J Korean Med Assoc.  2009 Sep;52(9):907-919. 10.5124/jkma.2009.52.9.907.

Effects of Exercise on Structural and Functional Changes in the Aging Brain

• Lee KJ
• Rhyu IJ

• KMID: 1936495
• DOI: http://doi.org/10.5124/jkma.2009.52.9.907

Abstract

Arapid increase in the elderly population has raised social awareness for maintaining the health of the elderly and initiated intense research in neurodegenerative diseases. Exercise can improve not only cardiovascular and musculoskeletal fitness, but also suppresses the symptoms of depression and anxiety, suggesting a possible role of exercise in the regulation of brain function. Based on a substantial body of literature, here we introduce the effects of exercise on the structural and functional changes in the aging brain, and also discuss the molecular and cellular effects of exercise and motor learning. Studies show that regular exercise in the elderly promotes neurocognitive function, prevents loss of brain tissue, and reduces the risk for neurodegenerative diseases and brain injury. Although the molecular mechanisms, by which exercise regulates brain function, has not been fully understood, recent cell biological and biochemical studies reveal that exercise increases neurogenesis in the hippocampus, elevates the levels of neurotrophins such as BDNF and IGF-1 to promote the survival of newly generated neurons. Exercise also induces angiogenesis in the motor cortex and cerebellum to enhance delivery of glucose and oxygen to neurons. Furthermore, complex motor skill learning increases the number of synapses to improve cognitive and motor function. Taken together, these findings clearly demonstrate that exercise serves as a behavioral intervention to prevent cognitive decline as well as neurodegenerative diseases. Thus long-term regular exercise in parallel with various learning experiences will be required to prepare successful aging. This study will provide fundamental insights into research in neurodegenerative diseases and a better understanding of the exercise effects in brain function.

Keyword

Exercise; Aging, Memory; Neurogenesis; Synapse; Neurotrophin; Angiogenesis

MeSH Terms

Aged
Aging
Anxiety
Brain
Brain Injuries
Brain-Derived Neurotrophic Factor
Cerebellum
Depression
Glucose
Hippocampus
Humans
Insulin-Like Growth Factor I
Learning
Motor Cortex
Motor Skills
Nerve Growth Factors
Neurodegenerative Diseases
Neurogenesis
Neurons
Oxygen
Synapses
Brain-Derived Neurotrophic Factor
Glucose
Insulin-Like Growth Factor I
Nerve Growth Factors
Oxygen

Reference

References

5. Kramer AF, Hahn S, Cohen NJ, Banich MT, McAuley E, Harrison CR, Chason J, Vakil E, Bardell L, Boileau RA, Colcombe A. Ageing, fitness and neurocognitive function. Nature. 1999; 400:418–419.

6. Laurin D, Verreault R, Lindsay J, MacPherson K, Rockwood K. Physical activity and risk of cognitive impairment and dementia in elderly persons. Arch Neurol. 2001; 58:498–504.

7. Colcombe SJ, Erickson KI, Raz N, Webb AG, Cohen NJ, McAuley E, Kramer AF. Aerobic fitness reduces brain tissue loss in aging humans. J Gerontol A Biol Sci Med Sci. 2003; 58:176–180.

8. Stummer W, Weber K, Tranmer B, Baethmann A, Kempski O. Reduced mortality and brain damage after locomotor activity in gerbil forebrain ischemia. Stroke. 1994; 25:1862–1869.

9. Birren JE, Schaie KW. Handbook of the psychology of aging. San Diego, CA: Academic Press;1996.

10. Yaffe K, Barnes D, Nevitt M, Lui LY, Covinsky K. A prospective study of physical activity and cognitive decline in elderly women: women who walk. Arch Intern Med. 2001; 161:1703–1708.

11. Barnes DE, Yaffe K, Satariano WA, Tager IB. A longitudinal study of cardiorespiratory fitness and cognitive function in healthy older adults. J Am Geriatr Soc. 2003; 51:459–465.

12. Dik M, Deeg DJ, Visser M, Jonker C. Early life physical activity and cognition at old age. J Clin Exp Neuropsychol. 2003; 25:643–653.

13. Colcombe S, Kramer AF. Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychol Sci. 2003; 14:125–130.

14. Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 2002; 25:295–301.

