The impact of moderate-intensity swimming exercise on learning and memory in aged rats: The role of Sirtuin-1

Document Type : Original Article


1 Suleyman Demirel University, Faculty of Medicine, Department of Physiology, Isparta, Turkey

2 Department of Pathology, Faculty of Veterinary Medicine, Burdur Mehmet Akif Ersoy University, Burdur, Turkey


Objective(s): The purpose of this study was to evaluate the effect of moderate-intensity swimming exercise on learning and memory by the Morris water maze test. Changes in the expressions of cyclic AMP-response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) proteins alternative pathway which were activated by sirtuin-1 (SIRT-1) were investigated.
Materials and Methods: The study included thirty-two male Sprague-Dawley rats (350-500 g, 11-12 and 15–16 months old). The rats were randomly divided into four groups with 8 rats in each group. The groups were designed as follows:  Control-1 (11-12 months), Exercise-1 (11-12 months), Control-2 (15-16 months), Exercise-2 (15-16 months). Moderate-intensity exercise was assigned for 30 min/day, 5 days/week, for the whole training period of 8 weeks.
Results: There were statistically significant differences between the groups on the third day (P=0.005) when swim speeds increased in the exercise groups. There was a statistically significant difference between Exercise 1 and Exercise 2 groups, the entries in the platform zone decreased in Exercise 2 group (P=0.026). While there were no histopathological findings observed in any group, increased  SIRT-1, BNDF, and CREB  expressions were seen in exercise groups compared with control groups.
Conclusion: In aged rats exercising at moderate intensity, increased expression of CREB and BDNF, and SIRT-1 could improve hippocampal-dependent memory.


