Therapeutic effects of curcumin on age-induced alterations in daily rhythms of clock genes and Sirt1 expression in the SCN of male Wistar rats

  • Kowshik Kukkemane
  • Anita JagotaEmail author
Research Article


The aging brain is linked to accumulation of oxidative stress and increase in damage to biomolecules which in turn may cause or promote circadian dysfunction by disruption of biological clock, the suprachiasmatic nucleus (SCN). Age associated alterations in clock gene expression in the SCN has been reported earlier. In the present study we have examined therapeutic effects of the antioxidant curcumin on age induced alterations in daily rhythms and levels of core clock genes in SCN of young [3 months (m)], middle (12 months) and old (24 months) male Wistar rats. Curcumin was administered orally at ZT-11, 1 hour (h) before the onset of darkness. The effect of curcumin administration on daily rhythms and levels of expression of clock genes such as rBmal1, rPer1, rPer2, rCry1, rCry2 and rRev-erbα as well as on the clock modulator rSirt1 were studied. There was restoration of phase of rPer1, rPer2, rCry1, rCry2 and daily pulse of rPer2 in middle aged animals. However, in old aged rats the phase and daily pulse of rPer1 were restored with curcumin treatment. rSirt1 did not show age related alterations in its transcript levels though the rhythms were abolished in old aged rat SCN. Pearson correlation analysis showed that curcumin administration to 12 and 24 months animals had resulted in restorations of several correlations among clock genes which were found to be altered/abolished in age matched control groups. In addition, strong interlocking interactions between rSirt1 and clock genes were observed in young age which were disrupted with aging and curcumin administration resulted in partial restoration.


Curcumin SCN Clock genes Sirt1 Aging 



This work is supported by ICMR Grant (Ref. No. 55/7/2012-/BMS) to AJ. KK is thankful to DST-INSPIRE for SRF.

Supplementary material

10522_2018_9794_MOESM1_ESM.docx (1.3 mb)
Supplementary Figure S1. Representative Dissociation curves for β-actin, Per1, Per2, Cry1, Cry2, Bmal1, Rev-erbα and Sirt1 genes showing specific amplification (DOCX 1281 kb)