15. Berchtold NC, Kesslak JP, Pike CJ, Adlard PA, Cotman CW. Estrogen and exercise interact to regulate brain-derived neurotrophic factor mRNA and protein expression in the hippocampus. Eur J Neurosci. 2001; 14:1992–2002.

16. Klintsova AY, Greenough WT. Synaptic plasticity in cortical systems. Curr Opin Neurobiol. 1999; 9:203–208.

17. Fordyce DE, Wehner JM. Physical activity enhances spatial learning performance with an associated alteration in hippocampal protein kinase C activity in C57BL/6 and DBA/2 mice. Brain Res. 1993; 619:111–119.

18. van Praag H, Shubert T, Zhao C, Gage FH. Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci. 2005; 25:8680–8685.

19. Dishman RK, Heath GW, Washburn R. Physical activity epidemiology. Champaign, IL: Human Kinetics;2004.

20. Wendel-Vos GC, Schuit AJ, Feskens EJ, Boshuizen HC, Verschuren WM, Saris WH, Kromhout D. Physical activity and stroke. A metaanalysis of observational data. Int J Epidemiol. 2004; 33:787–798.

21. Selkoe DJ, Schenk D. Alzheimer's disease: molecular understanding predicts amyloid-based therapeutics. Annu Rev Pharmacol Toxicol. 2003; 43:545–584.

22. Friedland RP, Fritsch T, Smyth KA, Koss E, Lerner AJ, Chen CH, Petot GJ, Debanne SM. Patients with Alzheimer's disease have reduced activities in midlife compared with healthy control-group members. Proc Natl Acad Sci USA. 2001; 98:3440–3445.

23. Adlard PA, Perreau VM, Pop V, Cotman CW. Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease. J Neurosci. 2005; 25:4217–4221.

24. Toole T, Hirsch MA, Forkink A, Lehman DA, Maitland CG. The effects of a balance and strength training program on equilibrium in Parkinsonism: A preliminary study. Neuro-Rehabilitation. 2000; 14:165–174.

25. Reuter I, Engelhardt M, Stecker K, Baas H. Therapeutic value of exercise training in Parkinson's disease. Med Sci Sports Exerc. 1999; 31:1544–1549.

26. Tillerson JL, Cohen AD, Philhower J, Miller GW, Zigmond MJ, Schallert T. Forced limb-use effects on the behavioral and neurochemical effects of 6-hydroxydopamine. J Neurosci. 2001; 21:4427–4435.

27. Cohen AD, Tillerson JL, Smith AD, Schallert T, Zigmond MJ. Neuroprotective effects of prior limb use in 6-hydroxy-dopamine-treated rats: possible role of GDNF. J Neurochem. 2003; 85:299–305.

28. Taub E, Uswatte G, Pidikiti R. Constraint-Induced Movement Therapy: a new family of techniques with broad application to physical rehabilitation-a clinical review. J Rehabil Res Dev. 1999; 36:237–251.

29. Molteni R, Zheng JQ, Ying Z, Gomez-Pinilla F, Twiss JL. Voluntary exercise increases axonal regeneration from sensory neurons. Proc Natl Acad Sci USA. 2004; 101:8473–8478.

30. Small SA, Tsai WY, DeLaPaz R, Mayeux R, Stern Y. Imaging hippocampal function across the human life span: is memory decline normal or not? Ann Neurol. 2002; 51:290–295.

31. Colcombe S, Kramer AF, McAuley E, Erickson K, Scalf P. Cardiovascular fitness training and changes in brain volume as measured by voxel-based morphometry. Paper presented Meeting Soc Psychophysio Res New Mexico. 2004.

32. Cabeza R, Grady CL, Nyberg L, McIntosh AR, Tulving E, Kapur S, Jennings JM, Houle S, Craik FI. Age-related differences in neural activity during memory encoding and retrieval: a positron emission tomography study. J Neurosci. 1997; 17:391–400.

33. Colcombe SJ, Kramer AF, Erickson KI, Scalf P, McAuley E, Cohen NJ, Webb A, Jerome GJ, Marquez DX, Elavsky S. Cardiovascular fitness, cortical plasticity, and aging. Proc Natl Acad Sci USA. 2004; 101:3316–3321.

34. Altman J. Autoradiographic investigation of cell proliferation in the brains of rats and cats. Anat Rec. 1963; 145:573–591.

