Advertisement

AGE

, Volume 38, Issue 5–6, pp 393–404 | Cite as

Tart cherry supplementation improves working memory, hippocampal inflammation, and autophagy in aged rats

  • Nopporn Thangthaeng
  • Shibu M. Poulose
  • Stacey M. Gomes
  • Marshall G. Miller
  • Donna F. Bielinski
  • Barbara Shukitt-Hale
Original Article

Abstract

High consumption of fruits and vegetables has been associated with reduced risk of debilitating diseases and improved cognition in aged populations. These beneficial effects have been attributed to the phytochemicals found in fruits and vegetables, which have previously been shown to be anti-inflammatory and modulate autophagy. Tart cherries contain a variety of potentially beneficial phytochemicals; however, little research has been done to investigate the effects of tart cherry on the aging brain. Therefore, the purpose of this study was to determine if tart cherry supplementation can improve cognitive and motor function of aged rats via modulation of inflammation and autophagy in the brain. Thirty 19-month-old male Fischer 344 rats were weight-matched and assigned to receive either a control diet or a diet supplemented with 2 % Montmorency tart cherry. After 6 weeks on the diet, rats were given a battery of behavioral tests to assess for strength, stamina, balance, and coordination, as well as learning and working memory. Although no significant effects were observed on tests of motor performance, tart cherry improved working memory of aged rats. Following behavioral testing, the hippocampus was collected for western/densitometric analysis of inflammatory (GFAP, NOX-2, and COX-2) and autophagy (phosphorylated mTOR, Beclin 1, and p62/SQSTM) markers. Tart cherry supplementation significantly reduced inflammatory markers and improved autophagy function. Daily consumption of tart cherry reduced age-associated inflammation and promoted protein/cellular homeostasis in the hippocampus, along with improvements in working memory. Therefore, addition of tart cherry to the diet may promote healthy aging and/or delay the onset of neurodegenerative diseases.

