Abstract
The temporal expression pattern of the circadian clock genes are known to be altered/attenuated with advance in age. Withania somnifera (WS) essentially consists of numerous active constituents including withanolides is known to have antioxidant, anti-inflammatory and adaptogenic properties. We have earlier demonstrated therapeutic effects of hydro-alcoholic leaf extract of WS on the age-induced alterations in the levels and daily rhythms of various clock genes such as rBmal1, rPer1, rPer2 and rCry1. We have now studied effects of hydro-alcoholic leaf extract of WS on the age-induced alterations in the levels and daily rhythms of expression of SIRT1 (an NAD+ dependent histone deacetylase and a modulator of clock) and NRF2 (a clock controlled gene and a master transcription factor regulating various endogenous antioxidant enzymes) in addition to rRev-erbα in SCN of adult [3 months (m)], middle-aged (12 m) and old-aged (24 m) male Wistar rats. The daily rhythms of rNrf2 expression showed 6 h phase delay in middle age and 12 h phase advance in old age. WS restored rSirt1 daily rhythms and phase in old age whereas it restored the phase of rNrf2 in the SCN of both middle and old aged animals. At protein level, SIRT1 expression showed phase advances in 12 m and 24 m whereas NRF2 daily rhythms were abolished in both the age groups. WS restored the phase and daily rhythms of SIRT1 as well as NRF2 in 12 m old rats. However, rRev-erbα expression was found insensitive to WS treatment in all the age groups studied. Pairwise correlation analysis demonstrated significant stoichiometric interactions among rSirt1, rNrf2 and rRev-erbα in 3 m which altered with aging significantly. WS treatment resulted in differential restorations of such interactions.
Similar content being viewed by others
References
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 258:93–96
Arellanes-Licea E, Caldelas I, De Ita-Perez D, Diaz-Munoz M (2014) The circadian timing system: a recent addition in the physiological mechanisms underlying pathological and aging processes. Aging Dis 5:406–418
Beynon AL, Coogan AN (2010) Diurnal, age, and immune regulation of interleukin-1beta and interleukin-1 type 1 receptor in the mouse suprachiasmatic nucleus. Chronobiol Int 27:1546–1563
Bonaconsa M, Malpeli G, Montaruli A, Carandente F, Grassi-Zucconi G, Bentivoglio M (2014) Differential modulation of clock gene expression in the suprachiasmatic nucleus, liver and heart of aged mice. Exp Gerontol 55:70–79
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254
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 9:1–16
Chang HC, Guarente L (2013) SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell 153:1448–1460
Chen Z, Yoo SH, Takahashi JS (2013) Small molecule modifiers of circadian clocks. Cell Mol Life Sci 70:2985–2998
Das A, Shanker G, Nath C, Pal R, Singh S, Singh HK (2002) A comparative study in rodents of standardized extracts of Bacopa monniera and Ginkgo biloba: anticholinesterase and cognitive enhancing activities. Pharmacol Biochem Behav 73:893–900
Deng XH, Bertini G, Palomba M, Xu Y, Bonaconsa M, Nygard M, Bentivoglio M (2010) Glial transcripts and immune-challenged glia in the suprachiasmatic nucleus of young and aged mice. Chronobiol Int 27:742–767
Duncan MJ, Prochot JR, Cook DH, Smith JT, Franklin KM (2013) Influence of aging on Bmal1 and Per2 expression in extra-SCN oscillators in hamster brain. Brain Res 1491:44–53
Fontana L (2009) Modulating human aging and age-associated diseases. BBA 1790:1133–1138
Gloston GF, Yoo S-H, Chen Z (2017) Clock-enhancing small molecules and potential applications in chronic diseases and aging. Front Neurol 8:1–12
Grabowska W, Sikora E, Bielak-Zmijewska A (2017) Sirtuins, a promising target in slowing down the ageing process. Biogerontology 18:447–476
Gupta M, Kaur G (2018) Withania somnifera as a potential anxiolytic and anti-inflammatory candidate against systemic lipopolysaccharide-induced neuroinflammation. NeuroMol Med 20:343–362
Haarman BBCM, Riemersma-Van der Lek RF, Burger H, Netkova M, Drexhage RC, Bootsman F, Mesman E, Hillegers MHJ, Spijker AT, Hoencamp E, Drexhage HA, Nolen WA (2014) Relationship between clinical features and inflammation-related monocyte gene expression in bipolar disorder: towards a better understanding of psychoimmunological interactions. Bipolar Disord 16:137–150