1. Roessel SV, Keijsers CJPW, Romijin MDM. Dementia as a predictor of morbidity and mortality in patients with delirium. Maturitas 2019; 125:63–69.
2. Hendrie HC, Smith-Gamble V, Lane KA, Purnell C, Clark DO, Gao S. The association of early life factors and declining incidence rates of dementia in an elderly population of african americans. J Gerontol 2018;73:82-89
3. Zhang L, Hu X, Luo J, Chen X, Huang R, Pei Z. Physical exercise improves functional recovery through mitigation of autophagy, attenuation of apoptosis and enhancement of neurogenesis after MCAO in rats. BMC Neuroscience 2013; 14:46.
4. Ng F, Wijaya L, Tang BL. SIRT1 in the brain-connections with aging-associated disorders and lifespan. Front Cell Neurosci 2015; 9:1-13.
5. Pingitore A, Lima GP, Mastorci F, Quinones A, Lervasi G, Vassalle C. Exercise and oxidative stress: Potential effects of anti-oxidant dietary strategies in sports. Nutrition 2015; 31: 916-922.
6. Liu-Ambrose T, Nagamatsu LS, Graf P, Beattie L, Ashe MC, Handy TC. Resistance training and executive functions: A 12-month randomized controlled trial. Arch Intern Med 2010; 170: 170-178.
7. Colcombe SJ, Kramer AF, Erickson KI, Scalf P, McAuley, E, Cohen NJ, et al. Cardiovascular fitness, cortical plasticity, and aging. PNAS 2004; 101;3316-3321. 
8. Liu-Ambrose T, Nagamatsu LS, Voss MW, Khan KM, Handy, TC. Resistance training and functional plasticity of the aging brain: A 12-month randomized controlled trial. Neurobiol Aging 2012 ;33;1690-1698.
9. Nagamatsu LS, Handy TC, Hsu CL, Voss M, Liu-Ambrose T. Resistance training promotes cognitive and functional brain plasticity in seniors with probable mild cognitive impairment. Arch Intern Med 2012; 172:666-668.
10. Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: Key roles of growth factor cascades and inflammation. Trends Neurosci 2007; 30:464-472.
11. Bechara RG, Lyne R, Kelly ÁM. BDNF-stimulated intracellular signalling mechanisms underlie exercise-induced improvement in spatial memory in the male Wistar rat. Behav Brain Res 2014; 275: 297-306.
12. Szuhany KL, Bugatti M, Otto MW. A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor. J Psychiatr Res 2015; 60:56-64.
13. Berchtold NC, Castello N, Cotman CW. Exercise and time-dependent benefits to learning and memory. Neuroscience 2010; 167:588-597.
14. Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci USA 2011; 108: 3017-3022
15. Marosi K, Mattson MP. BDNF mediates adaptive brain and body responses to energetic challenges. Trends Endocrinol Metab 2014; 25:89-98.
16. Minaii B, Moayeri A, Shokri S, Roudkenar MH, Golmohammadi T, Malek F, et al.  Melatonin improve the sperm quality in forced swimming test induced oxidative stress in nandrolone treated Wistar rats. Acta Med Iran 2014; 52;496-504.
17. Marcelino TB, Longoni A, Kudo KY, Stone V, Rech A, de Assis AM, et al. Evidences that maternal swimming exercise improves anti-oxidant defenses and induces mitochondrial biogenesis in the brain of young Wistar rats. Neuroscience 2013; 246:28-39.
18. Stone V, Kudo KY, Marcelino TB, August PM, Matte C. Swimming exercise enhances the hippocampal anti-oxidant status of female Wistar rats. Redox Rep 2015; 20:133-138.
19. Seo DY, Lee SR, Kim N, Ko KS, Rhee BD, Han J. Humanized animal exercise model for clinical implication.  Pflugers Arch 2014; 466:1673-1687.
20. Saygin M, Ozguner MF, Onder O, Doguc DK, Ilhan I, PekerY. The impact of sleep deprivation on hippocampal-mediated learning and memory in rats. Bratisl Med J 2017; 118: 408-416.
21. Diegues JC, Pauli JR, Luciano E, de Almeida Leme JAC, de Moura LP, Dalia RA, et al. Spatial memory in sedentary and trained diabetic rats: molecular mechanisms. Hippocampus 2014; 24:703-711.
22. Vorhees CV, Williams MT. Morris water maze: Procedures for assessing spatial and related forms of learning and memory. Nat Protoc 2006; 1:848–858.
23. Morris RG. Morris water maze. Scholarpedia 2008; 3:6315.
24. Erel O. A novel automated method to measure total anti-oxidant response against potent free radical reactions. Clin Biochem 2004; 37:112-119.
25. Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem 2005; 38:1103-1111.
26. Hansalik M, Skalicky M, Viidik A. Impairment of water maze behaviour with ageing is counteracted by maze learning earlier in life but not by physical exercise, food restriction or housing conditions. Exp Gerontol 2006; 41:169-174.