Keywords

Aging Cherry Montmorency tart cherries Memory Inflammation Autophagy 

Notes

Acknowledgments

This work was supported by USDA intramural funds and the Cherry Marketing Institute, Dewitt, MI. The authors would like to acknowledge the contributions of Francisco Ramirez for assistance with the western blots.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Ahmet I, Spangler E, Shukitt-Hale B, Joseph JA, Ingram DK, Talan M (2009) Survival and cardioprotective benefits of long-term blueberry enriched diet in dilated cardiomyopathy following myocardial infarction in rats. PLoS One 4:e7975. doi: 10.1371/journal.pone.0007975 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bhagwat S, Haytowitz D, Holden J (2014) USDA database for the flavonoid content of selected foods. Release 3:1Google Scholar
  3. Bickford P (1993) Motor learning deficits in aged rats are correlated with loss of cerebellar noradrenergic function. Brain Res 620:133–138CrossRefPubMedGoogle Scholar
  4. Bobe G, Wang B, Seeram NP, Nair MG, Bourquin LD (2006) Dietary anthocyanin-rich tart cherry extract inhibits intestinal tumorigenesis in APC(Min) mice fed suboptimal levels of sulindac. J Agric Food Chem 54:9322–9328. doi: 10.1021/jf0612169 CrossRefPubMedGoogle Scholar
  5. Brandeis R, Brandys Y, Yehuda S (1989) The use of the Morris water maze in the study of memory and learning. Int J Neurosci 48:29–69CrossRefPubMedGoogle Scholar
  6. Brayne C, Gill C, Paykel ES, Huppert F, O’Connor DW (1995) Cognitive decline in an elderly population—a two wave study of change. Psychol Med 25:673–683CrossRefPubMedGoogle Scholar
  7. Carney JM, Smith CD, Carney AM, Butterfield DA (1994) Aging- and oxygen-induced modifications in brain biochemistry and behavior. Ann N Y Acad Sci 738:44–53CrossRefPubMedGoogle Scholar
  8. Casadesus G, Shukitt-Hale B, Stellwagen HM, Zhu X, Lee HG, Smith MA, Joseph JA (2004) Modulation of hippocampal plasticity and cognitive behavior by short-term blueberry supplementation in aged rats. Nutr Neurosci 7:309–316. doi: 10.1080/10284150400020482 CrossRefPubMedGoogle Scholar
  9. de Fiebre NC, Sumien N, Forster MJ, de Fiebre CM (2006) Spatial learning and psychomotor performance of C57BL/6 mice: age sensitivity and reliability of individual differences. Age 28:235–253CrossRefPubMedPubMedCentralGoogle Scholar
  10. Elks CM, Reed SD, Mariappan N, Shukitt-Hale B, Joseph JA, Ingram DK, Francis J (2011) A blueberry-enriched diet attenuates nephropathy in a rat model of hypertension via reduction in oxidative stress. PLoS One 6:e24028. doi: 10.1371/journal.pone.0024028 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Ferretti G, Bacchetti T, Belleggia A, Neri D (2010) Cherry antioxidants: from farm to table. Molecules 15:6993–7005. doi: 10.3390/molecules15106993 CrossRefPubMedGoogle Scholar
  12. Galli RL, Bielinski DF, Szprengiel A, Shukitt-Hale B, Joseph JA (2006) Blueberry supplemented diet reverses age-related decline in hippocampal HSP70 neuroprotection. Neurobiol Aging 27:344–350CrossRefPubMedGoogle Scholar
  13. Goyarzu P, Malin DH, Lau FC, Taglialatela G, Moon WD, Jennings R, Moy E, Moy D, Lippold S, Shukitt-Hale B, et al. (2004) Blueberry supplemented diet: effects on object recognition memory and nuclear factor-kappa B levels in aged rats. Nutr Neurosci 7:75–83. doi: 10.1080/10284150410001710410 CrossRefPubMedGoogle Scholar
  14. Hauss-Wegrzyniak B, Vannucchi MG, Wenk GL (2000) Behavioral and ultrastructural changes induced by chronic neuroinflammation in young rats. Brain Res 859:157–166CrossRefPubMedGoogle Scholar
  15. He C, Levine B (2010) The Beclin 1 interactome. Curr Opin Cell Biol 22:140–149. doi: 10.1016/j.ceb.2010.01.001 CrossRefPubMedPubMedCentralGoogle Scholar
  16. He FJ, Nowson CA, MacGregor GA (2006a) Fruit and vegetable consumption and stroke: meta-analysis of cohort studies. Lancet 367:320–326CrossRefPubMedGoogle Scholar
  17. He YH, Zhou J, Wang YS, Xiao C, Tong Y, Tang JC, Chan AS, Lu AP (2006b) Anti-inflammatory and anti-oxidative effects of cherries on Freund’s adjuvant-induced arthritis in rats. Scand J Rheumatol 35:356–358CrossRefPubMedGoogle Scholar
  18. He FJ, Nowson CA, Lucas M, MacGregor GA (2007) Increased consumption of fruit and vegetables is related to a reduced risk of coronary heart disease: meta-analysis of cohort studies. J Hum Hypertens 21:717–728CrossRefPubMedGoogle Scholar
