The Circadian System and Aging of Drosophila

  • Jadwiga M. GiebultowiczEmail author
Part of the Healthy Ageing and Longevity book series (HAL, volume 7)


Circadian clocks generate daily rhythms in gene expression, cellular functions, physiological processes and behavior. The core clock mechanism is cell-autonomous and consists of molecular negative feedback loops that turn over with an endogenous circa 24 h period. While daily oscillations in the activity of clock genes and proteins are well understood in young fruit flies Drosophila melanogaster, much less is known about how the clock mechanism changes during organismal aging. Emerging data suggest that aging is associated with reduced expression of some core clock genes in peripheral head clocks, while a similar reduction may not occur in central clock neurons regulating behavioral rhythms. Clock-controlled processes also change with age. Similar as in humans, rest/activity rhythms tend to weaken with age in fruit flies, suggesting conservation of aging-related circadian impairments. The importance of circadian clocks for healthy aging is supported by observations that their genetic or environmental disruption is associated with reduced healthspan and lifespan . For example, arrhythmia caused by mutations in core clock genes lead to symptoms of accelerated aging in both flies and mammals, including neurodegenerative phenotypes. Despite the wealth of descriptive data, the mechanisms by which functional clocks confer healthspan and lifespan benefits are poorly understood. Recent studies in Drosophila discussed here are beginning to unravel causative relationships between circadian system and aging. They also suggest that clocks may be involved in inducing rhythmic expression of specific genes late in life in response to age-related increase in oxidative stress. The goal of this chapter is to summarize modest insights that were so far made into links between circadian system and aging and to illuminate the power of Drosophila for future mechanistic research in this important area.


Clock genes Clock-controlled genes Genome-wide gene expression Lifespan Healthspan Neurodegeneration 



The author thanks Eileen Chow for help with figures and reading of the manuscript as well as Dani Long for reading of the manuscript. Author’s research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under award number R01 AG045830 and R21AG052950 to JMG.


  1. Ali AA, Schwarz-Herzke B, Stahr A, Prozorovski T, Aktas O, von Gall C (2015) Premature aging of the hippocampal neurogenic niche in adult Bmal1-deficient mice. Aging (Albany NY)Google Scholar
  2. Balsalobre A, Damiola F, Schibler U (1998) A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93:929–937CrossRefPubMedGoogle Scholar
  3. Beaver LM, Klichko VI, Chow ES, Kotwica-Rolinska J, Williamson M, Orr WC, Radyuk SN, Giebultowicz JM (2012) Circadian regulation of glutathione levels and biosynthesis in Drosophila melanogaster. PLoS ONE 7:e50454CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bishop NA, Guarente L (2007) Genetic links between diet and lifespan: shared mechanisms from yeast to humans. Nat Rev Genet 8(11):835–844CrossRefPubMedGoogle Scholar
  5. Botella JA, Ulschmid JK, Gruenewald C, Moehle C, Kretzschmar D, Becker K, Schneuwly S (2004) The Drosophila carbonyl reductase sniffer prevents oxidative stress-induced neurodegeneration. Curr Biol 14(9):782–786CrossRefPubMedGoogle Scholar
