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Voluntary Exercise Promotes Beneficial Anti-aging Mechanisms in SAMP8 Female Brain

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Abstract

Regular physical exercise mediates health and longevity promotion involving Sirtuin 1 (SIRT1)-regulated pathways. The anti-aging activity of SIRT1 is achieved, at least in part, by means of fine-tuning the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway by preventing the transition of an originally pro-survival program into a pro-aging mechanism. Additionally, SIRT1 promotes mitochondrial function and reduces the production of reactive oxygen species (ROS) through regulating peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), the master controller of mitochondrial biogenesis. Here, by using senescence-accelerated mice prone 8 (SAMP8) as a model for aging, we determined the effect of wheel-running as a paradigm for long-term voluntary exercise on SIRT1-AMPK pathway and mitochondrial functionality measured by oxidative phosphorylation (OXPHOS) complex content in the hippocampus and cortex. We found differential activation of SIRT1 in both tissues and hippocampal-specific activation of AMPK. These findings correlated well with significant changes in OXPHOS in the hippocampal, but not in the cerebral cortex, area. Collectively, the results revealed greater benefits of the exercise in the wheel-running intervention in a murine model of senescence, which was directly related with mitochondrial function and which was mediated through the modulation of SIRT1 and AMPK pathways.

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References

  • Álvarez-López MJ, Castro-Freire M, Cosin-Tomas M, Sanchez-Roige S, Lalanza JF, Del Valle J, Párrizas M, Camins A, Pallás M, Escorihuela RM, Kaliman P (2013) Long-term exercise modulates hippocampal gene expression in senescent female mice. J Alzheimers Dis 33(4):1177–1190

    PubMed  Google Scholar 

  • Bamidis PD, Vivas AB, Styliadis C, Frantzidis C, Klados M, Schlee W, Siountas A, Papageorgiou SG. (2014) A review of physical and cognitive interventions in aging. Neurosci. Biobehav. Rev. S0149-7634(14)00075-X.

  • Bayod S, Del Valle J, Lalanza JF, Sanchez-Roige S, de Luxán-Delgado B, Coto-Montes A, Canudas AM, Camins A, Escorihuela RM, Pallàs M (2012) Long-term physical exercise induces changes in Sirtuin 1 pathway and oxidative parameters in adult rat tissues. Exp Gerontol 47(12):925–935

    Article  CAS  PubMed  Google Scholar 

  • Bayod S, Menella I, Sanchez-Roige S, Lalanza JF, Escorihuela RM, Camins A, Pallàs M, Canudas AM (2014) Wnt pathway regulation by long-term moderate exercise in rat hippocampus. Brain Res 16(1543):38–4

    Article  Google Scholar 

  • Bertoni-Freddari C, Fattoretti P, Giorgetti B, Grossi Y, Balietti M, Casoli T, Di Stefano G, Perretta G (2007) Synaptic and mitochondrial morphometry provides structural correlates of successful brain aging. Ann N Y Acad Sci 1097:51–53

    Article  PubMed  Google Scholar 

  • Brinton RD (2008) Estrogen regulation of glucose metabolism and mitochondrial function: therapeutic implications for prevention of Alzheimer’s disease. Adv Drug Deliv Rev 60(13–14):1504–1511

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Burkewitz K, Zhang Y, Mair WB. AMPK at the nexus of energetics and aging. (2014) Cell Metab. S1550-4131(14)00106-5.

  • Canto C, Auwerx J (2009) Caloric restriction, SIRT1 and longevity. Trends Endocrinol Metab 20:325–331

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Canudas AM, Gutierrez-Cuesta J, Rodríguez MI, Acuña-Castroviejo D, Sureda FX, Camins A, Pallàs M (2005) Hyperphosphorylation of microtubule-associated protein tau in senescence-accelerated mouse (SAM). Mech Ageing Dev 126(12):1300–1304

    Article  CAS  PubMed  Google Scholar 

  • Corbi G, Conti V, Scapagnini G, Filippelli A, Ferrara N (2012) Role of Sirtuins, calorie restriction and physical activity in aging. Front Biosci (Elite Ed) 4:768–778

    Article  Google Scholar 

  • Corradetti MN, Inoki K, Bardeesy N, DePinho RA, Guan KL (2004) Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev 18(13):1533–1538

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cosín-Tomás M, Alvarez-López MJ, Sanchez-Roige S, Lalanza JF, Bayod S, Sanfeliu C, Pallàs M, Escorihuela RM, Kaliman P (2014) Epigenetic alterations in hippocampus of SAMP8 senescent mice and modulation by voluntary physical exercise. Front Aging Neurosci 20(6):51

    Google Scholar 

  • del Valle J, Bayod S, Camins A, Beas-Zárate C, Velázquez-Zamora DA, González-Burgos I, Pallàs M (2012) Dendritic spine abnormalities in hippocampal CA1 pyramidal neurons underlying memory deficits in the SAMP8 mouse model of Alzheimer’s disease. J Alzheimers Dis 32(1):233–240