35. Kaplan MS, Hinds JW. Neurogenesis in the adult rat: electron microscopic analysis of light radioautographs. Science. 1977; 197:1092–1094.

36. Kaplan MS. Neurogenesis in the 3-month-old rat visual cortex. J Comp Neurol. 1981; 195:323–338.

37. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH. Neurogenesis in the adult human hippocampus. Nat Med. 1998; 4:1313–1317.

38. Gould E, Reeves AJ, Graziano MS, Gross CG. Neurogenesis in the neocortex of adult primates. Science. 1999; 286:548–552.

39. Gould E, Reeves AJ, Fallah M, Tanapat P, Gross CG, Fuchs E. Hippocampal neurogenesis in adult Old World primates. Proc Natl Acad Sci U S A. 1999; 96:5263–5267.

40. Kornack DR, Rakic P. Continuation of neurogenesis in the hippocampus of the adult macaque monkey. Proc Natl Acad Sci U S A. 1999; 96:5768–5773.

41. Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci. 1996; 16:2027–2033.

42. Lichtenwalner RJ, Forbes ME, Bennett SA, Lynch CD, Sonntag WE, Riddle DR. Intracerebroventricular infusion of insulinlike growth factor-? ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience. 2001; 107:603–613.

43. Van Praag H, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci. 1999; 2:266–270.

44. Russo-Neustadt A, Ha T, Ramirez R, Kesslak JP. Physical activity-antidepressant treatment combination: impact on brain-derived neurotrophic factor and behavior in an animal model. Behav Brain Res. 2001; 120:87–95.

45. Pencea V, Bingaman KD, Wiegand SJ, Luskin MB. Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J Neurosci. 2001; 21:6706–6717.

46. Shetty AK, Turner DA. In vitro survival and differentiation of neurons derived from epidermal growth factor-responsive postnatal hippocampal stem cells: inducing effects of brain-derived neurotrophic factor. J Neurobiol. 1998; 35:395–425.

47. Blomstrand E, Perrett D, Parry-Billings M, Newsholme EA. Effect of sustained exercise on plasma amino acid concentrations and on 5-hydroxytryptamine metabolism in six different brain regions in the rat. Acta Physiol Scand. 1989; 136:473–481.

48. Brezun JM, Daszuta A. Serotonin may stimulate granule cell proliferation in the adult hippocampus, as observed in rats grafted with foetal raphe neurons. Eur J Neurosci. 2000; 12:391–396.

49. Jin K, Sun Y, Xie L, Batteur S, Mao XO, Smelick C, Logvinova A, Greenberg DA. Neurogenesis and aging: FGF-2 and HB-EGF restore neurogenesis in hippocampus and subventricular zone of aged mice. Aging Cell. 2003; 2:175–183.

50. Fabel K, Fabel K, Tam B, Kaufer D, Baiker A, Simmons N, Kuo CJ, Palmer TD. VEGF is necessary for exercise-induced adult hippocampal neurogenesis. Eur J Neurosci. 2003; 18:2803–2812.

51. Gould E, McEwen BS, Tanapat P, Galea LA, Fuchs E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci. 1997; 17:2492–2498.

52. Cameron HA, McKay RD. Restoring production of hippocampal neurons in old age. Nat Neurosci. 1999; 2:894–897.

53. van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning, and longterm potentiation in mice. Proc Natl Acad Sci U S A. 1999; 96:13427–13431.

54. Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ. Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci. 1999; 2:260–265.

55. Snyder JS, Kee N, Wojtowicz JM. Effects of adult neurogenesis on synaptic plasticity in the rat dentate gyrus. J Neurophysiol. 2001; 85:2423–2431.

56. Schmidt-Hieber C, Jonas P, Bischofberger J. Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature. 2004; 429:184–187.

57. Ge S, Goh EL, Sailor KA, Kitabatake Y, Ming GL, Song H. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature. 2006; 439:589–593.

58. Lisman J. Long-term potentiation: outstanding questions and attempted synthesis. Philos Trans R Soc Lond B Biol Sci. 2003; 358:829–842.

59. Neeper SA, Gomez-Pinilla F, Choi J, Cotman CW. Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain. Brain Res. 1996; 726:49–56.

60. Campuzano R, Barrios V, Cuevas B, Asin-Cardiel E, Muela A, Castro JM, Fernandez-Ayerdi A, Cuevas P. Serum basic fibroblast growth factor levels in exercise-induced myocardial ischemia more likely a marker of endothelial dysfunction than a marker of ischemia? Eur J Med Res. 2002; 7:93–97.

