Skip to main content
SpringerLink
Log in

Exercise Training Protects Against Aging-Induced Cognitive Dysfunction via Activation of the Hippocampal PGC-1α/FNDC5/BDNF Pathway

  • Original Paper
  • Published:
NeuroMolecular Medicine Aims and scope Submit manuscript

Abstract

This study aimed to determine the effect of exercise training on cognitive functioning, and hippocampal PGC-1α, FNDC5, BDNF, and other cognition-related gene and protein expression in rats. Rats were divided into 4 groups based on age [3 months (young) vs. 20 months (aged)] and training status (control vs. exercise training). The rats that exercised voluntarily performed exercise training for 90 days, and then all the rats underwent several methods of behavioral assessment. Locomotor activity and spatial memory were lower but anxiety scores were higher in the aged control rats, than in the young control, young exercised, and aged exercised rats (P < 0.05). Hippocampal BDNF, FNDC5, PGC-1α, mTOR, ARC, cF-OS, ERK, SIRT, and FOXO expressions were lower, but NF-κB expressions were higher in the aged control rats than in the young control, young exercised, and aged exercised rats (P < 0.05). Similarly, hippocampal BDNF and FNDC5 protein expression were lower in the aged control rats than in the young control, young exercised, and aged exercised rats (P < 0.05). These findings show that aging-induced cognitive dysfunction is associated with a decrease in hippocampal expression of PGC-1α, FNDC5, and BDNF, and that exercise training might improve cognitive functioning via activation of these genes and proteins.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Aguiar, A. S. Jr., Castro, A. A., Moreira, E. L., Glaser, V., Santos, A. R., Tasca, C. I., et al. (2011). Short bouts of mild-intensity physical exercise improve spatial learning and memory in aging rats: Involvement of hippocampal plasticity via AKT, CREB and BDNF signaling. Mechanisms of Ageing and Development, 132(11–12), 560–567.

    Article  PubMed  CAS  Google Scholar 

  • Aid, T., Kazantseva, A., Piirsoo, M., Palm, K., & Timmusk, T. (2007). Mouse and rat BDNF gene structure and expression revisited. Journal of Neuroscience Research, 85(3), 525–535.

    Article  PubMed  CAS  Google Scholar 

  • Belviranli, M., Atalik, K. E., Okudan, N., & Gökbel, H. (2012). Age and sex affect spatial and emotional behaviors in rats: The role of repeated elevated plus maze test. Neuroscience, 227, 1–9.

    Article  PubMed  CAS  Google Scholar 

  • Belviranli, M., Okudan, N., Kabak, B., Erdoğan, M., & Karanfilci, M. (2016). The relationship between brain-derived neurotrophic factor, irisin and cognitive skills of endurance athletes. The Physician and Sportsmedicine, 44(3), 290–296.

    Article  PubMed  Google Scholar 

  • Belviranlı, M., & Okudan, N. (2015). The effects of Ginkgo biloba extract on cognitive functions in aged female rats: The role of oxidative stress and brain-derived neurotrophic factor. Behavioural Brain Research, 278, 453–461.

    Article  PubMed  CAS  Google Scholar 

  • Belviranlı, M., Okudan, N., Atalık, K. E., & Öz, M. (2013). Curcumin improves spatial memory and decreases oxidative damage in aged female rats. Biogerontology, 14(2), 187–196.

    Article  PubMed  CAS  Google Scholar 

  • Bergado, J. A., Almaguer, W., Rojas, Y., Capdevila, V., & Frey, J. U. (2011). Spatial and emotional memory in aged rats: A behavioral-statistical analysis. Neuroscience, 172, 256–269.

    Article  PubMed  CAS  Google Scholar 

  • Bonni, A., Brunet, A., West, A. E., Datta, S. R., Takasu, M. A., & Greenberg, M. E. (1999). Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science, 286(5443), 1358–1362.

    Article  PubMed  CAS  Google Scholar 

  • Boström, P., Wu, J., Jedrychowski, M. P., Korde, A., Ye, L., Lo, J. C., et al. (2012). A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature, 481(7382), 463–468.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Boulle, F., van den Hove, D. L., Jakob, S. B., Rutten, B. P., Hamon, M., van Os, J., et al. (2012). Epigenetic regulation of the BDNF gene: Implications for psychiatric disorders. Molecular Psychiatry, 17(6), 584–596.