  6. Brown SA (2014) Circadian clock-mediated control of stem cell division and differentiation: beyond night and day. Development 141(16):3105–3111CrossRefPubMedGoogle Scholar
  7. Chatterjee A, Hardin PE (2010) Time to taste: circadian clock function in the Drosophila gustatory system. Fly (Austin) 4(4):283–287CrossRefGoogle Scholar
  8. Chen KF, Possidente B, Lomas DA, Crowther DC (2014) The central molecular clock is robust in the face of behavioural arrhythmia in a Drosophila model of Alzheimer’s disease. Disease Models Mech 7(4):445–458CrossRefGoogle Scholar
  9. Chen CY, Logan RW, Ma TZ, Lewis DA, Tseng GC, Sibille E, McClung CA (2016) Effects of aging on circadian patterns of gene expression in the human prefrontal cortex. P Natl Acad Sci U S A 113(1):206–211CrossRefGoogle Scholar
  10. Cheng Y, Hardin PE (1998) Drosophila photoreceptors contain an autonomous circadian oscillator that can function without period mRNA cycling. J Neurosci 18(2):741–750PubMedGoogle Scholar
  11. Chow ES, Long DM, Giebultowicz JM (2016) Circadian rhythm in mRNA expression of the glutathione synthesis gene Gclc is controlled by peripheral glial clocks in Drosophila melanogaster. Physiol Entomol 41:369–377CrossRefPubMedGoogle Scholar
  12. Demontis F, Perrimon N (2010) FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging. Cell 143(5):813–825CrossRefPubMedPubMedCentralGoogle Scholar
  13. Erion R, King AN, Wu G, Hogenesch JB, Sehgal A (2016) Neural clocks and Neuropeptide F/Y regulate circadian gene expression in a peripheral metabolic tissue. eLife 5Google Scholar
  14. Forman HJ, Zhang H, Rinna A (2009) Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol Aspects Med 30(1–2):1–12CrossRefPubMedGoogle Scholar
  15. Frisch B, Hardin PE, Hamblen-Coyle MJ, Rosbash M, Hall JC (1994) A promoterless period gene mediates behavioral rhythmicity and cyclical per expression in a restricted subset of the Drosophila nervous system. Neuron 12:555–570CrossRefPubMedGoogle Scholar
  16. Giebultowicz JM (2001) Peripheral clocks and their role in circadian timing: insights from insects. Phil Trans R Soc B 356:1791–1799CrossRefPubMedPubMedCentralGoogle Scholar
  17. Giebultowicz JM (2004) Multiple oscillators. In: Sehgal A (ed) Molecular biology of circadian rhythms. Wiley, Hoboken, pp 213–230Google Scholar
  18. Giebultowicz JM, Hege D (1997) Circadian clock in malpighian tubules. Nature 386:664CrossRefPubMedGoogle Scholar
  19. Giebultowicz JM, Long DM (2015) Ageing and circadian rhythms. Curr Opin Insect Sci 7:82–86CrossRefPubMedPubMedCentralGoogle Scholar
  20. Giebultowicz JM, Riemann JG, Raina AK, Ridgway RL (1989) Circadian system controlling release of sperm in the insect testes. Science 245:1098–1100CrossRefPubMedGoogle Scholar
  21. Gill S, Le HD, Melkani GC, Panda S (2015) Time-restricted feeding attenuates age-related cardiac decline in Drosophila. Science 347(6227):1265–1269CrossRefPubMedPubMedCentralGoogle Scholar
  22. Hardin PE (2011) Molecular genetic analysis of circadian timekeeping in Drosophila. Adv Genet 74:141–173PubMedPubMedCentralGoogle Scholar
  23. Hardin PE, Panda S (2013) Circadian timekeeping and output mechanisms in animals. Curr Opin Neurobiol 23(5):724–731CrossRefPubMedPubMedCentralGoogle Scholar
  24. Helfrich-Forster C (2004) The circadian clock in the brain: a structural and functional comparison between mammals and insects. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 190(8):601–613CrossRefPubMedGoogle Scholar