  19. Hofer SM, Berg S, Era P (2003) Evaluating the interdependence of aging-related changes in visual and auditory acuity, balance, and cognitive functioning. Psychol Aging 18:285–305CrossRefPubMedGoogle Scholar
  20. Joseph JA, Bartus RT, Clody D, Morgan D, Finch C, Beer B, Sesack S (1983) Psychomotor performance in the senescent rodent: reduction of deficits via striatal dopamine receptor up-regulation. Neurobiol Aging 4:313–319CrossRefPubMedGoogle Scholar
  21. Joseph JA, Denisova N, Fisher D, Bickford P, Prior R, Cao G (1998) Age-related neurodegeneration and oxidative stress: putative nutritional intervention. Neurol Clin 16:747–755CrossRefPubMedGoogle Scholar
  22. Joseph JA, Shukitt-Hale B, Denisova NA, Bielinski D, Martin A, McEwen JJ, Bickford PC (1999) Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. J Neurosci 19:8114–8121PubMedGoogle Scholar
  23. Kang SY, Seeram NP, Nair MG, Bourquin LD (2003) Tart cherry anthocyanins inhibit tumor development in Apc(Min) mice and reduce proliferation of human colon cancer cells. Cancer Lett 194:13–19CrossRefPubMedGoogle Scholar
  24. Kelley DS, Rasooly R, Jacob RA, Kader AA, Mackey BE (2006) Consumption of Bing sweet cherries lowers circulating concentrations of inflammation markers in healthy men and women. J Nutr 136:981–986PubMedGoogle Scholar
  25. Kim DO, Heo HJ, Kim YJ, Yang HS, Lee CY (2005) Sweet and sour cherry phenolics and their protective effects on neuronal cells. J Agric Food Chem 53:9921–9927. doi: 10.1021/jf0518599 CrossRefPubMedGoogle Scholar
  26. Kirakosyan A, Seymour EM, Wolforth J, McNish R, Kaufman PB, Bolling SF (2015) Tissue bioavailability of anthocyanins from whole tart cherry in healthy rats. Food Chem 171:26–31. doi: 10.1016/j.foodchem.2014.08.114 CrossRefPubMedGoogle Scholar
  27. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402:672–676. doi: 10.1038/45257 CrossRefPubMedGoogle Scholar
  28. Lock K, Pomerleau J, Causer L, Altmann DR, McKee M (2005) The global burden of disease attributable to low consumption of fruit and vegetables: implications for the global strategy on diet. Bull World Health Organ 83:100–108PubMedPubMedCentralGoogle Scholar
  29. Malin DH, Lee DR, Goyarzu P, Chang YH, Ennis LJ, Beckett E, Shukitt-Hale B, Joseph JA (2011) Short-term blueberry-enriched diet prevents and reverses object recognition memory loss in aging rats. Nutrition 27:338–342. doi: 10.1016/j.nut.2010.05.001 CrossRefPubMedGoogle Scholar
  30. Martin KR, Wooden A (2012) Tart cherry juice induces differential dose-dependent effects on apoptosis, but not cellular proliferation, in MCF-7 human breast cancer cells. J Med Food 15:945–954. doi: 10.1089/jmf.2011.0336 CrossRefPubMedGoogle Scholar
  31. McCune LM, Kubota C, Stendell-Hollis NR, Thomson CA (2011) Cherries and health: a review. Crit Rev Food Sci Nutr 51:1–12. doi: 10.1080/10408390903001719 CrossRefPubMedGoogle Scholar
  32. Meijer AJ, Codogno P (2006) Signalling and autophagy regulation in health, aging and disease. Mol Asp Med 27:411–425CrossRefGoogle Scholar
  33. Miller MG, Shukitt-Hale B (2012) Berry fruit enhances beneficial signaling in the brain. J Agric Food Chem 60:5709–5715. doi: 10.1021/jf2036033 CrossRefPubMedGoogle Scholar
  34. Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11:47–60CrossRefPubMedGoogle Scholar
  35. Neville CE, Young IS, Gilchrist SE, McKinley MC, Gibson A, Edgar JD, Woodside JV (2013) Effect of increased fruit and vegetable consumption on physical function and muscle strength in older adults. Age (Dordr) 35:2409–2422. doi: 10.1007/s11357-013-9530-2 CrossRefGoogle Scholar
  36. Nurk E, Refsum H, Drevon CA, Tell GS, Nygaard HA, Engedal K, Smith AD (2010) Cognitive performance among the elderly in relation to the intake of plant foods. The Hordaland Health Study. Br J Nutr 104:1190–1201. doi: 10.1017/S0007114510001807 CrossRefPubMedGoogle Scholar
  37. Olanow CW (1993) A radical hypothesis for neurodegeneration. Trends Neurosci 16:439–444CrossRefPubMedGoogle Scholar
  38. Ou B, Bosak KN, Brickner PR, Iezzoni DG, Seymour EM (2012) Processed tart cherry products—comparative phytochemical content, in vitro antioxidant capacity and in vitro anti-inflammatory activity. J Food Sci 77:H105–H112. doi: 10.1111/j.1750-3841.2012.02681.x CrossRefPubMedGoogle Scholar