    Article  PubMed  CAS  Google Scholar 

  • Braidy, N., Poljak, A., Grant, R., Jayasena, T., Mansour, H., Chan-Ling, T., et al. (2015). Differential expression of sirtuins in the aging rat brain. Frontiers in Cellular Neuroscience, 9, 167.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bruel-Jungerman, E., Veyrac, A., Dufour, F., Horwood, J., Laroche, S., & Davis, S. (2009). Inhibition of PI3K-Akt signaling blocks exercise-mediated enhancement of adult neurogenesis and synaptic plasticity in the dentate gyrus. PLoS ONE, 4(11), e7901.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Burghardt, P. R., Fulk, L. J., Hand, G. A., & Wilson, M. A. (2004). The effects of chronic treadmill and wheel running on behavior in rats. Brain Research, 1019(1–2), 84–96.

    Article  PubMed  CAS  Google Scholar 

  • Chen, M. J., & Russo-Neustadt, A. A. (2005). Exercise activates the phosphatidylinositol 3-kinase pathway. Molecular Brain Research, 135(1–2), 181–193.

    Article  PubMed  CAS  Google Scholar 

  • Cooper, C., Moon, H. Y., & van Praag, H. (2017). On the run for hippocampal plasticity. In Cold Spring Harbor Perspectives in Medicine.

  • Cotman, C. W., Berchtold, N. C., & Christie, L. A. (2007). Exercise builds brain health: Key roles of growth factor cascades and inflammation. Trends in Neurosciences, 30(9), 464–472.

    Article  PubMed  CAS  Google Scholar 

  • D’Hooge, R., & De Deyn, P. P. (2001). Applications of the Morris water maze in the study of learning and memory. Brain Research Reviews, 36(1), 60–90.

    Article  PubMed  Google Scholar 

  • Duzel, E., van Praag, H., & Sendtner, M. (2016). Can physical exercise in old age improve memory and hippocampal function? Brain, 139(Pt 3), 662–673.

    Article  PubMed  PubMed Central  Google Scholar 

  • Eldomiaty, M. A., Almasry, S. M., Desouky, M. K., & Algaidi, S. A. (2017). Voluntary running improves depressive behaviours and the structure of the hippocampus in rats: A possible impact of myokines. Brain Research, 1657, 29–42.

    Article  PubMed  CAS  Google Scholar 

  • Erickson, K. I., Prakash, R. S., Voss, M. W., Chaddock, L., Heo, S., McLaren, M., et al. (2010). Brain-derived neurotrophic factor is associated with age-related decline in hippocampal volume. Journal of Neuroscience, 30(15), 5368–5375.

    Article  PubMed  CAS  Google Scholar 

  • Erickson, K. I., Prakash, R. S., Voss, M. W., Chaddock, L., Hu, L., Morris, K. S., et al. (2009). Aerobic fitness is associated with hippocampal volume in elderly humans. Hippocampus, 19(10), 1030–1039.

    Article  PubMed  PubMed Central  Google Scholar 

  • Fan, X., Wheatley, E. G., & Villeda, S. A. (2017). Mechanisms of hippocampal aging and the potential for rejuvenation. Annual Review of Neuroscience, 40, 251–272.

    Article  PubMed  CAS  Google Scholar 

  • Farmer, J., Zhao, X., van Praag, H., Wodtke, K., Gage, F. H., & Christie, B. R. (2004). Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo. Neuroscience, 124(1), 71–79.

    Article  PubMed  CAS  Google Scholar 

  • Gürtler, A., Kunz, N., Gomolka, M., Hornhardt, S., Friedl, A. A., McDonald, K., et al. (2013). Stain-Free technology as a normalization tool in Western blot analysis. Analytical Biochemistry, 433(2), 105–111.

    Article  PubMed  CAS  Google Scholar 

  • Haider, S., Saleem, S., Perveen, T., Tabassum, S., Batool, Z., Sadir, S., et al. (2014). Age-related learning and memory deficits in rats: Role of altered brain neurotransmitters, acetylcholinesterase activity and changes in antioxidant defense system. Age, 36(3), 9653.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hashemi, M. S., Ghaedi, K., Salamian, A., Karbalaie, K., Emadi-Baygi, M., Tanhaei, S., et al. (2013). Fndc5 knockdown significantly decreased neural differentiation rate of mouse embryonic stem cells. Neuroscience, 231, 296–304.