  25. Helfrich-Forster C (2005) Neurobiology of the fruit fly’s circadian clock. Genes Brain Behav 4(2):65–76CrossRefPubMedGoogle Scholar
  26. Hendricks JC, Finn SM, Panckeri KA, Chavkin J, Williams JA, Sehgal A, Pack AI (2000) Rest in Drosophila is a sleep-like state. Neuron 25(1):129–138CrossRefPubMedGoogle Scholar
  27. Hendricks JC, Lu S, Kume K, Yin JC, Yang Z, Sehgal A (2003) Gender dimorphism in the role of cycle (BMAL1) in rest, rest regulation, and longevity in Drosophila melanogaster. J Biol Rhythms 18(1):12–25CrossRefPubMedGoogle Scholar
  28. Hooven LA, Sherman KA, Butcher S, Giebultowicz JM (2009) Does the clock make the poison? Circadian variation in response to pesticides. PLoS ONE 4(7):e6469CrossRefPubMedPubMedCentralGoogle Scholar
  29. Hughes ME, Grant GR, Paquin C, Qian J, Nitabach MN (2012) Deep sequencing the circadian and diurnal transcriptome of Drosophila brain. Genome Res 22(7):1266–1281CrossRefPubMedPubMedCentralGoogle Scholar
  30. Ivanchenko M, Stanewsky R, Giebultowicz JM (2001) Circadian photoreception in Drosophila: functions of cryptochrome in peripheral and central clocks. J Biol Rhythms 16:205–215CrossRefPubMedGoogle Scholar
  31. Karpowicz P, Zhang Y, Hogenesch JB, Emery P, Perrimon N (2013) The circadian clock gates the intestinal stem cell regenerative state. Cell Rep 3(4):996–1004CrossRefPubMedPubMedCentralGoogle Scholar
  32. Katewa SD, Akagi K, Bose N, Rakshit K, Camarella T, Zheng X, Hall D, Davis S, Nelson CS, Brem RB, Ramanathan A, Sehgal A, Giebultowicz JM, Kapahi P (2016) Peripheral circadian clocks mediate dietary restriction-dependent changes in lifespan and fat metabolism in Drosophila. Cell Metab 23(1):143–154CrossRefPubMedGoogle Scholar
  33. Keegan KP, Pradhan S, Wang JP, Allada R (2007) Meta-analysis of Drosophila circadian microarray studies identifies a novel set of rhythmically expressed genes. PLoS Comp Biol 3(11):e208Google Scholar
  34. Klarsfeld A, Rouyer F (1998) Effects of circadian mutations and LD periodicity on the life span of Drosophila melanogaster. J Biol Rhythms 13(6):471–478CrossRefPubMedGoogle Scholar
  35. Klichko VI, Chow ES, Kotwica-Rolinska J, Orr WC, Giebultowicz JM, Radyuk SN (2015) Aging alters circadian regulation of redox in Drosophila. Frontiers Genet 6:83CrossRefGoogle Scholar
  36. Koh K, Evans JM, Hendricks JC, Sehgal A (2006) A Drosophila model for age-associated changes in sleep: wake cycles. Proc Natl Acad Sci U S A 103(37):13843–13847CrossRefPubMedPubMedCentralGoogle Scholar
  37. Kondratov RV, Kondratova AA, Gorbacheva VY, Vykhovanets OV, Antoch MP (2006) Early aging and age-related pathologies in mice deficient in BMAL1, the core component of the circadian clock. Genes Dev 20(14):1868–1873CrossRefPubMedPubMedCentralGoogle Scholar
  38. Kondratova AA, Kondratov RV (2012) The circadian clock and pathology of the ageing brain. Nat Rev Neurosci 13(5):325–335PubMedPubMedCentralGoogle Scholar
  39. Konopka RJ, Benzer S (1971) Clock mutants of Drosophila melanogaster. Proc Natl Acad Sci U S A 68:2112–2116CrossRefPubMedPubMedCentralGoogle Scholar
  40. Kretzschmar D, Hasan G, Sharma S, Heisenberg M, Benzer S (1997) The swiss cheese mutant causes glial hyperwrapping and brain degeneration in Drosophila. J Neurosci 17(19):7425–7432PubMedGoogle Scholar
  41. Krishnan B, Levine JD, Lynch MK, Dowse HB, Funes P, Hall JC, Hardin PE, Dryer SE (2001) A new role for cryptochrome in a Drosophila circadian oscillator. Nature 411(6835):313–317CrossRefPubMedGoogle Scholar