  39. Polidori MC, Pratico D, Mangialasche F, Mariani E, Aust O, Anlasik T, Mang N, Pientka L, Stahl W, Sies H, et al. (2009) High fruit and vegetable intake is positively correlated with antioxidant status and cognitive performance in healthy subjects. J Alzheimers Dis 17:921–927. doi: 10.3233/JAD-2009-1114 PubMedGoogle Scholar
  40. Poulose SM, Bielinski DF, Carrihill-Knoll K, Rabin BM, Shukitt-Hale B (2011) Exposure to 16O-particle radiation causes aging-like decrements in rats through increased oxidative stress, inflammation and loss of autophagy. Radiat Res 176:761–769. doi: 10.1667/RR2605.1 CrossRefPubMedGoogle Scholar
  41. Poulose SM, Carey AN, Shukitt-Hale B (2012) Improving brain signaling in aging: could berries be the answer? Expert Rev Neurother 12:887–889. doi: 10.1586/ern.12.86 CrossRefPubMedGoogle Scholar
  42. Poulose SM, Bielinski DF, Shukitt-Hale B (2013) Walnut diet reduces accumulation of polyubiquitinated proteins and inflammation in the brain of aged rats. J Nutr Biochem 24:912–919. doi: 10.1016/j.jnutbio.2012.06.009 CrossRefPubMedGoogle Scholar
  43. Poulose SM, Bielinski DF, Carrihill-Knoll KL, Rabin BM, Shukitt-Hale B (2014a) Protective effects of blueberry- and strawberry diets on neuronal stress following exposure to (56)Fe particles. Brain Res 1593:9–18. doi: 10.1016/j.brainres.2014.10.028 CrossRefPubMedGoogle Scholar
  44. Poulose SM, Fisher DR, Bielinski DF, Gomes SM, Rimando AM, Schauss AG, Shukitt-Hale B (2014b) Restoration of stressor-induced calcium dysregulation and autophagy inhibition by polyphenol-rich acai (Euterpe spp.) fruit pulp extracts in rodent brain cells in vitro. Nutrition 30:853–862. doi: 10.1016/j.nut.2013.11.011 CrossRefPubMedGoogle Scholar
  45. Rajawat YS, Hilioti Z, Bossis I (2009) Aging: central role for autophagy and the lysosomal degradative system. Ageing Res Rev 8:199–213. doi: 10.1016/j.arr.2009.05.001 CrossRefPubMedGoogle Scholar
  46. Rendeiro C, Spencer JP, Vauzour D, Butler LT, Ellis JA, Williams CM (2009) The impact of flavonoids on spatial memory in rodents: from behaviour to underlying hippocampal mechanisms. Genes Nutr 4:251–270. doi: 10.1007/s12263-009-0137-2 CrossRefPubMedPubMedCentralGoogle Scholar
  47. Rendeiro C, Vauzour D, Rattray M, Waffo-Teguo P, Merillon JM, Butler LT, Williams CM, Spencer JP (2013) Dietary levels of pure flavonoids improve spatial memory performance and increase hippocampal brain-derived neurotrophic factor. PLoS One 8:e63535. doi: 10.1371/journal.pone.0063535 CrossRefPubMedPubMedCentralGoogle Scholar
  48. Salminen A, Kaarniranta K, Kauppinen A, Ojala J, Haapasalo A, Soininen H, Hiltunen M (2013) Impaired autophagy and APP processing in Alzheimer’s disease: the potential role of Beclin 1 interactome. Prog Neurobiol 106-107:33–54. doi: 10.1016/j.pneurobio.2013.06.002 CrossRefPubMedGoogle Scholar
  49. Seeram NP, Bourquin LD, Nair MG (2001a) Degradation products of cyanidin glycosides from tart cherries and their bioactivities. J Agric Food Chem 49:4924–4929CrossRefPubMedGoogle Scholar
  50. Seeram NP, Momin RA, Nair MG, Bourquin LD (2001b) Cyclooxygenase inhibitory and antioxidant cyanidin glycosides in cherries and berries. Phytomedicine 8:362–369CrossRefPubMedGoogle Scholar
  51. Sehitoglu MH, Farooqi AA, Qureshi MZ, Butt G, Aras A (2014) Anthocyanins: targeting of signaling networks in cancer cells. Asian Pac J Cancer Prev 15:2379–2381CrossRefPubMedGoogle Scholar
  52. Seymour EM, Singer AA, Kirakosyan A, Urcuyo-Llanes DE, Kaufman PB, Bolling SF (2008) Altered hyperlipidemia, hepatic steatosis, and hepatic peroxisome proliferator-activated receptors in rats with intake of tart cherry. J Med Food 11:252–259. doi: 10.1089/jmf.2007.658 CrossRefPubMedGoogle Scholar
  53. Seymour EM, Lewis SK, Urcuyo-Llanes DE, Tanone II, Kirakosyan A, Kaufman PB, Bolling SF (2009) Regular tart cherry intake alters abdominal adiposity, adipose gene transcription, and inflammation in obesity-prone rats fed a high fat diet. J Med Food 12:935–942. doi: 10.1089/jmf.2008.0270 CrossRefPubMedGoogle Scholar
  54. Shaughnessy KS, Boswall IA, Scanlan AP, Gottschall-Pass KT, Sweeney MI (2009) Diets containing blueberry extract lower blood pressure in spontaneously hypertensive stroke-prone rats. Nutr Res 29:130–138. doi: 10.1016/j.nutres.2009.01.001 CrossRefPubMedGoogle Scholar