    Article  PubMed  CAS  Google Scholar 

  • Hovens, I. B., Schoemaker, R. G., van der Zee, E. A., Heineman, E., Nyakas, C., & van Leeuwen, B. L. (2013). Surgery-induced behavioral changes in aged rats. Experimental Gerontology, 48(11), 1204–1211.

    Article  PubMed  Google Scholar 

  • Jenwitheesuk, A., Boontem, P., Wongchitrat, P., Tocharus, J., Mukda, S., & Govitrapong, P. (2017). Melatonin regulates the aging mouse hippocampal homeostasis via the sirtuin1-FOXO1 pathway. EXCLI Journal, 16, 340–353.

    PubMed  PubMed Central  Google Scholar 

  • Jodeiri Farshbaf, M., Ghaedi, K., Megraw, T. L., Curtiss, J., Shirani Faradonbeh, M., Vaziri, P., et al. (2016). Does PGC1α/FNDC5/BDNF elicit the beneficial effects of exercise on neurodegenerative disorders? Neuromolecular Medicine, 18(1), 1–15.

    Article  PubMed  CAS  Google Scholar 

  • Kohman, R. A., Rodriguez-Zas, S. L., Southey, B. R., Kelley, K. W., Dantzer, R., & Rhodes, J. S. (2011). Voluntary wheel running reverses age-induced changes in hippocampal gene expression. PLoS ONE, 6(8), e22654.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Koscak Tivadar, B. (2017). Physical activity improves cognition: Possible explanations. Biogerontology, 18(4), 477–483.

    Article  PubMed  Google Scholar 

  • Küçük, A., Gölgeli, A., Saraymen, R., & Koç, N. (2008). Effects of age and anxiety on learning and memory. Behavioural Brain Research, 195(1), 147–152.

    Article  PubMed  Google Scholar 

  • Leal, G., Bramham, C. R., & Duarte, C. B. (2017). BDNF and hippocampal synaptic plasticity. Vitamins and Hormones, 104, 153–195.

    Article  PubMed  CAS  Google Scholar 

  • Li, D. J., Li, Y. H., Yuan, H. B., Qu, L. F., & Wang, P. (2017). The novel exercise-induced hormone irisin protects against neuronal injury via activation of the Akt and ERK1/2 signaling pathways and contributes to the neuroprotection of physical exercise in cerebral ischemia. Metabolism, 68, 31–42.

    Article  PubMed  CAS  Google Scholar 

  • Liu, P., Zou, D., Yi, L., Chen, M., Gao, Y., Zhou, R., et al. (2015). Quercetin ameliorates hypobaric hypoxia-induced memory impairment through mitochondrial and neuron function adaptation via the PGC-1α pathway. Restorative Neurology and Neuroscience, 33(2), 143–157.

    PubMed  CAS  Google Scholar 

  • Lloyd, B. A., Hake, H. S., Ishiwata, T., Farmer, C. E., Loetz, E. C., Fleshner, M., et al. (2017). Exercise increases mTOR signaling in brain regions involved in cognition and emotional behavior. Behavioural Brain Research, 323, 56–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lovatel, G. A., Elsner, V. R., Bertoldi, K., Vanzella, C., Moysés Fdos, S., Vizuete, A., et al. (2013). Treadmill exercise induces age-related changes in aversive memory, neuroinflammatory and epigenetic processes in the rat hippocampus. Neurobiology of Learning and Memory, 101, 94–102.

    Article  PubMed  CAS  Google Scholar 

  • Luellen, B. A., Bianco, L. E., Schneider, L. M., & Andrews, A. M. (2007). Reduced brain-derived neurotrophic factor is associated with a loss of serotonergic innervation in the hippocampus of aging mice. Genes, Brain and Behavior, 6(5), 482–490.

    Article  CAS  Google Scholar 

  • Marosi, K., Bori, Z., Hart, N., Sárga, L., Koltai, E., Radák, Z., et al. (2012). Long-term exercise treatment reduces oxidative stress in the hippocampus of aging rats. Neuroscience, 226, 21–28.