He B, Nohara K, Park N, Park Y, Guillory B, Zhao Z, Garcia JM, Koike N, Lee CC, Takahashi JS, Yoo S, Chen Z (2016) The small molecule nobiletin targets the molecular oscillator to enhance circadian rhythms and protect against metabolic syndrome. Cell Metab 23:610–621
Hofman MA, Swaab DF (1994) Alterations in circadian rhythmicity of the vasopressin-producing neurons of the human suprachiasmatic nucleus (SCN) with aging. Brain Res 651:134–142
Hofman MA, Swaab DF (2006) Living by the clock: the circadian pacemaker in older people. Ageing Res Rev 5:33–51
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, New York, pp 111–129
Jagota A, de la Iglesia HO, Schwartz WJ (2000) Morning and evening circadian oscillations in the suprachiasmatic nucleus in vitro. Nat Neurosci 3:372–376
Jagota A, Kalyani D (2010) Effect of melatonin on age induced changes in daily serotonin rhythms in suprachiasmatic nucleus of male Wistar rat. Biogerontology 11:299–308
Jagota A, Kowshik K (2017) Therapeutic effects of ashwagandha in brain aging and clock dysfunction. In: Kaul S, Wadhwa R (eds) Science of ashwagandha: preventive and therapeutic potentials. Springer, Cham, pp 437–456
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 18:615–630
Jagota A, Reddy MY (2007) The effect of curcumin on ethanol induced changes in suprachiasmatic nucleus (SCN) and pineal. Cell Mol Neurobiol 27:997–1006
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 478:1376–1381
Kamphuis W, Cailotto C, Dijk F, Bergen A, Buijs RM (2005) Circadian expression of clock genes and clock-controlled genes in the rat retina. Biochem Biophys Res Commun 330:18–26
Konar A, Shah N, Singh R, Saxena N, Kaul SC, Wadhwa R, Thakur MK (2011) Protective role of Ashwagandha leaf extract and its component withanone on scopolamine-induced changes in the brain and brain-derived cells. PLoS ONE 6:e27265
Kukkemane K, Jagota A (2019) Therapeutic effects of curcumin on age induced alterations in daily rhythms of clock genes and Sirt1 expression in the SCN of male Wistar rats. Biogerontology 20:405–419
Lacoste MG, Ponce IT, Golini RL, Delgado SM, Anzulovich AC (2017) Aging modifies daily variation of antioxidant enzymes and oxidative status in the hippocampus. Exp Gerontol 88:42–50
Laemmli UK (1970) Cleavage of structural proteins during the assembly of the Head of Bacteriophage T4. Nature 227:680–685
Lafontaine-Lacasse M, Richard D, Picard F (2010) Effects of age and gender on Sirt 1 mRNA expressions in the hypothalamus of the mouse. Neurosci Lett 480:1–3
Lee J, Moulik M, Fang Z, Saha P, Zou F, Xu Y, Nelson DL, Ma K, Moore DD, Yechoora VK (2013) Bmal1 and β-cell clock are required for adaptation to circadian disruption, and their loss of function leads to oxidative stress-induced β-cell failure in mice. Mol Cell Biol 33:2327–2338
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCt Method. Methods 25:402–408
Manchanda S, Mishra R, Singh R, Kaur T, Kaur G (2017) Aqueous leaf extract of Withania somnifera as a potential neuroprotective agent in sleep-deprived rats: a mechanistic study. Mol Neurobiol 54:3050–3061
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. Biogerontology 13:511–524
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. Biogerontology 15:257–268
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 16:109–123
Mattis J, Sehgal A (2016) Circadian rhythms, sleep, and disorders of aging. Trends Endocrinol Metab 27:192–203
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 42:147–154
Pandey A, Bani S, Dutt P, Satti NK, Suri KA, Qazi GN (2018) Multifunctional neuroprotective effect of Withanone, a compound from Withania somnifera roots in alleviating cognitive dysfunction. Cytokine 102:211–221
Panchawat S (2011) In vitro free radical scavenging activity of leaves extracts of Withania somnifera. Anc Sci Life 3:40–43
Park K, Kang HM (2004) Cloning and circadian expression of rat Cry1. Mol Cells 18:256–260
Park I, Lee Y, Kim H, Kim K (2014) Effect of resveratrol, a SIRT1 activator, on the interactions of the CLOCK/BMAL1 complex. Endocrinol Metab 29:379–387
Patel SA, Velingkaar NS, Kondratov RV (2014) Transcriptional control of antioxidant defense by the circadian clock. Antioxid Redox Signal 20:2997–3006
Pekovic-Vaughan V, Gibbs J, Yoshitane H, Yang N, Pathiranage D, Guo B, Sagami A, Taguchi K, Bechtold D, Loudon A, Yamamoto M, Chan J, van der Horst GTJ, Fukada Y, Meng Q (2014) The circadian clock regulates rhythmic activation of the NRF2/glutathione mediated antioxidant defense pathway to modulate pulmonary fibrosis. Genes Dev 28:548–560
