, Volume 16, Issue 6, pp 775–788 | Cite as

Middle age onset short-term intermittent fasting dietary restriction prevents brain function impairments in male Wistar rats

  • Rumani Singh
  • Shaffi Manchanda
  • Taranjeet Kaur
  • Sushil Kumar
  • Dinesh Lakhanpal
  • Sukhwinder S. Lakhman
  • Gurcharan KaurEmail author
Research Article


Intermittent fasting dietary restriction (IF-DR) is recently reported to be an effective intervention to retard age associated disease load and to promote healthy aging. Since sustaining long term caloric restriction regimen is not practically feasible in humans, so use of alternate approach such as late onset short term IF-DR regimen which is reported to trigger similar biological pathways is gaining scientific interest. The current study was designed to investigate the effect of IF-DR regimen implemented for 12 weeks in middle age rats on their motor coordination skills and protein and DNA damage in different brain regions. Further, the effect of IF-DR regimen was also studied on expression of energy regulators, cell survival pathways and synaptic plasticity marker proteins. Our data demonstrate that there was an improvement in motor coordination and learning response with decline in protein oxidative damage and recovery in expression of energy regulating neuropeptides. We further observed significant downregulation in nuclear factor kappa B (NF-κB) and cytochrome c (Cyt c) levels and moderate upregulation of mortalin and synaptophysin expression. The present data may provide an insight on how a modest level of short term IF-DR, imposed in middle age, can slow down or prevent the age-associated impairment of brain functions and promote healthy aging by involving multiple regulatory pathways aimed at maintaining energy homeostasis.


Dietary restriction Biogerontology Cognition Motor co-ordination Synaptic plasticity Energy homeostasis 



Intermittent fasting—dietary restriction


Neuropeptide Y




3 months old young rats


Middle aged ad libitum fed rats


Middle aged dietary restricted rats



The current research work was funded by the Indian Council of Medical Research (ICMR) under the National Task Force Project—an initiative on aging research. Rumani Singh is thankful to ICMR and Taranjeet Kaur and Shaffi Manchanda are thankful to UGC for the research fellowship grant during the entire course of study. Infrastructure provided by University Grants Commission (UGC), India under UPE and CPEPA schemes and Department of Biotechnology (DBT), India under DISC facility is highly acknowledged.