  1. Abe H, Honma S, Namihira M, Tanahashi Y, Ikeda M, Honma K (1998) Circadian rhythm and light responsiveness of BMAL1 expression, a partner of mammalian clock gene Clock, in the suprachiasmatic nucleus of rats. Neurosci Lett 258:93–96CrossRefGoogle Scholar
  2. Asher G, Gatfield D, Stratmann M, Reinke H, Dibner C, Kreppel F, Mostoslavsky R, Alt FW, Schibler U (2008) SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134:317–328CrossRefGoogle Scholar
  3. Ayissi VBO, Ebrahimi A, Schluesenner H (2014) Epigenetic effects of natural polyphenols: a focus on SIRT1-mediated mechanisms. Mol Nutr Food Res 58:22–32CrossRefGoogle Scholar
  4. Banerjee S, Ji C, Mayfield JE, Goel A, Xiao J, Dixon JE, Guo X (2018) Ancient drug curcumin impedes 26S proteasome activity by direct inhibition of dual-specificity tyrosine-regulated kinase 2. PNAS 32:8155–8160CrossRefGoogle Scholar
  5. Banks G, Nolan PM, Peirson SN (2016) Reciprocal interactions between circadian clocks and aging. Mamm Genome 27:332–340CrossRefGoogle Scholar
  6. Braidy N, Poljak A, Grant R, Jayasena T, Mansour H, Chan-Ling T, Smythe G, Sachdev P, Guillemin GJ (2015) Differential expression of sirtuins in the aging rat brain. Front Cell Neurosci 9:167CrossRefGoogle Scholar
  7. Calabrese V, Cornelius C, Mancuso C, Pennisi G, Calafato S, Bellia F, Bates TE, Giuffrida Stella AM, Schapira T, Dinkova Kostova AT, Rizzarelli E (2008) Cellular stress response: a novel target for chemoprevention and nutritional neuroprotection in aging, neurodegenerative disorders and longevity. Neurochem Res 33:2444–2471CrossRefGoogle Scholar
  8. Chang H, Guarente L (2011) SIRT1 Mediates central circadian control in the SCN by a mechanism that decays with aging. Cell 153:1448–1460CrossRefGoogle Scholar
  9. Cheng YF, Guo L, Xie YS, Liu YS, Zhang J, Wu QW, Li JM (2013) Curcumin rescues aging-related loss of hippocampal synapse input specificity of long term potentiation in mice. Neurochem Res 38:98–107CrossRefGoogle Scholar
  10. Chomczynski P, Sacchi N (2006) Single-step method of RNA isolation by acid guanidinium thiocyanatephenol-chloroform extraction: twenty-something years on. Nat Protoc 1:581–585CrossRefGoogle Scholar
  11. Dong S, Zeng Q, Mitchell ES, Xiu J, Duan Y, Li C, Tiwari JK, Hu Y, Cao X, Zhao Z (2012) Curcumin Enhances neurogenesis and cognition in aged rats: implications for transcriptional interactions related to growth and synaptic plasticity. PLoS ONE 7:e31211CrossRefGoogle Scholar
  12. Duncan MJ, Prochot JR, Cook DH, Tyler SJ, Franklin KM (2013) Influence of aging on Bmal1 and Per2 expression in extra—SCN oscillators in hamster brain. Brain Res 1491:44–53CrossRefGoogle Scholar
  13. Eckert GP, Schiborr C, Hagl S, Abdel-Kader R, Müller WE, Rimbach G, Frank J (2013) Curcumin prevents mitochondrial dysfunction in the brain of the senescence-accelerated mouse-prone 8. Neurochem Int 62:595–602CrossRefGoogle Scholar
  14. Farajnia S, Meijer JH, Michel S (2015) Age-related changes in large-conductance calcium-activated potassium channels in mammalian circadian clock neurons. Neurobiol Aging 36:2176–2183CrossRefGoogle Scholar
  15. Froy O (2011) Circadian Rhythms, Aging, and life span in mammals. Physiology 26:225–235CrossRefGoogle Scholar
  16. Gall CV, Weaver DR (2008) Loss of responsiveness to melatonin in the aging mouse suprchiasmatic nucleus. Neurobiol Aging 29:464–470CrossRefGoogle Scholar
  17. Gloston GF, Yoo SH, Chen ZJ (2017) Clock-enhancing small molecules and potential applications in chronic diseases and aging. Front Neurol 8:100CrossRefGoogle Scholar
  18. Grabowska W, Sikora E, Bielak-Zmijewska A (2017) Sirtuins, a promising target in slowing down the ageing process. Biogerontology.
  19. Hatcher H, Planalp R, Cho J, Torti FM, Torti SV (2008) Curcumin: from ancient medicine to current clinical trials. Cell Mol Life Sci 65:1631–1652CrossRefGoogle Scholar
  20. Hofman MA, Swaab DF (2006) Living by the clock: the circadian pacemaker in older people. Ageing Res Rev 5:33–51CrossRefGoogle Scholar
  21. Jagota A (2006) Suprachiasmatic nucleus: the Center for circadian timing system in mammals. Proc Indian Natl Sci Acad 71:275–288Google Scholar
  22. Jagota A (2012) Age-induced alterations in biological clock: therapeutic effects of melatonin. In: Thakur MK, Rattan SIS (eds) Brain aging and therapeutic interventions. Springer, Netherlands, pp 111–129CrossRefGoogle Scholar