    PubMed  Google Scholar 

  • Eilam R, Davidson A, Gozes I, Segal M (1999) Locomotor activity causes a rapid up-regulation of vasoactive intestinal peptide in the rat hippocampus. Hippocampus 9(5):534–541

    Article  CAS  PubMed  Google Scholar 

  • Fernández-Marcos PJ, Auwerx J (2011) Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr 93(4):884S–890S

    Article  PubMed Central  PubMed  Google Scholar 

  • Fone KC, Porkess MV, Fone KC, Porkess MV (2008) Behavioural and neurochemical effects of post-weaning social isolation in rodents-relevance to developmental neuropsychiatric disorders. Neurosci Biobehav Rev 32(6):1087–1102

    Article  CAS  PubMed  Google Scholar 

  • Giralt A, Saavedra A, Carretón O, Arumí H, Tyebji S, Alberch J, Pérez NE (2013) PDE10 inhibition increases GluA1 and CREB phosphorylation and improves spatial and recognition memories in a Huntington’s disease mouse model. Hippocampus 23(8):684–695

    Article  CAS  PubMed  Google Scholar 

  • Guarente L (2001) SIR2 and aging—the exception that proves the rule. Trends Genet 17(7):391–392

    Article  CAS  PubMed  Google Scholar 

  • Gutierrez-Cuesta J, Tajes M, Jiménez A, Coto-Montes A, Camins A, Pallàs M (2008) Evaluation of potential pro-survival pathways regulated by melatonin in a murine senescence model. J Pineal Res 45(4):497–505

  • Hardie DG (2011) AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev 25(18):1895–1908

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hubbard BP, Sinclair DA (2014) Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol Sci 35(3):146–154

    Article  CAS  PubMed  Google Scholar 

  • Imtiaz B, Tolppanen AM, Kivipelto M, Soininen H (2014) Future directions in Alzheimer’s disease from risk factors to prevention. Biochem Pharmacol 88(4):661–670

    Article  CAS  PubMed  Google Scholar 

  • Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 26;115(5):577–590

    Article  Google Scholar 

  • Kaliman, P., Párrizas, M., Lalanza, J.F., Camins, A., Escorihuela, R.M. Pallàs, M. (2011) Neurophysiological and epigenetic effects of physical exercise on the aging process. Ageing Res Rev, 10: 475-786

  • Lan F, Cacicedo JM, Ruderman N, Ido Y (2008) SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem 283:27628–27635

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Loprinzi PD, Herod SM, Cardinal BJ, Noakes TD (2013) Physical activity and the brain: a review of this dynamic, bi-directional relationship. Brain Res 1539:95–104

    Article  CAS  PubMed  Google Scholar 

  • Marosi K, Bori Z, Hart N, Sárga L, Koltai E, Radák Z, Nyakas C (2012) Long-term exercise treatment reduces oxidative stress in the hippocampus of aging rats. Neuroscience 13;226:21–28

    Article  Google Scholar 

  • Navarro A, Boveris A (2007) The mitochondrial energy transduction system and the aging process. Am J Physiol Cell Physiol 292(2):C670–C686

    Article  CAS  PubMed  Google Scholar 

  • Navarro A, Gomez C, López-Cepero JM, Boveris A (2004) Beneficial effects of moderate exercise on mice aging survival, behavior, oxidative stress, and mitochondrial electron transfer. Am J Physiol Regul Integr Comp Physiol 286(3):R505–R511

    Article  CAS  PubMed  Google Scholar 

  • Nomura Y, Okuma Y (1999) Age-related defects in lifespan and learning ability in SAMP8 mice. Neurobiol Aging 20(2):111–115

    Article  CAS  PubMed  Google Scholar 

  • Onyango IG, Lu J, Rodova M, Lezi E, Crafter AB, Swerdlow RH (2010) Regulation of neuron mitochondrial biogenesis and relevance to brain health. Biochim Biophys Acta 1802(1):228–234

    Article  CAS  PubMed  Google Scholar 

  • Pallàs M, Pizarro JG, Gutierrez-Cuesta J, Crespo-Biel N, Alvira D, Tajes M, Yeste-Velasco M, Folch J, Canudas AM, Sureda FX, Ferrer I, Camins A (2008) Modulation of SIRT1 expression in different neurodegenerative models and human pathologies. Neuroscience 154(4):1388–1397

    Article  PubMed  Google Scholar 

  • Porquet D, Casadesús G, Bayod S, Vicente A, Canudas AM, Vilaplana J, Pelegrí C, Sanfeliu C, Camins A, Pallàs M, del Valle J (2013) Dietary resveratrol prevents Alzheimer’s markers and increases life span in SAMP8. Age (Dordr) 35(5):1851–1865

    Article  CAS  Google Scholar 

  • Quiroz-Baez R, Flores-Domínguez D, Arias C (2013) Synaptic aging is associated with mitochondrial dysfunction, reduced antioxidant contents and increased vulnerability to amyloid-β toxicity. Curr Alzheimer Res 10(3):324–331

