chung P., Kisielewski A., Zhang L.L., et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003;425:191–196. PubMed

Rogina B., Helfand S.L. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc. Natl. Acad. Sci. USA. 2004;101:15998–16003. PubMed PMC

Tissenbaum H.A., Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature. 2001;410:227–230. PubMed

Wood J.G., Rogina B., Lavu S., Howitz K., Helfand S.L., Tatar M., Sinclair D. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004;430:686–689. PubMed

Bordone L., Guarente L. Calorie restriction, SIRT1 and metabolism: Understanding longevity. Nat. Rev. Mol. Cell. Biol. 2005;6:298–305. PubMed

Imai S. The NAD World: A new systemic regulatory network for metabolism and aging—Sirt1, systemic NAD biosynthesis, and their importance. Cell Biochem. Biophys. 2009;53:65–74. PubMed PMC

Asher G., Gatfield D., Stratmann M., Reinke H., Dibner C., Kreppel F., Mostoslavsky R., Alt F.W., Schibler U. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell. 2008;134:317–328. PubMed

Ramsey K.M., Marcheva B., Kohsaka A., Bass J. The clockwork of metabolism. Annu. Rev. Nutr. 2007;27:219–240. PubMed

Liu C., Li S., Liu T., Borjigin J., Lin J.D. Transcriptional coactivator PGC-1alpha integrates the mammalian clock and energy metabolism. Nature. 2007;447:477–481. PubMed

Lin J., Puigserver P., Donovan J., Tarr P., Spiegelman B.M. Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta), a novel PGC-1-related transcription coactivator associated with host cell factor. J. Biol. Chem. 2002;277:1645–1648. PubMed

Scarpulla R.C. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol. Rev. 2008;88:611–638. PubMed

Andersson U., Scarpulla R.C. Pgc-1-related coactivator, a novel, serum-inducible coactivator of nuclear respiratory factor 1-dependent transcription in mammalian cells. Mol. Cell. Biol. 2001;21:3738–3749. PubMed PMC

Handschin C., Spiegelman B.M. The role of exercise and PGC1alpha in inflammation and chronic disease. Nature. 2008;454:463–469. PubMed PMC

Ichida M., Nemoto S., Finkel T. Identification of a specific molecular repressor of the peroxisome proliferator-activated receptor gamma Coactivator-1 alpha (PGC-1alpha) J. Biol. Chem. 2002;277:50991–50995. PubMed

Anderson R.M., Barger J.L., Edwards M.G., Braun K.H., O’Connor C.E., Prolla T.A., Weindruch R. Dynamic regulation of PGC-1alpha localization and turnover implicates mitochondrial adaptation in calorie restriction and the stress response. Aging Cell. 2008;7:101–111. PubMed PMC

St-Pierre J., Drori S., Uldry M., Silvaggi J.M., Rhee J., Jager S., Handschin C., Zheng K., Lin J., Yang W., et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell. 2006;127:397–408. PubMed

Valle I., Alvarez-Barrientos A., Arza E., Lamas S., Monsalve M. PGC-1alpha regulates the mitochondrial antioxidant defense system in vascular endothelial cells. Cardiovasc. Res. 2005;66:562–573. PubMed

Southgate R.J., Bruce C.R., Carey A.L., Steinberg G.R., Walder K., Monks R., Watt M.J., Hawley J.A., Birnbaum M.J., Febbraio M.A. PGC-1alpha gene expression is down-regulated by Akt- mediated phosphorylation and nuclear exclusion of FoxO1 in insulin-stimulated skeletal muscle. FASEB J. 2005;19:2072–2074. PubMed

Russell A.P., Feilchenfeldt J., Schreiber S., Praz M., Crettenand A., Gobelet C., Meier C.A., Bell D.R., Kralli A., Giacobino J.P., Deriaz O. Endurance training in humans leads to fiber type-specific increases in levels of peroxisome proliferator-activated receptor-gamma coactivator-1 and peroxisome proliferator-activated receptor-alpha in skeletal muscle. Diabetes. 2003;52:2874–2881. PubMed

Jager S., Handschin C., St-Pierre J., Spiegelman B.M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc. Natl. Acad. Sci. USA. 2007;104:12017–12022. PubMed PMC

Gwinn D.M., Shackelford D.B., Egan D.F., Mihaylova M.M., Mery A., Vasquez D.S., Turk B.E., Shaw R.J. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell. 2008;30:214–226. PubMed PMC

Cunningham J.T., Rodgers J.T., Arlow D.H., Vazquez F., Mootha V.K., Puigserver P. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature. 2007;450:736–740. PubMed

Canto C., Gerhart-Hines Z., Feige J.N., Lagouge M., Noriega L., Milne J.C., Elliott P.J., Puigserver P., Auwerx J. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. 2009;458:1056–1060. PubMed PMC

Jordan S.D., Lamia K.A. AMPK at the crossroads of circadian clocks and metabolism. Mol. Cell. Endocrinol. 2012 in press. PubMed PMC