  42. Krishnan N, Kretzschmar D, Rakshit K, Chow E, Giebultowicz J (2009) The circadian clock gene period extends healthspan in aging Drosophila melanogaster. Aging 1(11):937–948CrossRefPubMedPubMedCentralGoogle Scholar
  43. Krishnan N, Rakshit K, Chow ES, Wentzell JS, Kretzschmar D, Giebultowicz JM (2012) Loss of circadian clock accelerates aging in neurodegeneration-prone mutants. Neurobiol Dis 45(3):1129–1135CrossRefPubMedGoogle Scholar
  44. Kuintzle RC, Chow ES, Westby TN, Gvakharia BO, Giebultowicz JM, Hendrix DA (2017) Aging induces de novo rhythmic expression of oxidative stress-responsive genes. Nat Commun 8:14529CrossRefPubMedPubMedCentralGoogle Scholar
  45. Kula-Eversole E, Nagoshi E, Shang Y, Rodriguez J, Allada R, Rosbash M (2009) Surprising gene expression patterns within and between PDF-containing circadian neurons in Drosophila. Proc Natl Acad Sci U S A 107(30):13497–13502CrossRefGoogle Scholar
  46. Kumar S, Mohan A, Sharma VK (2005) Circadian dysfunction reduces lifespan in Drosophila melanogaster. Chronobiol Int 22(4):641–653CrossRefPubMedGoogle Scholar
  47. Long DM, Blake MR, Dutta S, Holbrook SD, Kotwica-Rolinska J, Kretzschmar D, Giebultowicz JM (2014) Relationships between the circadian system and Alzheimer’s disease-like symptoms in Drosophila. PLoS ONE 9(8):e106068CrossRefPubMedPubMedCentralGoogle Scholar
  48. Longo VD, Panda S (2016) Fasting, circadian rhythms, and time-restricted feeding in healthy lifespan. Cell Metab 23(6):1048–1059CrossRefPubMedPubMedCentralGoogle Scholar
  49. Lowrey PL, Takahashi JS (2011) Genetics of circadian rhythms in mammalian model organisms. Adv Genet 74:175–230PubMedPubMedCentralGoogle Scholar
  50. Luchak JM, Prabhudesai L, Sohal RS, Radyuk SN, Orr WC (2007) Modulating longevity in Drosophila by over- and underexpression of glutamate-cysteine ligase. Ann N Y Acad Sci 1119:260–273CrossRefPubMedGoogle Scholar
  51. Luo W, Chen WF, Yue Z, Chen D, Sowcik M, Sehgal A, Zheng X (2012) Old flies have a robust central oscillator but weaker behavioral rhythms that can be improved by genetic and environmental manipulations. Aging Cell 11(3):428–438CrossRefPubMedPubMedCentralGoogle Scholar
  52. Metaxakis A, Tain LS, Gronke S, Hendrich O, Hinze Y, Birras U, Partridge L (2014) Lowered insulin signalling ameliorates age-related sleep fragmentation in Drosophila. PLoS Biol 12(4):e1001824CrossRefPubMedPubMedCentralGoogle Scholar
  53. Musiek ES (2015) Circadian clock disruption in neurodegenerative diseases: cause and effect? Frontiers Pharmacol 6:29CrossRefGoogle Scholar
  54. Nakamura TJ, Nakamura W, Yamazaki S, Kudo T, Cutler T, Colwell CS, Block GD (2012) Age-related decline in circadian output. J Neurosci 31(28):10201–10205CrossRefGoogle Scholar
  55. Nakamura TJ, Nakamura W, Tokuda IT, Ishikawa T, Kudo T, Colwell CS, Block GD (2015) Age-related changes in the circadian system unmasked by constant conditions (1,2,3). eNeuro 2(4)Google Scholar
  56. Ng FS, Tangredi MM, Jackson FR (2011) Glial cells physiologically modulate clock neurons and circadian behavior in a calcium-dependent manner. Curr Biol 21(8):625–634CrossRefPubMedPubMedCentralGoogle Scholar
  57. Nitabach MN, Taghert PH (2008) Organization of the Drosophila circadian control circuit. Curr Biol 18(2):R84–R93CrossRefPubMedGoogle Scholar
  58. Pittendrigh CS (1960) Circadian rhythms and circadian organization of the living systems. Cold Spring Harbor Symp Quant Biol 25:159–182CrossRefPubMedGoogle Scholar