27. Tsai SF, Ku NW, Wang TF, Yang YH, Shih YH, Wu SY, et al. Long-term moderate exercise rescues age-related decline in hippocampal neuronal complexity and memory. Gerontology 2018; 64: 551-561.
28. Inoue K, Hanaoka Y, Nishijima T, Okamoto M, Chang H, Saito T. et al. Long-term mild exercise training enhances hippocampus-dependent memory in rats. Int J Sports Med 2015; 36: 280-285.
29. Wang XQ, Wang GW. Effects of treadmill exercise intensity on spatial working memory and long-term memory in rats. Life Sci 2016; 149: 96-103.
30. Van Praag H, Shubert T, Zhao C, Gage FH. Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neuroscience 2005; 25:8680-8685.
31. Abadi THN, Vaghef L, Babri S, Mahmood-Alilo M, Beirami M. Effects of different exercise protocols on ethanol-induced spatial memory impairment in adult male rats. Alcohol 2013; 47:309-316.
32. Vanzella C, Neves JD, Vizuete AF, Aristimunha D, Kolling J, Longoni A, et al.  Treadmill running prevents age-related memory deficit and alters neurotrophic factors and oxidative damage in the hippocampus of Wistar rats. Behav Brain Res 2017; 334:78-85.
33. Garcia-Mesa Y, Colie S, Corpas R, Cristofol R, Comellas F, Nebreda AR, et al. Oxidative stress is a central target for physical exercise neuroprotection against pathological brain aging. J Gerontol A Biol Sci Med Sci 2016; 71:40-49.
34. Camiletti-Moiron D, Aparicio VA, Aranda P, Radak Z. Does exercise reduce brain oxidative stress? A systematic review. Scand J Med Sci Sports 2013; 23:202-212.
35. Baek SS, Kim SH. Treadmill exercise ameliorates symptoms of Alzheimer disease through suppressing microglial activation-induced apoptosis in rats. J Exerc Rehabil 2016; 12:526-534.
36. Cechella JL, Leite MR, Rosario AR, Sampaio TB, Zeni G. Diphenyl diselenide-supplemented diet and swimming exercise enhance novel object recognition memory in old rats. Age 2014; 36:9666.
37. Aguiar Jr AS, Boemer G, Rial D, Cordova FM, Mancini, G, Walz R, et al. High-intensity physical exercise disrupts implicit memory in mice: involvement of the striatal glutathione anti-oxidant system and intracellular signaling. Neuroscience 2010; 171:1216-1227.
38. Vaynman S, Ying Z, Gomez-Pinilla F. Interplay between brain-derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity. Neuroscience 2003; 122:647-657.
39. Cheng M, Cong J, Wu Y, Xie J, Wang S, Zhao Y, et al.  Chronic swimming exercise ameliorates low-soybean-oil diet-induced spatial memory impairment by enhancing BDNF-mediated synaptic potentiation in developing spontaneously hypertensive rats. Neurochem Res 2018; 43:1047-1057.  
40. Acheson A, Conover JC, Fandl JP, DeChiara TM, Russell M, Thadani A, et al. A BDNF autocrine loop in adult sensory neurons prevents cell death. Nature 1995; 374:450-453.
41. Ghodrati-Jaldbakhan S, Ahmadalipour A, Rashidy-Pour A, Vafaei A, Gorji HM, Alizadeh M. Low- and high-intensity treadmill exercise attenuates chronic morphine-induced anxiogenesis and memory impairment but not reductions in hippocampal BDNF in female rats. Brain Res 2017; 1663:20-28.
42. Griesbach GS, Hovda DA, Gomez-Pinilla F, Sutton RL. Voluntary exercise or amphetamine treatment, but not the combination, increases hippocampal brain-derived neurotrophic factor and synapsin I following cortical contusion injury in rats. Neuroscience 2008; 154:530-540.
43. Aarse J, Herlitze S, Manahan-Vaughan D. The requirement of BDNF for hippocampal synaptic plasticity is experience-dependent. Hippocampus 2016; 26:739-751.
44. Fahimi A, Baktir MA, Moghadam S, Mojabi FS, Sumanth K, McNerney MW, et al. Physical exercise induces structural alterations in the hippocampal astrocytes: Exploring the role of BDNF-TrkB signaling. Brain Struct Funct 2017; 222:1797-1808.
45. Vaynman S, Ying Z, Gomez-Pinilla F.  Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci 2004; 20: 2580-2590.
46. Chen MJ, Russo-Neustadt AA. Running exercise-induced up-regulation of hippocampal brain-derived neurotrophic factor is CREB-dependent. Hippocampus 2009; 19:962-972.
47. Sun BF, Wang QQ, Yu ZJ, Yu Y, Xiao CL, Kang CS, et al.  Exercise prevents memory impairment induced by arsenic exposure in mice: Implication of hippocampal BDNF and CREB. PloS one 2015; 10:e0137810.
48. Liu W, Xuen X, Xia J, Liu J, Qi Z. Swimming exercise reverses CUMS-induced changes in depression-like behaviors and hippocampal plasticity-related proteins. J Affect Disord 2018; 227:126-135.