    Article  PubMed  CAS  Google Scholar 

  • Marosi, K., & Mattson, M. P. (2014). BDNF mediates adaptive brain and body responses to energetic challenges. Trends in Endocrinology & Metabolism, 25(2), 89–98.

    Article  CAS  Google Scholar 

  • Mattson, M. P. (2012). Evolutionary aspects of human exercise—Born to run purposefully. Ageing Research Reviews, 11(3), 347–352.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Miyawaki, C. E., Bouldin, E. D., Kumar, G. S., & McGuire, L. C. (2017). Associations between physical activity and cognitive functioning among middle-aged and older adults. The Journal of Nutrition, Health & Aging, 21(6), 637–647.

    Article  CAS  Google Scholar 

  • Okudan, N., & Belviranlı, M. (2017). Long-term voluntary exercise prevents post-weaning social isolation-induced cognitive impairment in rats. Neuroscience, 360, 1–8.

    Article  PubMed  CAS  Google Scholar 

  • Pardon, M. C., Pérez-Diaz, F., Joubert, C., & Cohen-Salmon, C. (2000). Age-dependent effects of a chronic ultramild stress procedure on open-field behaviour in B6D2F1 female mice. Physiology & Behavior, 70(1–2), 7–13.

    Article  CAS  Google Scholar 

  • Peters, M., Bletsch, M., Stanley, J., Wheeler, D., Scott, R., & Tully, T. (2014). The PDE4 inhibitor HT-0712 improves hippocampus-dependent memory in aged mice. Neuropsychopharmacology, 39(13), 2938–2948.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pietrelli, A., Lopez-Costa, J., Goñi, R., Brusco, A., & Basso, N. (2012). Aerobic exercise prevents age-dependent cognitive decline and reduces anxiety-related behaviors in middle-aged and old rats. Neuroscience, 202, 252–266.

    Article  PubMed  CAS  Google Scholar 

  • Qiu, J., Dunbar, D. R., Noble, J., Cairns, C., Carter, R., Kelly, V., et al. (2016). Decreased Npas4 and Arc mRNA Levels in the hippocampus of aged memory-impaired wild-type but not memory preserved 11β-HSD1 deficient mice. Journal of Neuroendocrinology, 28(1).

  • Rattan, S. I. (2012). Biogerontology: From here to where? The Lord Cohen Medal Lecture-2011. Biogerontology, 13, 83–91.

    Article  PubMed  Google Scholar 

  • Rodgers, R. J., & Dalvi, A. (1997). Anxiety, defence and the elevated plus-maze. Neuroscience & Biobehavioral Reviews, 21(6), 801–810.

    Article  CAS  Google Scholar 

  • Salehpour, M., Khodagholi, F., Zeinaddini Meymand, A., Nourshahi, M., & Ashabi, G. (2017). Exercise training with concomitant nitric oxide synthase inhibition improved anxiogenic behavior, spatial cognition, and BDNF/P70S6 kinase activation in 20-month-old rats. Applied Physiology, Nutrition, and Metabolism, 30, 1–9.

    Google Scholar 

  • Schmittgen, T. D., & Livak, K. J. (2008). Analyzing real-time PCR data by the comparative C(T) method. Nature Protocols, 3(6), 1101–1108.

    Article  PubMed  CAS  Google Scholar 

  • Steiner, J. L., Murphy, E. A., McClellan, J. L., Carmichael, M. D., & Davis, J. M. (2011). Exercise training increases mitochondrial biogenesis in the brain. Journal of Applied Physiology, 111(4), 1066–1071.

    Article  PubMed  CAS  Google Scholar 

  • Stranahan, A. M., & Mattson, M. P. (2012). Metabolic reserve as a determinant of cognitive aging. Journal of Alzheimer’s Disease, 30(Suppl 2), S5–S13.

    Article  PubMed  CAS  Google Scholar 

  • Teufel, A., Malik, N., Mukhopadhyay, M., & Westphal, H. (2002). Frcp1 and Frcp2, two novel fibronectin type III repeat containing genes. Gene, 297(1–2), 79–83.

    Article  PubMed  CAS  Google Scholar 

  • Torma, F., Bori, Z., Koltai, E., Felszeghy, K., Vacz, G., Koch, L., et al. (2014). Eating habits modulate short term memory and epigenetical regulation of brain derived neurotrophic factor in hippocampus of low- and high running capacity rats. Brain Research Bulletin, 107, 54–60.