  23. Jagota A, Kalyani D (2010) Effect of melatonin on age induced changes in daily serotonin rhythms in suprachiasmatic nucleus of male wistar rat. Biogerontology 11:299–308CrossRefGoogle Scholar
  24. Jagota A, Mattam U (2017) Daily chronomics of proteomic profile in aging and rotenone-induced Parkinson’s disease model in male Wistar rat and its modulation by melatonin. Biogerontology 18:615–630CrossRefGoogle Scholar
  25. Jagota A, Reddy MY (2007) The effect of Curcumin on ethanol induced changes in Suprachiasmatic nucleus (SCN) and Pineal. Cell Mol Neurobiol 27:997–1006CrossRefGoogle Scholar
  26. Jagota A, de la Iglesia HO, Schwartz WJ (2000) Morning and evening circadian oscillations in the suprachiasmatic nucleus in vitro. Nat Neurosci 3:372–376CrossRefGoogle Scholar
  27. Jia N, Sun Q, Su Q, Chen G (2016) SIRT1-mediated deacetylation of PGC1α attributes to the protection of curcumin against glutamate excitotoxicity in cortical neurons. Biochem Biophys Res Commun 478:1376–1381CrossRefGoogle Scholar
  28. Kondratov VR, Vykhovanets O, Kondratova AA, Antoch PM (2009) Antioxidant N-acetyl-l-cysteine ameliorates symptoms of premature aging associated with the deficiency of the circadian protein BMAL1. Aging 1:979–987CrossRefGoogle Scholar
  29. Kunieda T, Minamino T, Katsuno T, Tateno K, Nishi J, Miyauchi H, Orimo M, Okada S, Komuro I (2006) Cellular senescence impairs circadian expression of clock genes in vitro and in vivo. Circ Res 3:532–539CrossRefGoogle Scholar
  30. Lao CD, Ruffin MT 4th, Normolle D, Heath DD, Murray SI, Bailey JM, Boggs ME, Crowell J, Rock CL, Brenner DE (2006) Dose escalation of a curcuminoid formulation. BMC Complement Altern Med 6:10CrossRefGoogle Scholar
  31. Liu F, Chang HC (2017) Physiological links of circadian clock and biological clock of aging. Protein Cell. Google Scholar
  32. Liu C, Li S, Liu T, Borjigin J, Lin JD (2007) Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Nature 447:477–481CrossRefGoogle Scholar
  33. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔ Ct Method. Methods 25:402–408CrossRefGoogle Scholar
  34. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217CrossRefGoogle Scholar
  35. Manikonda PK, Jagota A (2012) Melatonin administration differentially affects age-induced alterations in daily rhythms of lipid peroxidation and antioxidant enzymes in male rat liver. Biogerentology 13:511–524CrossRefGoogle Scholar
  36. Masri S, Sassone-Corsi P (2014) Sirtuins and the circadian clock: bridging chromatin and metabolism. Sci Signal 7:1–7CrossRefGoogle Scholar
  37. Mattam U, Jagota A (2014) Differential role of melatonin in restoration of age-induced alterations in daily rhythms of expression of various clock genes in suprachiasmatic nucleus of male Wistar rats. Biogerentology 15:257–268CrossRefGoogle Scholar
  38. Mattam U, Jagota A (2015) Daily rhythms of serotonin metabolism and the expression of clock genes in suprachiasmatic nucleus of rotenone-induced Parkinson’s disease male Wistar rat model and effect of melatonin administration. Biogerontology 16:109–123CrossRefGoogle Scholar
  39. Musiek ES (2015) Circadian clock disruption in neurodegenerative diseases: cause and effect? Front Pharmacol 6:1–6CrossRefGoogle Scholar
  40. Musiek ES, Lim MM, Yang G, Bauer AQ, Qi L, Lee Y, Roh JH, Ortiz-Gonzalez X, Dearborn JT, Culver JP, Herzog ED, Hogenesch JB, Wozniak DF, Dikranian K, Giasson BI, Weaver DR, Holtzman DM, Fitzgerald GA (2013) Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. J Clin Invest 123:5389–5400CrossRefGoogle Scholar
  41. Nachiyar RK, Subramanian P, Tamilselvam K, Manivasagam T (2011) Influence of aging on the circadian patterns of thiobarbituric acid reactive substances and antioxidants in Wistar rats. Biol Rhythm Res 42:147–154CrossRefGoogle Scholar
  42. Nakahata Y, Kaluzova M, Grimaldi B, Sahar S, Hirayama J, Chen D, Guarente LP, Sassone-Corsi P (2008) The NAD + -dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134:329–340CrossRefGoogle Scholar
  43. Nakamura TJ, Takasu NN, Nakamura W (2016) The suprachiasmatic nucleus: age-related decline in biological rhythms. J Physiol Sci 66:367–374CrossRefGoogle Scholar
  44. Oike H, Kobori M (2008) Resveratrol regulates circadian clock genes in Rat-1 fibroblast cell lines. Biosci Biotechnol Biochem 72:3038–3040CrossRefGoogle Scholar