    Article  CAS  PubMed  Google Scholar 

  • Radak Z, Koltai E, Taylor AW, Higuchi M, Kumagai S, Ohno H, Goto S, Boldogh I (2013) Redox-regulating Sirtuins in aging, caloric restriction, and exercise. Free Radic Biol Med 58:87–97

    Article  CAS  PubMed  Google Scholar 

  • Reddy PH, Beal MF (2008) Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends Mol. Med 14(2):45–53

  • Salminen A, Kaarniranta K (2012) AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev 11(2):230–241

    Article  CAS  PubMed  Google Scholar 

  • Shaw RJ (2009) LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol 196(1):65–80

    Article  CAS  Google Scholar 

  • Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, Cantley LC (2004) The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci U S A 101(10):3329–3335

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Stefanatos R, Sanz A (2011) Mitochondrial complex I: a central regulator of the aging process. Cell Cycle 10(10):1528–1532

    Article  CAS  PubMed  Google Scholar 

  • Tajes M, Gutierrez-Cuesta J, Ortuño-Sahagun D, Camins A, Pallàs M (2009) Anti-aging properties of melatonin in an in vitro murine senescence model: involvement of the Sirtuin 1 pathway. J Pineal Res 47(3):228–237

    Article  CAS  PubMed  Google Scholar 

  • Takeda T (2009) Senescence-accelerated mouse (SAM) with special references to neurodegeneration models, SAMP8 and SAMP10 mice. Neurochem Res 34(4):639–659

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Liang Y, Vanhoutte PM (2011) SIRT1 and AMPK in regulating mammalian senescence: a critical review and a working model. FEBS Lett 585(7):986–994

    Article  CAS  PubMed  Google Scholar 

  • WHO, Global health and aging. (2011) Edited by: World Health Organization and US National Institute of Aging. 32 pp.

  • Zheng Z, Chen H, Li J, Li T, Zheng B, Zheng Y, Jin H, He Y, Gu Q, Xu X (2012) Sirtuin 1-mediated cellular metabolic memory of high glucose via the LKB1/AMPK/ROS pathway and therapeutic effects of metformin. Diabetes 61(1):217–228

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

We thank Maggie Brunner, M.A., for revising the language and style of the manuscript. This study was supported by grants SAF2010-15050 (PK), PSI2008-06417-C03-03 (RME), and SAF-2012-39852 (MP) from the “Ministerio de Educación y Ciencia” and 2009/SGR00893 from the “Generalitat de Catalunya.” S.B. was supported by a predoctoral fellowship (APIF) from the University of Barcelona. J.F.L. was supported by a predoctoral fellowship from the Generalitat de Catalunya (FI-DGR 2011).

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Authors and Affiliations

  1. Unitat de Farmacologia i Farmacognòsia. Facultat de Farmàcia, Institut de Biomedicina (IBUB), Universitat de Barcelona, Nucli Universitari de Pedralbes, 08028, Barcelona, Spain

    Sergi Bayod & Mercè Pallàs

  2. Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain

    Sergi Bayod & Mercè Pallàs

  3. Institut de Neurociències, Departamento. de Psiquiatria i Medicina Legal, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain

    Jaume F. Lalanza & Rosa M. Escorihuela

  4. División de Biotecnología y Salud, Escuela de Medicina, Instituto Tecnológico y de Estudios Superiores de Monterrey, Campus Guadalajara, Guadalajara, 45201, Jalisco, Mexico

    Carolina Guzmán-Brambila

  5. Instituto de Investigación en Ciencias Biomédicas (IICB), CUCS, Universidad de Guadalajara, Sierra Mojada No. 950, Col. Independencia, Guadalajara, 44340, Jalisco, Mexico

    Daniel Ortuño-Sahagun

  6. School of Psychology, University of Sussex, Falmer, Brighton, BN1 9QG, UK

    Sandra Sanchez-Roige

  7. Instituto de Investigaciones Biomédicas de Barcelona IIBB-CSIC, c/Rosselló 161, 6th floor, 08036, Barcelona, Spain

    Perla Kaliman

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  1. Sergi Bayod
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  2. Carolina Guzmán-Brambila
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  3. Sandra Sanchez-Roige
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  4. Jaume F. Lalanza
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  5. Perla Kaliman
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  6. Daniel Ortuño-Sahagun
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  7. Rosa M. Escorihuela
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  8. Mercè Pallàs
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Corresponding author

Correspondence to Mercè Pallàs.

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Sergi Bayod and Carolina Guzmán-Brambila contributed equally to this work.

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Bayod, S., Guzmán-Brambila, C., Sanchez-Roige, S. et al. Voluntary Exercise Promotes Beneficial Anti-aging Mechanisms in SAMP8 Female Brain. J Mol Neurosci 55, 525–532 (2015). https://doi.org/10.1007/s12031-014-0376-6

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  • DOI: https://doi.org/10.1007/s12031-014-0376-6

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