  59. Rakshit K, Giebultowicz JM (2013) Cryptochrome restores dampened circadian rhythms and promotes healthspan in aging Drosophila. Aging Cell 12:752–762CrossRefPubMedPubMedCentralGoogle Scholar
  60. Rakshit K, Krishnan N, Guzik EM, Pyza E, Giebultowicz JM (2012) Effects of aging on the molecular circadian oscillations in Drosophila. Chronobiol Int 29(1):1–10CrossRefGoogle Scholar
  61. Reddy AB, O’Neill JS (2010) Healthy clocks, healthy body, healthy mind. Trends Cell Biol 20(1):36–44CrossRefPubMedPubMedCentralGoogle Scholar
  62. Rezaval C, Berni J, Gorostiza EA, Werbajh S, Fagilde MM, Fernandez MP, Beckwith EJ, Aranovich EJ, Sabio y Garcia CA, Ceriani MF (2008) A functional misexpression screen uncovers a role for enabled in progressive neurodegeneration. PLoS One 3(10):e3332Google Scholar
  63. Rodriguez J, Tang CH, Khodor YL, Vodala S, Menet JS, Rosbash M (2013) Nascent-seq analysis of Drosophila cycling gene expression. Proc Natl Acad Sci U S A 110(4):E275–E284CrossRefPubMedPubMedCentralGoogle Scholar
  64. Seay DJ, Thummel CS (2011) The circadian clock, light, and cryptochrome regulate feeding and metabolism in Drosophila. J Biol Rhythms 26(6):497–506CrossRefPubMedPubMedCentralGoogle Scholar
  65. Sehadova H, Glaser FT, Gentile C, Simoni A, Giesecke A, Albert JT, Stanewsky R (2009) Temperature entrainment of Drosophila’s circadian clock involves the gene nocte and signaling from peripheral sensory tissues to the brain. Neuron 64(2):251–266CrossRefPubMedGoogle Scholar
  66. Shaw P (2003) Awakening to the behavioral analysis of sleep in Drosophila. J Biol Rhythms 18(1):4–11CrossRefPubMedGoogle Scholar
  67. Tanoue S, Krishnan P, Krishnan B, Dryer SE, Hardin PE (2004) Circadian clocks in antennal neurons are necessary and sufficient for olfaction rhythms in Drosophila. Curr Biol 14(8):638–649CrossRefPubMedGoogle Scholar
  68. Umezaki Y, Yoshii T, Kawaguchi T, Helfrich-Forster C, Tomioka K (2012) Pigment-dispersing factor is involved in age-dependent rhythm changes in Drosophila melanogaster. J Biol Rhythms 27(6):423–432CrossRefPubMedGoogle Scholar
  69. Wang L, Karpac J, Jasper H (2014) Promoting longevity by maintaining metabolic and proliferative homeostasis. J Exp Biol 217(Pt 1):109–118CrossRefPubMedPubMedCentralGoogle Scholar
  70. Wijnen H, Young MW (2006) Interplay of circadian clocks and metabolic rhythms. Annu Rev Genet 40:409–448CrossRefPubMedGoogle Scholar
  71. Xu K, Zheng X, Sehgal A (2008) Regulation of feeding and metabolism by neuronal and peripheral clocks in Drosophila. Cell Metab 8(4):289–300CrossRefPubMedPubMedCentralGoogle Scholar
  72. Xu K, DiAngelo JR, Hughes ME, Hogenesch JB, Sehgal A (2011) The circadian clock interacts with metabolic physiology to influence reproductive fitness. Cell Metab 13(6):639–654CrossRefPubMedPubMedCentralGoogle Scholar
  73. Yu EA, Weaver DR (2011) Disrupting the circadian clock: gene-specific effects on aging, cancer, and other phenotypes. Aging (Albany NY) 3(5):479–493CrossRefGoogle Scholar
  74. Zhang R, Lahens NF, Ballance HI, Hughes ME, Hogenesch JB (2014) A circadian gene expression atlas in mammals: Implications for biology and medicine. Proc Natl Acad Sci U S A 111(45):16219–16224CrossRefPubMedPubMedCentralGoogle Scholar
  75. Zheng X, Sehgal A (2010) AKT and TOR signaling set the pace of the circadian pacemaker. Curr Biol 20(13):1203–1208CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Integrative BiologyOregon State UniversityCorvallisUSA

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