61. Trejo JL, Carro E, Torres-Aleman I. Circulating insulinlike growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J Neurosci. 2001; 21:1628–1634.

62. Schobersberger W, Hobisch-Hagen P, Fries D, Wiedermann F, Rieder-Scharinger J, Villiger B, Frey W, Herold M, Fuchs D, Jelkmann W. Increase in immune activation, vascular endothelial growth factor and erythropoietin after an ultramarathon run at moderate altitude. Immunobiology. 2000; 201:611–620.

63. Wagner JP, Black IB, DiCicco-Bloom E. Stimulation of neonatal and adult brain neurogenesis by subcutaneous injection of basic fibroblast growth factor. J Neurosci. 1999; 19:6006–6016.

64. Aberg MA, Aberg ND, Hedbacker H, Oscarsson J, Eriksson PS. Peripheral infusion of IGF-? selectively induces neurogenesis in the adult rat hippocampus. J Neurosci. 2000; 20:2896–2903.

65. McAllister AK, Katz LC, Lo DC. Neurotrophins and synaptic plasticity. Annu Rev Neurosci. 1999; 22:295–318.

66. Neeper SA, Gomez-Pinilla F, Choi J, Cotman C. Exercise and brain neurotrophins. Nature. 1995; 373:109.

67. Gomez-Pinilla F, Ying Z, Opazo P, Roy RR, Edgerton VR. Differential regulation by exercise of BDNF and NT-3 in rat spinal cord and skeletal muscle. Eur J Neurosci. 2001; 13:1078–1084.

68. Schaaf MJ, De Kloet ER, Vreugdenhil E. Corticosterone effects on BDNF expression in the hippocampus. Implications for memory formation. Stress. 2000; 3:201–208.

69. Woolley CS, Gould E, McEwen BS. Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res. 1990; 531:225–231.

70. Watanabe Y, Gould E, McEwen BS. Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res. 1992; 588:341–345.

71. Byrne A, Byrne DG. The effect of exercise on depression, anxiety and other mood states: a review. J Psychosom Res. 1993; 37:565–574.

72. Carro E, Nunez A, Busiguina S, Torres-Aleman ?. Circulating insulinlike growth factor ? mediates effects of exercise on the brain. J Neurosci. 2000; 20:2926–2933.

73. Arsenijevic Y, Weiss S. Insulin-like growth factor-? is a differentiation factor for postmitotic CNS stem cell-derived neuronal precursors: distinct actions from those of brain-derived neurotrophic factor. J Neurosci. 1998; 18:2118–2128.

74. Markowska AL, Mooney M, Sonntag WE. Insulin-like growth factor-1 ameliorates age-related behavioral deficits. Neuroscience. 1998; 87:559–569.

75. Schwarz AJ, Brasel JA, Hintz RL, Mohan S, Cooper DM. Acute effect of brief low- and high-intensity exercise on circulating insulinlike growth factor (IGF) ?, ?, and IGF-binding protein-3 and its proteolysis in young healthy men. J Clin Endocrinol Metab. 1996; 81:3492–3497.

76. Reinhardt RR, Bondy CA. Insulin-like growth factors cross the blood-brain barrier. Endocrinology. 1994; 135:1753–1761.

77. Carro E, Trejo JL, Busiguina S, Torres-Aleman I. Circulating insulinlike growth factor ? mediates the protective effects of physical exercise against brain insults of different etiology and anatomy. J Neurosci. 2001; 21:5678–5684.

79. Farkas E, De Jong GI, de Vos RA, Jansen Steur EN, Luiten PG. Pathological features of cerebral cortical capillaries are doubled in Alzheimer's disease and Parkinson's disease. Acta Neuropathol (Berl). 2000; 100:395–402.

80. Farkas E, Luiten PG. Cerebral microvascular pathology in aging and Alzheimer's disease. Prog Neurobiol. 2001; 64:575–611.

81. Hengemihle JM, Abugo O, Rifkind J, Spangler E, Danon D, Ingram DK. Chronic treatment with human recombinant erythropoietin increases hematocrit and improves water maze performance in mice. Physiol Behav. 1996; 59:153–156.