Lamia K.A., Sachdeva U.M., DiTacchio L., Williams E.C., Alvarez J.G., Egan D.F., Vasquez D.S., Juguilon H., Panda S., Shaw R.J., et al. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science. 2009;326:437–440. PubMed PMC

Vieira E., Nilsson E.C., Nerstedt A., Ormestad M., Long Y.C., Garcia-Roves P.M., Zierath J.R., Mahlapuu M. Relationship between AMPK and the transcriptional balance of clock-related genes in skeletal muscle. Am. J. Phyiol. Endocrinol. Metab. 2008;295:1032–1037. PubMed

Wullschleger S., Loewith R., Hall M.N. TOR signaling in growth and metabolism. Cell. 2006;124:471–484. PubMed

Anderson R.M., Weindruch R. Metabolic reprogramming in dietary restriction. Interdiscip. Top. Gerontol. 2007;35:18–38. PubMed PMC

Schieke S.M., Finkel T. Mitochondrial signaling, TOR, and life span. Biol. Chem. 2006;387:1357–1361. PubMed

Lerin C., Rodgers J.T., Kalume D.E., Kim S.H., Pandey A., Puigserver P. GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1alpha. Cell Metab. 2006;3:429–438. PubMed

Nemoto S., Fergusson M.M., Finkel T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha} J. Biol. Chem. 2005;280:16456–16460. PubMed

Rodgers J.T., Lerin C., Haas W., Gygi S.P., Spiegelman B.M., Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. 2005;434:113–118. PubMed

Gerhart-Hines Z., Rodgers J.T., Bare O., Lerin C., Kim S.H., Mostoslavsky R., Alt F.W., Wu Z., Puigserver P. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J. 2007;26:1913–1923. PubMed PMC

Bitterman K.J., Anderson R.M., Cohen H.Y., Latorre-Esteves M., Sinclair D.A. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J. Biol. Chem. 2002;277:45099–45107. PubMed

Bhaskar P.T., Hay N. The two TORCs and Akt. Dev. Cell. 2007;12:487–502. PubMed

Hahn-Windgassen A., Nogueira V., Chen C.C., Skeen J.E., Sonenberg N., Hay N. Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J. Biol. Chem. 2005;280:32081–32089. PubMed

Kenyon C. The plasticity of aging: Insights from long-lived mutants. Cell. 2005;120:449–460. PubMed

Liu H., Fergusson M.M., Castilho R.M., Liu J., Cao L., Chen J., Malide D., Rovira I.I, Schimel D., Kuo C.J., et al. Science. 2007;317:803–806. PubMed

Cao R., Lee B., Cho H.Y., Saklayen S., Obrietan K. Photic regulation of the mTOR signaling pathway in the suprachiasmatic circadian clock. Mol. Cell. Neurosci. 2008;38:312–324. PubMed PMC

Zheng X., Sehgal A. AKT and TOR signaling set the pace of the circadian pacemaker. Curr. Biol. 2010;20:1203–1208. PubMed PMC

Steel C.G., Vafopoulou X. Physiology of circadian systems. In: Saunders D.S., editor. Insect Clocks. 3rd ed. Elsevier; Amsterdam, The Netherlands: 2002. pp. 115–188.

Saunders D.S., Henrich V.C., Gilbert L.I. Induction of diapause in Drosophila melanogaster: Photoperiodic regulation and the impact of arrhythmic clock mutations on time measurement. Proc. Natl. Acad. Sci. USA. 1989;86:3748–3752. PubMed PMC

Denlinger D.L. Regulation of diapause. Annu. Rev. Entomol. 2002;47:93–122. PubMed

Socha R. Pyrrhocoris apterus (Heteroptera)—an experimental model species: A review. Eur. J. Entomol. 1993;90:241–286.

Dolezel D., Zdechovanova L., Sauman I., Hodkova M. Endocrine-dependent expression of circadian clock genes in insects. Cell Mol. Life Sci. 2008;65:964–969. PubMed PMC

Gade G., Hoffmann K.H., Spring J.H. Hormonal regulation in insects: Facts, gaps, and future directions. Physiol. Rev. 1997;77:963–1032. PubMed

Kodrik D. Adipokinetic hormone functions that are not associated with insect flight. Physiol. Entomol. 2008;33:171–180.

Das S., Meier O.W., Woodring J.P. Diel rhythms of adipokinetic hormone, fat body response, and haemolymph lipid and sugar levels in the house cricket. Physiol. Entomol. 1993;18:233–239.

Cymborowski B. Daily changes in synthesis and accumulation of neurosecretion in the brain of the house crickets. J. Interdisciplin. Cycle Res. 1983;14:111–116.