  55. Shukitt-Hale B (1999) The effects of aging and oxidative stress on psychomotor and cognitive behavior. Age (Omaha) 22:9–17. doi: 10.1007/s11357-999-0002-7 CrossRefGoogle Scholar
  56. Shukitt-Hale B, Mouzakis G, Joseph JA (1998) Psychomotor and spatial memory performance in aging male Fischer 344 rats. Exp Gerontol 33:615–624CrossRefPubMedGoogle Scholar
  57. Shukitt-Hale B, Smith DE, Meydani M, Joseph JA (1999) The effects of dietary antioxidants on psychomotor performance in aged mice. Exp Gerontol 34:797–808CrossRefPubMedGoogle Scholar
  58. Shukitt-Hale B, Galli RL, Meterko V, Carey A, Bielinski DF, McGhie T, Joseph JA (2005) Dietary supplementation with fruit polyphenolics ameliorates age-related deficits in behavior and neuronal markers of inflammation and oxidative stress. Age (Dordr) 27:49–57. doi: 10.1007/s11357-005-4004-9 CrossRefGoogle Scholar
  59. Shukitt-Hale B, Carey A, Simon L, Mark DA, Joseph JA (2006) Effects of Concord grape juice on cognitive and motor deficits in aging. Nutrition 22:295–302CrossRefPubMedGoogle Scholar
  60. Shukitt-Hale B, Carey AN, Jenkins D, Rabin BM, Joseph JA (2007) Beneficial effects of fruit extracts on neuronal function and behavior in a rodent model of accelerated aging. Neurobiol Aging 28:1187–1194CrossRefPubMedGoogle Scholar
  61. Shukitt-Hale B, Cheng V, Joseph JA (2009a) Effects of blackberries on motor and cognitive function in aged rats. Nutr Neurosci 12:135–140. doi: 10.1179/147683009X423292 CrossRefPubMedGoogle Scholar
  62. Shukitt-Hale B, Kalt W, Carey AN, Vinqvist-Tymchuk M, McDonald J, Joseph JA (2009b) Plum juice, but not dried plum powder, is effective in mitigating cognitive deficits in aged rats. Nutrition 25:567–573. doi: 10.1016/j.nut.2008.10.018 CrossRefPubMedGoogle Scholar
  63. Shukitt-Hale B, Bielinski DF, Lau FC, Willis LM, Carey AN, Joseph JA (2015) The beneficial effects of berries on cognition, motor behaviour and neuronal function in ageing. Br J Nutr:1–8Google Scholar
  64. Sumien N, Heinrich KR, Sohal RS, Forster MJ (2004) Short-term vitamin E intake fails to improve cognitive or psychomotor performance of aged mice. Free Radic Biol Med 36:1424–1433. doi: 10.1016/j.freeradbiomed.2004.02.081 CrossRefPubMedGoogle Scholar
  65. Tall JM, Seeram NP, Zhao C, Nair MG, Meyer RA, Raja SN (2004) Tart cherry anthocyanins suppress inflammation-induced pain behavior in rat. Behav Brain Res 153:181–188. doi: 10.1016/j.bbr.2003.11.011 CrossRefPubMedGoogle Scholar
  66. Traustadottir T, Davies SS, Stock AA, Su Y, Heward CB, Roberts LJ 2nd, Harman SM (2009) Tart cherry juice decreases oxidative stress in healthy older men and women. J Nutr 139:1896–1900. doi: 10.3945/jn.109.111716 CrossRefPubMedPubMedCentralGoogle Scholar
  67. Whishaw IQ (1985) Formation of a place learning-set by the rat: a new paradigm for neurobehavioral studies. Physiol Behav 35:139–143Google Scholar
  68. Williams CM, El Mohsen MA, Vauzour D, Rendeiro C, Butler LT, Ellis JA, Whiteman M, Spencer JP (2008) Blueberry-induced changes in spatial working memory correlate with changes in hippocampal CREB phosphorylation and brain-derived neurotrophic factor (BDNF) levels. Free Radic Biol Med 45:295–305. doi: 10.1016/j.freeradbiomed.2008.04.008 CrossRefPubMedGoogle Scholar
  69. Willis LM, Shukitt-Hale B, Cheng V, Joseph JA (2009) Dose-dependent effects of walnuts on motor and cognitive function in aged rats. Br J Nutr 101:1140–1144. doi: 10.1017/S0007114508059369 CrossRefPubMedGoogle Scholar
  70. Youdim KA, Shukitt-Hale B, Martin A, Wang H, Denisova N, Bickford PC, et al. (2000) Short-term dietary supplementation of blueberry polyphenolics: beneficial effects on aging brain performance and peripheral tissue function. Nutr Neurosci 3:383–397CrossRefGoogle Scholar

Copyright information

© American Aging Association (outside the USA) 2016

Authors and Affiliations

  • Nopporn Thangthaeng
    • 1
  • Shibu M. Poulose
    • 1
  • Stacey M. Gomes
    • 1
  • Marshall G. Miller
    • 1
  • Donna F. Bielinski
    • 1
  • Barbara Shukitt-Hale
    • 1
  1. 1.USDA-ARS, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts UniversityBostonUSA

Personalised recommendations