    Article  PubMed  CAS  Google Scholar 

  • Torras-Garcia, M., Costa-Miserachs, D., Coll-Andreu, M., & Portell-Cortés, I. (2005). Decreased anxiety levels related to aging. Experimental Brain Research, 164(2), 177–184.

    Article  PubMed  Google Scholar 

  • van Praag, H., Shubert, T., Zhao, C., & Gage, F. H. (2005). Exercise enhances learning and hippocampal neurogenesis in aged mice. Journal of Neuroscience, 25(38), 8680–8685.

    Article  PubMed  CAS  Google Scholar 

  • Vanzella, C., Neves, J. D., Vizuete, A. F., Aristimunha, D., Kolling, J., Longoni, A., et al. (2017). Treadmill running prevents age-related memory deficit and alters neurotrophic factors and oxidative damage in the hippocampus of Wistar rats. Behavioural Brain Research, 334, 78–85.

    Article  PubMed  CAS  Google Scholar 

  • Vivar, C., Potter, M. C., & van Praag, H. (2013). All about running: Synaptic plasticity, growth factors and adult hippocampal neurogenesis. Current Topics in Behavioral Neurosciences, 15, 189–210.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang, S. J., Zhao, X. H., Chen, W., Bo, N., Wang, X. J., Chi, Z. F., et al. (2015). Sirtuin 1 activation enhances the PGC-1α/mitochondrial antioxidant system pathway in status epilepticus. Molecular Medicine Reports, 11(1), 521–526.

    Article  PubMed  CAS  Google Scholar 

  • Wrann, C. D. (2015). FNDC5/irisin—Their role in the nervous system and as a mediator for beneficial effects of exercise on the brain. Brain Plasticity, 1(1), 55–61.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wrann, C. D., White, J. P., Salogiannnis, J., Laznik-Bogoslavski, D., Wu, J., Ma, D., et al. (2013). Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metabolism, 18(5), 649–659.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wu, H., Zhao, J., Chen, M., Wang, H., Yao, Q., Fan, J., et al. (2017). The anti-aging effect of erythropoietin via the ERK/Nrf2-ARE pathway in aging rats. Journal of Molecular Neuroscience, 61(3), 449–458.

    Article  PubMed  CAS  Google Scholar 

  • Xu, B. (2013). BDNF (I)rising from exercise. Cell Metabolism, 18(5), 612–614.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yan, B. C., Jiang, D., Wang, J., Zhang, Y., Zhu, X., Xu, P., et al. (2018…). Both decreased Akt expression and mTOR phosphorylation are related to decreased neuronal differentiation in the hippocampal alveus of aged mice. Aging Clinical and Experimental Research, 30(7), 737–743.

    Article  PubMed  Google Scholar 

  • Zhao, H., Alam, A., San, C. Y., Eguchi, S., Chen, Q., Lian, Q., et al. (2017). Molecular mechanisms of brain-derived neurotrophic factor in neuro-protection: Recent developments. Brain Research, 1665, 1–21.

    Article  PubMed  CAS  Google Scholar 

  • Zigmond, M. J., & Smeyne, R. J. (2014). Exercise: Is it a neuroprotective and if so, how does it work? Parkinsonism & Related Disorders, 20(Suppl 1), S123–S127.

    Article  Google Scholar 

Download references

Acknowledgements

This study was supported by the Selçuk University Scientific Research and Project Committee (project number: 15401171). The authors would like to thank Scott Evans for English language editing.

Author information

Authors and Affiliations

  1. Department of Physiology, School of Medicine, Selçuk University, Konya, 42131, Turkey

    Muaz Belviranlı & Nilsel Okudan

Authors
  1. Muaz Belviranlı
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nilsel Okudan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Muaz Belviranlı.

Ethics declarations

Conflict of interest

There are no conflicts of interest—financial or otherwise—related to the material presented herein.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Belviranlı, M., Okudan, N. Exercise Training Protects Against Aging-Induced Cognitive Dysfunction via Activation of the Hippocampal PGC-1α/FNDC5/BDNF Pathway. Neuromol Med 20, 386–400 (2018). https://doi.org/10.1007/s12017-018-8500-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12017-018-8500-3

Keywords

Search

Navigation