  1. Adams MM, Shi L, Linville MC, Forbes ME, Long AB, Bennett C, Newton IG, Carter CS, Sonntag WE, Riddle DR, Brunso-Bechtold JK (2008) Caloric restriction and age affect synaptic proteins in hippocampal CA3 and spatial learning ability. Exp Neurol 211:141–149PubMedCentralCrossRefPubMedGoogle Scholar
  2. Bertrand HA, Jeremiah T, Herlihy T, Yuji I, Yu BP (1998) Dietary restriction. In: Yu BP (ed) Methods in aging research. CRC Press, Florida, pp 271–300CrossRefGoogle Scholar
  3. Cadiacio CL, Milner TA, Gallagher M, Pierce JP (2003) Hilar neuropeptide Y inter-neuron loss in the aged rat hippocampal formation. Exp Neurol 183:147–158CrossRefPubMedGoogle Scholar
  4. Cardoso A, Silva D, Magano S, Pereira PA, Andrade JP (2014) Old-onset caloric restriction effects on neuropeptide Y and somatostatin-containing neurons and on cholinergic varicosities in the rat hippocampal formation. Age 36(6):1–14CrossRefGoogle Scholar
  5. Castellano JM, Bentsen AH, Mikkelsen JD, Tena-Sempere M (2010) Kisspeptins: bridging energy homeostasis and reproduction. Brain Res 10:129–138CrossRefGoogle Scholar
  6. Chung HY, Kim HJ, Kim KW, Choi JS, Yu BP (2002) Molecular inflammation hypothesis of aging based on the anti-aging mechanism of calorie restriction. Microsc Res Tech 59:264–272CrossRefPubMedGoogle Scholar
  7. Davies AH, Kelly A, Dhanrajan TM, Lynch MA, Rodrıguez JJ, Stewart GM (2003) Synaptophysin immunogold labelling of synapses decreases in dentate gyrus of the hippocampus of aged rats. Brain Res 986:191–195CrossRefPubMedGoogle Scholar
  8. Deocaris CC, Widodo N, Shrestha BG, Kaur K, Ohtaka M, Yamasaki K, Kaul SC, Wadhwa R (2007) Mortalin sensitizes human cancer cells to MKT-077-induced senescence. Cancer Lett 252(2):259–269CrossRefPubMedGoogle Scholar
  9. Djordjevic MA, Perovic M, Tesic V, Tanic N, Rakic L, Ruzdijic S, Kanazir S (2010) Long-term dietary restriction modulates the level of presynaptic proteins in the cortex and hippocampus of the aging rat. Neurochem Int 56:250–255CrossRefGoogle Scholar
  10. Feng J, Bianchi C, Sandmeyer JL, Sellke FW (2005) Bradykinin preconditioning improves the profile of cell survival proteins and limits apoptosis after cardioplegic arrest. Circulation 112:190–195Google Scholar
  11. Fernandez-Fernandez R, Martini AC, Navarro VM, Castellano JM, Dieguez C, Aguilar E, Pinilla L, Tena-Sempere M (2006) Novel signals for the integration of energy balance and reproduction. Mol Cell Endocrinol 25:127–132CrossRefGoogle Scholar
  12. Gonzales MM, Tarumi T, Eagan DE, Tanaka H, Vaghasia M, Haley AP (2012) Indirect effects of elevated body mass index on memory performance through altered cerebral metabolite concentrations. Psychosom Med 74:691–698Google Scholar
  13. Goto S, Takahashi R, Radak Z, Sharma R (2007) Beneficial biochemical outcomes of late-onset dietary restriction in rodents. Ann N Y Acad Sci 1100:431–441CrossRefPubMedGoogle Scholar
  14. Higami Y, Yu BP, Shimokawa I, Masoro EJ, Ikeda T (1994) Duration of dietary restriction: an important determinant for the incidence and age of onset of leukemia in male F344 rats. J Gerontol 49:B239–B244CrossRefPubMedGoogle Scholar
  15. Hsu KS, Huang CC, Liang YC, Wu HM, Chen YL, Lo SW, Ho WC (2002) Alterations in the balance of protein kinase and phosphatase activities and age-related impairments of synaptic transmission and long-term potentiation. Hippocampus 12:787–802CrossRefPubMedGoogle Scholar
  16. Kaul SC, Deocaris CC, Wadhwa R (2007) Three faces of mortalin: a housekeeper, guardian and killer. Exp Gerontol 42:263–274CrossRefPubMedGoogle Scholar
  17. Kim DW, Choi JH (1999) Effects of age and dietary restriction on animal model SAMP8 mice with learning and memory impairments. J Nutr Health Aging 4(4):233–238Google Scholar
  18. Kochlamazashvili G, Senkov O, Grebenyuk S, Robinson C, Xiao MF, Stummeyer K, Gerardy-Schahn R, Engel AK, Feig L, Semyanov A, Suppiramaniam V, Schachner M, Dityatev A (2010) Neural cell adhesion molecule-associated polysialic acid regulates synaptic plasticity and learning by restraining the signaling through GluN2B-containing NMDA receptors. J Neurosci 30:4171–4183CrossRefPubMedGoogle Scholar
  19. Kumar S, Kaur G (2013) Intermittent fasting dietary restriction regimen negatively influences reproduction in young rats: a study of hypothalamo-hypophysial-gonadal axis. PLoS One 8:e52416PubMedCentralCrossRefPubMedGoogle Scholar
  20. Lee JH, Jung KJ, Kim JW, Kim HJ, Yu BP, Chung HY (2004) Suppression of apoptosis by calorie restriction in aged kidney. Exp Gerontol 39:1361–1368CrossRefPubMedGoogle Scholar
  21. Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz AG, Ahn BW, Shaltiel S, Stadtman ER (1990) Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol 186:464–478CrossRefPubMedGoogle Scholar
  22. Liu R, Liu IY, Bi X, Thompson RF, Doctrow SR, Malfroy B, Baudry M (2003) Reversal of age-related learning deficits and brain oxidative stress in mice with superoxide dismutase/catalase mimetics. Proc Natl Acad Sci USA 100:8526–8531PubMedCentralCrossRefPubMedGoogle Scholar