Kodrik D., Socha R., Simek P., Zemek R., Goldsworthy G.J. A new member of the AKH/RPCH family stimulates locomotory activity in the firebug Pyrrhocoris apterus (Heteroptera) Insect Biochem. Mol. Biol. 2000;30:489–498. PubMed

Maxova A., Kodrik D., Zemek R., Socha R. Diel changes in adipokinetic response and walking activity of Pyrrhocoris apterus (L.) (Heteroptera) in relation to physiological status and wing dimorphism. Eur. J. Entomol. 2001;98:433–438.

Hodkova M. Regulation of diapause and reproduction in Pyrrhocoris apterus (L.) (Heteroptera)—neuroendocrine outputs (mini-review) Entomol. Sci. 1999;2:563–566.

Kodrik D., Socha R., Syrova Z. Developmental and diel changes of adipokinetic hormone in CNS and haemolymph of the flightless wing-polymorphic bug, Pyrrhocoris apterus (L.) J. Insect Physiol. 2003;49:53–61. PubMed

Kodrik D., Socha R., Syrova Z., Zemek R. The effect of constant darkness on the content of adipokinetic hormone, adipokinetic response and walking activity in macropterous females of Pyrrhocoris apterus (L.) Physiol. Entomol. 2005;30:248–255.

Hodkova M., Syrova Z., Dolezel D., Sauman I. Period gene expression in relation to seasonality and circadian rhythms in the linden bug, Pyrrhocoris apterus (Heteroptera) Eur. J. Entomol. 2003;100:267–273.

Syrova Z., Sauman I., Giebultowicz J.M. Effects of light and temperature on the circadian system controlling sperm release in moth Spodoptera littoralis. Chronobiol. Int. 2003;20:809–821. PubMed

Lee G., Park J.H. Hemolymph sugar homeostasis and starvation-induced hyperactivity affected by genetic manipulations of the adipokinetic hormone-encoding gene in Drosophila melanogaster. Genetics. 2004;167:311–323. PubMed PMC

Katewa S.D., Demontis F., Kolipinski M., Hubbard A., Gill M.S., Perrimon N., Melov S., Kapahi P. Intramyocellular fatty-acid metabolism plays a critical role in mediating responses to dietary restriction in Drosophila melanogaster. Cell Metab. 2012;16:97–103. PubMed PMC

Klebanov S., Diais S., Stavinoha W.B., Suh Y., Nelson J.F. Hyperadrenocorticism, attenuated inflammation, and the life-prolonging action of food restriction in mice. J. Gerontol. A Biol. Sci. Med. Sci. 1995;50:B78–B82. PubMed

Balsalobre A., Brown S.A., Marcacci L., Tronche F., Kellendonk C., Reichardt H.M., Schutz G., Schibler U. Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science. 2000;289:2344–2347. PubMed

Le Minh N., Damiola F., Tronche F., Schutz G., Schibler U. Glucocorticoid hormones inhibit food-induced phaseshifting of peripheral circadian oscillators. EMBO J. 2001;20:7128–7136. PubMed PMC

Downs J.L., Urbanski H.F. Aging-related sex-dependent loss of the circulating leptin 24-h rhythm in the rhesus monkey. J. Endocrinol. 2006;190:117–127. PubMed

Cincotta A.H., Schiller B.C., Landry R.J., Herbert S.J., Miers W.R., Meier A.H. Circadian neuroendocrine role in age-related changes in body fat stores and insulin sensitivity of the male Sprague-Dawley rat. Chronobiol. Int. 1993;10:244–258. PubMed

Bubenik G.A., Konturek S.J. Melatonin and aging: Prospects for human treatment. J. Physiol. Pharmacol. 2011;62:13–19. PubMed

Benloucif S., Masana M.I., Dubocovich M.L. Light-induced phase shifts of circadian activity rhythms and immediate early gene expression in the suprachiasmatic nucleus are attenuated in old C3H/HeN mice. Brain Res. 1997;747:34–42. PubMed

Davidson A.J., Yamazaki S., Arble D.M., Menaker M., Block G.D. Resetting of central and peripheral circadian oscillators in aged rats. Neurobiol. Aging. 2008;29:471–477. PubMed PMC

Li H., Satinoff E. Changes in circadian rhythms of body temperature and sleep in old rats. Am. J. Physiol. 1995;269:R208–R214. PubMed

Valentinuzzi V.S., Scarbrough K., Takahashi J.S., Turek F.W. Effects of aging on the circadian rhythm of wheel-running activity in C57BL/6 mice. Am. J. Physiol. 1997;273:R1957–R1964. PubMed

Weinert D., Waterhouse J. Daily activity and body temperature rhythms do not change simultaneously with age in laboratory mice. Physiol. Behav. 1999;66:605–612. PubMed

Rakshit K., Krishnan N., Guzik E.M., Pyza E., Giebultowicz J.M. Effects of aging on the molecular circadian oscillations in Drosophila. Chronobiol. Int. 2012;29:5–14. PubMed PMC

Hurd M.W., Ralph M.R. The significance of circadian organization for longevity in the golden hamster. J. Biol. Rhythms. 1998;13:430–436. PubMed