  45. Partch CL, Green CB, Takahashi JS (2014) Molecular architecture of the mammalian circadian clock. Trends Cell Biol 24:90–99CrossRefGoogle Scholar
  46. Pazo D, Cardinali DP, Cano P, Reyes Toso CA, Esquifino AI (2002) Age-related changes in 24-h rhythms of norepinephrine content and serotonin turnover in rat pineal gland: effect of melatonin treatment. Neurosignals 11:81–87CrossRefGoogle Scholar
  47. Preitner N, Damiola F, Zakany J, Duboule D, Albrecht U, Schibler U (2002) The orphan nuclear receptor REV-ERBα controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110:251–260CrossRefGoogle Scholar
  48. Quintas A, de Solís AJ, Díez-Guerra FJ, Carrascosa JM, Bogónez E (2012) Age-associated decrease of SIRT1 expression in rat hippocampus: prevention by late onset caloric restriction. Exp Gerontol 47:198–201CrossRefGoogle Scholar
  49. Rakshit K, Giebultowicz JM (2013) Cryptochrome restores dampened circadian rhythms and promotes health span in aging Drosophila. Aging Cell 12:752–762CrossRefGoogle Scholar
  50. Reddy MY, Jagota A (2015) Melatonin has differential effects on age-induced stoichiometric changes in daily chronomics of serotonin metabolism in SCN of male Wistar rats. Biogerontology 16:285–302CrossRefGoogle Scholar
  51. Reeta KH, Mehla J, Gupta YK (2009) Curcumin is protective against phenytoin-induced cognitive impairment and oxidative stress in rats. Brain Res 1301:52–60CrossRefGoogle Scholar
  52. Reppert SM, Weaver DR (2002) Coordination of circadian timing in mammals. Nature 418:935–941CrossRefGoogle Scholar
  53. Shen LR, Parnell LD, Ordovas JM, Lai CQ (2013) Curcumin and aging. BioFactors 39:133–140CrossRefGoogle Scholar
  54. Sreejayan Rao MN (1994) Curcuminoids as potent inhibitors of lipid peroxidation. J Pharm Pharmacol 46:1013–1016CrossRefGoogle Scholar
  55. Sun Q, Jia N, Wang W, Jin H, Xu J, Hu H (2014) Activation of SIRT1 by curcumin blocks the neurotoxicity of amyloid-β 25–35 in rat cortical neurons. Biochem Biophys Res Commun 448:89–94CrossRefGoogle Scholar
  56. Takahashi JS (2017) Transcriptional architecture of the mammalian circadian clock. Nat Rev Genet 18:164–179CrossRefGoogle Scholar
  57. Tsai YM, Chien CF, Lin LC, Tsai TH (2011) Curcumin and its nano-formulation: the kinetics of tissue distribution and blood–brain barrier penetration. Int J Pharm 416:331–338CrossRefGoogle Scholar
  58. Ukai-Tadenuma M, Yamada RG, Xu H, Ripperger JA, Liu AC, Ueda HR (2011) Delay in feedback repression by cryptochrome 1 is required for circadian clock function. Cell 144:268–281CrossRefGoogle Scholar
  59. Vidal B, Vázquez-Roque RA, Gnecco D, Enríquez RG, Floran B, Díaz A, Flores G (2017) Curcuma treatment prevents cognitive deficit and alteration of neuronal morphology in the limbic system of aging rats. Synapse 71:e21952CrossRefGoogle Scholar
  60. Vriend J, Reiter RJ (2015) Melatonin feedback on clock genes: a theory involving the proteasome. J Pineal Res 58:1–11CrossRefGoogle Scholar
  61. Wang N, Yang G, Jia Z, Zhang H, Aoyagi T, Soodvilai S, Symons JD, Schnermann JB, Gonzalez FJ, Litwin SE, Yang T (2008) Vascular PPARgamma controls circadian variation in blood pressure and heart rate through Bmal1. Cell Metab 8:482–491CrossRefGoogle Scholar
  62. Wang HM, Zhao YX, Zhang S, Liu GD, Kang WY, Tang HD, Ding JQ, Chen SD (2010) PPARgamma agonist curcumin reduces the amyloid-beta-stimulated inflammatory responses in primary astrocytes. J Alzheimers Dis 20:1189–1199CrossRefGoogle Scholar
  63. Yagita K, Tamanini F, Yasuda M, Hoeijmakers JH, van der Horst GT, Okamura H (2002) Nucleocytoplasmic shuttling and mCRY-dependent inhibition of ubiquitylation of the mPER2 clock protein. EMBO J 21:1301–1314CrossRefGoogle Scholar
  64. Yan ST, Shigeyoshi YT, Okamura H (1999) Per1 and Per2 gene expression in the rat suprachiasmatic nucleus: circadian profile and the compartment-specific response to light. Neuroscience 94:141–150CrossRefGoogle Scholar
  65. Zhao J, Zhao Y, Zheng W, Lu Y, Feng G, Yu S (2008) Neuroprotective effect of curcumin on transient focal cerebral ischemia in rats. Brain Res 1229:224–232CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Neurobiology and Molecular Chronobiology Laboratory, Department of Animal Biology, School of Life SciencesUniversity of HyderabadHyderabadIndia

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