  23. Liu HX, Zhang JJ, Zhen P, Zhang Y (2005) Altered expression of MAP-2, GAP-43 and synaptophysin in the hippocampus of rats with chronic cerebral hypoperfusion correlates with cognitive impairment. Mol Brain Res 139:169–177CrossRefPubMedGoogle Scholar
  24. Mansuy MI (2003) Calcineurin in memory and bidirectional plasticity. Biochem Biophys Res Commun 311:1195–1208CrossRefPubMedGoogle Scholar
  25. Martin B, Mattson MP, Maudsley S (2006) Caloric resitriction and intermittent fasting: two potential diets for successful brain aging. Ageing Res Rev 5:332–353PubMedCentralCrossRefPubMedGoogle Scholar
  26. Melanson EL, Astrup A, Donahoo WT (2009) The relationship between dietary fat and fatty acid intake and body weight, diabetes, and the metabolic syndrome. Ann Nutr Metab 55:229–243CrossRefPubMedGoogle Scholar
  27. Morris RG, Moser EI, Riedel G, Martin SJ, Sandin J, Day M, O’Carroll C (2003) Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory. Philos Trans R Soc London B: Biol Sci 358:773–786CrossRefGoogle Scholar
  28. Navarro MV, Tena-Sempere M (2012) Neuroendocrine control by kisspeptins: role in metabolic regulation of fertility. Nat Rev Endocrinol 8:40–53CrossRefGoogle Scholar
  29. Onyango IG, Khan SM (2006) Oxidative stress, mitochondrial dysfunction, and stress signaling in Alzheimer’s disease. Curr Alz Res 3:339–349CrossRefGoogle Scholar
  30. Park DC, Lautenschlager G, Hedden T, Davidson NS, Smith AD, Smith PK (2002) Models of visuospatial and verbal memory across the adult life span. Psychol Aging 17:299–320CrossRefPubMedGoogle Scholar
  31. Przekop F, Ciechanowska M (2012) Kisspeptin (kiss 1) network signaling of hypothalamic gonadotropin-releasing hormone (GnRH) neurons. J Anim Feed Sci 21:397–424Google Scholar
  32. Rutten BP, Vander Kolk NM, Zandvoort V, Bayer MA, Steinbusch TA, Schmitz C (2005) Age-related loss of synaptophysin immunoreactive presynaptic boutons within the hippocampus of APP751SL, PS1M146L, and APP751SL/PS1M146L transgenic mice. Am J Pathol 167:161–173PubMedCentralCrossRefPubMedGoogle Scholar
  33. Sandi C, Touyarot K (2006) Mid-life stress and cognitive deficits during early aging in rats: individual differences and hippocampal correlates. Neurobiol Ageing 27:128–140CrossRefGoogle Scholar
  34. Sarkar D, Fisher PB (2006) Molecular mechanisms of aging-associated inflammation. Cancer Lett 236:13–23CrossRefPubMedGoogle Scholar
  35. Saxena N, Katiyar SP, Liu Y, Grover A, Gao R, Sundar D, Kaul SC, Wadhwa R (2013) Molecular interactions of Bcl-2 and Bcl-xL with mortalin: identification and functional characterization. Biosci Rep 33(5):797–806CrossRefGoogle Scholar
  36. Sen CK (2001) Antioxidant and redox regulation of cellular signaling: introduction. Med Sci Sports Exerc 33:368–370CrossRefPubMedGoogle Scholar
  37. Serrano F, Klann E (2004) Reactive oxygen species and synaptic plasticity in the aging hippocampus. Ageing Res Rev 3:431–443CrossRefPubMedGoogle Scholar
  38. Sharma S, Singh R, Kaur M, Kaur G (2010) Late-onset dietary restriction compensates for age-related increase in oxidative stress and alterations of HSP 70 and synapsin1 protein levels in male Wistar rats. Biogerontology 11:197–209CrossRefPubMedGoogle Scholar
  39. Singh R, Lakhanpal D, Kumar S, Sharma S, Kataria H, Kaur M, Kaur G (2011) Late-onset intermittent fasting dietary restriction as a potential intervention to retard age-associated brain function impairments in male rats. Age (Dordr) 34:917–933CrossRefGoogle Scholar
  40. Um JH, Kim SJ, Kim DW, Ha MY, Jang JH, Kim DW, Chung BS, Kang CD, Kim SH (2003) Tissue-specific changes of DNA repair protein Ku and mtHSP70 in aging rats and their retardation by caloric restriction. Mech Ageing Dev 124:967–975CrossRefPubMedGoogle Scholar
  41. Valassi E, Scacchi M, Cavagnini F (2008) Neuroendocrine control of food intake. Nutr Metab Cardiovasc Dis 18:158–168CrossRefPubMedGoogle Scholar
  42. Wang P, Wang WP, Sun-Zhang WHX, Yan-Lou FYH (2008) Impaired spatial learning related with decreased expression of calcium/calmodulin-dependent protein kinase IIα and cAMP-response element binding protein in the pentylenetetrazol-kindled rats. Brain Res 1238:108–117CrossRefPubMedGoogle Scholar
  43. Zimmermann MB, Aeberli I (2008) Dietary determinants of subclinical inflammation, dyslipidemia and components of the metabolic syndrome in overweight children: a review. Int J Obes 32:S11–S18CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Rumani Singh
    • 1
  • Shaffi Manchanda
    • 2
  • Taranjeet Kaur
    • 2
  • Sushil Kumar
    • 2
  • Dinesh Lakhanpal
    • 3
  • Sukhwinder S. Lakhman
    • 4
  • Gurcharan Kaur
    • 2
    Email author
  1. 1.Department of Pharmacology and Experimental TherapeuticsBoston University School of MedicineBostonUSA
  2. 2.Department of BiotechnologyGuru Nanak Dev UniversityAmritsarIndia
  3. 3.Department of BiotechnologyKanya Maha VidyalayaJalandharIndia
  4. 4.Department of Pharmaceutical, Social and Administrative SciencesD’Youville College School of PharmacyBuffaloUSA

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