Popa-Wagner A, Buga AM, Dumitrascu DI, Uzoni A, Thome J, Coogan AN (2017) How does healthy aging impact on the circadian clock? J Neural Transm 124:89–97
Preitner N, Damiola F, Luis-Lopez-Molina ZJ, 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 110:251–260
Pritchett D, Reddy AB (2017) No FAD, No CRY: redox and circadian rhythms. Trends Biochem Sci 42:497–499
Qi G, Mi Y, Fan R, Zhao B, Ren B, Liu X (2017) Tea polyphenols ameliorates neural redox imbalance and mitochondrial dysfunction via mechanisms linking the key circadian regular Bmal1. Food Chem Toxicol 110:189–199
Ray S, Reddy AB (2016) Cross-talk between circadian clocks, sleep-wake cycles, and metabolic networks: dispelling the darkness. BioEssays 38:394–405
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 16:285–302
Reddy VDK, Jagota A (2014) Effect of restricted feeding on nocturnality and daily leptin rhythms in OVLT in aged male Wistar rats. Biogerontology 15:245–256
Reppert SM, Wever DR (2002) Coordination of circadian timing system. Nature 418:935–941
Savage K, Firth J, Stough C, Sarris J (2018) GABA— modulating phytomedicines for anxiety: a systematic review of preclinical and clinical evidence. Phytother Res 32:3–18
Takahashi JS (2017) Transcriptional architecture of the mammalian circadian clock. Nat Rev Genet 18:164–179
Thummadi NB, Jagota A (2019) Aging renders desynchronization between clock and immune genes in male Wistar rat kidney: chronobiotic role of curcumin. Biogerontology 20:515–532
Touitou Y (2001) Human aging and melatonin Clinical relevance. Exp Gerontol 36:1083–1100
Travnickova-Bendova Z, Cermakian N, Reppert SM, Sassone-Corsi P (2002) Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity. Proc Natl Acad Sci USA 99:7728–7733
Vernace VA, Schmidt-Glenewinkel T, Figueiredo-Pereira ME (2007) Aging and regulated protein degradation: who has the UPPer hand? Aging Cell 6:599–606
Vinod C, Jagota A (2016) Daily NO rhythms in peripheral clocks in aging male Wistar rats: protective effects of exogenous melatonin. Biogerontology 17:859–871
Vinod C, Jagota A (2017) Daily Socs1 rhythms alter with aging differentially in peripheral clocks in male Wistar rats: therapeutic effects of melatonin. Biogerontology 18:333–345
von Gall C, Weaver DR (2008) Loss of responsiveness to melatonin in the aging mouse suprachiasmatic nucleus. Neurobiol Aging 29:464–470
Vosko AM, Schroeder A, Loh DH, Colwell CS (2007) Vasoactive intestinal peptide and the mammalian circadian system. Gen Comp Endocrinol 152:165–175
Wadhwa R, Konar A, Kaul SC (2016) Nootropic potential of Ashwagandha leaves: beyond traditional root extracts. Neurochem Int 95:109–118
Wende A, Young M, Chatham J, Zhang J, Rajasekaran NS, Darley-Usmar VM (2016) Redox biology and the interface between bioenergetics, autophagy and circadian control of metabolism. Free Radic Biol Med 100:94–107
Wu Y-H, Zhou J-N, Van Heerikhuize J, Jockers R, Swaab DF (2007) Decreased MT1 melatonin receptor expression in the suprachiasmatic nucleus in aging and Alzheimer’s disease. Neurobiol Aging 28:1239–1247
Wyse CA, Coogan AN (2010) Impact of aging on diurnal expression patterns of CLOCK and BMAL1 in the mouse brain. Brain Res 1337:21–31
Xu YQ, Zhang D, Jin T, Cai D, Wu Q, Lu Y, Liu J, Klaassen CD (2012) Diurnal Variation of Hepatic Antioxidant Gene Expression in Mice. PLoS ONE 7:e44237
Yan L, Takekida S, Shigeyoshi Y, Okamura H (1999) Per1 and Per2 gene expression in the rat suprachiasmatic nucleus: circadian profile and the compartment-specific response to light. Neuroscience 94:141–150
Zhang H, Davies KJA, Forman HJ (2015) Oxidative stress response and Nrf2 signaling in aging. Free Radic Biol Med 88:314–336
Acknowledgements
The work is supported by DBT (102/IFD/SAN/5407/2011-2012), ICMR (Ref. No. 55/7/2012-/BMS), UPE II, DST Purse Grants to AJ. KK is thankful to DST-INSPIRE for SRF.
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Kukkemane, K., Jagota, A. Therapeutic effects of hydro-alcoholic leaf extract of Withania somnifera on age-induced changes in daily rhythms of Sirt1, Nrf2 and Rev-erbα in the SCN of male Wistar rats. Biogerontology 21, 593–607 (2020). https://doi.org/10.1007/s10522-020-09875-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10522-020-09875-x