82. Schwarz RD, Callahan MJ, Coughenour LL, Dickerson MR, Kinsora JJ, Lipinski WJ, Raby CA, Spencer CJ, Tecle H. Milameline (CI-979/RU35926): a muscarinic receptor agonist with cognition-activating properties: biochemical and in vivo characterization. J Pharmacol Exp Ther. 1999; 291:812–822.

83. Avery RA, Franowicz JS, Studholme C, van Dyck CH, Arnsten AF. The alpha-2A-adrenoceptor agonist, guanfacine, increases regional cerebral blood flow in dorsolateral prefrontal cortex of monkeys performing a spatial working memory task. Neuropsychopharmacology. 2000; 23:240–249.

84. Swain RA, Harris AB, Wiener EC, Dutka MV, Morris HD, Theien BE, Konda S, Engberg K, Lauterbur PC, Greenough WT. Prolonged exercise induces angiogenesis and increases cerebral blood volume in primary motor cortex of the rat. Neuroscience. 2003; 117:1037–1046.

85. Vissing J, Andersen M, Diemer NH. Exercise-induced changes in local cerebral glucose utilization in the rat. J Cereb Blood Flow Metab. 1996; 16:729–736.

86. Fordyce DE, Wehner JM. Physical activity enhances spatial learning performance with an associated alteration in hippocampal protein kinase C activity in C57BL/6 and DBA/2 mice. Brain Res. 1993; 619:111–119.

87. Swain RA, Theien BE, Dutka MV, Wiener EC, Greenough WT. Rapid induction of cerebellar angiogenesis in the adult rat following exercise. Soc Neurosci Abst. 1997; 23(1575):(614.17).

88. Rhyu IJ, Boklewski J, Ferguson B, Lee KJ, Lange H, By-theway J, Lamb J, McCormick K, Williams N, Cameron J, Greenough WT. Exercise training associated with increased cortical vascularization in adult female cynomolgus monkeys. Soc Neurosci Abst. 2003; 29:920. .1.

89. Ding YH, Luan XD, Li J, Rafols JA, Guthinkonda M, Diaz FG, Ding Y. Exercise-induced overexpression of angiogenic factors and reduction of ischemia/reperfusion injury in stroke. Curr Neurovasc Res. 2004; 1:411–420.

90. Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol. 2000; 425:479–494.

91. Chang FL, Greenough WT. Transient and enduring morphological correlates of synaptic activity and efficacy change in the rat hippocampal slice. Brain Res. 1984; 309:35–46.

92. Geinisman Y, de Toledo-Morrell L, Morrell F, Persina IS, Rossi M. Age-related loss of axospinous synapses formed by two afferent systems in the rat dentate gyrus as revealed by the unbiased stereological dissector technique. Hippocampus. 1992; 2:437–444.

93. DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol. 1990; 27:457–464.

94. Zhan SS, Beyreuther K, Schmitt HP. Quantitative assessment of the synaptophysin immunoreactivity of the cortical neuropil in various neurodegenerative disorders with dementia. Dementia. 1993; 4:66–74.

95. Ito M. Mechanisms of motor learning in the cerebellum. Brain Res. 2000; 886:237–245.

96. Black JE, Isaacs KR, Anderson BJ, Alcantara AA, Greenough WT. Learning causes synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of adult rats. Proc Natl Acad Sci USA. 1990; 87:5568–5572.

97. Kleim JA, Swain RA, Armstrong KA, Napper RM, Jones TA, Greenough WT. Selective synaptic plasticity within the cerebellar cortex following complex motor skill learning. Neurobiol Learn Mem. 1998; 69:274–289.

98. Kim HT, Kim IH, Lee KJ, Lee JR, Park SK, Chun YH, Kim H, Rhyu IJ. Specific plasticity of parallel fiber/Purkinje cell spine synapses by motor skill learning. Neuroreport. 2002; 13:1607–1610.

99. Jones TA, Chu CJ, Grande LA, Gregory AD. Motor skills training enhances lesion-induced structural plasticity in the motor cortex of adult rats. J Neurosci. 1999; 19:10153–10163.

100. Kozorovitskiy Y, Gross CG, Kopil C, Battaglia L, McBreen M, Stranahan AM, Gould E. Experience induces structural and biochemical changes in the adult primate brain. Proc Natl Acad Sci USA. 2005; 102:17478–17482.